Professional Documents
Culture Documents
Furanoside Rhee
Furanoside Rhee
Furanoside Rhee
DISSERTATION
By
*****
2004
Dissertation Committee:
Adviser
Department of Chemistry
ABSTRACT
Part One: The Barton-McCombie reaction has been widely acknowledged for the efficient deoxygenation
of 2o alcohols through radical process. For the chain process, the radical source initially generated by the
catalytic amount of AIBN attacks the thiocarbnyl sulfur to produce a radical intermediate that is cleaved at
the β-position to give alkyl radicals. Although the sp3 carbon centered radicals have been used commonly
deoxygenation of alcohol has never been considered as a precursor of radical cyclization. However, the
when suitable radical acceptors are appropriately placed. Moreover, structurally rare examples of N-
furanosides and N-pyranosides have been synthesized efficiently from carbohydrate-derived imidazoyl and
triazoyl thioates by utilizing the new Barton’s radical-mediated methodology. Depending on the radical
acceptors, glycosides with either C2-carbon or C2-amino substituents are formed. The C2 stereogenic center
of the N-pyranosides formed via exo-hept-6-enyl type radical cyclization can also be controlled by the
stereochemistry of the radical acceptor. While (E)-olefin acceptors make allo/altro mixture, (Z)-olefin
alleneynes, allene aldehydes, and allene ketones with R3Sn-SiR’3 is a useful tactic for the synthesis of
synthetically interesting heterocyclic and/or carbocyclic compounds. Although the reaction has a broad
tolerance to functional groups, operationally simple procedure, and high catalytic turnover and
regioselcetivity, the applications of the silylstannylated carbocyclization to further transformation are rare.
The palladium catalyzed silylstannylation/cyclization of 1, 6-diynes gives two atropisomeric isomers with
axial chirality. The silylstannyl dienes themselves do not take part in Diels-Alder reactions, but the
ii
removal of Sn has been achieved efficiently under acidic condition and the resulting silyldienes have
restored this reactivity. In this study a number of fused carbocyclic or heterocyclic compounds were made
by the Diels-Alder reaction and the regioselectivity was controlled by steric effects. This regioselective
Diels-Alder route has been used for the synthesis of an intermediate for a Papulacandin D core synthesis.
iii
Dedicated to the late Distinguished Professor Glen A. Russell,
who was past from being an excellent chemist and also a great human being.
He is my eternal mentor.
iv
ACKNOWLEDGMENTS
I do not know how I can express my gratitude to my advisor Dr. RajanBabu. He did willingly take
care of me when I was at the most difficult time, and has continually supported me to continue my graduate
studies at the Ohio State University. I understand that if he had not welcomed me as one of his students, I
would not be here right now. He also spent a lot of time to improve not only the quality of my dissertation
but also my poor English. His suggestions were really essential for the current shape of this dissertation.
I also have to thank to Professors Jon Parquette and Gideon Fraenkel, who are my degree program
committee members. The first chapter of this research was initiated by Dr. Brian Bliss, and his Ph. D.
dissertation was the most important source for my research. I am also deeply indebted to the former and
present members of Prof. RajanBabu’s group. Dr. Seunghoon Shin always gave me keen criticisms in
chemistry as well as in my personal life, and Dr. Mei-huey Lin has shown me her endless kindness and help
in the lab. I know I had to have much more difficult time without them. I would also like to thank to
Sandeep Apte, who has exchanged his thoughts with me and listened seriously my opinion. Drs.
Kumareswaran, Zhang, and Saha in the group gave me lots of inspiration in chemistry. I am really lucky to
have known these nice people at OSU. Prof. Woonphil Baik, Dr. Hyun Joo Lee, and the member of Prof.
Baik’s group are the people I have to express my appreciation for their continued support and
encouragement since my undergraduate days at Myong Ji University. I also have to thanks to Dr. Jeong-
Seok Han. For the last five years, I have started my lab work with his hello in the morning, refreshed by
the small coffee break with him, and shared my thoughts as well as the life outside the laboratory. Finally,
I would like to acknowledge to the Myong Ji Univeristy Alumni Association for the Fellowship.
Most of all, I thank to my parents for their love and sacrifice, which made this dissertation
possible.
v
VITA
PUBLICATIONS
1. “Stereochemical control in radical cyclization route to N-glycoside: Role of protecting group and of
the configuration (E versus Z) of the acceptor”, Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V.
vi
2. “A New Reaction Manifold For the Barton Rdical Intermediates. Synthesis of N-Heterocyclic
furanosides and pyranosides via the Formation of the C1-C2 Bond”, Rhee, J. U.; Bliss, B. I.;
Halides through the SRN1 Mechanism”, Rhee, J. U.; Russell, G. A.; Baik, W. Tetrahedron Lett. 1998,
39, 8601.
4. “Reaction of p -Nitrobenzyl Halides with Dialkyl Phosphite Anions in Dimethyl Sulfoxide”, Russell,
5. “Microbial Deoxygenation of N-Oxides with Bakers' Yeast-NaOH”, Baik, W.; Kim, D. I.; Koo, S.;
Rhee, J. U.; Shin, S. H.; Kim, B. H. Tetrahedron Lett. 1998, 38, 845.
Mild Conditions”, Baik, W.; Yun, S.; Rhee, J. U.; Russell, G. A. J. Chem. Soc., Perkin Trans 1 1996,
1777.
7. “Oxidative Additon of Aryloxide Ions with Electron-Deficient Olefins”, Baik, W.; Min, B.; Choi, H.;
8. “Selective Reduction of Aromatic Nitroso Compounds with Bakers' Yeast under Neutral Conditions”,
Baik, W.; Rhee, J. U.; Lee, S. H.; Lee, N. H.; Kim, B. H.; Kim, K. S. Tetrahedron Lett. 1995, 36, 2793.
FIELDS OF STUDY
vii
TABLE OF CONTENTS
Page
Abstract ii
Dedication iv
Acknowledgments v
Vita vi
List of Tables xi
Chapters:
1. Synthesis of N-Furanosides and N-Pyranosides from Carbohydrates via 5- or 6-exo Trig Radical
Cyclization 1
1. 1. Introduction 1
1. 1. 1. The Mechanism of Barton-McCombie Deoxygenation 2
1. 1. 2. Applications of the Barton-McCombie Reaction 4
1. 2. 1. 1. The Intramolecular Cyclization by Barton’s Radical 4
1. 2. 1. 2. The 5- and 6-Exo-trig Intramolecular Cyclization of Alkyl Radicals 12
1. 2. 1. 3. The 5- exo-dig Intramolecular Cyclization of Alkyl Radicals 18
1. 2. 1. 4. The Intermolecular Radical Addition of Alkyl Radicals 20
1. 2. 1. 5. The Miscellaneous Reactions 24
1. 2. 1. 6. The Formation of N-Glycoside via 6-exo-trig Cyclization 27
viii
1. 2. Synthesis of Substrates for Radical Cyclization 31
1. 2. 1. Preparation of Precursors for 6-Exo Trig Radical Cyclization 31
1. 2. 2. Preparation of Precursors for 5-Exo Trig Radical Cyclization 52
1. 2. 3. 1,4-Migration of a tert-Butyldimethylsilyl (TBS) group: An Expeditious of
Synthesis of Substrates 61
1. 2. 4. Preparation of Precursor for 5-Exo Trig Radical Cyclization from D-Glucose 67
ix
3. 1. Introduction 188
3. 2. Retrosynthesis of Papulacandin D and Preparation of Diynes 199
3. 3. Palladium Catalyzed Silastannylation of Diynes 202
3. 4. Nickel and Rhodium Catalyzed Silastannylation of Diynes 213
3. 5. Dynamic NMR Studies of Silastanylated 1,3-Dienes, 3-93 and 3-94 216
3. 6. Bromination and Destannylation of Silylstannylated D-gluconosubstituted
(Z,Z)-1,3-Dienes 227
3. 7. Exploratory Studies on Desilylation of the Vinylsilanes 230
3. 8. Diels-Alder Reaction of Vinylsilanes 231
3. 9. Conclusion 240
Bibliography 454
x
LIST OF TABLES
Table Page
1. 1. The 1,4-TBS Group Migration in a Variety of Conditions 63
1. 2. The Effect of Triphenylphosphineoxide in TBS Migration 65
1. 3. The 1,4-TBS Group Migration with a Variety of Olefins 66
1. 4. 6-Exo trig Ring Closure of 1-196 80
1. 5. 6-Exo trig Radical Ring Closure of 1-208 85
1. 6. Selected Chemical Shifts and Coupling Constants of N-Pyranoside 90
1. 7. 6-Exo trig Radical Ring Closure of Substrate 1-235 92
1. 8. 6-Exo trig Radical Ring Closure of Substrate 1-193 95
1. 9. 6-Exo trig Radical Ring Closure of Substrate 1-247 97
1. 10. 6-Exo trig Radical Ring Closure of Substrate 1-248 99
1. 11. 6-Exo trig Radical Ring Closure of Substrate 1-249 100
1. 12. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-254 101
1. 13. 6-Exo trig Radical Ring Closure of Substrate 1-250 102
1. 14. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-256 103
1. 15. 6-Exo trig Radical Ring Closure of 1-251 108
1. 16. 6-Exo trig Radical Ring Closure of 1-269 109
1. 17. 6-Exo trig Radical Ring Closure of 1-271 110
1. 18. 6-Exo trig Radical Ring Closure of 1-272 and 1-273 111
1. 19. The Chemical Shift and Coupling Constant for β-altro-1-275 114
1. 20. 6-Exo trig Radical Ring Closure of 1-276 115
1. 21. 5-Exo trig Ring Closure of 1-281 118
1. 22. Selected Chemical Shifts and Coupling Constants of N-Furanoside 1-282 121
1. 23. 5-Exo trig Ring Closure of 1-298 123
1. 24. 6-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-[1, 3]dioxane-
4(R)-carbaldehyde Derivatives 126
1. 25. A Variety of 5-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-
[1, 3]dioxane-4(R)-carbaldehyde Derivatives 132
1. 26. Radical Reaction with TTMSH 136
xi
2. 1. Preliminary Results for the Asymmetric Silystannylation of Alleneynes 160
2. 2. Bromination of Vinyl Stannylsilane 2-42 by NBS in Dichloromethane 164
2. 3. Tandem Carbocyclization/Silastannylation of Bis(allenes) 166
2. 4. Tandem Carbocyclization/Silastannylation of 1,6-Dynes 167
2. 5. Destannylation of Silastannylaed 1,3-Dienes 169
2. 6. Diels-Alder Reaction of Vinylsilane 2-67 173
2. 7. Diels-Alder Reaction of Vinylsilane 2-75 174
2. 8. Diels-Alder Reaction of Vinylsilane 2-88 179
2. 9. Diels-Alder Reaction of Vinylsilane 2-68 with Various Dienophiles 184
2. 10. Diels-Alder Reaction of Vinylsilane 2-75 with Various Dienophiles 187
xii
LIST OF SCHEMES
Scheme Page
1. 1. The Mechanism of Barton-McCombie Deoxygenation 3
1. 2. The Mechanism for Inefficient β-Cleavage of the Barton’s Radical 3
1. 3. The Alternative Mechanism for Deoxygenation, SH2 Mechanism 4
1. 4. The Mechanism for the Formation of Thiolactone and Phenyl Migration 7
1. 5. The Mechanism of Phenyl Migration in the Barton’s Radical in a Tricyclic Ring 9
1. 6. The Mechanism for the Fukuyama Indole Synthesis 10
1. 7. The Mechanism for Thiocarbamate (Y = O), Thioamide (Y = CR2),
and Thiourea (Y = NR2) Cyclization 11
1. 8. The Intramolecular Carboxylation Approach to Podophyllootoxine 12
1. 9. Stereospecific Construction of Spirocyclic Ring by Intramolecular Radical Cyclization 20
1. 10. The Possible Pathways for Radical Addition to Alkenes 23
1. 11. The Mechanism for the Imidoyl Radical Mediated Cyclization 26
1. 12. Mechanism for the Formation of Pyran Ring System via 6-Exo-trig Ring Closing
Mediated by the Barton’s Radical 28
1. 13. Proposed Routes for the Formation of N-Glycosides 30
1. 14 . Synthetic Routes to Prepare Substrates 1-80 31
1. 15. Synthetic Route to Prepare Substrates 1-82 32
1. 16. Synthetic Route to Prepare Substrates 1-85 33
1. 17. Synthetic Route to Prepare Substrates 1-86 33
1. 18. Synthetic Route to Prepare Substrates 1-88 34
1. 19. Synthetic Route to Prepare Substrates 1-90 35
1. 20. Synthetic Route to Prepare Substrates 1-93 35
1. 21. Failed Attempts to Prepare Thiocarbmate of Hydrazone Derivatives 36
1. 22. Proposed Mechanism for the Formation of 1-95 37
1. 23. The Synthesis of Diphenylhydrazone Derivatives 38
1. 24. Thiocarbamation of 1-79 39
1. 25. Failed Attempts to Prepare Hydrazone Substrates 40
1. 26. Failed Attempts to Prepare Thiocarbamate I 40
xiii
1. 27. Failed Attempts to Prepare Thiocarbamate II 41
1. 28. Failed Attempts to Prepare Thiocarbamate III 42
1. 29. The Mechanism of the Formation of 1-106 43
1. 30. Failed Attempts for Thiocarbonates 43
1. 31. Thiocarbamation of Unactivated Olefin 1-109 44
1. 32. Thiocarbamation of 2-81 with 1,1’-Thiocarbonylditriazole 45
1. 33. Preparation of Benzimidazole Derivative 1-111 46
1. 34. Alternative Preparation of Benzimidazole Derivative 1-111 47
1. 35. Preparation of Indole Derivatives 47
1. 36. Failed Attempts to Prepare Adenines 48
1. 37. Preparation of Triazole Derivative from 1-89 49
1. 38. Preparation of Benzimidazole Derivatives 50
1. 39. Synthetic Route to Prepare Substrates 50
1. 40. Synthetic Route to Prepare Substrates 1-127 51
1. 41. Synthesis of 6-Exo trig Radical Precursor 1-133 from Maltose Monohydrate 52
1. 42. Synthesis 1-138 from γ-Lactone 53
1. 43. Synthesis of 5-Exo trig Radical Precursor 1-138 from Maltose Monohydrate 53
1. 44. Failed Attempts to Prepare Radical Reaction Precursor from 1-138 54
1. 45. Reaction of 1-139 with Phenylmagnesium Bromide 55
1. 46. Preparation of Nitrile, Oxime, and Hydrazone Substituted Olefins 55
1. 47. TBS Group Migration in MeOH 56
1. 48. Preparation of Thiocarbamates 57
1. 49. Failed Attepts to Prepare N, N’-Diphenyl hydrazone Derivative 58
1. 50. Deprotection of a TBS Goup of Thiocarbamate Derivatives 58
1. 51. Proposed 5-Exo trig Process for the Formation of Pyrolidines 59
1. 52. Failed pathway to prepare thiocarbamate 1-158 60
1. 53. Mechanism of TBS Group Migration 61
1. 54. The Synthesis of 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 67
1. 55. Synthesis of α,β-Unsaturated Ester and Its Thiocarbamate Derivatives 69
1. 56. Synthesis of Hydrazone and Oxime and Its Thiocarbamate Derivatives 72
1. 57. Synthesis of Hydrazones and Its Thiocarbamate Derivatives 74
1. 58. The Mechanism of 6-Exo-trig Radical Cyclization of Substrate 1-196 78
1. 59. The Stereoselctivity of allo/altro Conformation by 6-Exo-trig Radical Cyclization 88
1. 60. Rationalization of the Distribution of Products 89
1. 61. Rationalization of Stereoselectivity of 1-235; allo and altro Conformations 93
1. 62. Rationalization of the Distribution of Products from 1-250 106
xiv
1. 63. Proposed pathway to β-D-altropyranosyl 1H-benzimidazole 1-277 and
D-ribo-hex-1-enopyranosyl 1H-benzimidazole 1-278 116
1. 64. The Mechanism for the Formation of N-Furanoside via 5-Exo-trig Radical Cyclization 121
1. 65. Rationalization of Diastereomers for 1-282 via 5-Exo trig Radical Cyclization 122
1. 66. The Rationalization of the Stereochemistry for the Radical Cyclization of 3-107 123
1. 67. Origin of Stereoselectivity at C2 of the N-Furanoside 129
1. 68. Propsed Mechansim for Radical Mediated 1,3-Migration of Oxime Derivative 1-196 137
xv
LIST OF FIGURES
Figure Page
1. 1. Chair-like Transition States in 5-Hexenyl Radical Cyclization 15
1. 2. Rationalization of Stereochemistry of D-Glucopyranose Derivatives;
Chair-like/Boat-like Transition States 16
1. 3. Rationalization of Cis Selectivity of 5-Hexyl Radicals 17
1. 4. The Rationalization of the Stereochemistry of Tandem Radical Cyclization
under Barton’s Deoxyzanation Conditions 27
1. 5. Rationalization of the Stereochemistry of 3-5 by Chair Conformation 82
1. 6. nOe Experiment of altro 1-197 83
1. 7. Origin of the altro-Selectivity in the (Z)-Acceptors 86
1. 8. Anomeric Stabilization in Pyranosyl Radicals 87
1. 9. The Representative Results of nOe for 1-203 96
1. 1. Substrates for 6-Exo trig Radical Cyclization 98
1. 11. Products for 6-Exo trig Radical Cyclization. 98
1. 12. The Representative Results of nOe for 1-258 104
1. 13. The Representative Results of nOe for 1-260 105
1. 14. The Representative Results of nOe for 1-274-β 112
1. 15. The Representative Results for nOe of 1-274-α 113
1. 16. The Representative Results for nOe of β-altro-1-275 114
1. 17. Representative Results for nOe of 1-286-α 127
1. 18. Representative Results for nOe of 1-286-β 128
1. 19. Representative Substrates for 5-exo-trig Radical Cyclization 131
1. 20. Representative Products for 5-exo-trig Radical Cyclization 131
1. 21. Substrates and Products for the Radical Reaction with TTMSH 135
1. 22. The Representative results for nOe of syn-1-310 138
1. 23. The Representative Results for nOe of anti-1-310 138
2. 1. Phosphine Ligands and Chemical Shift Reagents Used in Silylstannylation Stidies 159
2. 2. Structures of 2-89 and 2-90 172
xvi
2. 3. Representative nOe Results for 2-89 176
2. 4. Representative nOe Results for 2-90 177
2. 5. Representative nOe Results for 2-118 177
2. 6. Representative nOe Results for 2-133 178
2. 7. Representative Products of Diels-Alder Reaction (Eq. 36) 183
2. 8. Representative Products of Diels-Alder Reaction (Eq. 37) 186
2. 9. Representative Products of Diels-Alder Reaction (Eq. 38) 186
xvii
LIST OF ABBREVIATIONS
xviii
EWG electron withdrawing group
equiv. equivalent(s)
FAB fast atom bombardment (in mass spectrometry)
FID flame ionization detector
FT fourier transfer
g gram(s)
GC gas chromatography
h hour(s)
HRMS high-resolution mass spectrum
Hz hertz
Im imidazole
IR infrared spectroscopy
J coupling constant (in NMR)
L liter(s)
µ micro
m multiplet (spectral)
M moles per liter
mCPBA meta-chloroperoxybenzoic acid
Me methyl
min minute(s)
mM milimoles per liter
mol mole(s)
Mp melting point
MS molecular sieves
Ms methanesulfonyl (mesyl)
m/z mass to charge ratio (in mass spectrometry)
NBS N-bromosuccinimide
NMR nuclear magnetic resonance
NOE nuclear Overhauser effect
NOESY nuclear Overhauser effect spectroscopy
Ph phenyl
PMB 4-methoxybenzyl
Ppm part per million (in NMR)
PPTS pyridinium p-toluenesulfonate
Prep TLC preparative thin layer chromatography
pyr pyridine
xix
q quartet (spectral)
Rf retention factor (in chromatography)
rt room temperature
s singlet (spectral)
TAS tris-dimethylamminosulfonium
TBAF tetra-n-butylammonium fluoride
TBDPS tert-butyldimethylsilyl
TBS tert-butyldimethylsilyl
TLC thin layer chromatography
THF tetrahydrofuran
Ts 4-toluenesulfonyl (tosyl)
TTMSH tris(trimethylsilyl)silane
xx
CHAPTER 1
1. 1. Introduction
during the last few decades, and the importance of the transformation has been increasing in the organic
syntheses, particularly in total synthesis of natural products and carbohydrate chemistry. 1 One of the most
conventional strategies for the deoxygenation is the reduction of suitable alcohol derivatives such as
tosylate, mesylate, and sulphate.2 Another important strategy for the transformation is the nucleophilic
replacement of the hydroxyl group by halogen or thiolate with subsequent reductive dehalogenation3 or
desulfurization. 4 Although those strategies proved to be very efficient methodologies for the
deoxygenation of simple, sterically unhindered alcohols, they have instinctively ionic nature, which causes
difficulties in application to complex, sterically hindered hydroxyl groups and rearrangement and/or
elimination reactions intervene. Fortunately, the drawback of ionic type reaction could be overcome by
radicals as the intermediates in the reaction because radicals are much less susceptible to these
complications. Moreover, the neutral reaction conditions in radical reactions are ideally suited for the total
synthesis of complex natural products with poly functional groups. The radical mediated deoxygenation
involves three distinctive steps: (a) conversion of a suitable alcohol derivative to a radical intermediate, (b)
fragmentation of a C-O bond by β-cleavage into an alkyl radical, (c) reaction with a hydrogen donor to
afford the corresponding hydrocarbons. Especially, the initial step, the conversion of alcohol derivatives to
radical intermediates, can be categorized into three sub-groups based on the way of the formation of a
radical intermediate: (a) addition of radical source to CO or heterocarbonyl group, (b) electron transfer to
1
activated double bond with formation of radical, (c) photolytic excitation of a π system forming the triplet
state.
The deoxygenation of an alcohol via a thiocarbonyl derivatives is the most widely used
methodology in the first category, and it is generally known as the Barton-McCombie reaction.1 The utility
of Barton’s deoxygenation has been increasing since its first report in 19755 because of the mild conditions,
efficiency, convenience, selectivity, and high conversion yield. Moreover, this reaction is one of the best
ways to remove sterically hindered hydroxyl groups,6, 7 which cannot be deoxygenated by traditional SN2
type reactions. Another advantage of the Barton’s radical mediated deoxygenation is that there is no
rearrangement of the products,1b which are commonly found with cationic or anionic deoxygenations. For
the mild and efficient deoxygenation, the desired hydroxyl group has to be first converted to
hypophosphorous acid,15a or the corresponding 1-ethylpiperidinium salt15b are used as hydrogen sources.
Scheme 1.1 shows the general mechanism of Barton-McCombie deoxygenation. 5,16 For the chain
reaction, radical source is initially generated by the catalytic amount of AIBN, attacks the thiocarbonyl
sulfur to produce a radical intermediate 1-2 (the Barton’s radical), which is cleaved at the β position to give
a thiocarbonate 1-3 and an alkyl radical 1-4. The alkyl radical 1-4 abstract a hydrogen from the radical
sources to give an alkane 1-7 and a tributyl stannyl radical, which is used for the radical chain process. The
Barton’s deoxygentation mechanism is supported by observing the key intermediate 1-2 in the EPR
spectrum.13 Absence of a carbonyl group in the IR spectrum of crude reaction mixture may imply the
intermediate 1-3 is unstable and dissociates immediately to 1-5 and 1-6. 16b Although the deoxygenation
mechanism for secondary alcohols is well established by Barton, the β-cleavage of 1-2 dependant on
2
Initiation
N N 2
CN CN CN
Propagation
n InH n
+ Bu3SnH + Bu3Sn
CN
S SnBu3 O
n S
Bu3 Sn + X C O R X C S SnBu3 + R
X C OR
n n
X = SMe, SPh, Imidazole, Ph, OPh, Bu3 SnX + S C O RH + Bu3Sn
When the X is H or CH3, inefficient fragmentation of the key intermediate 1-2 (the Barton’s
radical) results in this radical being trapped by excess tributyltin hydride. Unfortunately, the trapped
orthoester 1-10 is not observable under the standard condition because it can decompose easily to 1-9,
which can be isolated or further reduced to 1-12. The tin containing hemithioacetal 1-12 can be converted
to hemithioacetal 1-13, which is subjected to hydrolysis to ROH 1-14 during the workup and/or column
chromatography.
1-13 1-14
3
An alternate mechanism, (SH2 mechanism), for xanthate decomposition has been proposed by
Baker and Beckwith (Scheme 1.3).17 The alkoxythio radicals 1-9 generated by the SH2 mechanism
undergoes β-cleavage to give a carbonyl sulphide 1-6 and an alkyl radical 1-4. Hydrogen atom transfer
from tributyltin hydride is the last step to complete the chain mechanism via SH2 process. This alternative
mechanism is supported by the observation of key intermediate 1-9 in EPR spectrum at low temperature.17
S S
n n
+ Bu3 Sn Bu3 SnSMe + R O C S C O + R
RO SMe
1-8 1-9 1-6 1-4
n
Bu3SnH
n
RH + Bu3Sn
1-7
alcohols and its effectiveness for new carbon-carbon bond formation has multiplied during the past few
years. 18 The carbon-carbon bond formation can be divided into five sub-groups19: i) intramolecular
cyclization of the Barton’s radical intermediate20; ii) 5- and 6-exo-trig intramolecular cyclization of alkyl
radicals; iii) 5-exo-dig intramolecular cyclization of alkyl radicals; iv) intermolecular addition of the alkyl
Not until the middle of 1980 was an intramolecular cyclization using the Barton’s radical
Clive and his associate found12 an unexpected cyclic compound with or without methyl acrylate via 5-exo-
4
dig radical intramolecular cyclization (Eq. 1). However, because their initial goal was not 5-exo-dig
cyclized product but intermolecular-intramolecular cyclization, they did not further study the Barton’s
S N
Ph3SnH H
O C N O
with or without S (1)
C CO2Me H
C
Ph Ph
Bachi and Bosch were the first chemists to realize that the Barton’s deoxygenation can be
extended as a synthetic tool for new C-C bond formation and/or lactonization through 5-exo-dig and 5-exo-
trig radical processes. In their first communications,12 benzylthionolactone was made from a
dithiocarbonate through 5-exo-dig process (Eq. 2). However, the reaction could not be stopped after the
cyclization but was further reduced by the excess tributyltin hydride. After hydrolysis during the workup,
Ph Ph Ph
Bu3SnH
Bu3SnH
SMe
S S (2)
AIBN
O S O O
In 1988, however, Oshima reported23 that the same ditihiocarbonate could be cyclized through the
R R
R
+
Bu3SnH H3O
SMe
S O (3)
BEt3/O2 O O
O S
R = Ph, 78%, R = SiMe3, 98%
5
Because of the hydrolysis of bezylidene-γ-butyrothionolactone during the workup, the isolated
product was not thionolactone but bezylidene-γ-butyrolactone, and the yield was much higher than that
observed by Bachi. The same procedure was applied successfully for furnishing a ring-fused lactone with
Ph Ph
R
C
C Bu3SnH H3O+
SMe
S O (4)
O O
O S
The same year, Bachi and an associate extended24 their methodology to make thiolactones and
thionolactones through a 5-exo-trig process and suggested a mechanism involving the homolytic attack of
tributyl tin radical on the thioxo sulfur rather than the thio sulfur (Eq. 5).
Ph
Me Ph Ph
O Me Bu3SnH
O + S (5)
S S S O
spirohydroaromatic system after intramolecular radical addition on a phenyl substituted double bond, and
three years later he summarized10a the tributylstannane mediated intramolecular radical process of
thionocarboxylic acid derivatives involving intramolecular radical process in a full pape. The detailed
The Barton’s radical 1-9 can be cyclized to give intermediate 1-10 via 5-exo-trig mode. The
intermediate can be further reduced to 1-13 by excess tributyl tinhydride or added to the phenyl ring to lead
to a spirohydroaromatic ring 1-11 via 5-exo intramolecular cyclization. Rearomatization of the benzene
.
ring and elimination of Bu3SnS give a diphenylmethyl-γ-lactone 1-12. Reduced intermediate 1-13 is
6
subject to the elimination of Bu3SnOPh to lead thionolactone 1-14, which could be converted to
Ph Ph
Ph Ph
Ph Ph
O O O Bu3SnH O
Bu3Sn Bu3SnH
Ph
Ph
O S
O
O SSnBu3 1-14
1-11 o
Ph
Ph Ph
O
O
S
O
1-15
1-12
Scheme 1.4. The Mechanism for the Formation of Thiolactone and Phenyl Migration.
While Bachi and other research groups have concentrated on developing new C-C bond formation
mediated by the Barton’s radical intermediate and on studying the mechanistic problems, Yamamto and his
research group demonstrated independently26 a stereo-controlled lactone formation. They used homoallylic
xanthates as a precursor for the radical cyclization and trans product was isolated as the major products
(Eq. 6).
S
S
MeS O Bu3SnH Et
SSnBu3 O
Me
(6)
AIBN
Et Me Et
Et SMe
cis/trans = 4/96
7
The stereochemistry may be explained by chair like transition state (Eq. 6). However, ring fused
bicyclic thiolactones gave predominantly cis configuration possibly due to the ring strain of trans fused
MeS O S
H
Bu3SnH
O (7)
AIBN
cis/trans = 99/1
OTBS OTBS
H H
Bu3SnH
(8)
AIBN S
SMe
H H
OTBS O OTBS
S O
During the synthesis of (-)-supinidine from (+)-retronecine and (+)-heliotridine, interesting results
were observed by Zalkow. 27 (+)-Retronecine and (+)-heliotridine are epimers at C-7, and they can be
thiocarbonylated easily by phenoxythiocarbonyl chloride after protecting of the hyoxyl group at C-9. The
(+)-heliotridine thiocarbonyl derivative was successfully deoxygenated in good yield under the standard
Barton-McCombie deoxygenation conditions; 1.5 Equiv. of nBu3SnH and 0.2 Equiv. of AIBN in toluene,
stirring at 75 oC for 3 hours. However, the (+)-retronecine thiocarbonyl derivative gave a 5-exo-trig
8
The unexpected product can be explained by the mechanism shown in Scheme 1.5. Because the
radical intermediate of (+)-heliotridine thiocarbonyl derivative has an unfavorable geometry to cyclize the
ring due to the steric hindrance, Barton’s deoxygenation process is more favored than 5-exo-trig radical
cyclization. However, (+)-retronecine thiocarbonyl derivative has an excellent geometry for 5-exo-trig
S SSnBu3
OR3 SSnBu3
OR3 OR3
O H O H O H
O H O
H H
Bu3Sn O
N N N
1-19 1-20
Scheme 1.5. The Mechanism of Phenyl Migration in the Barton’s Radical in a Tricyclic ring.
Bachi and his group developed28 a new synthetic strategy involving a free radical process for the
_)-α-kainic acid from either racemic isocyanides or isothiocyanate. In another paper,29 they
synthesis of (+
reported natural (-)-α-kainic acid by using the Barton’s radical intermediate as the key intermediate (Eq.
10). The Barton’s radical was generated from N-alkenyl thioformamide with nBu3SnH/AIBN through the
Barton’s radical mechanism, and cyclized to give (-)-α-kainic acid as 12% overall yield from the starting
SEt SEt
H OTMS CO2H
OTMS n
S Bu3SnH
(10)
O
+ AIBN CO2tBu CO2tBu
H N CO2tBu N N
NC CO2tBu BOC BOC H
(-)-α-kainic acid
9
Fukuyama reported in 1999 30 the Barton’s radical intermediate could be used for the synthesis of
_)-catharanthin (Eq. 11). The key step involves 5-exo-trig radical process of
another natural product (+
thiocarbamate to furnish an indole ring, and aqueous hypophosphorous acid was used as the radical source
OAc
OAc Cbz Cbz
S H3PO2
N N N
(11)
AIBN/ Et3N
N N N
H CO2Me H CO2Me H CO2Me
In an earlier study,31 Fukuyama and his associates established a formal indole synthesis by using
the Barton’s radical pathways generated by thioamide derivative with AIBN or Et3B. In their
communication, two possible intermediates were proposed; one involves 5-exo-trig radical process to give
a sp3 carbon-centered intermediate containing a C-SSnBu3 bond, the other involves elimination of
HSSnBu3 to give a imidoyl radical species31b followed 5-exo-trig radical cyclization (Scheme 1.6).
H
R R
Bu3Sn R
R' SSnBu3
NH N N
SSnBu3 R'
H H
S R'
1-21 1-22 1-23
-Bu3SSnH
R
R
N R' N R'
H
1-24 1-25
10
More recently, Curran and Du used α-thioaminoalkyl radicals as synthetic equivalents of imidoyl
radicals and developed a formal synthetic route for carbocyclic and heterocyclic fused quinolines (Scheme
1.7).32 The α-thioaminoalkyl radicals are better synthetic intermediates than imidoyl radicals because they
are more stable. Moreover, the α-thioaminoalkyl radicals can be transformed to fused quinoline derivatives
R R R
TMST
S TTMS S 5-exo
X N Y N Y N Y
X X
H H STTMS
H
1,6 [O]
Y -HSTTMS Y
X N X N
S
H TTMS H
1-29 1-30
Scheme 1.7. The Mechanism for Thiocarbamate (Y = O), Thioamide (Y = CR2), and Thiourea (Y = NR2)
Cyclization.
A potent tubulin biding antimitoic agent, podophyllotoxin, was synthesized by Sherburn and his
colleagues in 2003 (Scheme 1.8).33 The core structure of podophyllotoxin, aryl tetrahydronaphthalen-
lactone 1-31, would originate from thionocarbonate 1-32 as a result of intramolecular delivery of the
carbonyl carbon to C-2 and an aromatic residue to C-1. The two new carbon-carbon bond formations were
achieved by utilizing the Baton-McCombie reaction via both 5-exo intramolecular cyclization and phenyl
11
O P P
H H H
O O O
H O H O O
2
O O O S
1
H O H O O
MeO
MeO OMe MeO OMe
MeO
OMe OMe OMe
1-31 1-32 H MR3 1-33
S MR3 MR3
elimination addition
P P
H H
O O
H O O
MR3 MR3
O S O S
H
O O
MeO
MeO
MeO MeO
OMe OMe
1-37 1-34
5-exo
elimination
P P
H H
O O
H O O
MR3 5-exo MR3
O S O S
H H
O O
MeO MeO
MeO MeO
OMe OMe
1-36 1-35
Carbon centered radicals 1-4 generated by β-cleavage of thiocarbonate 1-3 are important
intermediates in the Barton-McCombie deoxygenation (see Scheme 1.1). The newly generated radicals
undergo intramolecular trapping by a variety of radical acceptors as well as hydrogen transfer from
tributyltin hydride. To promote the intramolecular ring closing, it is required to make 5-hexenyl or 6-
12
heptenyl radical by the β-cleavage of the desired bond. There are a number of examples for 5-hexenyl
radicals via the Barton’s deoxygenation mechanism.1 Hart reported 34 the first example in this category in
1982. In the paper, his goal was synthesis of indolizidine, which was required to get a tricyclic lactam with
changing of the configuration at C-4 position. Fortunately, the hydroxyl group of the precursor could be
converted to xanthate in good yield, and the subsequent Barton’s deoxygenation performed to give a 5-
hexenyl radical, which was cyclized to give 2:1 mixture of tricyclic lactams in 74% yield (Eq. 12).
S
H H H H
MeS C O
Bu3SnH
4 H
CH3 H (12)
N AIBN N
O O
Paquette in 1985. 35 Their initial goal was the construction of the ophiobolin ring skeleton by oxy-anionic
[3.3]-sigma tropic approach. He could make the core structure of the ophiobolin involving a hydroxyl
group at C-5. The hydroxyl group could be converted to its xanthate and phosphate ester derivatives,
which were subject to deoxygenation. Unfortunately, the deoxygenation did not proceed, but 5-exo-trig
CH3
CH3 CH3
Bu3SnH Li/tBuOH
(13)
∆ EtNH2 / 0oC
5 CH3 67% CH3 5 CH3
76%
O O
SCH3 P (OEt)2
S O
1987. 5-Hexenyl radical was generated from the xanthate derivative of the pyranoside, and
13
OCH2Ph OCH2Ph OCH2Ph CO2Me
H H
Bu3SnH
O
O O
(14)
OBz O O
AIBN BzO
MeSC O H OH
H
OMe S OMe CH3 OMe CH3 OMe
The first 6-heptenyl radicals generated from bicyclo [3.1.1] heptanone by Barton’s deoxygenation
was reported by Snider,37 and β-copaene and β-ylangene were synthesized from the radical intermediates
via 6-exo-trig process (Eq. 15). The cyclization was performed with thiocarbamate derivatives under the
Bu3SnH
O
O H2C
H2C H2C H
S Im
t (15)
Bu3SnH BuOOH
SeO2
OR
H2C H CH2
OH
R = H, CH2SH
In the same year, Hanessian synthesized38 5- and 6-membered carbocycles from α,β-unsaturated
esters, which are made easily from the corresponding lactol by the Wittig reaction. Subsequent
thiocarbonylation and the Barton’s deoxygenation gave cyclized product in a good yield (Eq. 16 and 17).
CO2Et CO2Et
S Bu3SnH
O C SMe (16)
AIBN
CO2Me CO2Me
Bu3SnH
CH3 N Me
(17)
O C N AIBN
S
14
RajanBabu used 5-hexyl radicals generated form highly functionalized carbohydrates to develop
models to explain the stereochemistry of the radical ring closure using transition state models. 39, 40 The
deoxygenation of the precursor could generate the 5-hexyl radical, which was subjected to 5-exo-trig ring
closure. The stereochemistry of isolated product was determined by observing of acyl migrated product as
well as NOE, 1H, 13C spectra of the cyclized product and chemical correlation. The stereochemistry of the
product may be rationalized by “chair-like” transition state, which lead to a 1,5-cis products (Figure 1.1) as
the major componen. 41 A similar stereochemical outcome was observed with another glucopyranose
Im S
X
O
BnO Bu3SnH BnO X BnO X BnO X
+ + (18)
AIBN BnO OBn BnO OBn BnO OBn
BnO OBn
OBn OBn OBn OBn
CH2OBn
BnO
BnO H
BnO H
1-38
15
One of the most significant results from RajanBabu’s study is the stereoselective 1,5-trans product
deoxygenation (Eq. 19). The exclusive 1,5-trans product cannot be rationalized by chair-like transition
model,39,40, 41 which was commonly adopted for 5-membered radical ring closing. To understand these
unexpected products, he suggested39, 40, 41, 42, 43 a boat-like transition state (Figure 1.2). Because of the small
difference of energy between “chair-like” transition state and “boat-like” transition states (1kcal/mol),45 the
large substituent at C-4 forces the intermediate to orient predominantly in a boat-like conformation to
Im S
X
O X
O Bu3SnH O
(19)
AIBN
Ph O OBn Ph O OBn
OBn OBn
X = H, OMe
Ph O 2 Ph O 2
1 H 1
O . O
1,5-cis H
3 H 3 1,5-trans
H H H
5
4 4 H
H 5 H
1-39 1-40
16
The unusual 1,5-trans stereoselectivty of radical ring closing was used for the synthesis of Corey
lactone,42, 46 which is an important intermediate for the synthesis of prostagladin-like molecules48 from
Im S
OMe
O OH O OMe O OMe
HO O O
O
(20)
HO Ph O Ph O O
OH OBn OBn OBn
He also investigated44 the stereochemistry in 5-hexenyl radical cyclization by 4-substituted cis and
trans-2-(1-but-3-enyl) cyclohexyl radical generated by the Barton’s deoxygenation. When the substituents
are all in the most favorable position, 1,5-cis product was obtained as the major product via “chair-like”
transition state, in which the radical center in cyclohexane ring system interact from its axial face with the
olefin π* orbital. 1,5-Trans outcomes also can be explained by chair-like transition state with axial
preference of the butenyl group. However, stereoselectivity for the trans compounds is lower than those
for the cis compounds, because the population of the axial bulky group is energetically less favored (Figure
1.3).
H H
R H Ψ-axial
Ψ-axial
chair R boat
R H H
1-41 1-42 1-43
R H R
H
Ψ-axial
Ψ-eq
H
H H
H
chair
1-44 1-45
17
1. 1. 2. 3. The 5- Exo-dig Intramolecular Cyclization of Alkyl Radicals
has not been studied extensively, but was reported as early as in 1984. 48 Clive and his associates found
secondary alcohols can be converted into cyclic ketones by the Baton’s deoxygenation mechanism via 5- or
6-exo-dig intramolecular ring closing followed oxidative cleavage (for X=C) or by hydrolysis (for X=N)
(Eq. 21 and 22). The same protocol was applied for the synthesis of bicyclic ring, and similar results were
Im
H S C X
X X
R O R O R
C Ph3SnH
C (21)
n AIBN n
R' R' n R'
X = H, CN
Ph C5H11 Ph
H Ph
O
C (22)
81%
Ph
Ph
OH H
(23)
79%
O
OH H
C N C N
+ (24)
67% 11%
The 5-exo-dig radical ring closure is an efficient way to construct a double bond to a fused five-
membered ring. Especially, it is interesting that α-silyated radical mediated ring closure allows the double
bond migration by desilylation, which may construct a cyclic alkene frame. 49 Noyori and his associates
generated the α-silyated radical by either the photolysis of m-(trifluoromethyl)benzoate derivative or the
Barton’s deoxygenation of a xanthate derivative followed ring closure of the radical to give a high yield of
18
a bicyclic product (Eq.25). Desilylation of the bicyclic [3.3.0] octane gave the isocarbacyclin , which has
R R R
H X
R3Si O R3Si O
a or b
(25)
R' R'
R'' R' R''
R''
a, X = C(=S)SCH3, Bu3SnH/AIBN
b. X = COC6H4-m-CF3, hυ
CO2CH3
COOCH3
R3'Si
OR
R3'Si
RO HO
TBSO OR OH
OTBS
In 1988, Motherwell reported50 that alkynyl radicals could be used for regio-and stereospecific
(Scheme 1.9). The ring of cyclopropylcarbinyl radical may be opened by either bond breaking of a or b,
but the product analysis showed the bond breaking of a proceeded predominantly, which might imply the
reaction was kinetically controlled because the cleavage of a produced a primary radical which had higher
energy than a secondary radical generated by cleavage of b. The hex-5-ynyl radical could be closed easily
Eq. 27 is also noteworthy.50 An α,β-unsaturated ketone derivative was reduced chemo- and
stereoselectively by L-selectride, and their major epimer was isolated by aqueous workup. The isolated
epimer could be converted to the other epimer by Mitsunobu reaction51 followed solvolysis in the presence
of titanium tetraisopropoxide. After several steps, the desired thiocarbamates were obtained, and they were
subjected to radical cyclization via the Barton’s deoxygenation procedure. These two isomers were
19
CH2
Bu3Sn
(a)
H
. (b)
X H H
1-46 1-47 1-48
b
X a
Bu3SnH Bu3SnH
O OH
S S
O Im O Im
(27)
SiMe3 SiMe3
Me3Si
Me3Si
There are only a few papers covering intermolecular addition by the alkyl radical generated during
the Barton’s deoxygenation. The first paper in this area52 was reported by Giese in 1984. In his paper, α-
D-glucofuranose derivatives reacted with acylonitrile to give two anomers with 73:27 ratio, but α-D-
20
galactofuranose derivatives coupled diastereoselectively with the radical acceptor from exo-side. The
derivatives of deoxygalactopyranoside was also subjected to intramolecular C-C bond coupling, but the
O O O
X O R O
O Bu3SnH O O
O
+ (28)
O H2C=CHCN O O
O O R O
X
O R
Bu3SnH
O
O O (29)
O O H2C=CHCN O O
O O
A similar reaction was studied with D-glucopyranosyl derivatives by Araki’s group in 198753, but
only small amount of starting material was converted to alkyl radical via Barton’s mechanism, which led to
poor C-C bond formation. One-year later,54 however, they could generate successfully a ribofuranosyl
radical, which was trapped by dimethyl maleate in a 62% yield and the adduct was used as a precursor for a
COOMe
BzO O C SMe BzO BzO
O O COOMe O
COOMe Bu3SnH
S (31)
+ +
O O COOMe AIBN O O O O
During a study of tandem radical annulations to prepare carbocyclic compounds, Clive and his
research group investigated12 β-acetylenic radicals, which might be generated from ether α-halogeno-
21
ketones or thiocarbamate derivatives by Ph3SnH/AIBN (Eq. 32). The radical generated from halogen
derivative was trapped well by Michael-type radical acceptors through 5-exo-dig process, but the acetylenic
radical from thiocarbamate derivatives was not trapped effectively. Fortunately, another radical acceptor,
acrylonitrile, was used for the intermolecular-intramolecular tandem cyclization to give bicyclic
S N
H
O C N
Ph3SnH
CN (32)
C CN
C
Ph
Ph
In 1985, Keck reported55 that thiocarbamate, thiobenzoate, and xanthates derivatives could be
trapped into allytributylstannane. The best result was obtained after photolysis: the yield of reaction was
lower under thermal conditions in the presence of AIBN because 2-cyanopropyl radical from AIBN added
to the carbon rather than initiate the reaction (Eq. 33). However, if crotyltin-n-butylstannane was used for
the reaction instead of allytributylstannane, the carbon-centered radical was not trapped, but a simple
O O
O OBn O OBn
S Bu3SnH
O Bu3SnCH2CH=CH2 O (33)
X O
hυ or ∆
Bu3SnH
H
RX R RH + + Bu3Sn (34)
H3C SnBu3 H2C SnBu3
1985. 56 A carbon radical trapped by an alkene may give three different products depending on the
22
mechanism. The most common pathway is a with a hydrogen abstraction from radical donor such as
tributyltin hydride. The other pathway is radical addition-elimination process, which may be divided into
two sub-groups; one is pathway b which is commonly known as SH’ mechanism, 57 or the pathway c (the
proximal mechanism). Baldwin and his associate developed new consecutive radical addition-elimination
reactions, which might be applied for new carbon-carbon bond formation, via the proximal pathway c
(Scheme 1.10).
Y
A
+ B
R X
1-55
a
Y Y
b
R + + Y
X R X c R X
1-53 1-54 1-56
+ X
R
1-57
They generated radicals in the presence of excess amount of β-stannyl acrylate (2.0 equiv.). Half
of the radicals were reduced to deoxygenated product via the Barton’s deoxygenation mechanism and the
other half were trapped by the excess β-stannyl acrylate via the proximal pathway c. Although the yields
were low, the results are very useful because the radical addition-elimination gives preparatively useful
product under condition that are mild and neutral (Eq. 35).
23
CO2Et
O O
O O O
X O O
O Bu3SnCH=CHCO2Et
O +
O O
(35)
O O O
O
Finally, during the study of diastereoselective vinyl- and carbonyl-initiated intramolecular [3 atom
+ 2 atom] radical cyclization,58 Feldman found an interesting intermolecular version of the [3 atom + 2
atom] radical cyclization (Eq. 36). 59 The ring of a phenyl or gem-dichloro substituted cyclopropyl
.
thioamide can be opened by addition of Me3Sn to the thiocarbonyl group, and the resulting product can be
trapped by an electron deficient alkene to form 5-hexenyl radicals. Theses radicals undergo ring closure
R R R S
E X SSnMe3 X
X (Ph2COSnMe3)2
Z + Z (36)
Y PhH, reflux Y . Z Y
S E E
Most radical acceptors for intra or intermolecular cyclization are olefins; but oxime ether has also
been used as a radical acceptor. 60 In 1988, Bartlett reported that61 oxime derivatives are excellent radical
glucopyranose can be converted into benzyl oxime or methyl oxime derivatives with BnONH2•HCl or
MeONH2•HCl under the mild conditions. To generate 5-oxime radicals, the glucopyranose derivatives
were converted to phenylthiocarbonate derivatives, which were subjected to the Barton’s deoxygenation.
Exposure of these substrates to tributyltin hydride and AIBN under refluxing conditions gave
24
diastereomeric mixture of aminocyclo pentitiol, which had predominantly 1,5-cis selectivity like
OR' NHOR'
S N NHOR'
O OH OR OR OR
RO PhO O RO RO
+ (37)
RO OR OR RO OR RO OR
OR OR
OR
Radicals generated from thiocarbamates and their analogues are sp3 carbon centered radicals
containing a C-SSnBu3 bond, but Buchi first reported62 sp2 carbon centered radicals (imidoyl radicals) from
thiocarbamates. The imidoyl radicals are very attractive because they can be used as intermediates in the
synthesis of cyclic ketones. Especially, if the potential radical bearing group (e.g. phenyl group) is
substituted on the nitrogen of imidoyl radicals, a tandem cyclization may take place to afford
HN N N
NaH, Bu3SnCl
(38)
S SSnBu3
R
O Ph O Ph O
To make the imidoyl radicals, the bond between carbon-sulfur has to be broken and this is done by
using trialkyltin thioimidates rather than aryl or alkyl thioimidates (Scheme 1.11). 63 The imidoyl radical
can also be generated from N-benzyl(N-alkyl)thioamides because benzyl radical may be eliminated easily
from the substrates to afford trialkyltin thioimidates. The generated imidoyl radical was cyclized via 6-
exo-trig process to give enamines, which are subject to hydrolysis to afford ketone derivatives.
25
SnBu3
S Ph S SSnBu3
CH2Ph
Bu3Sn -PhCH2 Bu3Sn
N N N Me
Me Me
-(Bu3Sn)2S
O Ph O Ph O Ph
Ph [H2O] Ph
O Ph O O
Scheme 1.11. The Mechanism for the Imidoyl Radical Mediated Cyclization.
radical was reported by Tsai in 1999. 64 The α-stannyl radicals were generated from α-stannyl xanthate
derivatives with tributyltin hydride and AIBN, and the radicals attacked both a formyl group and an alkenyl
group at the same reaction rate via 5-exo ring closure (Eq. 39). The intramolecular cyclization of the α-
stannyl radical with a formyl group gave γ-stannyl alkoxy radicals, which were subject to 1,3-stannyl
radical migration followed by tandem 5-exo cyclization. The stereochemistry of the tandem cyclized
bicyclic products was trans, which might be rationalized by chair transition state in which the group on C-
O
O OH
H H
H
Bu3SnH
H
O SnBu3 + + + (39)
AIBN
Bu3Sn Bu3Sn
H
Me S S CH3 CH3 HO CH3 HO H CH3
26
H H 1 H
O O. OSnBu3
. SnBu3 SnBu3 .
3
2
H H H
H H
Figure 1.4. The Rationalization of the Stereochemistry of Tandem Radical Cyclization under Barton’s
Deoxyzanation Conditions.
Although sp3 carbon centered radicals 1-4 (Scheme 1.1) generated by β-cleavage of thiocarbonate
1-3 has been used as a precursors of 6-exo-trig ring closure,37,38 the Barton’s radical 1-2 has not been
considered as the precursor of the 6-exo-trig ring closure until a report by RajanBabu and Bliss (Eq. 40).65
Moreover, if O-phenyl thiocarbonate was used for the cyclization, they observed a phenyl group migration
via spiro aromatic system, which has been reported earlier by Bachi25 and Zalkow27.
OPh
S OTBS OTBS
O O O O
TBSO +
CO2R Ph
O O (40)
O O O CO2R O CO2R
Bliss initially studied the 6-exo-ring closure by using the Barton’s radical generated from O-
phenyl thiocarbonate (Eq. 40). They observed the phenyl group migration during the radical cyclization to
give 1-74, and proposed a mechanism involving spiro aromatic system (Scheme 1.12). The configuration
27
of the isolated 2-deoxy-δ-lactone was altro based on Wilcox’s results,66 conformational analysis, coupling
constant, and NOESY spectrum. However, reverse addition (slow dropping of a mixture of substrates and
AIBN in a solvent into a solution of tributyltin hydride via a syringe pump) might trap the α-methylene
radical generated by 6-exo-trig cyclization before the phenyl group migration to the methylene radical (k3 <
k4). Because excess amount of tributyltin hydride was used, the cyclized intermediate, orthoester, could
eliminate phenyltributyltin moiety, Bu3SnPh, to afford thionolactone, which was subject to further
Bu3Sn . OPh
SnBu3
S OTBS OTBS OTBS
O S
O S Bu3Sn
. O
TBSO O
O
CO2Et
Bu3SnH O
O O O O
O CO2Et O CO2Et
O CO2Et
Bu3SnS SnBu3
OTBS SnBu3 OTBS
OTBS
. OPh S S
a O O O O O
b k1 O k3 O
TBSO
Ph
CO2Et b
O
. Bu3SnH
.
Bu3SnH
O
O
O O O CO2Et O CO2Et O CO2Et
O O
1-75
Scheme 1.12. Mechanism for the Formation of Pyran Ring System via 6-Exo-trig Ring Closing Mediated
by the Barton’s Radical.
28
The cyclized compound 1-74 was obtained as a single isomer, and was chartacterized by 13C
NMR, which had two ester carbonyls at δ 171.5 and δ 170.6 ppm as well as a phenyl group. The
stereochemistry of the lactol 1-70 was assigned as altro configuration based on NOSEY data, and the
measured coupling constant between H-2 and H-3 was in agreement with the theoretical coupling constant
derived from Karplus equation, and the relatively big dipole-dipole correlation between H-2 and H-4 in
NOSEY may rationalize the allo configuration of compound 1-70. Unfortunately, the opposite
configuration of 1-70 and 1-74 at C-2 has not been explained at this point.
More interesting results have been achieved by changing the substrates from thiocarbonates to
thiocarbamates. Slow addition of thiocarbamate and AIBN in benzene to solution of tributyltin hydride
gave cyclized products, which are rare examples of N-heterocyclic-hexopyranosides (Eq. 41). They are
also branched chain N-glycosides. Moreover, this is not only the first example without elimination of
substituent X during the Barton’s radical mediated 5- or 6-exo-trig ring closure, but also a fundamentally
important new glycosylation reaction. Because of the aromatic center carbon at δc = 83.2 ppm in 13C NMR
spectrum, the isolated product was tentatively assigned as α configuration, and small J value (J1,2 = 3.2 Hz)
supported a cis relationship between C-1 and C-2 substituents. A new anomeric hydrogen peak appeared in
the 1H NMR spectrum on standing the sample at room temperature, and the J value was relatively large
(J1,2 = 8.5 Hz), which indicate isomerization to the β-anomer. Based on these results and compared with
the structural analysis of furanoside,60 Bliss concluded the N-glycoside had the allo configuration.
N
N OTBS N
S O N
Bu3SnH
O
TBSO (41)
AIBN
CO2tBu O
O CO2tBu
O O
The formation of N-glycoside is novel because thus far all radical cyclizations based on the
Barton’s deoxygenation lead the elimination of substituent X (see Scheme 1. 1, 1. 2, and 1. 3). However,
the initial study gave only 37% yield of the desired N-glycoside, and the structural analysis has not been
29
firm because of the lack of NOE or 2D NMR data. Moreover, the new synthetic route for the formation of
2-C branched glycosides is a fundamentally important methodology. Thus, for the general transformation
of carbohydrates to O-and N-glycosides, this work has to be extended to include 5-exo-trig ring closures.
Rare N-hexopyranoside
OTBS N
O N
A Glycosylation Reaction? New C-C Bond
O
O CO2tBu
N
N
OTBS
S OH
O X O O O
TBSO Y
O Y
O O HO OH
O
30
1. 2. Synthesis of Substrates for Radical Cyclization
electron withdrawing group (EWG) on the acceptor olefin. Synthesis of a substituted enoate from D-
ribonic-γ-lactone is shown in Scheme 1. 14. First, the two hydroxyl groups of 2 and 3 positions of
compound 1-76 were protected by acetone and iodine with small amount of anhydrous magnesium sulfate
OH OH OTBS OTBS
O O O O O O O OH OH
TBSO
a b c d
CO2R
HO OH O O O O O O O O
Scheme 1.14. Synthetic Routes to Prepare Substrates 1-80: (a) acetone, I2, anhydrous MgSO4, rt, 12 h,
94%; (b) TBSCl, imidazole, DMF, 0 oC 1 h and rt 9.5 h, 96%; (c) 1.5 M Dibal-H in toluene, Et2O, -78 oC, 2
h, >99%; (d) R = tBu, Ph3PCHCO2tBu, DME, rt, 4 h and reflux ,4 h, 92%. E/Z = 0.24/1.0; R = Et,
Ph3PCHCO2Et, DME, rt 102 h, 95%. E/Z = 0.32/1.0.
This compound may be used without further purification for the next step, but if it is necessary to
obtain a pure compound, it can be purified by recrystallyzation from pentane or flash column
mixture. In the case of R = tBu, the mixture was isolated by column chromatography to give 92% of
isolated yield with E/Z = 0.24/1.0, while 95% of isolated yield (E/Z = 0.32/1.0) was obtained with R = Et.
31
Alkyl-7-O-(tert-butyldimethylsilyl)-2,3-dideoxy-4,5-O-(isopropylidene)- D-ribo-hept-2-enoate
thiocarbonylimidazole 1-81 and 1-82 (E and Z) was prepared from 1-80 in 89-77% yield with freshly
prepared 1,1-thiocarbonyldiimidazole. THF or dichloroethane can be used as the solvent, and they do not
affect the yield. For convenience, the reaction mixture was not usually worked up, but the solvent was
N
N
S
TBSO OH O
a TBSO
CO2R CO2R
O O O O
Scheme 1.15. Synthetic Route to Prepare Substrates 1-81 and 1-82: (a) R = tBu (Z), 1,1’-thiocarbonyl
diimidazole, DMAP, dichloroethane, reflux, 13.5 h, 89%; R = tBu (E), 1,1’-thiocarbonyldiimidazole,
DMAP, dichloromethane, reflux, 10 h, 86%; R = Et (Z), 1,1’-thiocarbonyldiimidazole, DMAP, THF,
reflux, 17.5 h, 80%; R = Et (E), 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, overnight, 77%.
Another EWG substituted olefin was synthesized from the D-ribono-γ-lactol 1-79 with
mixture, which contained TBS group migrated compounds 1-84 and cyclized compounds 1-85 as well as
desired products 2-7. Further purification showed the major product was a mixture of (E)-1-83 and 1-85
(71%, ratio is 1:4), and they could not be isolated by traditional column chromatography. Because of a
serious loss of the product by column chromatography, no more purification was attempted. The combined
yield of the olefin compounds 1-83 and 1-84 and cyclized compound 1-85 were 85% after column
chromatography.
32
OTBS OTBS
O OH TBSO OH OH OTBS O
a
CN + CN + CN
O O O O O O O O
Scheme 1.16. Synthetic Route to Prepare Substrates 1-85: (a) Ph3PCHCN, toluene, rt 9 h, total isolated
yield 85% (E/Z = 0.9/1.0).
The thiocarbamation was applied to the mixture of 1-83 (E) and 1-85. Only compound 1-83 (E)
reacted with 1,1’-thiocarbonyldiimidazole to give compound 2-86 (E) in a yield of 79% based on 1-83 (E).
The cyclic ring of compound 1-85 did not open to make a desired product 1-86 (E), and the starting
material 1-85 was recovered almost quantitatively after column chromatography. The same condition was
used for the compound (Z)- 1-83. The reaction required longer time (24 h), but gave competitive yield
(86%).
N
N
OTBS S OTBS
CN O O CN O
TBSO OH
a TBSO
+ CN + CN
O O O O O O O
N
N
S
OH O
TBSO
b TBSO
CN CN
O O O O
Scheme 1.17. Synthetic Route to Prepare Substrates 1-86: (a) 1,1’-thiocarbonyldiimidazole, THF, DMAP,
reflux 10.5 h, 88% (based on 1-83 (E)) of 1-86 (E) isolated and 35% of 1-85 recovered (cis/trans =
1.0/0.09); (b) 1,1’-thiocarbonyldiimidazole, THF, DMAP, reflux 24 h, 86%.
33
A reaction with an unstabilized Wittig reagent was performed with D-ribono-γ-lactol 1-79 and
methylenetriphenylphosphorane in THF. The required phosphorane was made in situ from the
phosphonium salt and n-butyl lithium at -78 oC to rt. Slow addition of D-ribono-γ-lactol in THF -78 oC gave
immediately yellow solution, which was further stirred at rt for 2 h. A desired product 1-87 was isolated
as a 71% yield, and the isolated compound was reacted with freshly prepared 1,1’-thiocarbonyldiimidazole
and DMAP in THF. After flash column chromatography, a 69% of 1-88 was isolated as yellow oil of the
desired product.
N
N
OTBS S
O OH OH TBSO O
TBSO
a b
O O O O O O
Scheme 1.18. Synthetic Route to Prepare Substrates 1-88: (a) Ph3PCH3Br, nBuLi, THF, -78 oC to rt, 2 h,
71%; (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux 14 h, 85%.
radical process under the Barton-McCombie conditions (Chapter 1, Eq. 19). To generalize our
methodology for 5- and 6-exo-trig radical cyclization mediated by the Barton’s radical, O-methyoxime
ribono-γ-lactol 1-79 in absolute methyl alcohol under refluxing condition for 8 h. After column
chromatography, 66% of colorless oil was obtained as syn/anti mixtures, and they were subjected to the
thiocarbonylation with 1,1’-thiocarbonyldiimidazole. The desired product was obtained as yellow oil in an
34
N
N
OTBS S
O OH TBSO OH TBSO O
NOCH3 NOCH3
a b
O O O O O O
Scheme 1.19. Synthetic Route to Prepare Substrates 1-90: (a) H2NOCH3•HCl, pyridine, MeOH, reflux 5.5
h, 96% (syn/anti = 1.0/0.25). (b) 1,1’-thiocarbonyldiimidazole, THF, reflux 10.5 h, 92% (syn/anti =
1.0/0.32).
Another example for N-substituted substrates is shown in Scheme 1. 20 After stirring of D-ribono-
γ-lactone with N,N’- dimethylhydrazine in absolute methyl alcohol under reflux condition, a mixture of 1-
91 and 1-92 was isolated as yellow oil. The combined yield was 71% and the ratio of 1-91/1-92 was
1.0/0.16. These mixtures were used for the next experiment without further purification due to the
reacted with 1,1’-thiocarbonyldiimidazole and DMAP in THF under refluxing conditions for 12 h. After
flash column chromatography, 74% (syn/anti = 0.58/1.0) of desired product 1-93 was isolated.
N
N
OTBS S
OTBS
O OH TBSO OH O O
NN(CH3)2 NHN(CH3)2 b TBSO NN(CH3)2
a
+
O O O O O O O O
Scheme 1.20. Synthetic Route to Prepare Substrates 1-93: (a) N,N’-dimethylhydrazine, MeOH, reflux,
overnight, 71% (1-91/1-92 = 1.0/0.16). (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux 12 h, 74%
(syn/anti = 0.58/1.0).
35
The same reaction was performed with p-toluenesulfonylhydrazine under the traditional
conditions. Unfortunately, the isolated product was only a cyclic form like 1-94 as an α/β mixture, and no
acyclic olefin was obtained. After 7 h refluxing, however, all starting material 1-94 was consumed.
Initially, we anticipated opening of the cyclized ring, and thus the hydroxyl group would be converted to a
desired thiocarbamate, because it has been reported that the cyclic forms are in equilibrium with acyclic
forms.67 However, none of the expected product was produced. The only product characterized was 1-95.
N
N
S
OH O
TBSO NNHTs TBSO NNHTs
X
O O O O
1-94'
S N
OTBS OTBS OTBS N
O OH O O
a b
NHNHTs NNH
O O O O O O
Scheme 1.21. Failed Attempts to Prepare Thiocarbmate of Hydrazone Derivatives: (a) p-toluenesulfonyl
hydrazine, acetonitrile; (b) 1,1’-thiocarbonyldiimidazole, DMAP, dichloromethane, DMAP, reflux 7 h,
47%.
The formation of 1-95 may be explained by the proposed mechanism shown in Scheme 1. 26.
Because of excellent nucleophilicity of the nitrogen of tosylhydrazone derivatives, the thiocarbonyl group
of 1,1-thiocarbonyldiimidazole can be attacked, which may lead to the unexpected compound 1-95. 1H
NMR spectra shows that one H peak disappears by addition of D2O, which accounts for the hydrogen
connected to a nitrogen. Moreover, 13C NMR shows a singlet peak at 118 ppm, which may imply a C=N
group.
36
OTBS OTBS OTBS
Ts S Ts S
O O H O
NHNHTs S N N C Im N N C Im
+ Im C Im H
O O O O O O B
1-94
OTBS OTBS
S
O O H
N N C Im N N S
H
O O O O N
N
1-95
Therefore, we chose diphenyl hydrazine, which can make an acyclic forms like 1-99 and 1-100,
and performed the thiocarbamation under the traditional refluxing conditions. However, all attempts failed
and no starting material was detected on TLC. Initially, we assumed the acidic environmental of the
reaction condition (the used diphenylhydrazine was a hydrochloride form) might cause the decomposition
of the starting material D-ribono-γ-lactone by the elimination of a TBS group. To resist the acidity of the
applied conditions, the protecting group was changed from a TBS to a TBDPS group as well as quenching
the hydrochloride by either triethyl amine or pyridine. The lactol 1-98 was made from TBDPS substituted
lactone 1-96 by the previously described method; protection of the hydroxyl groups at C-2 and C-3 and
then reduction of the lactone by Dibal-H at –78 oC. The TBSPS protected lactol 1-98 was stirred at rt for 3
days without quenching the HCl of diphenyl hydrazine by base. After column chromatography, a small
amount (less then 10%) of desired product was isolated with inseparable impurities. The diphenyl
hydrazine was quenched by triethyl amine, and the same reaction was performed ar rt for 48 hr.
Unfortunately, more than 90% of starting material 1-98 was recovered. Finally, we found the desired
product 1-99 was made more efficiently after treating the diphenyl hydrazine hydrochloride in prydine at rt
for 30 min. The pyridine treated 1-99 was stirred in methyl alcohol at rt for 24 h. The isolated yield of
hydrazone product 1-99 was approximately 55%, but still some impurities could not be removed from the
37
products. The same condition could be applied successfully for a TBS group substituted D-ribono-γ-lactone
1-79. The neutralized reaction mixture by pyridine was stirred at rt for 24 h, and the mixture was purified
by column chromatography, eluting with hexane:EtOAc = 10:1 solution containing 1% triethyl amine.
Even though about 10 % of stating D-ribono-γ-lactone was recovered, 66% (based on recovered starting
material) of desired product 1-100 was isolated without any significant impurities. The mixture of 1-99
was subject to thiocarbamation under the traditional condition. Even though all of the starting material was
consumed as indicated by TLC, no significant amount of desired product was isolated. Fortunately, the
pure 1-100 was converted to the desired thiocarbamate derivative under the similar condition in a high
yield (98%).
N
N
OTBDPS OTBDPS OTBDPS S
O O O O OH TBDPSO OH O
O
NHNPh2 TBDPSO NNPh2
a b c
X
HO OH O O O O O O d O O
N
N
OTBS S
O OH TBSO OH O
NNPh2 TBSO NNPh2
c d
O O O O O O
Scheme 1.23. The Synthesis of Diphenyl Hydrazone Derivatives: (a) acetone, I2, MgSO4, rt, 12 h, 98%; (b)
1.5 M Dibal-H in tolune, Et2O, -78oC, 4 h, 82%; (c) Ph2NNH2•HCl, pyridine, MeOH, rt, 24 h, 55% for 1-
99, 66% for 1-100; (d) 1-99, ImC(=S)Im, DMAP, THF, reflux, 12 h, all starting material decomposed; 1-
100, ImC(=S)Im, DMAP, THF, reflux, 24 h, reflux, 20 h, 98%.
38
The cyclic TBS protected -D-ribofuranose 1-79 are equilibrium with acyclic D-ribofuranose 1-79’
in a solution. If the acyclic D-ribofuranose 1-79’ react with 1, 1’-thiocarbonyldiimidazole under our
standard reaction condition for thiocarbamation, we can make an aldehyde substituted precursor for 6-exo
trig radical cyclization via the Barton’s radical intermediate. It is well known aldehyde is a reasonable
radical acceptor due to its strong electron withdrawing ability, which may lead better yield in radical
cyclization. If the reaction is successful, moreover, we may install easily a free hydroxyl group at C-2
The reaction was performed with 1, 1’-thiocarbonyldiimidazole and catalytic amount of DMAP in
THF under refluxing condition for 21h. Although small amount of starting material 2-4 was remaining, the
reaction was stoped due to deterioration of the product as shown by TLC, and the product was purified the
new product by column chromatography. Unfortunately, the isolated product was not the desired product
N
N OTBS OTBS N
S TBSO OH O OH O O N
O a O
TBSO a
O X S
O O O O O O
O O
Scheme 1.24. Thiocarbamation of 1-79: (a) ImC(=S)Im, DMAP, THF, reflux, 21 h 24% (29% based on
recovered starting material)
with methylamine hydrochloride and p-chlorophenyl hydrazine hydrochloride. The applied method was
similar to the above; after quenching the corresponding HCl by pyridine, the mixture of hydrazine and the
sugar were refluxed or stirred at rt as a mixture in absolute alcohol under nitrogen atmosphere until no
39
more starting material was detected on TLC. Even though all starting material was consumed, we failed to
OTBS
TBSO OH H O OH TBSO OH
N N Cl a b NCH3
X X
O O O O O O
1-79
Scheme 1.25. Failed Attempts to Prepare Hydrazone Substrates: (a) p-Cl-C6H4NHNH2•HCl, MeOH,
reflux, decomposed; (b) CH3NH2•HCl, MeOH, reflux, decomposed.
It is well established that phenyl isocyanate reacts with an alcohol and catalytic amount of triethyl
amine to give a carbamate. With olefin substituent 1-80, the reaction was successful and desired products
were isolated from 91 to 84% yield. The next step was thiocarbonylation of 1-104 by Lawesson’s reagent.
Unfortunately, no significant amount of desired product was isolated after refluxing or warming in toluene
or benzene.
NH NH
O S
OH O O
TBSO
a TBSO b TBSO
CO2R CO2R X CO2R
O O O O O O
1-80 1-104 I
Scheme 1.26. Failed Attempts to Prepare Thiocarbamate I: (a) tBu (E), PhNCO, Et3N, benzene, overnight,
91%; Et (Z), PhNCO, Et3N, benzene, overnight, 84%; (b) Lawesson’s reagent, benzene or toluene, reflux,
overnight, all starting material decomposed.
40
The same reaction was performed with phenyl thioisocyanate and triethyl amine in benzene.
Although prolonged reaction times were used, the reaction was not successful because of the lower
electrophilicity of thiocarbonyl group compared to that of the carbonyl group. After column
chromatography, most starting material was recovered. To overcome the low electrophilicity of phenyl
thioisoycanate, 2.0 equivalents of BF3•OEt2 was added along with 1.2 equivalents of Et3N.
NH
OTBS S
CO2R
O TBSO OH O
a or b TBSO
c
CO2R X CO2R
O O O O O O
1-105 1-80 II
Scheme 1.27. Failed Attempts to Prepare Thiocarbamate II; (a) R = tBu (E), Et3N, PhNCS, benzene,
reflux, overnight. (b) R= tBu (Z), Et3N, BF3•OEt, PhNCS, benzene, reflux, 2h. (c) R = tBu (Z), NaH, THF, -
78 oC to rt, 5.5 h 87% (α/β = 0.56/1.0); Et (Z), NaH, THF, -78 oC to rt, 1.5 h, 95% (β only).
Unfortunately, all starting material decomposed under 2 h refluxing. Finally, the hydroxyl group
of the substrate was deprotonated first by mineral oil free NaH in dried THF at –78 oC (to rt), and then
phenyl thioisocyanate was added slowly followed stirring at rt. However, the deprotonated substrate of 1-
80 cyclized via a 5-exo-trig mode before it added to phenyl thioisocyanate, and compound 1-105 was the
only isolated product. To reduce the favored 5-exo-trig-cyclization of deprotonated substrate of `1-80 and
enhance the coupling with phenyl thioisocyanate, the addition of reactants was reversed (the solution of 1-
80 was slowly added to the mixture of phenyl thioisocyanate and sodium hydride in THF at –78 oC or 0 oC),
but those attempts failed and gave the same cyclized compound 1-105.
41
To avoid the 5-exo cyclization, the substrate 1-80 was treated with the (Bu3Sn)2O to make a tin
ether (ROSnR3), which could react with PhNCS to give the thiocarbamate due to better nucleophilcity of
the tin ether oxygen compound to the hydroxyl oxygen. However, the desired product was not isolated,
and only product was α,β-unsaturated lactone 1-106, formed in a 55% yield.
NH
O
S Bu3Sn
O O OH TBSO O
TBSO
TBSO TBSO a or b
CO2R X CO2R X CO2R
O O O O O O O O
Scheme 1.28. Failed Attempts to Prepare Thiocarbamate III: (a) R = Et (Z), (Bu3Sn)2O, PhNCS, toluene,
reflux 55%; (b) R = tBu (E), (Bu3Sn)2O, toluene, reflux, 3%.
The proposed mechanism for the formation of compound 1-106 is shown in Scheme 1. 29. The
oxygen of tin ether may attack the carbonyl group of an α,β-unsaturated ester to give a cyclized 7-
membered unsaturated intermediate 1-107. There are two possible mechanisms; in the pathway a, the α,β-
unsaturated lactone is formed by 1, 3-tin migration followed by removal of RO-SnBu3. In the other
pathway b, Bu3Sn+ should be removed first and followed the removal of –OR. It has been known that an
ester group can be hydrolyzed by (Bu3Sn)2O to an acid.68 However, this is the first example of an α,β-
unsaturated lactone formation by (Bu3Sn)2O. Although the lactone ring 1-106 can be constructed in a good
yield with R=Et, the yield was lower (~3%) with a bulky substituent R=tBu. It has been known68 that the
42
RO O SnBu3
O
TBSO -[RO-SnBu3]
O O
RO O- Sn O
Bu3Sn RO
Bu3Sn migration
O +O TBSO O
TBSO OH TBSO O or
TBSO
CO2R
-Bu3Sn+
O O O O O O RO O- O O
-OR
O
1-80 1-107 1-106
TBSO
O O
Benzoyl chloride is an excellent protecting reagent for 1o and 2 o alcohols. Especially, if we have
radical cyclization mediated by the Barton’s radical. The hydroxyl group of 1-80 was coupled with
benzoyl chloride to give a benzoate in pyridine as a good yield. The isolated benzoate derivative 1-108 was
subject to thiocarbonylation by Lawesson’s reagent in benzene under refluxing condition for more than 30
hr. Unfortunately, almost 100% of starting material was recovered after flash column chromatography.
O S
TBSO OH
O b O
a TBSO TBSO
CO2tBu
O O
CO2tBu X CO2tBu
O O O O
1-80 1-108
Scheme 1. 30. Failed Attempts for Thiocarbonates: (a) PhCOCl, pyridine, 0 oC to rt, overnight, 73%. (b)
Lawesson’s Reagent, benzene, reflux, 30 hr all starting material was recovered.
43
When an EWG is substituted on the olefin of substrates, the deprotonation of hydroxyl group leads
to cyclization via 5-exo-trig even at very low temperature (see Scheme 1.31). To avoid this unwanted
NH
S
TBSO OH O
a
TBSO
+ PhNCS
O O O O
1-87 1-109
Scheme 1. 31. Thiocarbamation of Unactivated Olefin 1-109: (a) NaH, THF, rt, 11 h, 96%.
After the substrate was deprotonated by NaH at rt, phenylthioisocyanate was added and the
mixture was stirred at rt for 11 h to give compound 1-109. The proton NMR of isolated compound was
complex, but presence of an olefin (1 H of multiplet at 5.69-6.01 ppm 2 H of multiplet at 5.11-5.32 ppm)
and a thioamide functionality (1H of broad singlelet at 0.53 ppm, which accounts for NH hydrogen of
thioamide) was obvious. The structure can be further confirmed by both 13C NMR (thioamide carbonyl
group at 187.0 ppm, olefin carbon at 117.5 and 122.1 ppm) and IR spectrum (thioamide I peak at 1539 cm-
1
, thioamide II peak 1381cm-1, thiocarbonyl group at 1597 cm-1, and NH asymmetric stretching hydrogen
bond 3241 cm-1). We tried to purify the compounds several times by column chromatography and by Prep
TLC, but they always show the same spectra. Because it has been reported30 some thiocarbamate can
undergo slow amide rotation at rt, which account for the complex 1H spectrum, we used this compound for
Although a series of symmetrical thioureas has been available in the literature, most of them are
less moisture sensitive and thus expected to have lower reactivity comparing to 1,1-thiocarbonyl
44
diimidazole. One thiourea of particular interest is the 1,1-thiocarbonyl di-(1,2,4-triazole) which is more
reactive than imidazole substituted thiourea. For example, 1,1-thiocarbonyl di-(1,2,4-triazole) reacts with
The thocarbamation was performed with 1,1’-thiocarbonylditriazole and DMAP under reflux
condition. Unfortunately, the low reactivity of 1,1’-thiocarbonylditriazole led to low yield of the desired
product 1-110. Prolonged the reaction time and addition of more 1,1’-thiocarbonylditriazole did not
improve the reaction and only 28% (70% based on recovered starting material) of 1-110 and starting
material were recovered after column chromatography. The structural assignment was straightforward with
the compound exhibiting the two singlet peaks at down field (at 8.02 and 8.85 ppm) in 1H NMR spectrum.
The thiocarbonyl group was confirmed by observing a singlet peak at 180.69 ppm in 13C NMR spectrum
N N
N
S
TBSO OH O
a TBSO
CO2tBu CO2tBu
O O O O
1-80 1-110
We attempted the thiocarbmation of 1-80 under the standard thiocarbamation condition: refluxing
Unfortunately, no desired product was obtained and 69% of starting material 1-80 was recovered after
column chromatography. Bliss reported in his Ph. D. dissertation that the thiocarbamation of 1-80 was
45
successfully achieved in 80% at -33 oC. He first deprotoned the hydroxyl group of 1-80 to increase the
the exactly same procedure, only starting material 1-80 was recovered quantitatively after purification by
column chromatography. In the next we attempt slightly modified Bliss’ procedure: deprotonation by
sodium hydride at rt. Fortunately, we could isolate the desired product 1-111 as 46% yield (based on
recovered starting material) by column chromatography, but there is still more room to improve the yield of
this reaction.
N
S
OH O OH
TBSO a or b TBSO c TBSO
CO2tBu X CO2tBu CO2tBu
O O O O O O
conditions (the pKa of imidazole is known as 18.6 in DMSO and the pKa of benzimidazole is16.4 in
DMSO).69 Gratifyingly, our expectation was realized by heating the mixture of 1-81, benzimidazole and
catalytic amount of DMAP at 130 oC. After heating for 13 h, the desired product 1-111 was isolated as
85% yield based on recovered starting material, and spectroscopic results of the isolated product was in
46
N
N
N N
S S
O O
TBSO a TBSO
CO2tBu CO2tBu
O O O O
1-81 1-111
Scheme 1.34. Alternative Preparation of Benzimidazole Derivative 1-111: (a) benzimidazole, DMAP,
heating at 130 oC, 13 h, 62% (85% based on recovered 1-81).
To make more number of thiocarbamate we used indole and 1, 1’-thiocarbonyldiindole under our
optimized reaction condition. However, the reaction of 1-81 with indole and catalytic amount of DMAP at
high temperature failed. We also attempted thiocarbaamtion not only with 1, 1’-thiocarbonyldiindole and
DMAP under refluxing condition, but also with 1, 1’-thiocarbonyldiindole and NaH to increase the
nucleophilicity. However, all attempts were unsuccessful and the stating material either decomposed or
N
N N
S S OH
O a O b or c TBSO
TBSO X TBSO X CO2tBu
CO2tBu CO2tBu O O
O O O O
Scheme 1.35. Preparation of Indole Derivatives: (a) indole, DMAP, heating at 130 oC, 10 h, 1-81 91%; (b)
1, 1’-thiocarbonyldiindole, DMAP. THF, reflux, 12h, decomposed; (c) 1, 1’-thiocarbonyldiindole, NaH,
DME, rt, 12h, 1-80 94%.
47
Our ultimate goal of this research was the synthesis of natural and/or unnatural nucleoside
synthesis via 5- or 6-exo radical cyclization, readily available nucleoside base such as adenine was chosen
for further exploration. The reactions were performed with either thiocarbonyldi(N-benzoyladenine) and 1-
80 or N-benzoyladenine and 1-81. Unfortunately, none of them was successful in our hands and the only
isolated compounds were 1-80 and 1-81 as 58% yield and 27% yield, respectively.
NHBz
N
N
N
N N
S N S
OH O O
TBSO a TBSO b TBSO
CO2tBu X CO2tBu X CO2tBu
O O O O O O
Scheme 1.36. Failed Attempts to Prepare Adenines: (a) thiocarnonyldi (N-benzoyladenine), THF,
refluxing, 30h, 1-80 58%; (b) N-benzoyladenine, DMAP, heating at 130 oC, 10 h, 1-81, 37%.
imidazole derivatives was applied, but used 1,1’-thiocarbonylditriazole for the thiocarbamation instead of
some starting material was recovered in spite of prolonged reaction time (38% recovered) and the desired
product 1-116 was isolated as 74% of yield. The isolated product was a syn/anti mixture in a ratio of
1.69/1.00 based on 1H NMR analysis. The configuration of the product was assigned by 1H NMR spectrum
with the characteristic peak of hydrazone appearing at 7.34 ppm (d, J = 7.6 Hz, 1H) for syn comound and at
6.88 ppm (d, J =5.4 Hz, 1H) for anti compoundnd. Two pairs of hydrogen peaks on the triazole ring at δ
8.05 and 8.92 ppm for the syn isomer, and 8.05 and 8.93 ppm for the anti isomer was also observed. One
48
pair of thiocarbonyl peaks at down filed in 13C NMR spectrum was further support of the structural
To increase the yield the hydroxyl group of 1-89 was deprotected at -78 oC by sodium hydride and
the reaction was performed at -78 oC to rt. Unfortunately, no product was observed on TLC anaysis and
only starting material was recovered as 62% yield. The hydroxyl group was also deprotonated at rt by
sodium hydride followed by stirring the mixture with 1,1’-thiocarbonylditriazole in DME at rt. However,
intermoecular nucleophilic substitution was not observed at all, and the isolated products were not only
starting material 1-89 but also a cyclic compound 1-116 formed via intramolecular nucleoplic 5-exo
cyclization.
N N
N
S
O TBSO OH O
TBSO NHOCH3 NOCH3 NOCH3
b or c a TBSO
O O O O O O
Scheme 1.37. Preparation of Triazole Derivative from 1-89: (a) 1,1’-thiocarbony ditriazole, DMAP, THF,
reflux, 16 h, 45% (74% based on recovered 1-89); (b) NaH, THF, -78 oC to rt, 1-89 62% recovered; (c)
NaH, THF, rt, 1-89 45% recovered, cyclic product 1-116, 16%.
Nucleophilic substitution of imidazole to adenine was performed with 1-89 and adenine in THF
under refluxing condition. Because, in general, purines are alkylated under basic condition almost
exclusively at N9 position with small amount of N7 alkylation occurring under neutral condition, we
expected the adenine may replace the imidazole functionality in thiocarbamate 1-89. Unfortunately, we
could not find any positive evidence for the formation of adenine substituted thiocarbamate 1-117.
49
NH2
N
N
N
N N
S S N
O O
a or b
TBSO NOCH3 TBSO NOCH3
X
O O O O
1-89 1-117
Scheme 1.38. Preparation of Benzimidazole Derivatives: (a) adenine, THF, refluxing, 46 h, 1-89 72%
recovered; (b) adenine, THF, DMAP, 46 h, 1-89 recovered in 61% yield.
Scheme 1.39 shows an attempted procedure for making an N-aziridinoimine, which could act as a
radical acceptor. The ring opening of styrene oxide 1-118 was performed with sulfuric acid in water at rt in
good yield (83% yield). The mesylation of styrene glycol had to be performed at -15 oC otherwise large
amount of dimerized product was formed as the major product, and the desired product 1-120 was isolated
as only 7% yield. In the next step 1-amino-2-phenylaziridine was obtained almost quantitatively after
stirring it with hydrazine hydrate in pentane at rt. Unfortunately, the 1-amino-2-phenylaziridine did not
react with 1-79 (see Scheme 1.14, p. 31), and only 1-122 was isolated as the major product (71%). It is
assumed that the precursor 1-121 reacts with acetone generated from deprotecting of the starting hemiacetal
CH3
Ph
O OH OMs N N
OH CH3
OMs d 1-122
Ph
a b c N NH2
X
OH Ph
1-118 1-119 1-120 1-121 TBSO
N N
O O
Scheme1.39. Synthetic Route to Prepare Substrates: (a) H2SO4, H2O, 25oC, 83% (b) MsCl, pyridine, -15
o
C, 66%, (c) NH2NH2•H2O, pentane, rt, 100%, (d) 1-79, ethyl alcohol, 0oC, 71%.
50
For 6-exo trig radical cyclization the substrate 1-127 was prepared from easily available TBDPS
protected 2(3H)-furanone 1-123 in three steps. The furanone was reduced to the corresponding lactol by
Dibal-H in Et2O at-78 oC. After routine work-up with saturated disodium tartrate, the cured product was
subjected to olefination with stabilized Wittig reagent, Ph3PCHCO2Et, with catalytic amount of benzoic
O OH
OH OP
a O b PO O HO O
O +
OP OP
OEt OEt
1-123 1-124 1-125 1-126
P = TBDPS
N
OH N
c
PO O
O S
OEt TBDPSO O
Scheme 1.40. Synthetic Route to Prepare Substrates 1-127: (a) 1.5 M Dibal-H in toluene, Et2O, -78 oC,
>99%, (b) Ph3PCHCO2Et, cat. DME, rt, 34h, 1-125: 64% (E only), 1-126: 3% (E only). (c) 1, 1’-
thiocarbonyldi-imidazole, DMAP, dichloromethane, reflux, 22h, 83%.
The desired olefin 1-125 was isolated as the major product with E configuration, and small
amount of TBDPS migrated compound 1-126 was isolated by column chromatography (3%). The EWG
substituted olefin further reacted with 1, 1’-thiocarbonyldiimidazole under standard conditions for
monohydrate 1-128, which is very cheap sugar.70 This compound may act as a useful precursor of
compound 1-133, which could be subjected to 6-exo-trig radical ring closure. After protection of the
hydroxyl group of 1-129 as a TBS group, the lactone 1-130 was reduced to the corresponding lactol 1-131
51
by Dibal-H at –78 oC, which was subjected to olefination by a stabilized Wittig reagent. After refluxing of
the olefin 1-132 with 1, 1’-thiocarbonyldiimidazole and DMAP in THF for 12 h, the thiocarbamated
compound 1-133 was isolated as 90% yield, which can be used for a precursor of 6-exo trig radical
cyclization.
HOH2C HO OH O O
O a b c
HO O OH O O
O
HO OH CH2OH HO TBSO
OH N
OH
d e O S
O O
O
TBSO TBSO OEt
TBSO OEt
1-131 1-132 1-133
Scheme 1.41. Synthesis of 6-Exo trig Radical Precursor 1-133 from Maltose Monohydrate: (a) NaOH,
H2O2, H2O, 70 oC, 24 h, 80%; (b) TBSCl, imidazole, DMF, 0 oC 15 min then rt 27 h, >99%; (c) 1.5 M
Dibal-H in toluene, Et2O, -78 oC, >99%; (d) Ph3PCHCO2Et, toluene, reflux, 2.5 h, 86% (E/Z =4.4/1.0); (e)
1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, 12h, 90%.
1. 2. 2. Preparation of Precursor for 5-Exo trig Radical Cyclization from Maltose Monohydrate
(S)-3-Hydroxy-γ-lactone 1-129 can be prepared from maltose monohydrate 1-128 in one step.
This compound may act as a useful precursor of compound 1-138, which could be subjected to 5-exo-trig
radical ring closure. After protection of the hydroxyl group of 1-129 as a p-methoxybenzyl ether, the
lactone was reduced to lactol 1-135 at –78 oC, which was subjected to olefination by a stabilized Wittig
reagent. Protection of the substrate 1-136 by a TBS group and subsequent removal or the PMB group by
DDQ gave a precursor 1-138. This route has been well established in the literature,71 but it requires total 5
steps from the (S)-3-hydroxy-γ-lactone 1-129 and several protection and deprotection procedures.
52
O O OH
a b c
O O O
HO PMBO PMBO
HO TBSO TBSO
Scheme 1.42. Synthesis 1-138 from γ-Lactone: (a) PMB-trichloroacetimidate, CSA, CH2Cl2, rt, 16 h, 39%;
(b) 1.5 M Dibal-H in toluene, -78 oC, 1.5 h, 86%; (c) Ph3PCHCO2Et, toluene, reflux, 2 h, 61% (E/Z
=1.0/0.1); (d) TBSCl, imidazole, DMF, 0 oC 10 min then rt 12 h, 69%; (e) DDQ, CH2Cl2, H2O, rt, 1.5 h,
40%.
a PMB group, and then reduce lactone 1-130 to lactol 1-131 followed by olefination with (carbethoxyl-
methylene)triphenyl-phosphorane, 1-132 may be prepared in a high yield (Scheme 1.43, two steps 86%,
E/Z =4.4/1.0). The compound 1-132 was converted easily to 1-138 in absolute methyl alcohol with triethyl
amine as a catalyst via 1,4-TBS group migration (for more detail, see section 1.23).72 Subsequently,
thiocarbamation was successfully performed under the standard protocol described previously. After
column chromatography the desired product 1-139 was obtained as 90% yield.
Scheme 1. 43. Synthesis of 5-Exo trig Radical Precursor 1-138 from Maltose Monohydrate: (a) Et3N,
MeOH, rt; (E) 87%; (Z) 68%, (b) 1,1’-thiocarbonyldiimidazole, DMAP, THF, reflux, 90%.
53
(E)-Ethyl 6-hydoxy-5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-2-hexenoate 1-138 was reacted
with 1, 1’-thiocarbonylditirazole and DMAP in THF solution under reflux conditions with the hope of
making triazole substituted thiocarbamate. After 6h refluxing most starting material decomposed and the
desired product was not formed at all. Next, we turned our goal to make a thiocarbonate from the olefin 1-
138. The initial plan was to make a benzoate, which may be further converted to thiobenzoate by
Lawesson’s reagent. However, we discarded this plan because the first step, benzoylation of 1-138, was
not successful under two representative conditions for the bezoylation: DMAP, CH2Cl2, and rt, and DMAP,
pyridine, 0 oC to rt.
N
N
N OEt
OH
OEt a b or c OEt
O S O O
X O
X
O TBSO O
Scheme 1.44. Failed Attempts to Prepare Radical Reaction Precursor from 1-138: (a) 1, 1’-
thiocarbonylditirazole, DMAP, THF, 6h, reflux, 1-138 16% recovered ; (b) benzoyl chloride, DMAP,
CH2Cl2, rt, 1-138 100% reccovered; (c) benzoyl chloride, DMAP, pyridine, 0 oC to rt, starting material
decomposed.
in diethyl ether at 0 oC to rt. After 26 h reaction, most starting material was recovered and no desired
Several nitrile, oxime, and hydrazone substituted olefins were made from (S)-3-TBS-γ-lactol 1-
131 in DME, CH2Cl2, or absolute methyl alcohol under refluxing (Scheme 1.46). The isolated yield was in
the range of 80% to 26%. Because the applied condition was basic, the TBS group of 1-140 migrated with
54
an EWG group substituted olefin via 1, 4-TBS migration (see Chapter 1, section 1.23 for detailed study of
1, 4-TBS migration) to give 1-145 as a minor product. The TBS group of N,N-dimethylhydrazone
substituted olefin also migrated easily to give 1-148 as the major product and only 26% of the desired
product 2-64 was obtained. The isolated products, 1-143 and 1-148 both were assigned as anti
configuration based on 1H NMR spectra shown the characteristic peaks at 6.61 (t, J = 5.4 Hz) ppm and 6.68
N a
O S OEt X O S OEt
O O
TBSO TBSO
1-139
Scheme 1.45. Reaction of 1-139 with Phenylmagnesium Bromide: (a) PhMgBr, Et2O, 0 oC to rt, 26h, 1-
139 77% recovered.
OH
OH OH
b a
Y
X O X
1-131
Y = NNHC6H -Cl 1-140 X = CN
Y = NCH3 1-141 X = NOCH3
Y = NNHTs 1-142 X = NOH
1-143 X = NN(CH3)2
1-144 X = NNPh2
Scheme 1.46. Preparation of Nitrile, Oxime, and Hydrazone Substituted Olefins: (a) X = CN, Ph3PCHCN,
DME, rt, 24 h, 63% (E/Z =1.0/0.45) of 1-140 5% of 1-145, X = NOCH3, CH3ONH2, pyridine, CH2Cl2,
reflux, 43 h, 36%; X = NOH, NH2OH•HCl, pyridine, CH2Cl2 and H2O, rt, 21.5 h, 80%; X = NN(CH3)2,
H2NN(CH3)2, MeOH, rt, 6h, 26%, 1-149 63%; X = NNPh2, Ph2NNH2•HCl, pyridine, MeOH, rt, 2 h, 65%;
(b) Y = NNHC6H4-Cl, Cl-C6H4NHNH2•HCl, pyridine, MeOH, rt, 3h, decomposed; Y = CH3N,
CH3NH2•HCl, CH2Cl2, H2O, reflux, decomposed; Y = NNHTs , H2NNHTs•HCl, MeOH, reflux,
decomposed.
55
The desired compound could be made after stirring the mixture with pyridine at rt, and the
isolation of hydrazone derivatives can be facilated by addition of 1% Et3N during the column
chromatography. Although many of nitrile, oxime, and hydrazone substituted olefin were made from (S)-3-
TBS-γ-lactol 1-131, it was difficult to make some hydrazone substituted compounds under the applied
reaction condition because the TBS group is easily destroyed in spite of using excess amount of pyridine to
quench the acid in situ (similar result was observed in previously, see Scheme 1.23 in p. 38)
The substrates shown in Scheme 1.47 were subjected to the TBS migration with bases in methyl
alcohol. More detailed studies of TBS migration are discussed in section 1.2.3 and the results are
summarized in Table 1.1, 1.2, and 1.3 at end of this chapter. The 1, 4-TBS migration was applied for
preparing the precursors of 5-exo-trig radical cyclization, which will be discussed later in section 1. 2. 3.
The TBS migration works well with either an electron deficient acceptor or imine-containing
substituents. However, if a strong EWG such as CN is substituted, some of starting material would cyclize
via 5-exo-trig mode before the TBS migration. Because the starting material and product are prone to
equilibrium, it is impossible to get the only desired product, but they can be separated by column
chromatography and the major product is a 1,4-TBS-migrated compound. If the reaction is repeated, useful
OH OTBS
a
Y X
TBSO HO
Scheme 1.47. TBS Group Migration in MeOH: (a) 1-132, Et3N, MeOH, rt; X = CHCO2Et (E), 87%, X =
CHCO2Et (Z), 68%; 1-140, X = CHCN (E and Z) 86%; 1-141, X = NOCH3, 100%; 1-142 X = NOH, 80%;
21-143 X = NN(CH3)2, 33%; 1-144, X = NNPh2, 100%.
56
If the isolated 1-138 (E) was thiocarbamated with 1,1’-thiocarbonyldiimidazole in dichlorometh-
ane or THF to 1-139 in a 90% yield. The same thiocarbamation was performed with compound 1-145 in
the similar conditions of the above procedure, but the isolated yield of desired product 1-150 was moderate
(68%). Diphenyl hydrazone substituted subatrate 1-149 could be converted to thiocarbamate derivatives 1-
N N
N b OTBS a N
S X X (or Y)
S
HO
Y X
OTBS OTBS
Y = NOCH3 1-138 X = CHCO2Et 1-139 X = CHCO2Et
1-145 X = CHCN 1-150 X = CHCN
1-146 X = NOCH3 1-151 X = NNPh2
1-149 X = NNPh2
dimethylsilyl]oxy}-2-hexenoate 1-138, we further studied the reaction with hydrazone derivative 1-149
because of the interesting phenyl group migration that has been reported in the intramolecular cyclization
of Barton’s radical intermediate. After 46 h all starting material was consumed, only a single product was
isolated in 50% yield by column chromatography. The hydroxyl group of the substrate 1-149 was
successfully protected by a benzoyl group, but the silyloxy group at C-3 and hydrogen at C-2 eliminated
during the reaction. We did not optimize the reaction further to make the phenyl substituted substrate.
57
OH a
a
NNPh2
O O X O O
NNPh2 NNPh2
TBSO
TBSO
1-151 1-149
Scheme 1.49. Failed Attepts to Prepare N, N’-Diphenyl hydrazone Derivative: (a) benzoyl chloride,
DMAP, CH2Cl2, rt, 46h, 50%.
migrated product. Moreover, it is very difficult to isolate the desired product only because they decompose
easily during column chromatography: They have very similar Rf values. To overcome these limitations,
the mixture of 1-133 (E and Z) and 1-139 (E and Z) was reacted without column chromatography, and
thiocarbamation was performed with the mixture under the traditional condition. The combined yield of
the mixture of 1-152 (E and Z) and 1-153 (E and Z) was 69% (total 4 compounds and they have almost the
same Rf values). Unfortunately, it was impossible to isolate all 4 products, but only two mixtures were
obtained as a mixture of (E)-1-133 and 1-139 and a mixture of (Z)-1-133 and 1-39.
N N N N
N N N N
a
S + S OEt S + S OEt
O O
O O
OTBS OEt OTBS OH OEt OH
Scheme 1.50. Deprotection of a TBS Goup of Thiocarbamate Derivatives: (a) TBAF, THF, 0 oC to rt.
58
After several failed attempts to separate them by column chromatography, the (E)-1-133 and (E)-
1-139 mixture was treated by TBAF at 0 oC to rt to give desilyated products 1-152 and 1-153, with the hope
that may have different Rf values. However, those compounds have the same Rf value, and we failed to
separate them by column chromatography. No further attempt was made to desilyate of a mixture of (Z)-1-
H
OEt n
Bu3SnH N Ph
HN S
TBSO
O CO2Et
TBSO
1-154 1-155
a OH OEt a OH OEt
HN S OEt
X O O
O
TBSO TBSO
TBSO
1-154 1-138 1-156
20 20
[α] D= -0.82 (c 1.84, CHCl3) [α] D= +0.62 (c 0.97, CHCl3)
Scheme 1.51. Proposed 5-Exo trig Process for the Formation of Pyrolidines: (a) PPh3, DEAD, PhCSNH2,
THF, 0 oC to rt for 30 min, then reflux for 12 hr, 67%.
Pyrrolidines like 1-155 are widely present in the nature. If we can make thioamide derivatives like
1-154, they can be subjected to 5-exo-trig-radical process to give pyrrolidine derivative 1-155 via the
Barton’s radical intermediate. The 2o hydroxyl group of the compound 1-138 may be a subjected to the
Mitsnobu reaction. We tried the conversion of the 2o hydroxyl group to a thioamide group under the
standard Mitsuniobu condition, but the coupling between hydroxyl group and thioamide was not successful
and we isolated only a single product which has the same spectroscopic characteristrics of 1-138. Based on
59
opposite optical rotation value we assigned the isolated product was 1-156: the optical rotation value for 1-
20 20
138, [α] D = -0.82 (c 1.84, CHCl3); for 1-156, [α] D = +0.62 (c 0.97, CHCl3).
To make phenyl substituted thiocarbamate, phenylisocyanate was reacted with compound 1-138
under reflux condition. The reaction was completewithin several hours with an excellent yield, and the
isolated compound 1-1557 was subject to Lawesson’s reagent in toluene. However, the desired product
was not formed after 16 h refluxing and all starting material completely decomposed. Because of the
difficulty of thiocarbonylation by Lawesson’s reagent, an attempt was made react the substrate 1-138 with
thioisocyanate to make desired product. Unfortunately, however, the attempts were not successful because
NHPh
OH OEt O O OEt
a
O O b
NHPh
TBSO TBSO X
1-138 1-157 O S OEt
OTBS
OH OEt
X TBSO
1-158
c d or e
O
O
CO2Et
TBSO
1-159 1-138
Scheme 1.52. Failed pathway to prepare thiocarbamate 1-158: (a) PhNCO, Et3N, benzene, reflux, 5 h,
96%. (b) Lawesson’s reagent, toluene, reflux, 16 h, decomposed. (c) PhNCS, NaH, THF, rt, 3 h, 56%, (d)
PhNCS, Et3N, benzene, reflux, 24 h, Most srarting material was recovered, (e) (Bu3Sn)2O, PhNCS, tolene,
reflux, decomposed.
Alternatively, the substrate 1-138 was refluxed with (Bu3Sn)2O and PhNCS in toluene because tin
ether RO-SnBu3 may have better nucleophicity than alcohol. Unfortunately, most starting material
decomposed. To overcome the low electrophilicity of the thiocarbonyl group, the hydroxyl group of
60
substrate 1-138 was deprotonated by sodium hydride at low temperature and added thioisocyanate at rt, but
only cyclized compound 1-159 was isolated as a major compound (56% yield).
Substrates
The TBS group is widely used as a protecting group because of easy installation and removal from
1o or 2o hydroxyl groups. It has been reported that the migration of O-silylated group can be promoted in
the presence of bases in a variety of solvents such as DMF, DMSO, CH2Cl2, and MeOH. The intermediate
for the migration possibly involves penta-coordinated silicon, which may be in a 5- or 6-membered cyclic
ring. Even though the 1o silyloxy group is preferred to 2o silyloxy group, it is not possible to get 1o O-
protected product alone because of the equilibrium between 1o and 2o silyloxy groups. While most research
groups have concentrated on studying 2o to 2o migration of TBS group, few references deal with the 2o to 1o
migration of silyl groups. In this section, such a silyl migration is described. This strategy was
successfully applied to shorten a reaction scheme by saving protecting/deprotecting steps (see Scheme 1.46
and 1.47).
OH O OEt
OH
O O H+
H3C Si O OEt O
TBSO OEt t
Bu CH3 TBSO
Table 1.1 shows a detailed study of 1, 4-TBS migration with a variety of bases and solvents. To
find the best conditions for the 1, 4-TBS group migration in our substrates, we studied the reaction
61
systematically under the different conditions such as use of different bases, equivalents of bases, and
solvents. Because we realized a TBS group could migrate from C-5 to C-6 during the olefination of
substrate 2-53 (see Scheme 1.47), initially we started the investigation with ethylene triphenylphosphorane
as a base under different conditions. First, the migration was evaluated in absolute methyl alcohol with
1-138 based on GC analysis (Entry 3). However, the prolonged reaction time (36 h) did not increase
significantly the ratio of 1-132 to 1-138 because they are in equilibrium in solution (Entry 4). When
another protic solvent, isopropyl alcohol (Entry 6), was used as the solvent instead of methyl alcohol, the
reaction did not proceed at all even after 48 h stirring at rt; and only starting material 1-138 was detected by
GC analysis. Earlier investigation67shows the TBS migration works well in aprotic solvents as well as
protic solvents, and dichloromethane is one of the commonly used aprotic solvent for TBS migration.
When dichloromethane was used as the solvent in our system, however, the only detectable compound was
starting material after 24 h (Entry 5). At this time, more common organic and inorganic bases were tested.
Use of K2CO3 resulted in deprotonation of the hydroxyl group and cyclization to give 1-159 via 5-exo-trig
within 1 hour (Entry 7). A strong organic base DBU also gave the cyclic compound (Entry 2), but DABCO
gave 10% of desired product 1-138 after 24 h at rt (Entry 1). When 1.0 equivalent of pyridine was used for
the reaction, no compound 1-159 was found even after 4 days at rt (Entry 14), but 2.0 equivalents of
pyridine under the same condition converted 5% of 1-132 to 1-138 after 48 h stirring (Entry 15). The
conversion was promoted without any base in absolute methyl alcohol but it was very slow (Entry 16).
After several attempts, we found triethyl amine is the best catalyst for the 1, 4-TBS migration in methyl
alcohol. The best conditions were found to be using 4.0 equivalents of triethyl amine (Entry 9, 10, and 11);
but there was no big difference if more than 2 equivalents of bases were used; excess amount of triethyl
amine suppressed the TBS migration (or accelerate the equilibrium) to give the almost 1 to 1 ration of 1-
132 and 1-138 (Entry 12). Moreover, the TBS group migration did not proceed at all without added methyl
alcohol (thus, 80% of the starting material could be isolated under these conditions, Entry 13).
62
OH OH OEt O CO2Et
base
O
O
+
(%)b
3 1.0 MeOH 17 51 49 0
4 MeOH 36 55 45 0
8 1.0 MeOH 72 30 70 0
9 2.0 MeOH 48 24 76 0
10 3.0 MeOH 48 21 79 0
12 2 mL MeOH 48 42 58 0
13 2 mL No Solv. 48 100 0 0
63
Table 1.2 demonstrates the effect of triphenylphophine oxide on the TBS group migration. The
hex-2-enonate 1-132 in three steps without any purification (see Scheme 1.45 and 1.47). The product
contains some solid phosphine oxide even after several filtrations. The crude product was dissolved in
absolute methyl alcohol, and required base was added as shown in Table 1.2. The table shows that
triphenylphosphine oxide might work as a base in the TBS migration (Entry 5 compare with Entry 16 in
Table 1). When some organic bases or 1 equivalent of ethylene phosphorane was added, the starting
material 1-132 was converted to 1-138. Addition of excess (5.0 Eq.) Et3N promoted the cyclization of 1-
Table 1.3 shows the result of TBS migration in different olefinic substrates. The yield is based on
recovered starting material, and the numbers in parenthesis are isolated yields. The TBS migration was not
affected by substituents, but more cyclized product was isolated when a CN group was substituted (Entry 7
and 8). Because a CN is a strong EWG, the cyclized product can be formed more easily. Those silyl group
migrations do work well with a nitrogen substituted olefins. When the substituent is NOCH3, 41% of
product was obtained after 48 h (Entry 9), but the yield increased to 69% after 72 h stirring at rt (Entry 10).
Unfortunately, prolonged reaction does not help to increase the yield significantly (71%, Entry 11), but
decrease the yield of recovered starting material; the yield based on recovered starting material decreased
from 100% to 88%. The similar results were observed with diphenyl hydrazone derivative. After 96 h
reaction, 65% of desired product was obtained by column chromatography (Entry 15). The yield accounts
for 100% based on recovered starting material. However, prolonged reaction time led low recovery of
starting material, and the yield decreased up to 82% based on the recovered starting material (Entry 16).
The TBS group of oxime-substituted derivative could also be migrated from 2o position to 1o position and
the isolated yield was 62% after 7 days stirring at rt (Entry 12). Unfortunately, dimethyl substituted
compound decomposed easily at rt, which caused the low yield of migrated product as well as low recovery
64
OH OH OEt O CO2Et
base
O
O
+
(%)a
65
OH OH O X
base
X +
X
TBSO TBSO TBSO
1-161 1-162
66
1. 2. 4. Preparation of Precursors for 5-Exo trig Radical Cyclization from D-Glucose
Conformational control by preexisting ring can often be used to improve the stereoselectivity of
radical annulation processes. To explore this possibility in the present context, we prepared a series of
thiocarbonyl imidazolides starting from readily available D-glucose 1-163 and subjected them to the
cyclization conditions.
The synthetic route is shown in Scheme 1.54 First, two hydroxyl groups at C-5 and C-6 were
protected by benzaldehyde dimethyl acetal in DMF. Because of the reaction is reversible, the unavoidable
byproduct, methyl alcohol, has to be removed successively from the reaction mixture by house vacuum
during the reaction period. After column chromatography eluting with EtOAc (with 1% of Et3N), the
desired product 4,6-O-benzylidene-D-glucopyranose 1-165 was isolated as 56% yield. Two carbons of the
benzylidene glucose were degraded by 2.02 equivalent of sodium periodate and 8 N sodium hydroxide
HO O
O O Ph O OH
a H b O
OH OH OH OH Ph O OH O
O O
OH Ph O HO O Ph
CHO O
OH OH
The 1H and 13C NMR spectra of the crude mixture were complex, but they implied that the crude
mixture contained at least three compounds. We also could not find the characteristic peaks for the
aldehyde functionality of 1-165 at down field in 13C NMR spectrum. Moreover, five carbon peaks between
67
57 and 96 ppm may imply the carbons are associated with oxygen functionality and the compound was
tentatively assigned the structure 1-165’, which is presumably in equilibrium with 1-165.
The crude mixture was isolated from the reaction mixture by column chromatography, but the
isolated yield was much lower than expected, and the purified compound showed the exactly same 1H and
13
C NMR spectra and the same Rf values on TLC analysis. Although the crude mixture itself is enough to
use in the next reaction, we pre-dissolved it in ethyl acetate and dried under vacuum to minimize inorganic
1-166 and 1-167 were formed as a E/Z mixture, which could be separated by column chromatography. The
ratio of E/Z was dependent on the solvent used. For example, the E/Z of 2-88 was 1.0/1.9 with toluene as
the solvent, but the ratio decreased to 1.0/2.4 with DME without any significant change of the isolated
yield. Interestingly, if tert-butyl (triphenylphosphoranylidene)acetate was used as the Wittig reagent, the
E/Z ratio of 2-89 increased up to 1.0/5.5 despite the use of toluene as the solvent.
(E)-1-168, and (Z)-1-168 were subject to thiocarbamation with 1,1’-thiocarbonyldiimidazole and catalytic
amount of DMAP in THF under the refluxing condition. Most products were isolated as pure forms by
column chromatography, but 1-172 and 1-174 were slightly contaminated with unknown isomers. The
isolated yield of the products range from excellent (96%) to good (70%), and each of the compounds were
To explore more examples of 5-exo-trig radical cyclizations, oxime and hydrazone derivatives
were made from 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-165, and the results are
summarized in Scheme 1.56. The desired compound could be synthesized excellent to good yield, and they
were isolated by column chromatography. The isolated O-methyl oxime derivative 1-175 and O-benzyl
68
Ph O O Im Ph O O Im
O O
S S
EtO2C CO2Et
1-169 1-170
d e
Ph O OH
O
CO2Et
1-166
90% (E/Z = 1.0/2.4) with DME
90% (E/Z = 1.0/1.9) with toluene
Ph O O Im a
O
S h
NC O Ph O OH
Ph OH c O
O Ph O OH O
1-173 O O
HO O Ph
CHO O
i
Ph O O Im CN
O
1-168 1-165 1-165'
S
CN 93% (E/Z = 1.0/2.3) b
1-174 O
Ph OH
O
CO2tBu
1-167
82% (E/Z = 1.0/5.5)
f g
Ph O O Im O
Ph O Im
O O
S S
t
BuO2C CO2But
1-171 1-172
Scheme 1. 55. Synthesis of α,β-Unsaturated Ester and Its Thiocarbamate Derivatives: (a) Ph3PCHCO2Et,
toluene, 1.5h, 90% (α/β = 1.0/1.9), or Ph3PCHCO2Et, DME, 26h, 90% (α/β = 1.0/1.9); (b) Ph3CHCO2tBu,
toluene, 4h, 82% (α/β = 1.0/5.5); (c) Ph3PCHCN, toluene, 12h, 93% (α/β = 1.0/12.3); (d) Im(C=S)Im,
DMAP, THF, 33h, 96%; (e) Im(C=S)Im, DMAP, THF, 38h, 89%; (f) Im(C=S)Im, DMAP, THF, 6h, 81%;
(g) Im(C=S)Im, DMAP, THF, 28h, 70%; (h) Im(C=S)Im, DMAP, THF, 12h, 70%; (i) Im(C=S)Im, DMAP,
THF, 12h, 80%.
69
oxime derivative 1-176 were syn/anti mixture with a ratio of 1.0/0.18 and 1.0/0.14, respectively, and they
were inseparable by column chromatography. The ratio of syn/anti mixture was determined by the
characteristic peak of oxime in NMR spectroscopy. Generally, the carbon peak of the CH=N for the syn
isomer appears at higher field in 13C NMR but the hydrogen peak of the CH=N for anti is shown at higher
field in 1H NMR.
The hydrazones were found to exist as a single geometric isomer by NMR spectroscopy and they
were assigned as anti (E) isomers. The anti geometries were confirmed by their characteristic peaks on 1H
NMR, which were shown at δ 6.63 (d, J = 3.2 Hz) for 1-177, 7.30 (d, J = 6.0 Hz) for 1-178, 8.37 (app t, J =
2.7 Hz,) for 1-179, and 6.61 (d, J = 3.1 Hz) for 1-180.
procedure: refluxing with 1,1’-thiocarbonyldiimidazole and DMAP in THF. For example, 5(R)-hydroxy-
thiocarbonyldiimidazole and catalytic amount of DMAP in THF under refluxing condition for 20h. The
crude mixture was purified by column chromatography to give the corresponding imidazole thioate 2-103
as an inseparable syn/anti mixture. The compound was characterized by spectroscopic methods (1H NMR,
13
C NMR, and IR) as well as elemental analysis after column chromatography (91% isolated yield). The
isolated compound was a syn/anti mixture with a ratio of 1.0/0.13 determined by 1H NMR spectroscopy.
The characteristic peak for anti was shown at δ 6.91 (d, J = 5.3 Hz, 1H) but the characteristic peak for syn
isomer overlaped with the aromatic hydrogen peaks in the range of 7.47-7.52 ppm. The assignment was
further proved by comparing the characteristic carbon peaks shown at δ 145.08 and 145.90 for syn and anti,
respectively.
After thiocarbamation of the inseparable syn/anti mixture of O-benzyl oxime 1-176, two
stereoisomers were separated by column chromatography. Although the ratio of starting syn/anti mixture
of 1-176 was 1.0/0.14, we isolated almost pure (syn)-1-176/(anti)-1-176 with a ratio of 1.0/0.04 by column
chromatography. However, the pure (syn)-1-176 was in equilibrium with (anti)-1-176 in CDCl3 at rt., and
the ratio of the syn/anti increased up to 1.0/0.18 in an NMR tube in 3.5 days. A p-toluenesufonyl
70
hydrazone derivative was also made from 5(R)-hydroxy-2(R)-phenyl-[1, 3]dioxane-4(R)-carbaldehyde 1-
165.
In a previous case (see Scheme 1.25) we failed to make a (p-toluene)sufonyl hydrazone derivative
from the D-ribofuranose 1-79 because the (p-toluene)sufonyl hydrazone derivatives are in equilibrium
between cyclic (1-94) and acyclic (trans-1-94’), and the 1,1’-thiocarbonyldiimidazole reacted with only the
cyclic form 1-94’ to produce unwanted 1-95 as the major product. However, the 5(R)-hydroxy-2(R)-
alcohol to afford 1-178 as a 75% isolated yield in spite of the equilibrium between 1-165 and 1-165’.
For the tosylhydrazone the next step could proceed relatively easily under our standard
thiocarbamation condition with 1,1’-thiocarbonyldiimidazole and DMAP in THF, but the isolated yield was
moderate (48%) because it is difficult to isolate the product 1-184 by column chromatography. To increase
the yield, the hydrazone derivative 1-178 was used for the next step without separation. After routine
thiocarbamation under standard condition with crude 1-178, the desired product 1-184 was isolated as a
N-Aziridinyl imines were first used in radical reaction by Kim in 1991 and they have received
great attention in the area of radical chemistry since then. We were also attracted to this novel functional
group as a radical acceptor in hex-5-enyl and/or hep-6-enyl radical cyclizations. If the Braton’s radical
mediated intramolecular cyclization proceed with the N-aziridinyl imines substituted precursor, we may
open a new area to make 3-deoxy sugars, 3-deoxy N-pyranosides, and/or 3-deoxy N-furanosides.
Previously, we had failed to make an aziridine derivative from D-ribofuranose 1-79 (see Scheme 1.43),
because the 1-amino-2-phenylaziridine 1-121 reacts with acetone generated from deprotecting of the
starting hemiacetal 1-79 in ethyl alcohol to give 1-122 as the major product. Gratifyingly, the (R)-hydroxy-
of aziridine derivative 1-179. After column chromatography, the product was isolated as a mixture of two
isomers in 65% yield. The characteristic peak of this compound appears at δ 8.37 (major, app t, J = 2.7 Hz,
1H) in 1H NMR spectrum. Although the 1H NMR spectrum is very clean and it imply only one isomer
exists in the isolated product, the carbon peaks for the aziridine ring and imines split into two in 13C NMR
71
Ph O O Im Ph O O Im
O O
S S
NOBn NOCH3
1-182 1-181
h g
Ph O OH Ph O OH
O O
NOBn NOCH3
1-176 1-175
O Ph O OH
Ph O Im
O O
i b a
S
NNHPh2 NNPh2
c
1-183 Ph O OH
1-177 O O
O
Ph OH
O O
CHO HO O Ph
O
O O d
Ph O Im Ph OH
O j O
1-165 1-165'
S e
NNHTs NNHTs f
1-184
1-178
Ph O OH Ph O OH
O O
Ph
N N NN(CH3)2
1-179 1-180
k l
Ph O O Im Ph O O Im
O O
S S
N N NN(CH3)2
Ph
1-185 1-186
Scheme 1. 56. Synthesis of Hydrazone and Oxime and Its Thiocarbamate Derivatives: (a) CH3ONH2•HCl,
Pyr, MeOH, 5.5h, 91% (syn/anti = 1.0/0.18), (b) BnONH2•HCl, Pyr, MeOH, 3h, 53% (syn/anti = 1.0/0.14);
(c) Ph2NNH2•HCl, Pyr, MeOH, 3h, 86% (anti only); (d) pTsNHNH2, MeOH, 2.5h, 75% (anti only); (e) 1-
amino-2-phenylaziridine, MeOH, 5h, 65% (anti only); (f) (CH3)2NNH2, MeOH, 17.5h, 84% (anti only); (g)
Im(C=S)Im, DMAP, THF, 20h, 90% (syn/anti = 1.0/0.13); (h) Im(C=S)Im, DMAP, THF, 7.5h, 69%
(syn/anti = 1.0/0.04), (i) Im(C=S)Im, DMAP, THF, 27h, 90% (93% based on recovered 1-177, anti only);
(j) Im(C=S)Im, DMAP, THF, 12h, 43% from 1-165 (anti only); (k) Im(C=S)Im, DMAP, THF, 23h, 49%
(major/minor = 1.0/0.67); (h) Im(C=S)Im, DMAP, THF, 3h, 90% (anti only).
72
spectroscopy: δ 161.30 and 161.37 for C=NN, 40.44 and 40.61 for NNCH2CHPh, and 44.00 and 41.13 for
NNCH2CHPh. The thiocarbamation of 1-179 was also performed under our standard condition and the
desired product 1-185 was isolated by column chromatography. The isolated yield of the product was
relatively moderate (49%), and the NMR spectroscopy implies the isolated product is a mixture of two
isomers with a ratio of major/minor = 1.0/0.67. Unfortunately, we could not assign the exact conformation
Next we tured our attention to hydrazone as a radical acceptor in the synthesis of pyranosides
and/or furanosides via 5- or 6-exo radical cyclization mediated by the Barton’s radical intermediate. N-
carbaldehyde 1-165 in methyl alcohol at rt to give new hydrazones, 1-187 and 1-188. The crude mixture
was purified by recrystallization with 95% ethyl alcohol to give relatively good yield (72% and 89%) as
white solid forms. The acetohydrazone 1-187 was a mixture of two geometrical isomers with a ratio of
0.52/1.0. NMR spectra implied that the minor portion of 1-187 is syn isomer based on its characteristic
peak at δ 7.25 (d, J = 6.7Hz). The compound 1-188 was isolated as a single isomer after recrystallization.
One doublet (J = 6.3Hz) at very down filed (7.73 ppm) implied the configuration of the product is anti.
The hydrazones, 1-187 and 1-188, were reacted with 1, 1’-thiocarbonyldiimidazole and DMAP in
THF under refluxing condition until all staring material could not be formed on TLC analysis.
Unfortunately, the major portion of the crude mixture was not the desired products, but they still have
hydroxyl functionalities judged by IR spectroscopy. The IR spectra showed a very strong broad peak at
υ 3450 cm-1, which implies that the isolated products have hydroxyl group functionalities. More extensive
spectroscopy work and its interpretation were done with 1H and 13C NMR spectroscopy. For example, the
enamine functionality (C=N) of compound 1-189 can be confirmd by observing a peak at δ 7.01 ppm (d, J
= 5.3 Hz, DMSO-d6) in 1H NMR spectrum as well as a paek at δ 160.04 ppm in 13C NMR spectrum. A
siglet peaks at δ 176.22 ppm in 13C NMR spectrum implies that the compound has a thiocarbonyl group
(C=S). Surplisingly, the carbonyl peaks disappeared but a new hemiacetal peak was observed at δ 66.88
ppm in 13C NMR spectrum, which may be interpreted as the formation of rare heterocyclic seven-
membered ring with a hemiacetal. The molecualar weight measured by electrospray HRMS is 397.0940,
73
which is the exactly the same with the calculated molecular weight for C17H18N4O4SNaNa+ within less than
1.0 ppm difference. Based on those results we proposed the configuration of the products like 1-189 and 1-
192.
Ph O O
O Ph
N N OH
c S Im
1-189
O O
Ph
O
OH
X Ph
O
O Im
a S
NNHCPh NNHCPh
Ph O OH 1-187 O O
O 1-190
CHO
b
1-165
O O
Ph
O
OH
X Ph
O
O Im
S
NNHCCH3 NNHCCH3
Ph O
O OH 1-188 O 1-191 O
O
O
HO O Ph
O
d
1-165' Ph O O
O CH3
N N OH
S Im
1-192
Scheme 1. 57. Synthesis of Hydrazones and Its Thiocarbamate Derivatives: (a) PhC(=O)NHNH2, EtOH,
rt, 20h, 72% (anti only); (b) CH3C(=O)NHNH2, EtOH, rt, 20h, 89% (syn/anti = 0.52/1.0); (c) ImC(=S)Im,
DMAP, THF, reflux, 8h, 21%; (d) ImC(=S)Im, DMAP, THF, reflux, 10h, 32%.
74
1. 3. Radical Cyclization of Thiocarbamate and Thiocarbonate Precursors
RajanBabu and Bliss initially studied the 6-exo-ring closure by using the Barton’s radical
generated from O-phenyl thiocarbonate (Eq. 42). They observed the phenyl group migration during the
radical cyclization to give 1-194, and proposed a mechanism involving spiro aromatic system (Scheme
1.12, p. 28). However, the radical intermediate generated via 6-exo-trig mode was trapped by the reverse
addition of substrates (k3 < k4)-slow dropping of the mixture of the substrate and AIBN in benzene into a
solution of tributyltin hydride via a syringe pump. The excess tributyltin hydride forced formation of the
cyclized intermediate, orthoester 1-68, which eliminate phenoxytributyltin moiety, Bu3SnOPh, to make 1-
70 (or 1-195) before the phenyl group migration to the radical center (Scheme 1.16).
OPh
S OTBS OTBS
O O O O
TBSO +
CO2Et Ph
O O (42)
O O O CO2Et O CO2Et
The cyclized compound 1-194 was obtained as a single isomer, and was chartacterized by 13C
NMR, which had two ester carbonyls at δ 171.5 and δ 170.6 ppm as well as a phenyl group. The
stereochemistry of the lactone 1-194 was assigned as altro configuration based on NOSEY data, and the
measured coupling constant between H-2 and H-3 is agreement with the theoretical coupling constant
derived from Karplus equation. The stereochemistry of compound 1-195 at C-2 is opposite of comparing
with that of 1-194. Relatively big dipole-dipole correlation between H-2 and H-4 of 1-194 in NOSEY was
75
Bliss also found that the 6-exo-trig ring closure could be used for the synthesis of N-glycoside
after changing the substrate from thiocarbonates to thiocarbamates (Eq. 43). The structure of N-glycoside
was confirmed by finding an anomeric center at δ 83.2 ppm in 13C NMR spectrum as well as a
characteristic anomeric hydrogen peak at δ 5.5 ppm in the 1H NMR. The coupling constant of the anomeric
hydrogen is J1,2 = 3.3 Hz, which may be interpreted as a cis configuration between H-1 and H-2. The
chemical shift of the anomeric center moved downfiled to δ 6.2 ppm in 1H NMR spectrum upon
epimerization and the coupling constant J1,2 shifted from 3.3 Hz to 8.5 Hz.
N
N OTBS N
S O N
Bu3SnH
O
TBSO (43)
AIBN
CO2tBu O
O CO2tBu
O O
1-196 1-197
The formation of N-glycoside is novel because thus far all radical cyclizations based on the
Barton’s deoxygenation lead the elimination of substituent X (see Scheme 1.1, 1.2, and 1.3 in Chapter 1.1).
Moreover, the new synthetic route for the formation of 2-C branched glycosides is a fundamentally
important methodology. 68 However, the initial study gave only 37% yield of the desired N-glycoside, and
the structural analysis has not been firm because of the lack of nOe or 2D NMR data.
In this chapter, we will discuss the optimum condition for the radical cyclization via 6-exo-trig
radical ring closure mediated by the Barton’s radical, and will document extention of the cyclization to a 5-
1. 3. 2. The Optimum Condition for 6-Exo-trig Radical Cyclization by the Barton’s Radical
The experimental results are summarized in Table 4. First, the reaction was performed with the same
amount of substrates, radical sources, and initiator as described previously,65but the reaction mixture was refluxed
in either toluene or benzene. Surprisingly, the expected product 1-197 was not detected on TLC, but 1-202 was
76
isolated in a 33% yield after flash column chromatography (see Table 1.4 in p. 80). The thionolactone was
characterized by 13C NMR, which shows the thionolactone carbon at δ 218.4. The thionolactone functionality can
be further proved by IR spectrum, which has characteristic peaks of the thionoester at 1731 cm-1 and 1152 cm-1.64
The stereochemistry of C-2 has been assigned by a large coupling constant (12.3 Hz) between H-2 and H-3, which
may imply trans relationship. The formation of 1-202 can be rationalized by the proposed mechanism shown in
Scheme 1.58 When an EWG is substituted on an olefin of 1-195, the k1 is much faster than k2. Therefore, the
intermediate 1-199 can be formed easily, followed by the second intermediate 1-200. The orthothioamide 1-200
may have two pathways; one is k3, the other is k4. At high temperature the elimination pathway k4 is faster than
k3. To make a desired product 1-197, the reaction requires more than two equivalents of the tin hydride (Scheme
1.58) because one equivalent is used for C-SSnR bond formation and the other equivalent is used for a hydrogen
donation to radical centered carbon. Under the Bliss’ conditions (Entry 16),65 however, only 1.5 equivalents of
radical sources were used, which might lead the lower yield of cyclized product 1-197 due to the insufficient
radical and/or hydrogen sources. Therefore, we used excess amount of tin hydride. Unfortunately, when the
radical and hydrogen source, Bu3SnH, increased to 5 equivalents in toluene, all starting material decomposed
under refluxing condition (Entry 3 and 4) and no significant amount of product was isolated by column
chromatography. However, if the concentration of substrate and Bu3SnH decreased to 0.042M and 0.064M in
toluene, respectively, only dethionated compound 1-203 was isolated as 40% of yield. Because the concentration
of radical sources and substrate is one of the most important factors for the formation of radical cyclization, we
changed the concentration and addition rate. Gratifyingly, we found the following optimized condition for the 6-
exo trig radical cyclization: 0.047M substrate in benzene, 0.063M Ph3SnH in benzene, and 28 µL/min via a
syringe pump. If the concentration of radical source was high (0.2-0.4M, Entry 3 and 4), no desired product was
detected after reflux, but low concentration (0.037-0.080M) gave compound 1-197 or compound 1-202 at 90oC or
under refluxing condition respetvely. The concentration of substrate may also affect the cyclization. High
concentration of substrate (0.103-0.082M, Entry 1 and 2) gave compound 1-202 as a major product under the
refluxing condition, but low concentration (0.042M) led the desired compound 1-197 as a major product under the
same refluxing condition. It is noteworthy to point out the dropping rate of substrate is not critical for this 6-exo-
trig radical cyclization if it is less than 48 µL/min. The formation of 1-203 may be explained by the proposed
77
N
R3Sn N
S
O
TBSO
CO2tBu
O O
1-196
R3SnH/benzene
N SnR3 SnR3 N
OTBS OTBS OTBS
R3Sn N S S N
O O O
S k1 k1 N N k3
N N
k2
O
TBSO R3SnH R3SnH
O O O
CO2tBu CO2tBu
O CO2tBu O CO2tBu O
O O
78
mechanism in Scheme 1.58. As previously explained for the formation of 1-202, the elimination pathway k4 is
faster than k3 at high temperature (if >110 oC) to afford the thionolactone 1-202 as the major product. Because
excess amount of hydrogen source (5.0 equivalents of Bu3SnH) was used, the thionolactone might be further
reduced to 1-203. Although the high temperature forces the path k4, the hydrogen source Ph3SnH is an excellent
choice to force the pathway k3 (Entry 6): because it has been known65 Ph3SnH is a better hydrogen source than
Bu3SnH. For example, under the refluxing of toluene with Ph3SnH as the hydrogen source in the 6-exo trig
radical cyclization, most substrate 1-196 proceeded to give pyranoside 1-197 as the major product (47%) and only
part of 1-196 gave 1-203 (9%). The better efficiency of Ph3SnH than Bu3SnH in the Barton’s radical
intermediated cyclization was also proved by Entries 7 and 8. Those reactions were performed under the almost
identical reaction condition except for radical/hydrogen sources. When Bu3SnH was used as the hydrogen sources
in radical cyclization, the paranoside 1-197 was made in only 34% yield. Surprisingly, the change of hydrogen
source from Bu3SnH to Ph3SnH facilated the reaction and the isolated yield of 1-197 doubled from 34% to 62%.
Because we recognized the reaction to favor the pathway k4 to afford 1-202 and/or 1-203 at high temperature in
the previous experiment, the reaction temperature was decreased from 80 oC (refluxing condition) to 78 oC (oil-
bath temperature 90 oC). In this case, the pathway k3 is faster than k4 and the pyranoside 1-197 was made much
more efficiently (Entry 7 and Entry 9). To investigate the concentration effect, we fixed the concentration of
substrate and the addition rate, but doubled the concentration of hydrogen source in the reaction. As expected, the
formation of cyclized product 1-197 decreased with the high concentration of hydrogen source (Entry 9 and 10).
If temperature is too low (68 oC), only 3% of desired product was isolated because of insufficient energy for the
C-S bond breaking (Entry 15). We also explored the exo-hept-6-enyl radical cyclization with EPHP
(ethylpiperidine hypophosphite) as the radical/hydrogen source (Entry 16). Unfortunatealy, although all starting
material decomposed, we could not isolate any cyclized compound by column chromatography. Based on the
above results we chose Ph3SnH in benzene as the radical/hydrogen source and performed the reaction at 90oC
under very dilute concentration and slow addition rate (0.047M substrate in benzene and 0.063M Ph3SnH in
benzene. The addition rate of the substrats was 28 µL/min via a syringe pump). We were pleased that the reaction
proceeded very efficiently via 6-exo-trig process mediated by the Barton’s radical intermediate to give the desired
N-glycoside 1-197 in 71% yield, and no unwanted product 1-202 and/or 1-203 were observed in TLC analysis.
79
N
N OTBS N
OTBS OTBS
S N
O O S O
O
TBSO + +
CO2tBu O O
O
O O O CO2tBu O CO2tBu O CO2tBu
Entry R3SnH AIBN Solvents Tempr, Etc. 1-197 1-202 1-203 Comment
s
(Equiv) (Equiv)
Continued
80
Table 1. 4 continued
a. 0.103M Substrate in toluene, 0.077M Bu3SnH in toluene, 25 µL/min via a syringe pump
b. 0.082M Substrate in benzene, 0.080M Bu3SnH in benzene, 25 µL/min via a syringe pump
c. 0.100M Substrate in toluene, 0.200M Bu3SnH in toluene, 25 µL/min via a syringe pump
d. 0.120M Substrate in toluene, 0.400M Bu3SnH in toluene, 25 µL/min via a syringe pump
e. 0.042M Substrate in toluene, 0.064M Bu3SnH in toluene, 26 µL/min via a syringe pump
f. 0.047M Substrate in toluene, 0.064M Ph3SnH in toluene, 25 µL/min via a syringe pump
g. 0.042M Substrate in benzene, 0.064M Bu3SnH in benzene, 26 µL/min via a syringe pump
h. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 25 µL/min via a syringe pump
i. 0.038M Substrate in benzene, 0.038M Bu3SnH in benzene, 42 µL/min via a syringe pump
j. 0.037M Substrate in benzene, 0.069M Bu3SnH in benzene, 48 µL/min via a syringe pump
k. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump
l. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump.
m. 0.042M Substrate in benzene, 0.064M Ph3SnH in benzene, 26 µL/min via a syringe pump
n. 0.046M Substrate in benzene, 0.064M Ph3SnH in benzene, 27 µL/min via a syringe pump
o. 0.037M Substrate in benzene, 0.068M Bu3SnH in benzene, 48 µL/min via a syringe pump
p. 0.040M In toluene based on substate and 0.400M in toluene based on EPHP, two times one pot
addition of 0.120M AIBN in toluene,
q. 0.120M Substrate in benzene, 0.075M Bu3SnH in benzene, 24 µL/min via a syringe pump
r. Temperature of an oil bath measured by a thermo-coupled thermometer.
s. The temperature of reaction mixture measured by a thermo-coupled thermometer was 78 oC
t. E Substrate was used.
u. Normal addition: the mixture of Ph3SnH (5.0 Eq) and AIBN (0.5 Eq) in benzene was added to
the solution of substrate in benzene via a syringe pump
v allo-α:allo-β:altro-α:altro-β = 0.16:0.22:0.23:1.0.
w. EPHP (ethylpiperidine hypophosphite)
x. From Bliss’ dissertation.
81
1. 3. 3. The Rationalization of the Stereochemistry for 6-Exo-trig Radical Cyclization by the Barton’s
Radical
In the initial study of the reaction, Bliss isolated cyclized compound as a single diastereomer, and
assigned the compound as an α anomer (allo-1-197) based on the peak of C-1 in 13C NMR spectrum. He
also reported the pure anomer was prone to epimerization to give α/β mixture in a ratio of 72/28 on
standing in NMR solvents at rt. However, we failed to isolate the pure anomer; all isolated compounds
OTBS N
OTBS OTBS CO2But
X H
H 5 O 1 N O
H O Y H
4 2 X
H O
CO2But O 3 H H Y
O O H O CO2tBu O
OTBS
OTBS
X OTBS N H
H H
O
H O Y O N H
H H X
O
H
O O O O Y
CO2But O CO2tBu CO2But
Because the absolute stereochemistry of 1-197 at C-3, C-4, and C-5 are fixed from the known
stereochemistry of the starting material 1-195, the cyclized compound may have two conformation, allo-
chair forms (1-204 or 1-205) or altro-chair forms (1-206 or 1-207) rotated by a ring flip. Bliss assigned the
isolated compound as an allo-form based on the chemical shift of the anomeric carbon in 13C NMR (δ 83.2
ppm), which compared well with literature.72 He also measured the coupling constant J1,2 is 3.2 Hz, which
might be interpreted as cis relationship between C-1 and C-2. Based on these assignments, an α anomer
82
and cis relationship between C-1 and C-2, he concluded that the diastereomer has allo configuration (1-207,
X = H, Y = imidazole). However, we strongly doubt this assignment for the final product because the
small J value between H-2 and H-3 does not unequivocally support the equatorial substituent (axial H) at
C-2. Moreover, altro configuration may also have a similar coupling constant after calculation by Karplus
equation (1-206 or 1-207, for example) and his conclusion is not the based on NOE or 2D NMR
experiments. For further determination of the relationship between H-1 and H-2, we decided to perform
nOe experiments with the N-cycloside 1-197. Scheme 1.6 shows the result of nOe experiment.
3.3%
H OTBS CO2tBu
OTBS N 3.5%
4
O N
O N 5
H
N
O 2
O 3 1
O CO2tBu H 1.7% H
O 3.9% H
altro-1-197 5.0%
altro-1-197
When we irradiated at the frequency of H-1, strong enhancement of H-5 peak was found (5%),
which may imply the anomeric center should be β, because the stereochemistry of C-5 is fixed as shown in
the Figure 1. 6. Moreover, some interaction (3.3%) between the tBu group of TBS and imidazole has been
observed with irradiation of imidazole, which may further support the β anomeric center. We also found
some interaction (3.9%) between H-1 and H-2, which may imply the stereochemistry between H-1 and H-2
should be cis, and the configuration has to be altro. If the configuration of the cyclized compound is allo,
there has to be no relationship between these two hydrogens, because the dihedral angle is almost 180o in
83
the favorable chair/allo form. An enhancement of the tBu group of C-2 (3.5%) with irradiation of one of
imidazole hydrogen and small interaction (1.7 %) between H-2 and H-5 may also be used for the proving
the altro configuration. The relatively small interaction between H-2 and H-5 may be rationalized by the
equatorial H-2 in altro conformation. Because the stereochemistry of H-5 is fixed and the dihedral angle of
allo form is almost 180o, there should be no enhancement with irradiation of H-5 in the allo/chair
conformation. Finally, the cis relationship between H-1 and H-2 can be further supported by small
coupling constant J1,2 = 3.2 Hz, which measured in 1H NMR spectrum. The major product therefore should
Table 1.5 shows the result of hept-6-enyl radical cyclization of 1-208. When the E substrate was
used in the reaction (Entry 1 and 2), an allo/altro mixture was formed like in Table 1.4, Entry 14. The
product 1-210 was isolated as a mixture of cis/trans at C-2 and C-3 with a ratio of 0.2/1.0. The
diastereomer ratio of 1-209 and 1-210 was determined by GC before column chromatography and/or 1H
NMR after column chromatography. The results in the table may also imply that the concentration of
substrate does not affect the radical cyclization too much, but the concentration of radical sources is critical
for the 6-exo-trig radical cyclization. For example, when the substituent had E configuration, the same
compounds 1-209 and 1-210 were isolated by column chromatography, and the 1-209 has 4 diastereomers
detected by 1H NMR. When the substrate was more concentrated (from 0.014M to 0.032M) and Bu3SnH
was more diluted (from 0.172M to 0.063M), the yield of 1-209 increased from 42 to 59% while the yield of
1-210 decreased from 25 to 18% (the total yield increased from 67% to 77%). The Z substrate cyclized to
give two cyclized compounds 1-209 and 1-210 with an almost 1:1 ratio via radical process shown in
Scheme 62. The isolated compound 1-209 had only 2 diastereomers (altro) in a 82/18 ratio, while another
product 1-210 had only trans configuration. Gratifyingly, if the concentration of R3SnH in benzene
decreased from 0.189M to 0.064M and the radical/hydrogen source changed from Bu3SnH to Ph3SnH, the
formation of 1-210 was totally suppressed like in Table 4 and the yield of 1-209 increased up to 68%. It
can been explained that the k3 is much faster than k4 if Ph3SnH is used as radical/hydrogen source in hept-
6-enyl radical cyclization. Because the configuration of 1-209 was dependant on the configuration of 1-
208, the product in Entry 5 had only altro configuration with α/β anomeric mixture.
84
N
N OTBS N
OTBS
S N
O O
O
TBSO +
CO2Et O
O
O O O CO2Et O CO2Et
0.13: 0.05:1.0:0.31m
0:0:1.0:0.26 n
85
The difference in the stereoselectivities of (Z)- and (E)-olefin acceptors (the former giving
exclusively the altro-isomer, i.e. the C2-substituent in the β-configuration) is quite striking. This result
(Table 1.4 and 1.5) can be rationalized on the basis of the conformations of the putative intermediates that
lead to the altro- and allo- products (Figure 1. 7). Inspection of model suggests that there is an added
through-space interaction between the carboethoxy oxygen and the C5 (radical numbering) acetal oxygen in
the transition state 1-211 for the formation of the allo product(s). This is absence in the transition state 1-
212, which might explain why only altro products are obtained from the (Z)-acceptors. There is no such
clear distinction between the respective transition states leading from the (E)-olefin acceptor and a mixture
of allo- and altro-products are obtained in these cases (Scheme 1.59 in p. 85).
OTBS
1
O
O H
N
S 5 allo-product
O O
O H
R
1-211
TBSO
O 1 N
O H
O S O
altro-product
5
H O
R
1-212
Figure 1. 7. Origin of the altro-Selectivity in the (Z)-Acceptors (see Table 1.4 and 1.5).
The preponderance of the formation of the β-anomer in the pyranoside formation is highly
furanoside system, the α-conformation of glycosyl radical 1-213 would be expected to provise some
anomeric stabilization to the intermediates from which the β-glycoside are formed. It has to be pointed out
86
that in the altro isomers the β-glycoside formation will also be favored by the easy H delivery from α-face
to afford β-pyranoside as the major product in 6-exo trig radical cyclization (Figure 1. 8).
H Y
TBSO O
H α-pyranoside
O
H H Im
O
1-213-β
H Y
TBSO O
H β-pyranoside
Im
O
H H
O
1-213-α
Scheme 1.59 and 1.60 may explain the diastereomer distribution for the 6-exo-trig radical
cyclization of 1-208. When the substrate has a Z configuration, the transition states may be drawn as 1-214
or 1-215. If the transition state of the Z compound is 1-215, there is a large van der Waals repulsion
between the ester and γ-oxygen, but if the transition state is 1-214, the 1, 3-interaction is smaller than that
of 1-215; because there is only interaction between ester and γ-hydrogen. Therefore, cyclization of Z
compound would proceed through the transition state 1-218, which lead to altro configuration 1-222 with
two diastereomers (α and β) at an anomeric center. If the substituents have E configurations, the reaction
may proceed through 1-216 and 1-217 because there are no significant differences between these two
transition states. However, the 1-216 could be slightly favored over 1-217 because the product (1-223)
from the later is highly hindered. Therefore, the major cyclic compound of E of 1-208 should be the β-
altro form, 1-222, and some E substrate may also gave 1-223 configuration, which has a β-allo
configuration.
87
The Z-enoate acceptor
RO OTBS OTBS N
H O Im
OTBS O O N
O Im
S SnBu3
O
H S SnBu3
H O O
O O CO2R O CO2R
H
H OTBS
O Im OTBS OTBS N
Im
O O O N
H H S SnBu3 S SnBu3
O
O O
O H
O CO2R O CO2R
OR
1-215 1-219 1-223
88
CO2Et OTBS
H OTBS
Im
O H
H
Im H O H
O H
H H CO2Et
O H
H
OO
H OTBS most favorable
H O Im 1-226 1-230
O OEt
O Bu3SSn
O
OTBS
H OTBS CO2Et H
O H
H H
1-224 major H H
O Im
O
H H CO2Et
O Im H
OO
1-227 1-231
OTBS
H OTBS Im
H
O H
H H
Im O H
O H
H
H
O H
CO2Et OO CO2Et
H OTBS
1-228 1-232
H O Im
O
S SnBu3
O
OEt
OTBS
O H OTBS H
H H
1-225 minor H
O H
O Im
H H
O H
H
O Im
OO CO2Et
CO2Et
1-229 1-233
89
Entry Compounds Chemical shift Coupling constant Calculated
90
Conformation of the major product is assigned as shown in 1-226 by comparison of spectral
properties with those of altro-1-197 (Figure 1.6) and the measured coupling constant (J1,2) of 3.1 Hz.
Another possible conformation, 1-230 was not observed in the NMR. Compound 1-226 could be
epimerized to 1-227. An alternative conformation of 1-227 is 1-231. This might explain the large coupling
constant (8.9 Hz) J1,2 in the isomerized product. The minor allo products arise via 1-217 (Et)-minor. The
large coupling constant (J = 10.3 Hz) and up-field chemical shift (δ 5.31 ppm) is indicative of the
conformation 1-228, for one of allo-products. Epimerization would give the other allo-product, 1-229,
with a J1,2 of 7.0 Hz. Drieding models show dihedral angles of 51o, 169o, 180o, and 22o for the structures 1-
226, 1-227, 1-228, and 1-229, which are consistent with the observed coupling constant 3.1, 8.9, 10.3, and
7.0 Hz respectively (see Table 1.6 for selected chemical shifts and coupling constants).
Table 1.7 shows the result of radical cyclization of unsubstituted olefin substrates 1-234. When
Bu3SnH was used as the radical sources, the cyclized product 1-235 was isolated as 23%, but the yield
increased to 46% with Ph3SnH. The higher yield with Ph3SnH is reasonable because triphenyltin hydride is
a better hydrogen source. After column chromatography, 4 anomeric hydrogen peaks were found in 1H
NMR spectrum. The ratio was 0.32:1.0:0.26:0.55 (as estimated) from these peaks. The stereochemistry
has been determined by comparing the coupling constant of 1H NMR for altro/allo-1-203. The major
product was assigned as having altro configuration with β anomeric glycoside based on early assignment of
1-203. The si face attack may be explained by steric reasons. Because the 1-237 is a geometrically more
favored configuration (less 1,3-allylic interaction) than 1-238, the most favorable N-glycoside should be 1-
239. The small coupling constant J1,2 = 2.7 Hz suggests the cis relationship of the altro conformation of 1-
239. The anomeric hydrogen of the epimer of altro form was shown at δ 5.2 ppm with J1,2 = 16.2 Hz. The
minor product has allo conformation, and the ratio of α/β epimers was 0.46/1.0. The stereochemistry of
those epimers was assigned by the chemical shift and coupling constants, which were measured as 6.8 Hz
and 14.2 Hz respectively. A large coupling constant J = 14.2 Hz may support 1-241 as the β-anomer of the
allo form. After epimerization at C-1, the allo conformation may be drawn as 1-242. The ratio of
altro/allo conformation is 1.6, which is much smaller than that of 1-207 (altro/allo = 6.7). The less
stereoselectivity of 1-235 may be explained by the small steric effect difference between 1-237 and 1-238.
91
N
N OTBS N OTBS
N
S N O N
O
O
TBSO +
O
O CH3
O O O O
a. 0.052M substrate in benzene, 0.061M Bu3SnH in benzene, 29 µL/min via a syringe pump
b. 0.042M substrate in benzene, 0.064M Ph3SnH in benzene, 29 µL/min via a syringe pump
c. 0.046M substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump
d. Temperature of an oil bath
e. The diastereomer distribution; altro-α (1-240):altro-β (1-239):allo-α (1-242):allo-β (1-241)
f. The ratio of α/β = 0.37/1.0.
92
H OTBS OTBS
CH3 Im
O H
O Im H O H
H H CH3
H H
H O O H
O
H OTBS
most favorable
O
O Im 1-239 1-243
H
H
SSnBu3
O OTBS
H OTBS
1-237 CH3 H
O H
H O Im
O H
H H CH3
H Im
H O O H
O
1-240 1-244
OTBS H OTBS
H
H H
O O
O O H
H Im H
H H Im
CH3
O CH3
OTBS O
H
O 1-241 1-245
Im
O
H
H SSnBu3
O
H OTBS
H OTBS H
H H
1-238 O O
O O Im
H H H
H H H
Im
CH3 O CH3
O
1-242 1-246
93
1. 3. 4. 6-Exo-trig Radical Cyclization of Substrates Derived from D-Ribose
We performed the same reaction with O-phenylthiocarbonate 1-193 under our optimized reaction
conditions and the results are summarized in Table 1.8. First, we explored the reaction with Z substrate as
the reactant and tributyltin hydride (5.0 equivalents) as the radical/hydrogen source. Based on the
mechanism proposed by Bliss and the results from our radical cyclization for thiocarbamate 1-196 and 1-
208, we expected the yield of pyran derivative 1-195 would increase. After column chromatography,
however, phenyl-migrated lactone 1-194 and pyran derivative 1-195 were isolated in 31% and 38%,
respectively (Entry 2). The results may imply that the reaction pathway (k3 or k4, Scheme 1.16 in Chapter
1.1) is not dependant on the reactant addition order, and another mechanism has to be proposed to explain
both Bliss’ and our results. Because the excess amount of tin hydride forced the pathway k3, we might
expect the formation of phenyl migrated product 1-195 would be facilated if Ph3SnH is used as the
radical/hydrogen source. As expected, the product 1-195 was formed as the major product (71%) and only
small amount of 1-194 (3%) was isolated by column chromatography (Entry 3).
It has been reported that O-phenylthiocarbonate can be used for the 5-exo radical cyclization
mediated by the Barton’s radical intermediate. The cyclized radical intermediates can be further reduced to
thionolactone by excess trialkyltin hydride. More interestingly, the phenyl group of the thiocarbonate can
make a spiroaromatic ring in a 5-exo intramolecular cyclizartion to give the phenyl group migration (See
Scheme 1.4 and 1.5 in Chapter 1.1). Bliss reported65 that if O-phenylthiocarbonate 1-193 is used for the
radical cyclization, the phenyl group migration occurs via a spiro aromatic system. However, he found the
reverse addition (slow dropping of a mixture of substrates and AIBN into a solution of trialkyltin hydride)
might trap the α-methylene radical to give thionolactone, which is further reduced to pyran derivative 1-
195 as the major products. The mechanism proposed by Bliss is shown in Scheme 1.12 (p. 28), and he
concluded that the reaction pathway is dependant on the addition order of the substrate/trialkyltin hydride.
chromatography. The 1H NMR spectrum of the compound implied that the compound had a phenyl group,
but thiono carbonyl function (δ ≈ 190 ppm) could not be observed any more in the 13C NMR spectrum.
Two carbonyl peaks (δ = 171.5 and δ = 170.6) may suggest that the thiocarbonyl group was converted to
94
ester group via the mechanism as shown in the Scheme 1.12 (Chapter 1.1, p. 28). The stereochemistry of
the lactone was assigned as altro by Bliss based on conformational analysis, coupling constants, and
NOSEY data. Bliss also reported that the stereochemistry of 1-195 is allo based on coupling constants and
NOSEY spectra which showed a strong dipole-dipole interaction between H-2 and H-4. However,
comparision of the chemical shifts and coupling constant of 1-195 with 1-203 may imply that the structural
assignment has to be revised as altro because of the enhancement of COtBu, H7a and H7b peaks with
OPh
OTBS OTBS
S
O O O O
TBSO
Ph
CO2Et O O
O O O CO2Et O CO2Et
a. Bliss’ Dissertation
b. 0.012 M Substrate in benzene, 0.043 M Bu3SnH in benzene, 42 µL/min via a syringe pump
c. 0.047 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 26 µL/min via a syringe pump
d. Temperature of an oil bath
95
1.4%
1.6, 1.3%
3.3%
OTBS
H 0.7%, 0.6%
CO2tBu
OTBS
2.5, 1.9% 7
O 4
5 O
H
H
O O 2
3 1
O CO2tBu H 0.5%
H
O H
1-203
When a strong EWG is substituted on the olefin acceptor, 6-exo trig radical cyclizations mediated
by the Barton’s radical intermediate proceed very efficiently to give the corresponding altro or the mixture
described in earlier (see Table 1.4 and 1.5), (Z)- enoate gives better stereoselectivity at C2-position.
Moreover, the major product of the N-heterocyclic glycosides is β-anomer via the exo-hept-6-enyl type
radical cyclization. α,β-Unsaturated nitrile 1-247 (Figure 1.9) also may be used as an excellent radical
acceptor in the 6-exo trig radical cyclizations. When pure Z- isomers of the substrates were used for the
cyclization, we did not observe the formation of any of allo-isomers (Table 1.9, Entry 2). The isolated
product was a mixture of α/β-anomers of altro-1-252 with a ratio of 0.26 to 1.0 determined by 1H NMR
spectroscopy. As explained it in Scheme 1.66, the anomeric stabilization in pyranosyl radicals can be
rationalized in the formation of β-anomers as the major product. In sharp contrast to the results from Z-
isomers, use of E-isomers gave a mixture of altro-1-252 and allo-1-252 even though the major products
96
still have the altro-configuration (Entry 1) as expected from the previous results. It has to be pointed out
that the allo/altro ratio of the N-glycoside decreased to 0.10/1.0 compared to that of tbutyl enoates (1-196,
N
N N
OTBS
S N
O
O
TBSO
CN O
O O O CN
1-247 1-252
Conditions Yield
a. 0,047 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 16 µL/min via a syringe pump
b. 0.046 M Substrate in benzene, 0.063 M Ph3SnH in benzene, 21 µL/min via a syringe pump
c. altro-α: altro-β: allo-α: allo-β.
d. altro-α: altro-β.
e. Temperature of an oil bath
97
N N
OPh OPh N N
S S S S
O CO2Et O O CN O
TBSO TBSO TBSO TBSO
CO2Et CN
O O O O O O O O
N N
N N
N N N N
S S
O O O S O S
TBSO NOCH3 TBSO NN(CH3)2
TBDPSO O O
N N
OTBS OTBS OTBS OTBS
O N O N
O O O
Ph
O O O O NHOCH3
O CO2Et O CO2Et O CN O
N OTBS N N
OTBS OTBS
O N O N O N
98
The oxime ether substrate 1-248 which exists as mixtures of syn and anti isomers was investigated
for the 6-exo trig radical cyclization. Bliss performed65 the reaction with 2.5 equivalents of tributyltin
hydride as the radical/hydrogen source with 0.2 equivalents of AIBN in toluene. To initiate the radical
reaction the reaction mixture was irradiated by 500W incandescent lamp at 0 to 50 oC. Although the oxime
ether has been used widely as the radical acceptor in exo-hex-5-enyl cyclization and exo-hept-6-enyl
cyclization, he failed to isolate the corresponding cyclized compound 1-253 from the reaction of 1-248 via
N
N N
OTBS
S O N
O
TBSO NOCH3
O NHOCH3
O O O
1-248 1-253
99
Because we were aware of the 2.5 equivalents of tin hydride was not enough to cyclize the
glycoside via radical process, 5.0 equivalents of tributyltin hydride were used as the radical/hydrogen donor
along with 0.5 equivalent of AIBN in the reaction. However, no N-heterocyclic glycoside was observed
and all starting material 1-248 was decomposed under our reaction conditions. Interestingly, if 5.0
equivalent of triphenyltin hydride was used as the radical/hydrogen donors in the reaction, we could isolate
the desired N-glycoside in 83% yield as a four isomer mixture (Table 11). Because the substrate 1-248 is a
mixture of syn/anti, we could not avoid the formation of allo isomers in the reaction, but the major product
N
N N OTBS
OTBS
S N
O
O
TBSO NN(CH3)2 +
O NHN(CH3)2 O NHN(CH3)2
O O O O
a. 0.046 M Substrate in benzene, 0.063 M Bu3SnH in benzene, 21 µL/min via a syringe pump
b. 0.026 M Substrate in benzene, 0.080 M Ph3SnH in benzene, 42 µL/min via a syringe pump
c. altro-α: altro-β: allo-α: allo-β.
d. Temperature of an oil bath
When N,N’-dimethyl hydrazone was used as the radical acceptor in the Barton’s radical
intermediated reaction, deoxygenation (k2) is faster than 6-exo radical cyclization(k1) (p. 78, Scheme 1.62).
The deoxygenated radical intermediate 1-201 might be trapped by excess tin hydrid through the Barton-
100
McCombie deoxygenation mechanism, and gave deoxygenated product 1-255 in a 41% yield. Because the
dimethylsubstituted hydrazone is not as strong EWG as α,β-unsaturated esters, it is reasonable that the
deoxygenation process (k2) is faster than cyclization (k1) (see Scheme 1.58, p. 78). However, if we used
excess amount of triphenyltin hydride as the radical/hydrogen source instead of tributyltin hydride, the tin-
added radical intermediate 1-198 (p. 78) proceeds via the pathway k1 to afford an intermediate like 1-199
(p. 78) followed by C-SSnR bond breaking. The hydrazine substituted pyranoside 1-254 was isolated in
63% yield as a three diastereomer mixture, and the configuration was assigned by comparing the coupling
constant and chemical shift with the similar known products (Table 1.11).
N
OTBS
O N
O NHN(CH3)2
O
1-254
a
. The ratio was determined by 1H NMR after column chromatography.
Table 1.12. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-254.
substrates, which have three fixed stereochemistries at C3, C4, and C5. Our results imply that the
streochemisty of C2 can be controlled by the geometry of the substrate. If the substrate has Z configuration,
the products are altro (i.e. trans between C2 and C3). However, if the configuration of the substrate is E, the
products are a mixture of altro and allo (i.e. cis between C2 and C3).
101
To examine more detail the origin of stereoselectivity in exo-hep-6-enyl radical cyclizations, we
prepared two new compounds, 1-250 and 1-251 (p. 108) from carbohydrates. Each of them has only one
fixed stereochemistry at C6 and C5 , respectively. First, we performed the radical cyclization with the
substrate 1-250 under our optimized reaction conditions. Although the formation of cyclohexane
derivatives via exo-hep-6-enyl radical cyclization is 20-30 times slower than the exo-hex-5-enyl radical
cyclization, the reaction proceeded efficiently to give 1-imidazoyl pyranosides in a good yield (80%).
N N
OTBS
O N
O S
2
TBDPSO O
6 1
3
OEt CO2Et
1-250 1-256
Conditions Yield
a. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 24 µL/min via a syringe pump
b. Temperature of an oil bath
c. The ratio determined after column chromatography by 1H NMR (400 MHz).
Careful 1H NMR investigation of the crude products implied that only three isomers of the four
possible were present in a ratio of 1.0:0.38:0.09 via the exo-hep-6-enyl radical cyclization. Gratifyingly,
we could isolate two of the major product in a pure form, and the structural assignement was determined by
1D nOe experiment as well as coupling constants (J1,2) and chemical shift (ppm). Based on the
spectroscopic data the first and the second major products were assigned as 1-258 and 1-259, respectively.
Table 1.14 summarizes the chemical shift and coupling constants for the anomeric hydrogen of 1-258, 1-
102
259, and 1-260, and Figure 1.12 is the summary of the nOe experiment for the first major compound 1-258.
The large coupling constant (J1,2 = 9.9 Hz) for the anomeric hydrogen of hexapyranoside 1-258 may imply
that trans-diaxial configuration between H1 and H2. nOe Studies further confirm these assignment. For
example, we observed strong enhancement of some peaks during the irradiation of some frequencies: for 1-
The coupling constant for the second major compound is relatively small (J1,2 = 2.4 Hz), and the
calculated dihedral angle of the vicinal hydrogens is 56o from Karplus equation (3J = ACos2φ - 0.28, where
A= 8.5 for 0o ≤ φ ≤ 90 o and A= 9.5 for 90o ≤ φ ≤ 180 o). Because it has been known the coupling constants
(3J value) for equatorial-equatorial and equatorial-axial vicinal hydrogens are between 2-3 Hz, we may
draw three possible configurations for the pyranoside: 1-259 and 1-260. The result of the nOe experiment
for the second major product is summarized in Figure 1.13. Strong enhancement of the peaks at H3a and H5
was observed with the irradiation of H1, while the irradiation of H3a and H5 increased the peak of H1.
Moreover, a strong relationship between H2 and H3a was observed from the nOe experimental data. Based
on these results, we assigned the configuration of the product as a β-anomer (H1: axial, imidazole:
N N N
OTBS OTBS OTBS
O N O N O N
1
H NMR (400 MHz) CO2Et CO2Et CO2Et
1-258 1-259 1-260
Table 1. 14. The Chemical Shift and Coupling Constants of the Anomeric Hydrogen of 1-256.
103
4.4%
2.4%
H5
H1
H3a 2.8%
TBDPSO
2.7%
H H O Im
H6a H6b H7b
TBDPSO H4a 15.1% H7a
O
Im
CO2Et CO2Et
H 1.8% H3b 0.6%
1-258 H4b
H2
2.9%
7.5%
6.0% 2.7%
2.1%
104
4.6%
2.0%
1.5%
H5
3.1% H1
6.1% H3a
TBDPSO 5.2%
4.2%
H H O Im
H6a H6b
TBDPSO H4a
O
Im H2
H
H3b 4.6%
CO2Et H4b H7b
1-260
H7a CO2Et
105
CO2Et
H H H
O
TBDPSO
O H
Im
SnR3 CO2Et Im
H S TBDPSO
H
TBDPSO K1 1-258 1-264
O
Im
CO2Et
H CO2Et
H Im H
1-262 O
N TBDPSO
O Im
H
N CO2Et H
TBDPSO
H
O S
1-259 1-265
TBDPSO O
OEt
1-250 H H H H
O
TBDPSO
O H
SnR3 Im
H S H
TBDPSO Im
TBDPSO
O K2 CO2Et
Im CO2Et
1-260 1-267
CO2Et
1-263 H Im H H
TBDPSO O
O Im
H
H
H
TBDPSO
CO2Et CO2Et
1-261 1-268
We may rationalize the isomer distribution of 1-256 by Scheme 1.62. The Baron’s radical
intermediate has two possible chair-like conformations 1-262 and 1-263 for the transition state. The first
transition state 1-262 is a more favorable and undergoes the intramolecular exo-hep-6-enyl radical
cyclization. The intramolecular cyclization may lead two isomers, 1-258 and 1-259. Because 1-259 has
van der Wssls repulsion between an imidazole and an axial H5 hydrogen, the most favorable conformation
of pyranoside is 1-258 despite of small interaction between imidazole and ethyl ester. Although other
106
conformers, 1-264 and 1-265 may be drawn by ring flip, those are much less favorable than 1-258 and 1-
259 because axial position of the TBDPS protecting group and the resultant large 1,3 steric repulsions.
If the radical intermediate has the configuration 1-263 and the radical ring closure proceeds via
intramolecular 6-exo cyclization, we may draw two possible isomers, 1-260 and 1-261. As described
above, the isomer 1-261 is less favored because of the 1,3 steric repulsion between the imidazole and
hydrogen. Moreover, although axial ethyl ester substituted methylene is unfavorable, the steric interaction
between an imidazole and an axial H5 hydrogen of 1-259 are much bigger than 1,3 axial interaction of 1-
260. Thus, the 1-260 was formed as the second major product. Note that a long C-S bond reduces the
putative axial intereaction of the S-SnR3 group in the developing transition states, leading to the equatorial
orientation for the imidazole in the major products. The conformation 1-262 for the Barton’s radical
intermediate is probably more stable one (compared 1-263, no axial group) and cyclization should give all
Table 1.15 shows the results of the 6-exo-trig radical cyclization of substrate 1-251. The
reaction was performed under three different concentrations of substrate and radical sources in toluene or
benzene; decomposition of the all starting material 1-251 was observed under reflux condition. However,
the cyclized product 1-257 was isolated as 20% yield after slow addition of the mixture of substrate 1-251
The ratio of diastereomers of was 63:6:31, which was determined by GC before column
determined by 1H NMR. As we have done previously, using the concentration effect of the hydride and the
power of triphenyltin hydride as the hydrogen source, the isolated yield of the pyranoside could be
increased up to 79% under diluted concentration (0.064M Ph3SnH in benzene). Four possible isomers were
observed in a ratio of 0.21:1.0:0.78:0.22 in 1H NMR spectrum of the crude product. Because we failed to
isolate each of those isomers by column chromatography, the detail of the structures of the diastereomers
107
N
N
N
O N
O S
2
5 O
3 1 TBSO
TBSO OEt CO2Et
1-251 1-257
Conditions Yield
a. 0.047M Substrate in benzene, 0.064M Bu3SnH in benzene, 167 µL/min via a syringe pump
b. 0.067M Substrate in toluene, 0.059M Ph3SnH in toluene, 100 µL/min via a syringe pump
c. 0.043M Substrate in toluene, 0.085M Ph3SnH in toluene, 50 µL/min via a syringe pump
d. 0.070M Substrate in benzene, 0.392M Bu3SnH in benzene, 45 µL/min via a syringe pump
e. 0.058M Substrate in benzene, 0.064M Ph3SnH in benzene, 40 µL/min via a syringe pump
f. Temperature of an oil bath
g. Decomposed starting material.
h. The ratio determined by GC before column chromatography.
i. The ratio determined by 1H NMR before column chromatography
Table 1.16 shows the reaction of substrate 1-269 with radical source such as tributyltin hydride,
triphenyltin hydride, or EPHP (ethylpiperidinehypophosphoric acid ) salt. Unfortunately, the substrate did
not cyclize under our optimized conditions. When the concentration of the tin hydride was reduced
(0.08M), 19% (49% based on recovered starting material) of olefin 1-270 was formed.
108
NH
S TBSO OH
O
TBSO
O O
O O
1-269 1-270
Conditions Yield
a. 0.026M Substrate in benzene, 0.080M Bu3SnH in benzene, 42 µL/min via a syringe pump
b. 0.033M Substrate in benzene, 0.182M Bu3SnH in benzene, 42 µL/min via a syringe pump
c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump
d. 0.033M Substrate in benzene, 0.125M EPHP in benzene, 42 µL/min via a syringe pump
e. 0.025M Substrate in benzene, 0.050M Bu3SnH in benzene, 42 µL/min via a syringe pump
f. Yield is based on recovered starting material
g. Temperature of an oil bath
h. 1.0 M Et3B in THF
i. All starting material was decomposed
j. 85% of starting material was recovered
Although we changed the concentration of the tin hydride (0.182M), the desired product was not
formed via radical process, and only dethiocarbamated product 1-270 was isolated as a 48% yield. Because
we have found previousely that triphenyltin hydride is a better radical/hydrogen source in the radical
109
cyclization, we used it in the reaction of 1-269 under high dilution solution (0.046M substrate in benzene
and 0.063M Ph3SnH in benzene) (Entry 3). However, the reaction did not improve at all, and only the 1-
270 was isolated in a 50% yield. Alternative radical/hydrogen sources such as EPHP and radical raction
initiator (triethyl borane) also failed, andl all starting decomposed (Entry 4) or recovered (Entry 5).
Because we found that O-methyl oxime (Table 1.10) and N,N-dimethyl hydrazone (Table 1.11)
could be used as a radical acceptor in Braton’s radical mediated 6-exo trig cyclization, it was natural for as
to turn to diphenylhydrazone as the radicl acceptor. First, the substrate 1-271 was subjected to 6-exo trig
radical cyclization with tributyltin hydride. However, all starting material decomposed and no amount of
significant products was obtained after column chromatography. Although the hydride was changed from
tributyltin hydride to triphenyltin hydride, and more diluted conditions were employed, we still did not see
any cyclization.
N
N
S
O
TBSO NNPh2 X Decomposed
O O
1-271
Conditions Yield
a. 0.047M Substrate in benzene, 0.063M Bu3SnH in benzene, 35 µL/min via a syringe pump
b. 0.037M Substrate in benzene, 0.058M Ph3SnH in benzene, 25 µL/min via a syringe pump
c. Temperature of the oil bath
d. All starting material decomposed
110
Initially, Bliss studied the 6-exo radical cyclization with triazole substituted substrates 1-272 and
1-273, but claimed that starting material decomposed under his conditions. Because we found earlier that
use of 5.0 equivalents of triphenyltin hydride and reversed addition were the critical for the success of N-
glycosylation via radical process, the substrate 1-272 and 1-273 were exposed to that conditions, and the
N N
N OTBS N
S N
O
O N
TBSO X
O Y
O O O
a. 0.048M Substrate in benzene, 0.063M Ph3SnH in benzene, 27 µL/min via a syringe pump
b. Bliss’ dissertation: 0.050M substrate in toluene, 0.050M Bu3SnH in toluene.
c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump
d. Bliss’ dissertation: 0.050M substrate in toluene, 0.050M Bu3SnH in toluene.
e. Temperature of the oil bath.
f. altro-α/altro-β.
g. The isolated yielf of altro-β anomer. The number in the paranthesis is estimated yield from the
altro-α/altro-β ratio of the crude mixture.
Table 1. 18. 6-Exo trig Radical Ring Closure of 1-272 and 1-273.
111
The Z substrate 1-272 could be cyclized efficiently to give triazole substituted N-pyranoside 1-274
in an 87% yield, and the products have only altro configuration as expected from our previouse
observations. After column chromatography of the crude mixture, the α and β anomers were isolated as a
pure form, which were subjected to nOe experiment to determine the configuration of the products. The
results for the nOe experiment are shown in Figure 1.14 and 1.15. The altro configuration of the 1-274 -α
and 1-274-β is proved by the observation of strong nOe effects between H2 in the both anomers. The α/β
0.9%, 1.5%
2.5%, 2.5% 0.9%, 0.7%
H OTBS
N CO2tBu
OTBS 1.5%, 2.0%
4
1.2%, 1.4%
O N 5
O N
N H
N N
O 2
O 3 1
O CO2tBu H
2.8%
H
O H
3.8%
1-274-β
3.7%
112
1.7%
0.7%
H OTBS
OTBS N CO2tBu
1.2%
O N 4
O
N H
5
H
O O 2
3 1
O CO2tBu H 3.6% H
O N
4.5% N
1-274-α N
1.4%
The importance of O-methyl oximes in radical chemistry comes from the fact that they are not
only excellent radical accepors, but also they serve as latent amine functionalities in the products. We have
shown the O-methyl oximes can be used as a radical acceptor for the Barton’s radical mediated ring
closure. Another substrate with oxime functionality 1-273, a triazole derivative, was used in the
investigation of radical cyclization. The expected product 1-275 was efficiently made under our optimized
reaction conditions to give α/β mixture with only altro configuration. Surprisingly, only trace amount allo
isomers were observed in the analysis of the crude 1H NMR spectrum although a mixture of syn/anti
Although we failed to isolate the α-anomer of the 1-275 by column chromatography, the β-anomer
was isolated as a pure compound in a 46% yield. The isolated yield was relatively poor, but estimated yield
from the α/β ratio of the crude product in the 1H NMR spectrum was 78%, which is a comparable to other
similar cyclization. The configuration of the 1-275 was determined by not only nOe experiment, but by
chemical shift and coupling constants as well. For example, irradiation of H1 peaks enhanced the peak of
113
H5 proton with an axial position, and relatively small coupling constant (J1,2 = 3.4Hz) may imply that the
configuration of H1 and H2 are in axial-equatoral relationship; i.e. the relation of H1 and H2 is cis. Based on
those results as well as other spectroscopic data we assigned the isolated pure N-pyranoside as β-altro-1-
275.
1.2%
0.7%
H OTBS
OTBS N
NHOCH3
O N 4
O N
N H
5
N N
O NHOCH3 O 2
3 1
O H H
O 3.0%H
1-275-β 2.3%
Table 1. 19. The Chemical Shift and Coupling Constant for β-altro-1-275
114
Bliss also explored the radical cyclization of 1H-benzimidazole thiocarbamate 1-276 with
tributyltin hydride at 90 oC. Although he isolated the desired N-heterocyclic pyranoside 1-277, the yield
was extremely low (4%) and some sideproduct 1-278 was isolated in 6% yield. He tentatively assigned the
N-pyranoside 1-277 as altro and the anomeric hydrogen with an α-configuration. He also rationalized the
formation of 1-278 by the mechanism proposed in Scheme 1.79. Because we successfully made the 1H-
benzimidazole thiocarbamate 1-276 in the previouse study, the Barton’s radical mediated 6-exo trig radical
N N N
OTBS OTBS
S
O N O N
O
TBSO
+
CO2tBu O O
O O O CO2tBu O CO2tBu
Conditions Yield
115
We found two anomeric hydrogens from the crude reaction mixture at δ 5.43 (J = 7.4Hz) for altro-
α and at δ 5.91 (J = 3.9Hz) for altro-β in a ratio of 0.81/1.0 to 0.58/1.0, but could not find any evidence for
the formation of 1-278. Unfortunately, our best attempt to isolated pure 1-277 (and/or 1-278) failed and the
related yield is based on data on mixture of contaminated product (Table 2, Entry 3).
N
OTBS
O N
O
O CO2tBu
Bu3SnH
OTBS
SSnBu3 1-277
O
BzIm
H
O
O CO2tBu N
OTBS OTBS
SiO2 O BzIm O N
1-279 Lewis
H
Base
O O
O CO2tBu O CO2tBu
1-280 1-278
In the earlier experiments, we found that imidazole and triazole thioates derived from D-
ribofuranose upon addition to a large excess of an efficient hydrogen donor, underwent cyclization to give
surprisingly good yield of imidazoyl and triazoyl glycosides. As expected from configuration of radical
intermediate, all four possible stereoisomers were formed from E-substrate. However, the stereochemistry
of C2 could be controlled by using Z substrate. We also optimized the reaction conditions of 6-exo-trig
radical cyclizations. The optimized conditions are (i) 5 equivalents of alkyl tin hydride as a radical source,
116
(ii) 0.5 equivalent of AIBN as a radical initiator, and, (iii) 90 oC for the oil bath temperature. In order to get
a higher yield of cyclized compound, it is essential to keep a low concentration of hydrogen/radical sources
in solvents, and the temperature of the oil bath must be controlled carefully.
In this section, we record our attempts to extend the new synthetic method for the synthesis of N-
furanoside from commonly obtained sugar derivatives using these optimum reaction conditions. The 5-
exo-trig cycization was performed under a variety of reaction conditions with the following changes; (i)
hydrogen/radical sources, (ii) concentration of substrate as well as of hydrogen/radical sources, (iii) change
in addition rates via a syringe pump, (iv) the order of addition of reactants for generating the radical
Table 1.21 summarizes 5-exo-trig radical cyclization studies with Barton’s radical intermediate
derived from 1-281. All attempts failed under the refluxing toluene (about 110 oC) conditions. For
example, when 5.0 Eq. of Ph3SnH was used as a radical source along with 0.15 Eq. of radical initiator
AIBN at 110 oC (Entry 1), all the starting material (1-281) was consumed with no formation of significant
identifiable products. In the Entry 2, we changed the concentration of the substrate and the
hydrogen/radical source as well as the equivalents of radical initiator AIBN. There was no improvement in
terms of 5-exo-trig radical cyclization. To find a better radical/hydrogen source than Ph3SnH, we decided
to use excess equivalent of EPHP along with 1.0 Eq. of AIBN (Entry 3). However, the expected product 1-
282 or 1-283 was not isolated any of these conditions. Even though we changed the addition rate as well as
the concentration, the 5-exo-trig radial cyclization could not be successfully carried out (Entry 4 and 5).
Interestingly, cyclized thionolactone 1-283 was isolated in a 58% yield with a diluted concentration of
substrate and Bu3SnH at 110 oC (Entry 6). The isolated compound 1-283 was a mixture of two
diastereomers in a ratio of 2.1/1.0. The stereochemistry at C-4 is fixed and is the known from the
stereochemistry of 1-281. However, the configuration of C-2 is dependent on the stereoselectivity of the
cyclization. The ratio of cis/trans (or trans/cis) between C-2 and C-4 has been determined by the
integration of 1H NMR spectrum, and the thiocarbonyl function was confirmed by the chemical shift in the
13
C NMR spectrum, which was shown to have two characteristic peaks at δ 178.5 and 177.4 ppm.
117
N
N
N TBSO TBSO
N
O O S
O S OEt
H +
H H
O
TBSO CO2Et
CO2Et
1-281 1-282 1-283
Conditions Yield
Continued
118
Table 1.21 continued
a. 0.067M Substrate in toluene, 0.059M Ph3SnH in toluene, 100 µL/min via a syringe pump
b. 0.043M Substrate in toluene, 0.085M Ph3SnH in toluene, 50 µL/min via a syringe pump
c. 0.086M Substrate in toluene, 0.143M EPHP in toluene, 41 µL/min via a syringe pump
d. 0.061M Substrate in toluene, 0.087M EPHP in toluene, 83 µL/min via a syringe pump
e. A mixture of 0.021M substrate and 0.208M EPHP in toluene, addition of AIBN 333 µL/min via a syringe
pump
f. 0.021M Substrate in toluene, addition of 0.028M Bu3SnH in toluene, 150 µL/min via a syringe pump
g. 0.009M Substrate in benzene, 0.051M Bu3SnH in benzene, 62 µL/min via a syringe pump
h. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 45 µL/min via a syringe pump
i. 0.047M Substrate in benzene, 0.064M Bu3SnH in benzene, 26 µL/min via a syringe pump
j. 0.047M Substrate in benzene, 0.127M EPHP in benzene, 26 µL/min via a syringe pump
k. Isolated yield of compound 1-282
l. Isolated yield of compound 1-283
m. Temperature of an oil bath
n. The ratio of cis/trans or trans/cis based on 1H NMR
o. The ratio was determined after column chromatography (1-292: 1-294: 1-295: 1-297)
p. The ratio was not determined (1-292: 1-294: 1-295: 1-297)
q. The ratio was determined after work-up
119
However, we could not determine which isomer was the major product. The yield of the thionolactone
decreased from 58% to 7% in refluxing of benzene, but the desired N-furanoside was not found while the
ratio of cis/trans (or trans/cis) mixture changed to 1.2/1.0 based on the 1H NMR spectrum (Entry 7).
Surprisingly, if a mixture of 1-281 and 0.5 Eq. of AIBN in benzene (0.047M substrate in benzene)
was slowly added dropiwse into a mixture of 5.0 Eq. of nBu3SnH in benzene (0.064M Bu3SnH in benzene)
via a syringe pump at a rate of 26 µL/min at 90 oC of oil bath temperature, the desired N-furanoside was
obtained as an 88% of isolated yield (Entry 9). To improve the isolated yield of the cyclized product, we
performed the reaction with Ph3SnH as a radical source. Even though the Ph3SnH is known71 to be a better
hydrogen/radical source than Bu3SnH, the isolated yield of 1-282 decreased to 76% after column
chromatography. Entry 10 shows that EPHP can be used as a radical source and give the same yield of
cyclized compound with alkyl tin hydride. When EPHP was used for 5-exo-trig radical cyclization, the
The formation of N-furaoside can be explained by the mechanisms we proposed earlier for the 6-
exo-trig radical cyclization (Scheme 1.64 and 1.65, the structures are tentative; it is difficult to assign
stereochemistry based on nOe in 5-membered rings). Cyclization through the conformation 1-289 (Z =
(E)-CO2Et) would give the presumed major product 1-292. The minor products could be produced through
a chair-like transition state 1-290 (Z = (E)-CO2Et) or through a boat-like transition state 1-291 (Z = (E)-
CO2Et). Epimerization at C-1 would give the trans minor products 1-295 and 1-297. Only the product
presumably 1-292 was isolated as a pure compound and the structures of all the compounds are tentative.
The major product showed a signal (anomeric) at 6.03 ppm in 1H NMR. The chemical shift in relatively
down field region may imply cis relationship between H-1 and H-2 comparing with the chemical shifts of
1-203, 1-209, and 1-235 (see Table 1.6, p. 90). We assigned tentatively this peak as of β hydrogen based
on the chair-like transition state, 1-289, in Scheme 1.65. The second major product peak was shown to
have up field anomeric hydrogen (δ 5.55 ppm) with a smaller coupling constant, J = 5.5 Hz in 1H NMR,
which may be the epimerized product, 1-295, with trans configuration. Two other small peaks at 6.09 and
5.53 ppm could arise from 1-297 (α) and 1-294 (β). All configurations are tentative.
120
Entry Compounds Chemical shift Coupling constant
Table 1. 22. Selected Chemical Shifts and Coupling Constants of N-Furanoside 1-282.
N N
N N
N N TBSO TBSO
Ph 3 N
Sn O
N O
O S OEt k2 O S OEt k1 k3 SSnBu3
k1
SSnBu3
H H
O O
k2 k4
OEt
TBSO N
O
TBSO TBSO
1-287 O
N
O S
H H H
OEt
Scheme 1.64. The Mechanism for the Formation of N-Furanoside via 5-Exo-trig Radical Cyclization.
121
Im Im H
O major O O
H Im
TBSO TBSO TBSO
Z Ph3SnH Z Z
H H H
SSnPh3 H H
1-289 1-292 1-295
N
TBSO TBSO TBSO
N Im
Ph 3 Im H
Sn minor
O S H O SSnPh3 H O H O
H Im
CO2Et Ph3SnH
Z H H
Scheme 1.65. Rationalization of Diastereomers for 1-282 via 5-Exo trig Radical Cyclization.
It is obvious that an EWG can promote the 6-exo or 5-exo radical cyclizations. Table 1.23 shows
the result of 5-exo-trig radical cyclization of thiocarbamate derivatives substituted with a CN group. The
substrate used was E/Z mixture, and the reaction conditions were similar to the ones described above for
CO2Et. After flash column chromatography, two compounds, 1-299 and 1-300, were isolated. The isolated
product 1-299 has four diastereomers based on 1H NMR, and the absolute stereochemistry has been
tentatively assigned as before (Scheme 1.66). The major product presumably was 1-305, which has a cis
configuration between C-1 and C-2, and the second major was 1-307 with trans configuration. The
sturucture of the other diastereomers remain uncertain (see Table 1.12 for the chemical shifts and coupling
constants of the tentative assignment). Interestingly, 8% of 1-300 was isolated as a mixture (cis/trans).
122
N
N
N TBSO TBSO
N
O O
O S
H + H
CN H
TBSO CN
CN
Conditions Yield
a. 0.035M Substrate in benzene, 0.069M Bu3SnH in benzene, 42 µL/min via a syringe pump
b. Isolated yield of compound 1-299
c. Isolated yield of compound 1-299, cis/trans or tran/cis = 2:1 of 1-300
d. Temperature of an oil bath
e. The ratio of diastereomer determined by 1H NMR after column chromatography
(3-69:3-71:3-68:3-70, tentatively assigned)
Im
O Im H
SSnBu3 O O
TBSO H Im
TBSO H TBSO H
N H CN
H H
CN CN
N 1-302 1-304
Si 1-306
SnPh3
O S
CN
Re
TBSO Im
1-301 Im H
O SSnBu3 O O
H Im
TBSO TBSO TBSO
CN CN CN
H H H
H H
1-303 1-305 1-307
Scheme 1. 66. The Rationalization of the Stereochemistry for the Radical Cyclization of 3-107.
123
1. 3. 9. Stereochemical Control in 5-Exo trig Radical Cyclizaiton
Previously we found that the stereoselcetivity in the inherently less selective heptenyl radical
cyclization is considerably better when the Z-isomer of the radical acceptor is employed. Although
generally the intramolecular hex-5-enyl radical cyclization is more efficient in terms of isolated yield, the
low stereoselectivity at a C1-C2 bond is the major drawback of this reaction. For examples, earlier we
described that imidazole thioates derived from a 5- or 6-hydroxy-2-3-enoate (Eqs. 44 and 45) upon addition
to a large excess of efficient hydrogen donor, undergo cyclization to give surprisingly good yield of
imidazoyl glycosides. In both cases, not unexpectedly, mixtures of all possible stereoisomers of the
product 1-257and 1-282 are formed in this otherwise efficient transformation. Since major applications of
this chemistry are likely to be in the area of carbohydrates, we wondered whether the structural features
present in the potential class of substrates might offer solutions to this problem.
N
N
N
O N
Ph3SnH (5.0 Equiv)
O S
(44)
O benzene, 90 oC
TBSO
79%
TBSO OEt CO2Et
1-251 1-257
N
N
N TBSO
Ph3SnH (5.0 Equiv) N
O
O S OEt
benzene, 90 oC H H (45)
O 88%
TBSO CO2Et
1-281 1-282
The hydroxyl groups on the tether present opportunities for incorporating cyclic acetal-type
protecting groups, which through the resident conformational features, could influence the stereochemistry
of the annulation process. Since both furanosides and pyraosides of N-heterocycles appears to be
124
accessible through the Barton’s radical mediated cyclizations, which inlvolves the formation of C1-C2 bond,
we decide to study in some detail the effect of a various structural parameters of the substrate on the
coursce of this reaction. Thus we examined the effects of protecting groups and Z/E-configuration of
The starting material for the hex-5-enyl type cyclization studies was readily prepared from 4-6-O-
1.2.4, p.67). The radical cyclizations were carried out under conditions optimized for the formation of N-
glycosides. Thus in a typical reaction, 0.16 mmol of (E)-1-283 and 0.08 mmol of AIBN dissolved in 3.4
mL of benzene was added in ~2 h to 0.80 mmol of Ph3SnH in 12.5 mL of benzene in an oil bath at 90 oC.
The reaction was continued for another 30 min at that temperature and the solvent was removed. The
N
Ph O N
Ph O O N Ph3SnH O
O
O N (46)
S benzene/ 90 oC RO2C
H H
RO2C
1-283, R = Et 1-285, R = Et
t
1-284, R = Bu 1-286, R = tBu
As we had anticipated, the use of a cyclic acetal protecting group indeed results in an
improvement in the stereoselectivity of the reaction vis-á-vis the acyclic precursor 1-281 in Scheme 1.80
(see also Table 1.21, p. 118). The C2-substitutent in the N-glycoside is formed exclusively with a β-
orientation, irrespective of the geometry of the starting material 1-283 and 1-284. Although the isolated
yield of N-furanoside was moderate, triphenyltin hydride is a more efficient hydrogen donor than tributyltin
hydride. Other radical/hydrogen source like ethylpiperidine hypophosphite (EPHP) could be used in this
reaction, but isolated yield of the product was relatively poor (Entry 7).
125
N
Ph O N
Ph O O N Ph3SnH O
O
O N
S benzene/ 90 oC RO2C
H H
RO2C
1-283, R = Et 1-285, R = Et
t
1-284, R = Bu 1-286, R = tBu
Conditions Yield
0.66/1.0 k
0.97/1.0 k
0.89/1.0 k
a. 0.046M Substrate in benzene, 0.063M Bu3SnH in benzene, 29 µL/min via a syringe pump
b. 0.046M Substrate in benzene, 0.063M Bu3SnH in benzene, 28 µL/min via a syringe pump
c. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump
d. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump
e. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump
f. 0.010M Based on substrate and 0.050M based on Ph3SnH in benzene. The reagents was added all
together and stirred at 90 oC for 3h.
g. 0.046M Substrate in benzene, 0.126M EPHP in benzene, 28 µL/min via a syringe pump
h. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump
i. Ethylpiperidine hypophosphite
j. The ratio of α/β was determinded before column chromatography by 1H NMR.
k. The ratio of α/β was determinded after column chromatograpy.
l. The ratio was not determined.
126
The α- and β-glycoside can be separated by flash column chromatography, and the structures have
been rigorously established by spectroscopic methods. The position of C1-hydrogen gives a reliable
indication of the anomeric configuration. For the α-anomers the C1 hydrogen appears consistently δ 5.80 ±
1.0 ppm and for the β-anomer this proton appears at δ 6.15 ± 1.0 ppm. In addition, nOe studies further
confirm these assignments. For example, the altro-configuration at C2 can be assigned by the observation
of strong nOe effects between H2 and H4 and the β-configuration of the anomeric haydrogen is supported
H7 2.6% H5a
H3 1.5%
O H5e
Ph 1.4%
Ph O 1.6, 1.2% O
O O
O 6
H H1
BuO2tC ButO2C
N 2.7%
H4 0.5, 0.9%1.8, 0.8%
H
H2 Im
2.6%
N
1-286-α
1.9, 0.8%
H1→ Imd1 0.8 H2→ Imd2 0.8 H3→H7 6.6 H7→H3 5.9
H2→H1 0.8
127
The β-anomer 1-286-β was also assigned by nOe experiment. The observation of nOe effect
between H2 and H4, and H3 and H6, can be used as the evidence to support the altro-configuration at C2, and
the β assignement of the anomeric hydrogen may be rationalized by the istrong nteraction between H1 and
H7 2.6% H5a
H3 1.9, 1.1%
O H5e
Ph O N Ph
O 1.1, 0.6% O
O O
N
RO2C Im
6
H ButO2C
H H4 1.2%
3.1%
1-286-β H2 H1
3.4%
1.2%
H1→ Imd1 1.4 H3→H5a 2.6 H3→ Imd2 1.1 H7→H5a 2.5
It is known that in the Barton-McCombie reaction the slow step is the collapse of the 1-284 (see
Scheme 1.64, p.121). Since the rate of intramolecular addition to an activated acceptor is likely to be faster
than this decomposition, formation of cyclic product, especially in the presence of a sterically demanding,
H-atom donor, is not surprising. Analysis of the transition states that lead to the cyclic products provides a
satisfactory explanation for the exclusive β-orientation formation of the C2-substituent. Of the two possible
128
transition state (Scheme 1.67), one with ‘chair-like’ conformation 1-287 that leads to the C2-β product is
likely to be favored over the ‘boat-like’ transition state 1-291 that results in the C2-α substituent. In
depicting these structures the quasi-axial position at C1 is based on the reasonable assumption that C-S and
S-Sn bonds are significant longer than the C-N bond, and thus the imidazoyl moiety is likely to be sterically
more demanding. Homolytic cleavage of the C-S bond in 1-288 followed by H atom abstraction by the
resulting gkycosyl radical 1-290 will result in the two glycosides. Predictably, there is little difference
H
N H
Ph O Ph O N
O N O
O O N
S
X SnPh3 S
H SnPh3
"chair-like" X
1-287 1-288
H H
H H
Ph O N R3SnH Ph O N
O O
O N O N
H
H X H X
C2-substituent β
1-289 1-290
α- and β - furanosides
N
H H
N H
H O
H Ph O N
O
S SnR3 O N
O O
Ph H S
H X SnPh3
"boat-like" X
1-291 1-292
H
H
Ph O N
O
O N
H H
C2-substituent α X
1-293
(not formed)
129
Although stereoelectronic effects are known to play an important role in the capture of the
anomeric radicals by H-atom donor and electron deficient olefins, the conformation of the strained
bicycle[4.3.0]-system (e.g. 1-290) in the present context makes it difficult to achieve any preferential
Unstaturated precursors for the synthesis of 1-294 – 1-301 were prepared from the D-glucoside
thiocarbamtion with 1,1-thiocarbonyl diimidazole in THF or CH2Cl2 under reflux conditions, and the
results of exo-hex-5-enyl cyclization of the substrate 1-294 – 1-301 are shown in Table 1.25. The radical
cyclization was successfully carried out with oxime and hydrazone derivatives 1-294 – 1-301 with
exclusive β-orientation of the C2-substituent. The only exception is in the case of diphenylhydrazone 1-
298, which gave the only the α–anomer 1-307 in low yield (22 %) as well as reduced product 1-308 in 26%
yield (Entry 7). The modest selectivity in the anomeric hydrogen (α-anomers are preferred) of hydrzone 1-
297 and 1-298 can be explained by steric effect. If we doubled the hydrogen source and radical initiator
AIBN (i.e. 10.0 equivalents of Ph3SnH and 1.0 equivalent of AIBN, the concentration of Ph3SnH was
0.126M in benzene), the formation of the reduced product 1-308 increased up to 62% without significant
changing of the yield of 1-307 (Entry8). Oxime-based radical acceptors, O-methyloxime (1-295) and O-
benzyloxime (1-296) are efficient radical acceptors in the 5-exo radical cyclization to make N-furanosides.
Moreover, the E and Z isomers of 1-296 were separated relatively easily by column chromatography, and
we could study more precisely the role of oxime-configuration in stereochemical control via radical
cyclization (Entry 4 and 5). As the results of an EWG substituted olefins (Table 1.24 and Entry 1 and 2 in
Table 1.25), the configuration of oxime did not have any effect in terms of stereochemical control of C2 of
N-furanoside 1-305 in spite of lower yield of cyclized product with the E substrate. Although O-
methyloxime substituted precursor 1-295 gave a slightly better yield than O-benzyloxime substituted
precursor 1-296, the formation of 1-304 as a byproduct is the major drawback of the radical acceptor in the
130
Ph O O Im Ph O O Im Ph O O Im O
O Ph O Im
O O O
S
S S S
CN NOCH3 N
NC OBn
(E)-1-294 (Z)-1-294 1-295 (E)-1-296
Ph O O Im Ph O O Im Ph O O Im
O O O
S S S
N NN(CH3)2 NNPh2
BnO
(Z)-1-296 1-297 1-298
O Ph O O Im O
Ph O Im Ph O Im
O O O
S S S
N N NNHTs
N
Ph
1-299 1-300 1-301
O Ph O Ph O OH Ph O
Ph O O
O O O O
O
Im H3COHN Im BnOHN Im
NC NOCH3
H H H H H H
Ph O Ph O Ph O Ph O OH
O O O O
O O O
(H3C)2NHN Im Ph2NHN H Ph2NHN
N
H H H Im H
1-306 1-307 1-308 1-309
131
Ph O O Im Ph O Ph O Ph O OH
O O + O + O
O O
Y X Im Y X Im
S
X H H X
Y H H H H Y
1.0/0.76p
1.0/0.68 p
1.0/0.32 p
Continued
Table 1. 25. A Variety of 5-Exo trig Radical Cyclization with 5(R)-Hydroxy-2(R)-phenyl-[1, 3]dioxane-
4(R)-carbaldehyde Derivatives
132
Table 1. 25. continued
a. 0.038M Substrate in benzene, 0.063M Ph3SnH in benzene, 25 µL/min via a syringe pump
b. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump
c. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump
d. 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 29 µL/min via a syringe pump
e. 0.047M Substrate in benzene, 0.064M Ph3SnH in benzene, 25 µL/min via a syringe pump
f 0.046M Substrate in benzene, 0.063M Ph3SnH in benzene, 21 µL/min via a syringe pump
g. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 28 µL/min via a syringe pump
h. 0.047M Substrate in benzene, 0.126M Ph3SnH in benzene, 22 µL/min via a syringe pump
i. 0.047M Substrate in benzene, 0.063M Ph3SnH in benzene, 26 µL/min via a syringe pump
j. 0.035M Substrate in benzene, 0.063M Ph3SnH in benzene, 24 µL/min via a syringe pump
k. 0.009M Substrate in benzene, 0.063M Ph3SnH in benzene, 112 µL/min via a syringe pump
l. All reagents were added together and heated at 90 oC for 3 h. 0.011M based on substrate and
0.053M Ph3SnH in toluene.
m. All reagents were added together and heated at 90 oC for 2 h. 0.010M based on substrate and
0.050M Ph3SnH in benzene.
n. All reagents were added together and heated at 90 oC for 6 h. 0.020M based on substrate and
0.100M Ph3SnH in benzene.
o The ratio was determined after column chromatography.
p. The ratio was determined by 1H NMR before column chromatography.
q. All starting materials decomposed.
133
Nitrile has been known as an excellent radical acceptor in some radical mediated cyclizations, and
the product will be, after hydrolysis, a ketone. The carbohydrate based nitrile 1-299 was made efficiently
from D-glucose in 5 steps by using the chemoselective transformation of oxime to nitriles, which was
developed in this Lab. Unfortunately, the nitriles in the sysnthesis of N-furanoside via radical cyclizaiton
were not effective radical acceptors. The only product from the reaction mixture was 1-309 in 50% yield.
substrates (1-300 and 1-301, respectively) for the 5-exo radical cyclization. Unfortunately, those
hydrazones could not take part in the reaction. Because of the low solubility of tosylhydrazone deriative 1-
301 in benzene, toluene, or acetonitrile, we could not use the revesed addition procedue, which was
developed for this type of reactions in our laboratory. Thus all reactants (substrate 1-301, triphenyltin
hydride, and AIBN) were mixed in one-pot and heated at 90 oC for 2-6 h. Although all starting materials
were consumed (TLC), we could not isolate any desired product. The azridine derivative 1-300 was also
Tris(trimethylsilyl)silane (TTMSH) has been used as an altenative for tin-based hydrides in radical
reaction with a variety of substrates. Especially, Curran and his associate found that cascade radical
(TTMSH) gave better resuts than in the presence of tributyltin hydride or hexamethylditin. Because the
reversible addition of the TTMS radical to the thiocarboyl group give stabilized radical intermediates and
they can be cyclized to give fused quinones via 5-exo trig radical pathway, we decided to try TTMSH as
the radical/hydrogen source under our optimized reaction condition for the synthesis of N-furanosides and
pyranosides.
The substrates and products for the radical reactions are shown in Scheme 1.88, and the results for
the reaction are summarized in Table 1.26. Surpisingly, under the thermal conditions, the major poroduct
of the radical reaction with the substrate (Z)-1-296 was neither cyclized product product 1-305 nor
deoxylated product 1-311, but another deoxygenated product, which was isolated as a 28% yield. After
134
carefull investigation of the product by 1D nOe NMR and 1D COSY NMR spectroscopy, we assigned it as
an O-benzyl oxime-migration product 1-310 with a trace amount of the deoxygenated product 1-311.
Although the major portion of product 1-310 could be isolated by column chrmoatgrapy and assigned it to
syn configuration, it was in equilibrium with the anti isomer at rt to give a syn/anti mixture in a ratio of
1.0/0.15. Morover, if we doubled the concentration of the TTMSH (Entry 3), the O-benzyl oxime-
The formation of 1-310 can be rationalized by a mechanism, which has a cyclpropanyl radical
intermediate 1-319 shown in Scheme 1.89. Although it has been found the 5-exo radical cyclization (k2)
of Barton’s radical intermediate 1-317 is faster than the deoxygenatiion pathway (k1), the cyclized radical
intermediates 1-321 could be reversible. The deoxygenated radical intermediate 1-318 can be added easily
to the C=N of O-benzyl oxime to give a cyclopropy intermediate 1-319. Ring open again via k4 pathway to
N
N N N
N Ph O O N Ph O O N Ph O O N
O O O
O S S S S
TBDPSO O N NNPh2
EtO2C BnO
OEt
1-250 (Z)-1-283 (Z)-1-296 (E)-1-298
N
O Ph O O O
Ph Ph Ph O N
O O O O
OBn S
N N N NH
BnO BnO
OBn
OTBS
Ph O Ph O OH S O
O Ph
O O O
O
Figure 1.21. Substrates and Products for the Radical Reaction with TTMSH.
135
Conditions
(%)
a. 0.047M Substrate in benzene, 0.0634M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC.
b. 0.05M Based on substrate and 0.225M based on TTMSH in benzene, hυ by a sunlamp.
c. 0.047M Substrate in benzene, 0.126M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC.
d. 0.05M Based on substrate and 0.225M based on TTMSH in benzene, heated at 90 oC for 6h.
e. 0.047M Substrate in benzene, 0.064M TTMSH in benzene, 28 µL/min via a syringe pump at 90 oC.
f. 0.046M Substrate in benzene, 0.063M TTMSH in benzene, 22 µL/min via a syringe pump at 90 oC.
g. 0.046M Substrate in benzene, 0.063M TTMSH in benzene, 23 µL/min via a syringe pump at 90 oC.
h. The ratio of syn/anti
i. Trance amount of 1-311 was observed in 1H NMR spectrum after column chrmoatogarphy.
j. Recovered (Z)-1-296.
k. The ratio of cis/trans.
136
Ph O Ph O TTMSH Ph O
O TTMSH O O
O O O
BnON Im BnOHN Im BnOHN Im
H STTMS H STTMS H H
k2
k1
k1 k3
TTMSH
Ph O O Im Ph O O Im Ph O H Ph O H
O O O O
S k2 S K3 K4
N N TTMS N N
BnO BnO BnO BnO
k6 TTMSH k5 TTMSH k4
Ph O O Im O O
Ph Ph
O O O
S OBn
NH N N
BnO BnO
TTMSH
Ph O
O
OBn
1-310 N
Scheme1.68. The Propsed Mechansim for Radical Mediated 1,3-Migration of Oxime Derivative 1-196 .
Although we added all reactant in one-pot and heated it at 90 oC, the cyclized product was not
formed and still the O-benzyl oxime-migrated product 1-310 was the major product in 47% yield (Entry 4).
Interestingly, we could not find 1-310 under photolytic conditions under a sunlamp. A small amount of
reduction product 1-312 (6%) was isolated along with recovered starting material (Entry 2).
We also investigated similar reactions of substates with a different radical acceptors such as N,N-
diphenyl hydrazone and α,β-unsaturated ester. We found the hydrazone functionality of substrate (E)-1-
298 migrated in the same fashion to give 3-147 as the major product and small amount of dethiocarbonated
product 1-313 was formed as the monor product (Entry 5). However, if the α,β-unsaturated ester was
137
4.2% 0.3%
2.0%
H1 H2a 2.0%
1.8%
Ph O
O O H2b
Ph H3 0.3%
OBn O
N 0.5% 0.9%
syn-1-310 OCH2Ph
H4 N
2.6%
2.1%
H1 H2a 1.8%
Ph O 1.3%
O O H2b
Ph H3
O
N
anti-1-310 OBn
H4 N
OCH2Ph
138
compounds, (E)-1-250 and (Z)-1-283, were used as the substrates, we could not observe the nigration
product but cyclized thinolactones, 1-315 and 1-316 were isolated as the major products.
1. 4. Conclusion
McCombie reaction) can participat in an exo-hex-5-enyl or exo-hept-6-enyl type radical cyclization when a
suitable radical acceptor (e. g. α,β-unsaturated ester, oxime ether, or hydrazone) is appropriately placed.
Carbohydrate derived imidazoyl and triazoyl thiourethanes with such acceptors, upon addition to excess of
a good hydride donor (reversible addition), undego efficient cyclization reactions to give N-heterocyclic
furanosides and pyranosides. Depending on the acceptor, glycosides with either 2-amino or C2-carbon
substitutent are formed. In the exo-hept-6-enyl cyclizations, the (Z)-olefin acceptors give excellent
stereoselectivity in the generation of the C2 stereogenic center. Only altro-isomers are formed. In all cases
both α- and β-glycosides are obtained. A moderate preference for the β-anomer in the pyranoside
formation may have its origin in the anomeric stabilization of the axial radical.
1. Explored a new general synthetic methodology for the synthesis of N-furanoside and N-pyranoside
from commonly available carbohydrates via 5 or 6-exo-trig radical cyclization involving the
2. The reaction was performed under a variety of conditions, and the reaction conditions were
optimized. The optimized reaction conditions are: (i) 5 equivalents of triphenyltin hydride as a
radical source, (ii) 0.5 equivalent of AIBN as a radical initiator, and, (iii) 90 oC for the oil bath
temperature.
3. Stereochemistry and mechanisms for the 5 and 6-exo-trig radical cyclizations mediated by the
139
4. Facile synthesis of differentially protected 5,6-dihydroxy hex-2-enoates and other corresponding
Further study should focus on the application of this new methodology for the synthesis of other
140
CHAPTER 2
REACTION OF VINYLSILANES
2. 1. Introduction
bis(allenes), 77 alleneynes, 78 allene aldehydes, 79 and allene ketones79 have been studied extensively during
the last decade because the resulting compounds may allow further transformations to a variety of
functional groups, operationally simple procedure, and high catalytic turnover and regioselectivity are
maybe realized in these reactions. The scopes of catalytic tandem addition/cyclization reactions have been
widely expanded by the use of a variety of bisfunctionalization reagents such as R3Sn-SiR’3,74-79 R3Sn-
BX2,80 R3Sn-SnR’3, 77 R3SnH, 81 and numerous transition metals such as palladium, rhodium, nickel,
titanium, and ruthenium. Palladium is the most commonly used catalysts in the transition metal catalyzed
The catalytic cycle for a typical X-Y (X-Y = R3Si-SnR’3) mediated cyclizations is likely initiated
by the oxidative addition of silylstannane to Pd(0) to give Pd(II) intermediate 2-2. The terminal alkyne is
then coordinated to the palladium center (2-4). Insertion of the coordinated triple bond of alkyne to the Pd-
141
Si bond affords palladium (II) complex 2-5 with the R group anti to the SiMe3 moiety. Subsequent
reductive elimination in 2-5 gives the silylstannylated product 2-6. The Z-configuration of 2-5 is solely
R SnBu3
Me3Si SnBu3
LnPd(0) 2-1
SiMe3
2-6
R 2-5 2-2
Ln = ligand
R
2-3
Me3Si Pd SnBu3
R
2-4
The first Sn-Si bifunctionalization was reported by Chenard and Mitchell independently in 1985.82
Chenard reported that silylstannane was efficiently added to cyclohexenone via exothermic Michael
addition by catalyzed “naked” cyanide catalyst (KCN/18-Crown-6, Bu4NCN, TASCN) in high yield (Eq.
1). He also examined the silylstannylation of acetylene in the presence of catalytic tetrakis(triphenyl-
phophine)palladi-um in THF. At the slightly high temperature (65 oC) the regio- and stereoselective
silylstannylation of acetylene proceeded to yield with Sn in the internal position (Eq 2). The
regioselectivity of the silylstannylation was not affected by the bulkiness of the tin, but the yield decreased
142
O OSiMe3
"naked" CN
+ Bu3SnSiMe3 (1)
SnBu3
R1 R1
R2 R2 R2 R2
R1 = R2 = H (75%)
R1 = Me; R2 = H (77%)
R1 = H; R2 = Me (68%)
(Ph3P)4Pd R SnMe3
R C C H + Bu3SnSiMe2tBu (2)
H SiMe2
CMe3
R = Ph (93%)
R = CH3(CH2)3 (74%)
R = iPr (67%)
R = tBu (10%)
R = NC(CH2)3 (90%)
allens. He used eventually the same substrates and palladium catalyst, which Chenard used in his reaction.
As shown in Eq. 3, a number of alk-1-ynes readily underwent a clean regio- and stereoselective addition to
afford alkenes possessing vicinal sily and stannyl substituents, except for methyl propiolate which gave a
1:1 mixture of two regioisomers. The product with Sn in the internal position increased up to 90% if the
reaction was performed at low temperature (0 oC) despite the required prolonged reaction times (48 h). The
cis configuration of the product was assigned by 1H NMR spectrum, which had a large coupling constant
for the trans-coupled vinyl proton with Sn (JSn-H = 165 – 211 Hz). The corresponding number for cis-JSn-H
= 56 – 60 Hz.
Following the above reports, Chenard studied more extensively the palladium-catalyzed
silylstannylation with a variety of acetylenes, solvents, and catalysts, to define the limitation and scope of
143
the reaction.83 He found that the reaction is limited to terminal acetylenes, presumably due to steric
consideration, and bulky terminal acetylenes are reluctant to undergo the silylstannylation. The reaction
has an excellent tolerance to the most functional groups (e.g. Cl, CN, OTHP, OH, and Me3Si), but the
reactivity of vicinal sily and stannyl substituents in terms of transmetallation, halogenation, and aluminum
HO H
SmMe3
1. BuLi/TMEDA Ph
Ph SnBu3 Ph X
I2
or (4)
SiMe3 SiMe3
N-fluoro-N-norbonyl-
p-toluenesulfonamide X = I (83%)
X = F (76%)
O
SnMe3
AlCl3 Ph
The silyltin olefins might be further transformed with acid chloride to β-silyl vinyl ketone via
Stille reaction. If the olefins has a large silyl group (e.g. Et3Si or tBuMe2Si), the Stille reaction product
vicinal silane underwent Nazarov cyclization without losing the silane group in the cyclized product (Eq.
5). It is surprising because Denmark reported that β-silyl divinyl ketones may cyclize to give
O O
O
SnBu3 CCl
Cl Cl BF3 Et2O
+ Cl (5)
SiMe2 SiMe2
CMe3 Me3CMe2Si
CMe3
58% 80%
144
Ikenaga and his associate performed84 the bisfunctioanlization of terminal alkynes with (tri-
alkylstannyl)dimethylsilane (HSiMe2SnR3). The major product for the phenylactylenereaction was 1,1-
(Eq. 6).
(Ph3P)4Pd R Me R SnMe2H
R C C H + Bu3SnSiMe2H Si + (6)
R Me H SiMe3
An excellent example of silylstannylation, which was applied for total synthesis of a natural
product, was reported by Kocieński and his colleagues in 1994. 85 They used the palladium-catalyzed
silylstannylation of terminal alkynes in the synthetic approach to the C26-C32 fragment of Rapamycin, a
Kocieński used a tin-silane reagent bounded on 2-methyl furan, to react with propyne with
tetrakis(triphenylphosphine)palladium in THF solutions (Eq. 7). The expected vicinal tin-silane derivative
possessing the tin at the internal position was obtained in modest yield with excellent stereo- and
regioselectivity.
H3C SnBu3
SnBu3
SiMe2 SiMe2
H3C Pd(PPh3)4
O + H O (7)
THF, 60 oC
CH3 CH3
49%
The scope of silylstannylation of triple bonds was further expended by Mitchell,86 and the results
were reported in 1987. He investigated the addition of the Si-Sn bond to non-terminal alkynes as well as
terminal alkynes with a variety of functional groups. For example, hydroxy-, alkoxy-, amino-, and ester
145
group substituted terminal alkynes were used for the reaction. The product was obtained exclusively with
(Z)-configuration, which might be isomerized to the (E)-isomer by irradiation in the UV region. Non-
terminal alkynes were more limited than terminal alkynes in the reaction. The non-terminal alkynes with
ether functionality did not undergo the Sn-Si bond addition to the triple bonds, or if it proceeded, the yield
was very low. Ester or amide functionalities prompted the reaction to give bisfunctionalized products with
poor regioselectivity. It has to be pointed out that the tin prefers to be on the carbon with a more EWG
substitutent.
Previously, Chenard studied83 extensively the silylstannylation of terminal alkynes with a series of
for Pd(PPh3)4 and Pd(OAc)2-triisopropyl phosphite, all other transition metal catalysts did not catalyze the
reaction. Mitchell also reported the silylstannylation of 1-alkoxyalkynes was not regio- and stereoselective.
The yield was low and the Pd(PPh3)4 catalyzed-reaction required relatively high temperature (60 – 70 oC) to
Pd(OAc)2 R OEt
R C C OEt + Si Sn C C (9)
Sn Si
CN
R = H, Me rt
run Sn Si R % Yielda
n H
3 Bu3Sn SiMe3 75 (>95:5)
146
Ito and his associates reported that the silylstannylation of terminal alkynes could be carried out
very efficiently at rt by using a new active palladium catalyst Pd(OAc)2 with tert-alkylisocyanide as a
ligand.87 For example, 1-ethoxy-1-propyne underwent silylstannylation using the above palladium catalyst/
and 1,1,3,3,-tetramethylbutyl isocyanide to give syn-adduct, in which the tin was located on the β-carbon
A similar silylstannylation of 1-alkoxy 1-propyne was performed with Pd(PPh3)4 and catalytic
amount of galvinoxyl at rt.85(b) The alkoxy alkyne 2-7 reacted very easily with Me3SiSnMe3 in bezene
solution to give syn-adduct 2-8 as a single regioisomer. The regiochemistry of the Sn-Si adduct was
reversed from the above results and the tin was located at the α-carbon from the oxygen (Eq. 10).
Bu
Bu SiMe3 Bu SiMe3
Pd(PPh3)4 BuLi/TMEDA
+ Me3Si SnMe3 (10)
galvinoxyl (cat) O SnMe3 -78 to -40 oC O H
O
benzene then H2O
OBn OBn
OBn δH = 6.19 (s)
in the presence of Pd(PPh3)4. As shown in Eq.11, excellent stereo- and regioselectivity (i.e. tin was located
at the α-carbon from the sulfur) was obtained but the yield was relatively low. The reaction could be
improved by using Pd2(dba)3 and tri-2-furylphosphine in THF, and had a great tolerance to a variety of
functional groups such as tetrahydropyranyl, hydroxyl, ethyl hydroxyl, methoxy, n-propyl, and 4-
phenylaryl ester.
R R
Pd2(dba)3 SiMe3
+ Me3Si SnMe3 (11)
tri-2-furylphosphine
PhS SnMe3
SPh
147
The palladium catalyzed reaction of Me3SiSnBu3 with propiolate was initially reported by
Mitchell (see Eq. 8). The addition of Sn-Si bond to the triple bond of the propiolate gave excellent regio-
and stereoselectives in the formation of α-stannyl-β-silylacrylate in 75% yield as expected in other terminal
additive, 2-12 was obtained as the product. Because the reaction of Me3SiSnBu3 with BnEt3NCl produced
the stannyl anion (or equivalent), it was expected that the reaction would give β-tributylstannyl acrylate 2-
10. The formation of the bis-stannylated product 2-12 has not been explained clearly, but the intermediate
OMe CO2Me
2-13 2-14
% Yield of 2-30
Me3SiSnMe3 based on 2-11 based on Sn-Si
1.0 Equiv. 46 93
2.0 Equiv. 91 92
indicated that the insertion of acetylene into Pd-Sn bond (stannlypalladation; path b, Eq. 13) has lower
activation energy (by 2 kcal/mol) than the insertion of the acetylene into Pd-Si (silapalladation; path a).89
However, the thermodynamic stability of the resulting vinyl palladium species is reversed: the kinetically
favored intermediate 2-17 is less stable than 2-16 (11 kcal/mol). Because the insertion of the Pd into Sn-Si
bond may be reversible, the thermodynamically stable intermediate is formed more favorably in the
reaction.
148
R
thermodynamic Si'R3
Compared to the dilastannylation of terminal acetylene in the presence of Pd(0), addition of Sn-Si
bond into alkenes has been studied rarely even though the insertion of Si-Si or Ge-Ge into ethylene or C=C
bonds is well-known. Tsuji first explored90 the silylstannylation of C=C double bonds of a variety of
substrates such as ethylene, norbornene, and benzonornonadiene in the presence of Pd(dba)2 and
tributylphosphine or triethylphosphine in toluene at high temperature (130 oC) (Eq.13). Because of steric
congestion, 1-hexene, styrene, cyclohexene, and cyclopentene did not react under the optimized condition.
Pd(da)2 SnR23
2 1
+ R3Sn SiMe2R
SiMe2R1 up to 95% (14)
PEt3 or PBu3
toluene, 130 oC
R1 = R2 = Me SnR23
R1 = Me, R2 = Bu SiMe2R1 upto 59%
R1 = OMe, R2 = Bu
R1 = tBu, R2 = Me
R1 = tBu, R2 = Bu
Although simple alkenes gave the silylstannylation in the presence of palladium(0) catalyst with a
phospine ligand, 1,3-dienes did not undergo silylstannylation under these conditions. With an extensive
survey of transition metal catalysts, Tsuji and his associate found that Pt(CO)2(PPh3)2 can catalyze the
insertion of Sn-Si bond into the 1,3-diene to give 1,4-silylstannation products in moderate to good yields.91
149
The reaction was highly regio- and stereoselective, and the spectral data showed that the product had (E)-
R4 R13SnCH2 R5
Pt(CO)2(PPh3)2
+ R13Sn SiR22R3 (15)
100 oC R
4
CH2SiR 2R
2 3
R5
trans
R1 = Me, nBu
2
R = Me
R3 = Me, tBu, Ph
R4 = H, Me, Ph
R5 = H, Me
In a study on the addition of Me3SiSnMe3 to allenes, Mitchell found the regioselectivity of the
reaction is dependant on the reaction temperature.92 For example, the palladium catalyzed silylstannylation
of 1,1-dimethylallene with Me3SiMe3 gave a 1:1 mixture of two regioisomers in refluxing THF. The
addition of Sn-Si bond into allenes occurred mainly on the more substituted double bond of the allenes with
the tin atom attached to the end carbon and silane atom attached to the central carbon (kinetic product).
The kinetic product was further isomerized in the presence of palladium(0) at 90 oC to give thermodynamic
product as the major product with a ratio of 4:1 via 1,3-Sn migration. Shortly after the preliminary
investigation, Mitchell and his associates reported full detail of the scope and region- and stereoselectivity
of palladium catalyzed Sn-Si bond addition to allenes. The formation of the kinetic product and its
isomerization to thermodynamic product (E/Z mixture) were consistently observed with a number of
substrates.
R
85 oC
Me3Sn SiMe3
R Pd(PPh3)4 (E/Z)
+ Me3Sn SiMe3 (16)
rt R
Me3Sn SiMe3
150
In the course of palladium catalyzed hydrostannation of alkoxyallenes, Koerber found93 that the
contrast with the results reported by Mitchell. 92 The product was exclusively one regioisomer (E/Z
isomers) and the Sn-Si addition preferred less substituted double bond with the silicon attached to the
2 : 1
The most recently, Cheng reported94 highly regio- and stereoselective silylstannylation of allenes
reaction proceeds via terminal addition of the allenes (not the 1,3-Sn migration) from the opposite face of
the allene’s substituent to minimize steric congestion. The silyl group is added to the central carbon while
the stannyl group is connected to the less substituted terminal carbon of the allenes. To explain the region-
and stereoselctivity, a mechanism involving face-selective coordination of allenes to palladium center was
proposed (Scheme 2.2): Once the palladium(0) is oxidized to Pd(II) by addition of Sn-Si, the less
substituted terminal bond is coordinated favorably to the palladium center from the opposite face of the
substituent R to avoid the steric demanding. The insertion of the double bond into Si-Pd bond gives π-ally
palladium complex, which is prone to reductive elimination to afford the (E)-vinylsilane and Pd(0).
2-18 2-19
E/Z = >99
Yield = 80-99%
151
R SnR13
Me3Si SnR13
H SiMe3 Pd(0)
2-19
SiMe3
R Pd Me3Si Pd SnR13
SnR13
S
2-21
Me3Si Pd SnR13 R
H H
2-18
R H
2-20
cyclization of 1,6-diynes assisted by trialkylsilyltrialkyltin reagents and Pd(0) catalyst with phosphine
reaction proceed in good yield with a great tolerance with a variety of functional group such as ethers,
Me3SiSnBu3 -40 oC
(19)
Pd2(dba)3 CHCl3
PR3 Me3Si SnBu3 MeSi SnBu3
The cyclized 1,4-disubstituted 1,3-diene with (Z, Z) configuration is a non-planar, helically chiral
structure because of the sterically demanding silicon and tin substitutents. The structure, stereochemistry,
and the fluxional nature of the compounds were unambiguously determined by NMR spectroscopy. VT
(various temperature) NMR studies have shown that the (Z, Z)-1,2-bis-alkylidenecyclopentane is highly
fluxional at 20 oC but is frozen at below -40 oC. The postulated reaction mechanism for the reaction
involves a typical Pd(0)-Pd(II) catalytic cycle (see Scheme 2.1). The reaction is initiated by oxidative
152
addition of Pd(0) into R3SnSiR’3. A successive coordination of the palladium complex to the diyne, cis-
silapalladation, cis-carbametallation, and reductive elimination gives silystanyl carbocycle and regenerate
the Pd(0).
2-22
X M Y
cis addition
2-23
cis-
X Y X carbametallation
Y
2-25 Y
M(0) M X
reductive
elimin. with retention 2-24
X-Y = R3SnSiR'3
distannylation. The trans stereochemistry of the same silylstannlylated dienes was unambiguously
determined by the large coupling constant (J = 13.3 Hz) at the ring junction, while derivatives of the cis-
distannylated compound were synthesized to determine the cis chemistry. The origin of the reversal of
stereochemistry of the carbocycles has not been fully explained, but one of the possible explanations lies in
the large steric congestion of the trimethylsilyl group due to shorter bond length of Si-C vis-á-vis the longer
Sn-C bond.
SiMe3 SnBu3
H H
Bu3SnSiMe3 Bu3SnSnBu3
TsN TsN TsN (20)
Pd(PPh3)4 Pd(PPh3)4
H H
SnBu3 SnBu3
153
Mori and his associates studied the palladium catalyzed tandem bifunctionalization/cyclization of
enynes with Me3SiSnBu3.74(a) Because the insertion of Sn-Si bond into alkynes is faster than the insertion
into alkenes, the silylstannylation (cis addition) occurs exclusively at the triple bond to give cis-adduct, in
which the silanes are connected at the end carbon of the alkynes. Carbametalation followed by reductive
elimination afford the cyclized product 2-27 with small amount of 2-28. He surveyed a long list of
palladium catalysts to optimize the enyne cyclization and the best results were obtained by using Pd(OH)2
on charcoal (Pearlman’s catalyst). The reaction of enyne, which has an EWG substituted alkenes, gave the
cyclized product in moderate yield while methyl substituted alkynes did not proceed in the catalytic
reaction.
palladium(0) and palladium(II), and he got the eventually same results as Mori.
Me3Si SiMe3
Bu3Sn
Bu3Sn
Pd(OH)2/C
+ Me3SiSnBu3 + (21)
THF, rt
EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et
yield (%)
entry catalyst temp 2-27 2-28
1 Pd(PPh3)4 50 oC 14 80
2 PdCl2(PPh3)2 reflux 7 48
3 Pd(OAc)2dppb reflux 20 34
4 Pd(COD)Cl4 rt 30
5 PdCl2 rt 42
6 Pd2(dba)3 rt 63
7 Pd/C rt 86
8 Pd(OH)2/C rt 90
The most important drawback of the cyclization of 1,6-diynes and bis(allenes) aided by
154
unsymmetrical substrates (Eq. 22).78 For example, the proline-derived diyne gave a 1:1 mixture of
regioisomeric products, which are inseparable by column chromatography. To circumvent this problem,
RajanBabu explored the silanstannylation of alleneynes, in which the allene and acetylene have different
N Pd2(dba)3/(C6F5)3P N
+ SnBu3 SiMe3 (22)
C6D6/60 oC
H H
Y
X
X = Me3Si; Y = Bu3Sn
X = Bu3Sn; Y = Me3Si
SnPh
Pd2(dba)3
E E
(C6F5)3P SiMe2tBu
E E
Ph3SnSiMe2tBu
2-29 rt, 17h 2-30
(>95%)
Bu3SnSiMe3
Pd(0), rt, 12h
SnBu3 X
Pd(0)
E 45 oC, 48h E
SiMe3
E E Y
(>95%)
alkylidenecyclopentanes via the addition of Sn-Si to the allenes. As shown in the silylstannylation of
allenes (see Eq. 18 and Scheme 2.2), the silyl group of the bifunctional reagents is added to the central
155
carbon while the stannyl group is connected to the less substituted terminal carbon of the allenes 2-30. This
intermediates can be isolated in some cases. The bisfuctionalized adducts can further cyclize to
cyclopentane in the presence of a Pd(0) catalyst via cis-carbametallation and reductive elimination (Scheme
2.5). A mechanism that would account for the observed results was proposed, which involves a typical
Si
E E
Pd(0)
E Sn
E
2-38 2-29
Sn + Si Sn
E
Si H
E
Si 2-39
E H
E 2-39 Sn Pd Si H
E
E Pd 2-34
Sn
2-36
E
H Si
Pd
E Sn
2-35
The most recent endeavor in the palladium catalyzed regio- and stereoselective tandem
aldehydes and allene ketones (Eq. 23).79 To find the optimum condition for both silylstannylation and
carbonyl-allyl addition, a variety of palladium and platinum catalysts were investigated. Although the
tandem reaction proceed in the presence of Pd(PPh3)4 in moderate yield, the best catalyst for this reaction is
(π-allyl)2Pd2Cl2.
156
SiMe3
SiMe3 H
(π-allyl)2Pd2Cl2 SnBu3 (π-allyl)2Pd2Cl2
X X
X (23)
O Bu3SnSiMe3 O
n n n OH
R R R
Although several bifunctionalization of alkynes, alkenes, and allenes and tandem silylstannylation/
silylstannylation is currently at an early stage, and there is a still room for further research. In this chapter
we will discuss more details of silylstannylation of symmetric diynes, alleneyne, and bis(allenes) as well as
Transition metal catalyzed synthesis of carbocyclic and heterocyclic compounds from olefinic and
acetylenic precursors is one of the most topical areas in organic chemistry. The catalytic method may be
used to cyclize a variety of substrates including dienes, diynes, bis(allenes), eneynes,, eneallenes, and
alleneynes by addition of bisfuctional reagents (X-Y) such as R3Si-SiR’3, R3Sn-Sn-R’3, R3Si-BR’2, R3Sn-
BR’2 as well as more traditional trialkyltin- and trialkylsilane-hydrides. The importances of R3Si-SnR3’ as
the bisfuctional reagents in carbocyclization have been steadily increasing because of the operationally
simple procedures, high catalytic turnover, and exceptionally good functional group tolerance. In addition
two different functional groups at the end of the cyclized products provide other opportunities for further
elaboration. Although these methodologies have a great regio- and stereoselectivities, no studies on
enantioselective silylstannylation have not been explored yet. Therefore, we decided to study the cycliztion
of alleneynes (2-40) with bifunction reagent, R3SnSiR’3 (2-41), in the presence of Pd(0)/Pd(II) and chiral
157
SnR3
The preliminary results on the asymmetric silylstannylation of alleneynes are summarized in Table
2.1. Initially we repeated the bisfunctionalization of the allenynes 2-40 with the non-chiral phosphine, tris-
previously to make a racemic mixture of 2-42 and 2-43 in 84% (>99% based on 1H NMR) and 71% (>95%
based on 1H NMR) yield, respectively. The cyclization of alleneynes was very clean and the isolated yield
of the product was similar or slightly better than previously reported by Shin. Once we have the cyclized
product 2-42 as a 1:1 racemic form, we extensively investigated ways to separate the racemic mixture.
Such endeavors included high performance column chromatography (HPLC) with OJ, OH, and OD
column, gas chromatography with chiral column, and chemical shift reagents such as Eu(hfc)3, Yb(hfc)3,
and Pr(hfc)3 for NMR spectroscopy. Although we failed to separate the racemic mixture by
chromatography (GC and HPLC), we were pleased to find that 1H NMR spectroscopy was useful when
The initial asymmetric silystannylations of the allenynes 2-40 were performed with a chiral phosphine
ligand 2-46 in the presence of Pd2(dba)3•CHCl3 at rt to give a cyclized product 2-42 in 76% yield (>93% by
1
H NMR). The enantiomeric excess (ee) of the mixture was 0-2% based on the 1H NMR spectrum with
chemical shift reagent Eu(hfc)3, which is known to come down-field shift of protons (entry 8) [The limits
of detection by this methods is no better than ∆ (±5%) ee]. To improve the ee and the yield we screened
common solvents for the reaction (Entry 1 and Entry 3 - Entry 7). Among the large number of solvents,
only benzene (or C6D6) gave appreciable reaction. If the reaction was performed at rt to 80 oC with the
same ligand (2-46), the ee increased to approximately to 8%, but isolated yield went down to 53% in spite
of high NMR yield (>95%) (Entry 9). Next, we examined the asymmetric induction with one of the most
158
well-known chiral phosphine ligands (R)-BINAP, 2-47, in the presence of Pd2(dba)3•CHCl3 at rt (Entry 10).
Although the reaction was very sluggish, the isolated yield is reasonably good yield (76%, >95% by NMR)
but the ee was still very low (~2%). To accelerate the rate of the reaction, temperature was increased to 45
o
C, but the reaction was still very slow (Entry 11). Even at temperature as high as 80 oC, the reaction was
not complete. Another chiral phophine ligand 2-48 was used for the asymmetric silastannylation of 2-40 in
the presence of Pd(0). Unfortunately, there was no reaction at rt and most starting material was recovered
(Entry 13).
Ph2P
PPh2
(C6F5)3P PPh2
N
PPh2
O OtBu
Eu Yb Pr
O O O
3 3 3
Figure 2. 1. Phosphine Ligands and Chemical Shift Reagents Used in Silylstannylation Stidies.
159
Conditions Yield (%)a eeb
11 Pd2(dba)3•CHCl3 2-47 45 oC 4d d
77 (>92) 4
17 PdCl2(PhCN)2 2-46 45 oC 3d 60 2
Continued
160
Table 2. 1. continued
phenylallyl)Cl]2
(37)
161
RajanBabu and Shin had reported that the palladium source was not critical in the silylstannylation
of allenynes but recognized definite trend in the reactivity, when used in conjunction with achiral
Keeping this in mind we extensively investigated a long list of palladium catalysts to maximize the
enatiomeric excess. Because Pd(II) is known as slightly better catalysts than Pd(0) in silastannylation of
allenynes, we chose PdCl2(PhCN)2 with chiral phosphine ligands 2-46 for the next transition metal catalyst.
As shown in Shin’s thesis, the R3Si-SnR’3 mediated cyclization proceeded very cleanly monitored by 1H
NMR spectrum of the reaction mixture. But the ee was not improved (Entry 14). Unfortunately,
alternative solvents (CD3CN or acetone-d6) and lower temperature (45 oC) did not affect the intramolecular
A control experiment, achiral phosphine ligand 2-45 was used as a reagent in the tandem
the previous results, Pd(II) catalysts were less effective than Pd(0) in the cycliztion except for
PdCl2(PhCN)2 (Table 2.1). Gratifyingly, we found that Pd(NH3)2(NO2)2 gave the best catalysts in the
control experiments. The crude reaction mixture of the cyclization was very clean and no other byproducts
were observed by 1H NMR analysis. After column chromatography, the isolated yield was 88% (>99%
based on 1H NMR), which is much higher than results with the best previous Pd-sources, Pd2(dba)3•CHCl3
and PdCl2(PhCN)2. Once we optimized the catalyst, we screened more elaborate BINAP-derived phospine
ligands for the bis-metallative cyclization with Ph3Sn-SiMe2tBu (Entry 26 – 30). Through the entries
prolonged reaction time and high reaction temperature caused decreased the isolated yield of the product 2-
42. The best ee achieved was only 8% by using a chiral posphine ligand 2-51 (Entry 30). No further
162
2. 3. Bromination of Silylstannanes
It has been reported that tin-halogen exchange on a vinyl moiety can be easily achieved by
treatment of the proper substrate with iodine or N-bromosuccinimide (NBS) in dichloromethane. While the
vinyl bromines are relatively stable at rt in the light, the vinyl iodines are light sensitive and decompose
alleneynes mediated by R3Si-SnR’3, the derivatization of the silylstannane adduct was required. First we
performed the tin-halogen exchange reaction with the racemic mixture of cyclic product 2-42 (or 2-44) and
EtO2C EtO2C
SiR'3 CH2Cl2 SiR'3
+ NBS (25)
SnR3 rt Br
EtO2C EtO2C
The transformation was quantitative (no other product was observed by TLC analysis except for
succinimide) and 92% and 89% of the halogenated vinyl silanes 2-55 and 2-56 were isolated by column
chromatography as a 1:1 racmic mixture. With the racemic mixture in our hands, we evaluated a number
of techniques to easily separate them. For example, HPLC with chiral columns (OJ, OH, and OD column),
GC with chiral columns, and lanthanide chemical shifting reagent such as Eu(hfc)3, Yb(hfc)3, and Pr(hfc)3
describe in the above section, asymmetric tandem bis-functionalization /cyclization of allenynes 2-40 was
performed with chiral phospine lignads in the presence of palladium(0) such as Pd2(dba)3•CHCl3 or
Pd(NH3)2(NO2)2. The isolated cyclic vinyl stannanelysilane 2-42 was brominated by NBS in
163
Condition Yield (%)a ee (%)
SnBu3 has been reported by Kang and his associates. The carbocyclization reaction proceeds via
silylstannylation and distannylation of bis(allenes) to form five-membered ring the presence of palladium
catalysts. The best results for the cyclization was achieved by using Pd(PPh3)4 in THF even though some
Pd(II) catalyst like [(π-allyl)2PdCl]2 could be used in the reaction. It has to point out that the
stereochemistry of the fused cyclic ring formed via silastannylation is trans while that formed via
distannylation is cis. Kepping this in mind we decided to perform a similar reaction with another tin-silane
reagent Ph3Sn-SiMe2tBu and a chiral phosphine ligand in the presence of palladium catalyst (Eq. 25).
164
EtO2C EtO2C EtO2C
Pd(0) or Pd(II) SiMe2tBu H
+ Ph3Sn SiMe2tBu + (26)
ligand SnPh3 SnPh3
EtO2C EtO2C EtO2C
2.3. First, the silylstannylation was investigated by using palladium(II) catalyst without any phosphine
ligand at rt. The reaction proceeded very smoothly to afford trans-fused cyclic ring 2-58 in 63% yield
(>95% yield based on 1H NMR) after column chromatography (Entry 1). The stereochemistry of the
cyclized product was unambiguously determined by the coupling constant between the two-fused
hydrogens (J = 15.6Hz). If phosphine ligand 2-46 (0.1 equivalent) was added to the reaction mixture, the
reaction was sluggish at rt; but was completed by heating at 80 oC to afford the cyclized product. Although
the 1H NMR spectrum of the crude mixture was a little complex, it was obvious that all starting material 2-
57 was consumed and the yield of the cyclizd product 2-58 was more than 90%. After column
chromatography, the crude mixture was isolated in 54% yield (Entry 2). Surprisingly, when (R)-BINAP 2-
47 was used as the phosphine ligand at 80 oC, we obtained not only the cyclic compound 2-58, but also
unexpected cyclized product 2-59 as the minor product (11% yield based on the 1H NMR analysis) (Entry
3). Although the formation of 2-59 has not been explained thoroughly at the present time, we decided to do
further investigation of the cyclization in the presence of another palladium(0) catalyst such as
Pd(NH3)2(NO2)2 or Pd2(dba)3•CHCl3. As observed in the previous experiments, the formation of the cyclic
products was dependent on the chiral phophine ligands added to the reaction mixture. Bis-functonalized
product 2-58 was isolated as the major product with chiral phosipine ligands: the only chiral phosphine
ligands derived from (R)-BINAP leads to the formation of 2-59 (see Table 2.3).
165
Condition Yield (%)a
1 [Pd(allyl)Cl]2 NO rt 30 63 (>95)
(R3Si-SnR3’) in the presence of Pd(0) to give novel, helically chiral 1, 2-dialkylidenecyclopentanes with
uncommon(Z, Z)-geometry at the double bonds. To investigate detail Diels-Alder reactions of vinyl silanes
duplicated the RajanBabu’s protocol for the cyclizattion of 1, 6-diynes with trialkylsilyltrialkystannanes
EtO2C EtO2C
Pd(0) SiR'
+ RSn SiR'
(C6F5)3P SnR
EtO2C EtO2C
Pd(0) SiR'
TsN + RSn SiR' TsN
(C6F5)3P SnR
166
(R3Si-SnR3’) in the presence of Pd(0) (Table 2. 4). As previously reported by RajanBabu and his students,
the cyclized product 2-62 was prepared in 66% yield. We also performed the silastannylation with a
bulkier tin-silane reagent 2-63, which has not been used in bisfunctionalization of diynes catalyzed by
palladium catalysts (Entry 2 and 3). Moreover, nitrogen substituted diene 2-61 gave the carbocyclic
Warren reported in her dissertation that the isolated yield of the 1, 2-dialkylidenecyclopentanes
decreases with increasing the bulkiness of the trialkylsilyltrialkystannanes (R3Si-SnR3’) even at the high
temperatures. Therefore, it is natural we expect the lower yield from the reaction. First, we ran a small
scale reaction in C6D6 at 80 oC. Although all staring materials were consumed within 6 h, we only obtained
24% of the cyclized product 2-63 in keeping with our expectation (Entry 2). We were pleased that the
isolated yield of the cyclized product increased up to 44% in the large scale reaction at 60 oC, but run for
longer periods.
2. 6. Destannylation of Csp2-Stannanes
acid (CSA) or p-toluenesulfonic acid (pTsOH) were previously used. Unfortunately, those acids were not
167
practical reagents for the hydrolysis of 2-62 because the procedure led to very low isolated yields of the
products. Alternatively we may use tin-lithium exchange by methyllithium in THF, followed by quenching
with ammonium chloride at 0 oC, but the yield was not improved in this case either. However, Shin found
that excess amount of carboxylic acid (5.0 equivalents), especially formic acid (HCO2H), could be used for
the selective synthesis of vinly Csp2-stannanes, 2-70. We investigated the scope of the reaction with a broad
EtO2C EtO2C
SiR' HCO2H SiR'
(28)
SnR CH2Cl2/rt
EtO2C EtO2C
afford the corresponding destannylated products in excellent yields. Because the ethyl esters of the 1, 2-
bis-dialkylidenecyclopentanes could also be hydrolyzed under the acidic conditions, excess formic acid or
longer reaction times were unfavorable for this transformation (Entry 1). The hydrolysis of the vinly Csp2-
stannanes was independent on the size of the stannanes, depended on the size of the vinyl silanes (Table
2.5) even though there are some exception. Because the substrates do not have acid sensitive functional
group, dialkylidenecyclopentanes involving nitrogen were more efficiently hydrolyzed under the acidic
condition (Eq. 28), and two excellent examples for the hydrolysis are in the Table 2.5 (Entry 9 and 10).
168
The destannylated products have to be kept in a refrigerator because they are prone to polymerization
A preliminary study of Diels-Alder reactions of silylstannyl diene 2-77 with a dienophile, maleic
anhydride 2-78, has been investigated by Warren and Shin. Although the maleic anhydride has been
reported as an excellent dienophiles in Diels-Alder reactions, Warren failed to obtain the corresponding
polycyclic product 2-79, probably due to severe steric hindrance of the diene (Eq. 30). She explained that
the silylstannyl dienes 2-77 behaves as two independent alkenes rather than a conjugated diene because it is
169
SiMe3
O O
CDCl3
SiMe3
MeO2C
SnBu3
+ O X MeO2C O (30)
rt
O O
SnBu3
2-77 2-78 2-79
Even though the silylstannyl dienes themselves do not take part in Diels-Alder reactions, the
removal of the bulky SnBu3 restores this reactivity because the 1, 3-diene is expected to have a near planar
geometry, to which the dienophiles may access more easily. Shin and Warren studied the Diels-Alder
reaction with the destannylated dienes 2-67 or 2-75 and an excellent dienophile, maleic anhydride 2-78.
The reaction proceeded very smoothly at rt or 60 oC to afford the expected polycyclic products 2-80 or 2-81
in an excellent yield. The configuration of the products was unambiguously determined by HMQC and
HMBC and the relative stereochemistry was based on the mechanism of endo transition state upon
SiMe3
O O
EtO2C CDCl3 EtO2C
SiMe3
+ O O
rt
EtO2C EtO2C
96% O
O
(31)
SiMe3
O O
SiMe3 CDCl3
TsN + O TsN O
rt
>99%
O O
On the other hand the Diels-Alder reaction of a simple vinylsilane 2-82 with methyl propiolate or
methyl acrylate has been studied independently by two research groups. However, the regioselectivity of
the cyclized product was very poor and yield of the products was relatively low. The preference of ortho- /
170
meta-substituted product is controlled by its intrinsic steric as well as electronic properties of the
trimethylsilyl group.
CO2CH3
+ + (32)
or ∆
CO2CH3
CO2CH3 CO2CH3
SiMe3 SiMe3 SiMe3
SiR
EtO2C X EtO2C
SiR Diels-Alder Reaction
+
EtO2C EtO2C X
H
2-67: R = Me3 2-85 Carbocyclic and heterocyclic (33)
2-68: R = Me2Ph compounds
SiR
X
SiR Diels-Alder Reaction
TsN + TsN
X
H
Although there is plenty of room for the investigation of regioselectivity controlled by steric
effects in the Diels-Alder reactions of vinylsilane dienes, only limited numbers of reference are available in
171
the literature. Thus, we decided to explore details of the regioselectivity of the Diels-Alder reaction with
vinylsilanes, 2-67, 2-68, and 2-75, which may be used for the synthesis of a variety of carbo- and
Me3Si Me3Si
EtO2C EtO2C
CO2Et H
EtO2C EtO2C
H CO2Et
(endo)-2-89 (exo)-2-89
Me3Si Me3Si
H CO2Et
EtO2C EtO2C
CO2Et H
EtO2C EtO2C
(endo)-2-90 (exo)-2-90
The representative results are shown in Table 2.6. To optimize the reaction conditions for the
Diels-Alder reaction of vinylsilane 2-67 we chose ethyl acrylate 2-87 as the dienophile, and performed the
reaction under various conditions. First, we carried out the reaction at a variety of temperatures with fixed
equivalents of the dienophile 2-87 (1.5 equivalents) and solvent (benzene). The reaction mixture was
analyzed by gas chromatography and identity of each peak was confirmed by high resolution mass
spectrometry. The reaction was very clear and the GC analysis implied there are no other products, except
for the starting material, and the expected cyclic products 2-89 and 2-90. With increasing of the reaction
temperature, the reaction rate increased, and most starting material was consumed within 24 h under
172
SiMe3 SiMe3
EtO2C CO2Et EtO2C EtO2C CO2Et
SiMe3
+ + (34)
EtO2C EtO2C CO2Et EtO2C
Condition
173
refluxing condition in xylene (140 oC) (Entry 5). Based on the GC and HRMS analysis of the product(s)
we found three regio- and stereoisomers of cyclic compound (2-89 and 2-90) resulted by in a ratio of
When we used higher boiling solvents such as toluene or xylene, the reaction proceeded faster
than in benzene and the portion of endo-2-90 and exo-2-89 increased. We also examined the reaction with
3.0 equivalents and 5.0 equivalents of ethyl acrylate, and the reaction required shorter reaction time with
increasing concentration of the dienophiles. The reaction was independent on solvents even though
prolonged reaction time was required with lower boiling point solvent. To consume completely the starting
vinylsilane diene 2-67, the reaction mixture had to be heated under xylene refluxing condition.
The vinylsilanes involving tosylamine were also subject to the regioselective Diels-Alder reaction under the
similar reaction condition (Table 2-7). The reaction was much slower than that of 2-67, but could be
completed without any byproduct formation at the prolonged reaction time (Entry 2). Gratifyingly, the GC
analysis implied that the cyclic product was an only mixture of endo-2-91 and endo-2-92.
SiMe3 SiMe3
CO2Et CO2Et
SiMe3
TsN + TsN + TsN (35)
CO2Et
Condition
174
2. 8. Regioselective Diels-Alder Reaction of Vinyl Silanes with Various Dienophines
After optimization of the reaction condition for the Diels-Alder reaction of vinylsilane dienes with
ethyl acrylate, we performed the reaction with other dienophiles, and the results are shown in Table 2.8.
When a substituted olefin with an electron withdrawing group (EWG) were used in the reaction as the
dienphiles, the vinylsilane dienes 2-67 took part in the Diels-Alder reaction to afford fused carbocyclic
products in excellent yield. However, if the substituent was an electron-donating group (EDG), the
reaction failed even after exposure to prolonged reaction times. Most cases the cyclized products were
isolated by column chromatography as a mixture of 2-93 and 2-94, and the ratio was determined before or
determined by nOe experiment while some of them are assigned tentatively. The representative results for
the nOe experiments for 2-89 and 2-90 are shown in Figures 2.3 and 2.4, respectively. For example, strong
enhancement of SiMe3 and H4a peaks was observed by irradiation of H2 and and H3, respectively, which is
greatly agreement with the endo- and cis-configuration at C2-C3. However, an interpretation of 1H NMR
spectrum of an inseparable mixture of 2-89 and 2-90 is difficult. Gratifyingly, the results of nOe
experiment supports that the major product is 2-89 in reaction shown in Eq. 34. The reaction appears to be
A more sterically demanding vinylsilane diene 2-68 was subjected to the Diels-Alder reaction with
an EWG-substituted olefins (Eq. 37). The reaction was performed under the optimized reaction conditions
to give the corresponding carbocyclic products. The results of reactions are summarized in Table 2.10 and
the corresponding products are shown in Figure 2.6. Based on the analysis of GC and TLC we assume that
the reaction was very clean with consumption of all starting material. The isolated yield of the fused cyclic
product is moderate probably due to instability of the compound upon the column chromatography. While
the Diels-Alder reaction of the vinylsilane 2-68 with ethyl- and tert-butyl acrylate gave a mixture of
regioisomers (Entry 1 and 2), a single diastereomer was obtained from the reaction with dimethyl- and
diethyl fumarate (Entry 5 and 6). The configuration of the products was unambiguously assigned by
extensive nOe studies, which are summarized in Figure 2.5. The trans relationship between C1 and C2 was
175
ascertained by the irradiation of the H1 peak leading to enhancement of the O-methyl peak at C2 while
another trans-relationship between C2-C3 was confirmed by the relatively small nOe effect.
2.7%
Me3Si SiMe3
H1 3.4%
1 H2b
MeO2C 2 MeO2C
H2a
2.6% OEt
MeO2C OEt MeO2C
3
4
H4a H3 1.5%
O H4b O
2-89
1.9%
SiMe3 H1
SiMe3 H2a
H3
H6a
176
2.5%
Me3Si O Me3Si O
H6b H1 2.9%
EtO2C EtO2C
OEt OEt
1.8% H2
EtO2C EtO2C 2.0%
H
H5b H3a 3b
H4a H4b
2-90
1.9%
SiMe3 2.2%
Me3Si O
O H H
1
MeO2C 2 MeO2C
NPh NPh
MeO2C 3 MeO2C
4
O H H O
H
2-118 0.6%
1.7% 3.0%
2.5%
SiMe3 SiMe3
SiMe3
177
1.5%
1.1%
1.3%
0.9%
PhMe2Si H1 O
PhMe2Si O
H6a H6b
1 MeO2C H2
MeO2C 2
OMe
OMe
0.9%
MeO2C OMe OMe
3 MeO2C
4 J5b H3
O H5a
2-133 H4a H4b O
H1 → H2 0.7 H2 → H3 0.9
178
SiMe3 SiMe3
EtO2C X EtO2C EtO2C X
SiMe3
+ + (36)
EtO2C EtO2C X EtO2C
Condition
CO2Me
MeO2C (1.0/0.08)
Continued
179
Table 2. 8 continued
Condition
Equiv
H3C CH3
16 O
Et
3.0 toluene xylene ↑↓ 48 h NR
17 O
Ac
3.0 toluene xylene ↑↓ 3d NR
Continued
180
Table 2. 8 continued
Condition
MeO2C
H3C
H3C
Continued
181
Table 2. 8 continued
Condition
CO2H
a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis.
b. The structures (endo-2-93/endo-2-94/exo-2-93) were tentatively assigned, and the numbers in the
parenthesis was determined before column chromatography.
182
Me3Si Me3Si O Me3Si Me3Si O
O O
2-89 2-90 2-95 2-96
Me3Si Me3Si O Me3Si Me3Si O
O O
2-97 2-98 2-99 2-100
Me3Si Me3Si O Me3Si Me3Si
183
SiMe2Ph SiMe2Ph
EtO2C X EtO2C EtO2C X
SiMe2Ph
+ + (37)
EtO2C EtO2C X EtO2C
Condition
MeO2C
EtO2C
Continued
184
Table 2. 9. continued
Condition
MeO2C
MeO2C
a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis.
b. The structures (endo-2-121/endo-2-122/exo-2-122) were tentatively assigned, and the numbers in the
parenthesis was determined before column chromatography.
185
Me2PhSi Me2PhSi O Me2PhSi Me2PhSi O
EtO2C EtO2C EtO2C EtO2C
OEt OtBu
t
OEt O Bu
EtO2C EtO2C EtO2C EtO2C
O O
2-123 2-124 2-125 2-126
O O O
2-131 O 2-132 2-133 2-134
OEt
TsN TsN TsN
OEt CH3
O O
2-91 2-92 2-139
186
Finally, we choose vinylsilane diene involving nitrogen 2-75 to examine the regioselectivity of the
Diels-Alder reaction (Eq. 39). The diene reacted efficiently with an EWG substituted-α,β-unsaturated
olefins such as ethyl acrylate, methyl vinylketone, and acrylonitrile to afford the corresponding cyclic
products shown in Figure 2.8. As we have demonstrated before, the reactions required high temperature
probably refluxing in xylene, 140 oC for completion the reaction within reasonable reaction time to get
SiMe3 SiMe3
X X
SiMe3
TsN + TsN + TsN (38)
X
Condition
6c O
Et
3.0 Toluene xylene ↑↓ 24 h NR
-d8
a. The yield is isolated yield. The yield in the parenthesis is determined by GC analysis.
b. The ratio and structures (endo-2-143/endo-2-144/exo-2-143) were tentatively assigned.
c. Run the reaction in a flame-sealed NMR tube.
187
2. 9. Conclusion
sylylstannylative cyclization of diynes and allenynes with various chiral phosphine ligands and palladium
catalysts. Although chiral GC and HPLC cannot separate the racemic mixtures of the silylystanylated
cyclic products, they can be separated easily by 1H NMR spectroscopy with chemical shift reagents such as
Eu(hfc)3 or Pr(hfc)3. The best enatiomeric excess (ee) was only 8%. The bifunctionalized 1,3- and 1,4-
dienes can be bromiated with NBS in dichloromethane at rt to give the corresponding vinyl bromide in
quantitative yield. After the bromination of the silylstannylative product, the ee was less than 1%.
We have also studied destannylation of the bifunctionalized 1,3- and 1,4-dienes under acidic
conditions. The optimized reaction conditions are 5.0 equivalent of formic acid (HCO2H) in
dichloromethane at rt to give the corresponding vinyl silanes in excellent to moderate yields. The reaction
is dependant on the size of silane substituents as well as the tin substituents. For example, tributyltin can be
efficiently destannylated in excellent yield, but triphenyltin cannot be easily destannylated under our
optimized conditions.
Finally, we have explored regioselective Diels-Alder reaction of the vinylsilanes with various
dienophines to afford carbocyclic and heterocyclic compounds. The reactions were optimized with 3.0
equivalents of dienophiles, toluene as the solvent, and refluxing in xylene bath (140 oC). The Diels-Alder
reaction proceeds quantitatively with various dienophiles such as ethyl acrylates, methyl vinyl ketone, or
maleic anhydride, and the distiribution of the regioisomers is controlled by the size of the vinyl silanes.
188
CHAPTER 3
3. 1. Introduction
During the last decade a number of strategies have been reported for the construction of
spiroketals, which are commonly found core structures in many biologically active compounds such as
polyether antibiotics, marine and plant toxins, insect pheromones and antiparistic agents.95 Among those
classes of compounds, a family of Paulacandins isolated from Papularia sphaerospema consists of four
members, Paulacandin A, B, C, and D with in vitro activity against Candida albicans and other fungi.96
Generally, these compounds inhibit the enzymes involved in biosynthesis of the fungal cell wall
All the Papulacandins contain both a β-C-glucoside and an α-O-glucoside as a key structural
unit.97 The Papulacandins A, B, and C, which are structurally close to another diglycoside Saricandin
isolated from Fusarium, have a spirocyclic diglycoside linked as esters to two hydroxyl groups at C3 and C6
of a glucopyranose core. Papulacandin D is a relatively simple monosaccharide with a long chain of fatty
acid. Papulacndin D, which has a C-arylglucosyl spiroketal nucleus, has received a great deal of attention
from synthetic chemists due to the synthetic challenge involved in the construction of the novel structure
189
OH
HO OR
O OH OH
HO HO
OH O O
O OH HO OH
O O O
O OH OH
Biosynthetic pathway
O O
OH Papulacandin A R = OH
3-1
O OH Papulacandin D
Papulacandin B R = 3-2
O
3-4
Papulacandin C R = 3-3
OH
OH
HO OR
O OH OH
HO HO
OH O O
O OH HO OH
O O O
O OH OH
Biosynthetic pathway
O O
OH OH
Saricandin R = 3-5 3-6
The first efforts to synthesize Papulacandin D were reported by Danishefsky and his associates in
1987 (Eq. 1).98 They used a Lewis acid-catalyzed, hetero-Diels-Alder reaction of Danishefsky’s diene 3-7
with benzaldehyde derivative 3-8 to prepare 2,3-dihydro-4H-pyran-4-one 3-9, which was further
methoxylated aryl glycoside. It has to be pointed out that oxidation of 3-dihydro-4H-pyran-4-one 3-9 with
190
3-chloroperoxy-benzoic acid (mCPBA) in methanol gave the methoxyhydrin 3-11 having the gluco, rather
than manno, configuration at C2. Moreover, the properly placed benzyl alcohol group of methyl glycoside
BnO OBn
OSiMe3 OBz CHO OBz
OBn O Ar O Ar
O
mCPBA
+ H H OMe
MeOH
OMe OBz BzO AcO OH
OBn O O OAc
OAc
(1)
BnO OBn AcO
OH
O O
NaOH AcO
OMe O
MeOH
HO OH OBz AcO OAc
OH OAc
3-12 3-13
Beau and his associates reported99 palladium(0) catalyzed coupling reaction of stannane-
substituted olefin 3-14 with protected benzyl alcohol 3-15 to give the C-arylated glycal 3-16, which might
spiroketalization sequence. The stereoselective epoxiation of the olefin in 3-16 may be achieved by
mCPBA at low temperature to afford two isomers 3-17 and 3-18 with the D-gluco configuration, but
hydroboration-oxidation of 1-C-arylated glycal 3-16 did not provide the desired spiroketal 3-17. The
protected spiroketal 3-17 was subjected to a double deprotection- protection sequence to give the core
structure of Papulacandin D, 3-19. They failed to convert undesired spiroketal 3-18 to the desired
spiroketal 3-17 by acid –catalyzed isomerization. During the deprotection of benzyl group in 3-17 and 3-
18, epimerization at the spiro center of 3-18 proceeds spontaneously to give the desired β-configuration. To
isolate efficiently the 1-C-arylated glycal, all hydroxyl groups have to be protected by Ac2O/pyr before
column chromatography.
191
OH Br
BnO
OBn Pd(0) Ph O
O O mCPBA
Ph O
O O +
SnBu3 Na2CO3 TBSO OBn
TBSO
OBn HO
3-14 3-15 3-16 (2)
Ph O AcO
BnO O AcO
Ph O O O
O O AcO OAc
O TMSO (1) TBAF AcO
OBn HO
TMSO + AcO
HO BnO (2) H2, Pd/C O
O
(3) Ac2O/Pyr
OBn
3-17 3-18 3-19
Friesen also used the palladium catalyzed coupling of aryl bromide 3-21 and stannyl glucal 3-20
for the synthesis of spiroketals.100 The coupling followed by stereoselective oxidative spiroketalization of
the derived C-arylglucal 3-22 leads to the synthesis of the spiroketal nucleus of the Papulacandin. Because
the acetyl protected C-arylglucal 3-22 did not take part in oxidative spiroketalizatioon, the protecting
groups had to be removed. The completion of the synthesis of 3-25 required not only stereoselective
installation of a hydroxyl group at C2 but also oxidative ketalization. These two transformations could be
achieved simultaneously by using dimethyl dioxirane (DMDO) via stereoselective α-epoxidation at C1-C2
bond followed by rapid intra molecular cyclization. Even though the spoiroketal 3-24 has unfavorable
OAc Br BnO
TBSO
TBSO OBn TBSO O
O Pd(II)
TBSO TBSO OBn
TBSO SnBu3 +
RO
OBn
3-20 3-21 3-22: R = Ac
3-23: R = H (3)
TBSO
TBSO O BnO
O TBSO
TBSO O
DMDO HO PPTS TBSO OBn
TBSO
BnO HO
O
OBn
3-24 3-25
192
Nucleophilic additions of organometallic reagents to lactones have been well-established, but the
application to total synthesis is limited because the basic reagents may abstract the α-hydrogen as well as
undergo nucleophilic addition. Bihovsky and his associate reported101 that the addition of aryllithium 3-27
to the tetra-O-benzylgluconolactone 3-26 gave C-arylglucosyl spiroketal nucleus 3-28 via nucleophilic
addition process, but the yield was very low (14% ) due to the formation of both unfavorable spiroketal 3-
29 and elimination product 3-30. However, if O-silyl protected aryllithium 3-31 was used as the
nucleophiles in the reaction, acyclic hydroxyl ketone 3-32 was formed as the major product. Although the
acyclic product do not cyclize to C-arylglucosyl spiroketals by exposure to hydrogen in the presence of
Pd(0)/C, desilylated acyclic hydroxyl ketones gave the desired spiroketal 3-33 as the only one
diastereomer.
BnO
LiO Li BnO O
OBn MOMO BnO O
OMOM BnO
O BnO O BnO
BnO + BnO OMOM +
BnO MOMO
BnO O BnO
O
OMOM
+
3-26 3-27 3-28 OBn 3-29 OMOM
O
OTBS Li BnO
OMOM BnO O
3-30 (4)
OMOM
3-31
MOMO OMOM
BnO H2, Pd/C MOMO
HO
BnO OH O
BnO HO OMOM
HO
BnO HO
O O
OTBS
3-32 3-33
Most strategies for the synthesis of the C-arylglucosyl spiroketal of Papulacandins nucleus
involve the sugar moiety as the electrophile and the aglycon as the nucleophile, except for Danishefsky’s
approach, which utilizes a hetero-Diels-Alder reaction to install a D-glucose moiety. However, the
193
nucleophilic addition of lithiated aryl reagents to D-gluconolactone is not a viable route due to the
Schmidt used fully protected acyclic aldehyde 3-34 as the electrophile in the synthesis of C-aryl-
glucosides.102 He developed two different tactics and arylated 3-38 was used as a common intermediate.
Nucleophilic addition of lithiated aryl to 3-34 and methyl ester derivative 3-36 is better than addition to D-
An efficient new approach for the stereoselective construction of the spiroketal moiety of
Papulacandins has been reported by Carretero and his associates (Eq. 6).103 They used fully protected D-
The stereoselective formation of the 1,6-dioxaspiro[4.5]decane 3-42 was achieved by a tandem ring
opening-ring closing sequence, which was initiated by the addition of the lithiated furan to the arabino
derivative. The reduction of 3-42 stereoselectively installed a hydroxyl group at equatorial position by
hydride addition from less hindered face. The final phase of this strategy is reductive elimination of the
sulfonyl group by treatment of 3-43 with Na(Hg) in MeOH to give the desired spiroketal 3-44. Further
transformation to the core structure of the natural Papulacandins has not been performed at this stage.
194
PhO2S
O O O (1) BuLi O NaBH4
+ O t
O O
Bu
t (2) 3-41 Si
SO2Ph Bu Si O OTMS O O
t (3) LiOH, H2O t
Bu
Bu
OTMS
3-40 3-41 3-42
t
(6)
PhO2S Bu
O Si
O t
Bu O
O O Na(Hg) O O
t
Bu t
Bu O O
Si HO
Na2HPO4 Si
t O OH O OH HO
Bu t
MeOH Bu O
OTMS OTMS
3-43 3-44 3-45
Brimble reported104 that if O-lithiated benzoamides 3-46 are added to lactones 3-47 by a
nucleophilic addition process, the lactone ring may open to give a keto-alcohol like 3-48, which can be
used as a precursor of aryl spiroketals. The keto-alcohol 3-48 could be cyclized immediately to 3-49 by
exposure to catalytic amount of p-toluenesulfonic acid (p-TsOH). An alternative route for the
spiroketalization has also been developed by the same group. The intermediate phthalide 3-51 was
be achieved by iodosobenzene diacetate and iodine under a sunlamp. The photo-stimulated ring closing
process involves a sequence of single electron transfer (SET), 1,5 H-migration, one electron oxidation by
O O
O
i t i
N Pr2 BuLi N Pr2 pTsOH
+ O
OH
O O
O
O
3-47 3-49
3-46 3-48
O
O
NiPr2 pTsOH
O
OH
OH
OH
3-50 3-51
195
Parker synthesized the C-arlyglycoside nucleus of Papulacandins by utilizing aromatization of
quinoles.105 She demonstrated that nucleophilic 1,2-addition of lithiated 3-53 to highly functionalized
quinone 3-54 gave derivative 3-55, which was subjected to reductive aromatization by Na2S2O4 in THF-
H2O solution. Further transformations were very tedious: protection of hydroxyl group by benzylation,
stereoselctive epoxidation from α-face, deprotection of the benzyl ether followed by spiroketalization, and
BnO O
AcO (1) K2CO3 Si (1) nBuLi Si
O O O
AcO O O
AcO O O
(2) tBu2Si(OTf)2 TIPSO (2)
TIPSO
O OBn OH
(3) TIPSCl
3-52 3-53 BnO 3-55 OBn
BF3 OEt2
(9)
O
3-54
Si TIPSO
BnO OBn O
(1) Na2S2O4 Si (1) mCPBA O
O O OTIPS
O O TIPSO
(2) BnBr (2) H2/Pd(C)
TIPSO HO
(3) TIPSCl O
OBn
3-56 3-57
derived from 3-58 by olefinatioon with unstabilized Wittig reagents gave 3-59, which was further subjected
to Achmatowicz oxidation for ring expansion and acid catalyzed spiroketalization to afford 3-60 (Eq.10).
Subsequently, Luche reduction and dihydroxylation was used to install hydroxyl groups at C4 and C2-C3
double bond, respectively, to give diastereomic mixtures of 3-62 with a ratio of 3:1. These could be
seperated by column chromatography. Because the configuration at C2 is reversed from the desired
equatorial position, a sequence of Dess-Martin oxidation, deprotection of pivaloyl ether, and stereoselective
196
OMe OMe OPiv OPiv
O (1) O MeO
O Ph3P CH2 NBS
O O
OMe
H (2) ADmix-α OH the 1M HCl
MeO OTBS MeO OTBS
(3) PivCl O
3-58 3-59 3-60
OPiv OPiv
MeO MeO
HO
(1) NaBH4 TBSO O OsO4 TBSO O (1) TBSCl
OMe OMe
HO (10)
(2) TBSCl (2) Dess-Martin
O O
3-61 3-62
OPiv OH
MeO MeO
TBSO O TBSO O
OMe (1) Dibal-H OMe
TBSO TBSO
O (2) LiAlH4 HO
O O
3-63 3-64
The first transition metal catalyzed alkyne cyclotrimerization for C-aryglycoside synthesis was
reported by McDonald in 1995 (Eq. 11).107 Fully protected D- gluconolactone 3-65 was subjected to
were further transformed to mixture of 3-66 by exposure to acetic anhydride/pyridine. The C-alkynyl-O-
propargyl substrate 3-67 was obtained by Lewis acid-catalyzed glycosylation of the anomeric acetate with
O-propargyl trimethylsilyl ether. After deprotection of the trimethylsilyl group by exposure to basic
aqueous hydroxide, cyclotrimerization of each anomer of diynes with saturated ethanolic solution of
acetylene gave the corresponding spirocyclic C-glycosides in the presence of Wilkinson’s catalyst
(ClRh(PPh3)3).
197
The first total synthesis of the Papulacandin D was achieved by Barrett in 1995 (Scheme 3. 2).108
He reported that the addition of lithiated aryl precursor 3-71 to fully protected gluconolactone 3-70 gave 3-
72 as an intermediate. The gluconolactone was protected as silyl ethers to circumvent the formation of
gluconolactone. Direct acidification resulted in partial desilylation and cyclization to afford the desired
spiroketal 3-73 as a single diastereomer. Under the resin mediated acidic condition (Amberlite IR-120), the
TBS and TMS groups could be discriminated from the TIPS groups, which are less acid sensitive. Before
coupling with fatty acid 3-75 by esterification, selective protection of the 4,6-diol unit of the tetrol 3-73 are
required to achieve the O-3-ester selectivly. The last phase to complete the total synthesis was the
esterification of the spiroketal 3-74 with anhydride 3-75 followed by global deprotection by treatment of
During the last decade extensive studies on the synthesis of Papulacandin family have been done,
but only one total synthesis has been successfully achieved by Barrett (Scheme 3. 1). The strategies for the
construction of C-arylglycoside nucleus of Papulacandin, which has a spiroketal form as a key component,
aryl lithium with protected gluconolactone, and e) condensation of aryl lithium with fully protected acyclic
precursors. Even though a number of strategies to construct C-arlyglycoside nucleus of the Papulacandins
and total synthesis of the Papulacandin D have been reported, there is still room for further investigations
(R3Sn-SiR’3) developed in our laboratory could be broadly applicable strategy for the synthesis of C-
arlyglycoside.
198
OH
i TIPSO OTIPS TIPSO
Pr3SiO OSiiPr3 TMSO
TMSO O Amberlite O
TMSO HO OTIPS
TMSO O t
BuLi TMSO IR-120 HO
TMSO +
Br TMSO HO
MeOH
TMSO Li O
O OTBS
OSitBuMe2
3-70 3-71 3-72 3-73
t
Bu2
OSiEt3 O O Cl
t Si TIPSO
t Bu2 O
Bu2Si(OTf)2 O Me
O OTIPS + O
HO
Me Me
HO Cl Cl
O
3-74 3-75
t t
Bu2 Bu2
Si TIPSO t Si TIPSO
t
Bu2 O Bu2 O
O O O O
O OTIPS HO OTIPS
DMAP O HO HO
O + O
O
Me
Me Me Me
Me Me
3-76 OSiEt3 3-77
OSiEt3
TASF
OH
TIPSO
HO O
O OTIPS
O HO
O
Me
Me Me
OH
3-78
Papulacandin D
199
3. 2. Retrosynthesis of Papulacandin D and Preparation of Diynes
The retrosynthesis of Papulacndin D is shown in the Scheme 3. 3.109 The molecule can be divided
into two parts: one is a C-arylglycoside nucleus 3-79 with 5-membered spiroketal and a 1,3-dihydroxyl-
benzene ring, and the other is a fatty acid 3-84 with 16 linear carbon chain. The total synthesis of the
Papulacandin D can achieved by chemoselective O-3 esterification of the C-arylglycoside 3-79 using the
fatty acid 3-84. The C-arylglycoside nucleus could be made from the spiroketal, 3-80, by Tamao-Fleming
oxidation followed by oxidative aromatization. The spiroketal 3-80 may be synthesized by regioselective
Diels-Alder reaction with 1,4-bifunctionalized (Z,Z)-1,3-diene 3-81. At this phase we can apply the
known procedure with fully protected tetra-benzyl D-glucose 3-83 in five steps.
R3
OBn HO OBn Si OBn
O O O SiR3
BnO OH BnO Y BnO SnR'3
BnO BnO BnO
BnO BnO X BnO
O O O
3-79 3-80 3-81
OBn
OH OBn
HO O
O BnO
O BnO BnO
HO OH BnO
BnO
O O BnO O
OH OH
O
3-83 3-82
D-Glucose
CH3 CH3
NH3+
OH
Papulacandin D -
O2C
3-78
3-87
Isoleucine
O OH OH
HO O
CH3 CH3 CH3 CH3 CH3 CH3
200
The synthesis of fatty acid 3-84 from isoleucine 3-87 has been documented by Barrett. The
isoleucine could be converted to the intermediate alkynol 3-85 by a sequence of double Wittig reaction and
propargylation. Separation of C7 epimers of 3-85 can be done successfully by kinetic resolution via
Sharpless epoxidation.
gluconopyranose 3-83. The gluconopyranose 3-83 was converted to δ-gluconolactone 3-88 by modified
Swern oxidation in large scale in 72% yield. The lactone can be used as a precursor in two synthetic routes
we explored for the preparation of diyne 3-82. First, the δ-gluconolactone was treated with trimethylsilyl
acetylene and n-butyllithium in THF at -78 oC. The reaction was completed within 2 h and all of the
lactone 3-88 was consumed (by TLC analysis). After work-up with a buffer solution, only two spots were
found on the TLC, but 1H NMR spectrum analysis implied that three acetylenes were present in the crude
mixture. Even though the α/β anomeric mixture (probably with one more acetylene isomer) has a small
difference of Rf value on TLC, we failed to isolate the pure compounds by column chromatograpy. Based
on the 1H NMR peaks, the ratio of three acetylenes was 0.41:1.00:0.89. At this stage we could not assign
configuration of the mixture, but we may assume that the last two acetylenes are the desired diynes with a
major α-anomer.
The mixture of three isomers 3-89 was subjected to further reaction with 3-
alkylation was very fast and all starting material disappeared as estimated by TLC after 2
h. The TLC analysis of the crude mixture was very clean and only one major spot was
mixture was still contaminated with an unidentified acetylene isomer. Based on 1H NMR
201
the α-anomer as a pure form but the isolated β anomer was contaminated with 17% α-
b g
OBn OBn
TMS TMS OBn
O c O d
BnO BnO O
BnO BnO TMS BnO
BnO BnO BnO
OH O BnO
O
3-89 3-90 3-82
Scheme 3. 3. Preparation of Diyne 3-82: (a) (CF3CO)2O, DMSO, CH2Cl2, -78 oC to -40 oC, 72%; (b) TMS-
C≡CH, nBuLi, THF, -78 oC, 73%; (c) TMS-C≡C-CH2OH, Montmorillonite K 10, CH2Cl2, rt, 98%; (d) 50%
aqueous NaOH, BnNEt3Cl, CH2Cl2/CH3CN, 0 oC to rt, 99%; (e) CH≡C-Li•EDA, THF, -78 oC, 91%; (f)
TMS-C≡C-CH2OH, Montmorillonite K 10, CH2Cl2, rt, 88%; (g) 50% aqueous NaOH, BnNEt3Cl,
CH2Cl2/CH3CN, 0 oC to rt, 87% (85% from 3-90).
Although the major portion of isolated products was still two anomeric mixtures which can be
separated by column chromatography, we did not try further purification due to the difficuty in the
separation, The anomeric mixture of 3-90 could be easily desilylated by exposure to 50% solution of
homogeneous solution small amount of benzyltriethylammonium chloride was added as a phase transfer
reagent. After aqueous work-up of the mixture, the two anomers could be separated on TLC although they
have a small difference in Rf values. Although the isolated β-anomer was contaminated with small amount
(<5%) of unknown compound, the α-anomer was isolated as a pure solid. The optical rotation value of the
20
α-anomer is [α] D = +21.0 (c 0.61 in CHCl3) and the 1H NMR spectrum was exactly in agreement with the
202
results reported by McDonald. Although we may assign tentatively the major portion as an α-anomer
based on the anomeric effect, McDonald did not determined its absolute configuration and our efforts were
not successful either (1H NMR, 13CNMR, COSY, and 1D nOe NMR anlysis) at this stage. However, the
absolute configuration of 3-82 may be deduced from the absolute configuration of silastannylated
compounds, which were unambiguously assigned by COSY and 1D nOe NMR experiments.
To suppress the formation of undesired byproducts, another route has been developed by using
nucleophilic addition of lithium acetylide diamine complex to D-gluconolactone 3-88 in THF at -78 oC gave
a complex mixture to afford low isolated yield of 3-92, a mixture of D-gluconolactone 3-88 in THF had to
be added to lithiumacetylide complex at -78 oC. Although only one spot was observed on TLC, complex
peaks between 2.53-2.73 ppm in 1H NMR spectrum suggested that the mixture involves at least five
acetylene containing products. If we performed O-alkylation with the crude mixture and 3-trimethylsilyl-2-
propyn-1-ol in the presence of Montmorillite K10, the expected C-alkynyl-O-propagy substrate 3-93 was
not made and the alkyneol 3-92 was recovered in 35% yield after column chromatography. Gratifyingly,
we prepared the O-alkylated product 3-93 in 88% yield after a simple filtration of the reaction mixture
through a short column (91% yield). The isolated C-alkynyl-O-propagyl substrate 3-93 was an
α/β anomeric mixture with a ratio of 0.68/0.32. The purified 3-93 could be easily desilylated under basic
conditions with catalytic amount of phase transfer reagent to afford 2-propynyl 1-C-ethynyl-2,3,4,6-tetra-
O-benzyl-D-glucopyranoside 3-92 in 87% yield. Because the TMS group can decompose easily during the
column chromatography, we performed the propagylation and desilanylation without purification in one
sequence. The α/β anomers of diyne 3-82 were successfully isolated in pure forms and the isolated yield
203
3. 3. Palladium Catalyzed Silastannylation of Diynes
With a gram quantities of pure α-anomers and slightly contaminated β-anomers (less than 5% of
cyclization was performed with Bu3Sn-SiMe2Ph under various conditions in an NMR tube in 0.05mmol
scale.
First, we explored the reaction under the optimized condition, which was developed in our
observed three new spots on TLC plate, and two of those decreased smoothly with prolonged reaction time
while the other spot increased. The same results were also observed in 1H NMR spectra analysis.
Gratifyingly, the crude mixture could be isolated easily by column chromatography eluting with non-polar
eluent (hexanr:EtOAc = 40:1) to give three cyclized compounds. The most and second non-polar
The configuration was unambiguously determined by COSY and 1D nOe NMR spectra. The stannane
substituted vinyl hydrogen of the bifunctionalized cyclic compounds can be easily confirmed by observing
a singlet peak with two small sidepeaks originating from 117Sn/119Sn coupling at down filed (5.94 ppm, JSn-
H = 39.5 for 3-93 and 6.38 ppm, JSn-H = 40.1 for 3-94 in C6D6), while silane substituted vinyl hydrogen
peaks of 3-93 and 3-94 were observed as a singlets at δ 6.06 and 5.56 ppm, respectively. The assignment of
the configuration was confirmed by COSY and 1D nOe experiments. For example, if we irradiated the
silane substituted vinyl hydrogen H9 3-93, the frequency for the H2 peak was enhanced, while the
irradiation of stannane substituted vinyl hydrogen H8 enhanced H7a and H7b peaks (H9→ H2, 4.1%; H8→
H7a, 1.1%; H8→ H7b, 1.3%). In sharp contrast to the results, irradiation of the silane substituted vinyl
204
4.1%
nOe
OBn H
6
4 H 9
O SiMe2Ph
BnO 2
BnO SnBu3
BnO 8
O
nOe H
7 H
H nOe
4.5%
nOe
OBn H
6 9
4 H
O SnBu3
BnO 2
BnO SiMe2Ph
BnO 8
O H
nOe
H
H nOe
205
hydrogen of 3-94 increased H7a and H7b peaks and irradiation of stannane substituted vinyl hydrogen
increased H9 peak. More comprehensive results for the nOe experiment are shown in Figure 3.2 and 3.3.
Unfortunately, we failed to assign unambiguously the configuration for the most polar product in
spite of extensive NMR study. However, the absence of a singlet peak coupled with Sn and two peaks at
high field (s, 5.83 ppm and d, J= 0.7Hz, 5.37ppm) may imply the cyclized compound 3-93 and 3-94 may be
coupled together to afford a dimerized product. The analysis of 13C NMR spectrum showed the chemical
shift pattern of the new compound is very similar to 3-93 or 3-94 except for absence of SnBu3 group. The
1
H and 13C NMR spectra showed the dimeric compound is not a single isomer. The molecular weight of
the compound was determined by high resolution mass spectrometer to give M+ = 1476, which is the
exactly same with dimeric compound 3-95. Because the NMR spectrum is complex we did not make any
attempt to assign the absolute configuration of the dimmer (tentative configurations of the dimeric products
BnO
OBn
BnO OBn
H O
O BnO
BnO O H
BnO H BnO
HH H
O
SiMe2Ph
H SiMe2Ph H
PhMe2Si H
OBn SiMe2Ph
HO H HH H
BnO
H BnO O H
BnO BnO
BnO O
BnO H O
H OBn
3-95 3-99
Once we had pure silylstannylated product 3-93 and 3-94 as well as the NMR spectra, a number of
complex of Pd (0) and Pd (II) were used as catalysts in the silastanylative cyclization of C-alkynyl-O-
propargy substrate 3-92 with Bu3Sn-SiMe2Ph, and the results are shown in Table 3.1. First, We examined
206
the reaction in the presence of Pd2(dba)3•CHCl3 because RajanBabu and Warren reported that this
palladium catalyst is the best for the R3Si-R3Sn’-mediated cyclization of 1,6-diynes. As Warren described
in her dissertation we performed the reaction with (C6F5)3P at 80 oC. Because the reaction is very fast at
that temperature, we could not avoid the formation of dimeric product 3-95 in this case (Entry 1). The
reaction was also performed at 60 oC and 40 oC, respectively. However, all silastannylative cyclic products
3-93 and 3-94 were converted to the dimeric product 3-95 in prolonged reaction time at 60 oC (Entry 2).
Although the formation of the dimeric product was suppressed at 40 oC, the dimeric product 3-95 was still
obtained as a byproduct (Entry 3). Fortunately, the tandem silastannylation-cyclization proceeds smoothly
at rt without the formation of the dimeric products. All C-alkynyl-O-propargyl substrate was consumed
within 3 h and only the cyclic product 3-93 and 3-94 were isolated in 87% yield with a ratio of 1.7/1.0 by
column chromatography (Entry 4). It has to be pointed out that because the Sn-Si mediated
bifunctionalization is extremely fast, the dimeric products can be made even at rt by exposure to prolonged
reaction time (10 h). We also performed the reaction without any phophine ligand (Entry 6). Surprisingly
the silystanylative cyclization proceeded smoothly to afford 3-93 and 3-94 in a reasonably good yield
without changing the ratio of 3-93 and 3-94. Although the reaction may go to completion to afford good
yield of cyclic product in the presence of Pd2(dba)3•CHCl3 , there is still room for further investigation in
terms of isolated yield of 3-93 and 3-94 as well as the ratio of 3-93/3-94.
After extensive search for various catalysts, we found that [Pd(allyl)Cl]2 and [Pd(1,3-di-
phenylallyl)Cl]2 are excellent catalysts for the reaction, but some dimeric product was still formed (Entry
16 and 17). Fortunately, the dimeric product was not formed at all with other Pd (II) catalysts such as
Pd(OAc)2 , PdCl2(NH3)2 , PdCl2 •2NaCl, PdCl2(CH3CN)2, and PdCl2(PhCN)2 . Although most these
catalysts are excellent for silastannylations, the reaction with PdCl2 •2NaCl or Pd(OAc)2 ) is relatively slow
(entry 16 and 17) and the reaction with PdCl2(CH3CN)2) gave slightly decreased the isolated yields of the
cyclic product (Entry 7). We found that the PdCl2(PhCN)2 is a catalyst comparable to Pd2(dba)3•CHCl3 in
terms of reaction time as well as the ratio of monomer/dimmer and isolated yield. Although Pd(PPh3)4 is an
excellent catalyst for the silastannylative cyclic reaction, the catalyst is less efficient than Pd2(dba)3•CHCl3
207
Conditions Ratio
Entry Pd Phosphine Temp Time Yield (%) 3-93 3-94 3-95 (?)
2 60 oC 36h 68 1.0
4 rt 3h 87 1.7 1.0
6 NO rt 2h 65 1.7 1.0
phosphine
13 40h 68 1.0
phenylallyl)Cl]2
Table 3.1. The summary of Cyclization with a Variety of Pd (0) and Pd (II).
208
(Entry 9). Finally, we ran the reaction in the presence of palladium amine complex, but found the catalysts
are less efficient than other palladium catalysts in terms of reactivity and regioselectivity (Entry 11 to 14).
silastanylation of asymmetrical diynes 3-92, and the silystannylated cyclic product was obtained as a
mixture of two regioisomers 3-93 and 3-94 with a ratio of 1.4/1.0 - 1.8/1.0 depending on the palladium
catalysts (Table 3.1). To improve the ratio of the major product, we decided to explore various phosphine
ligands in the presence of Pd2(dba)3•CHCl3, and the results are in Table 3.2. First, we were attracted to
were used in the reaction, the bifunctionalized cyclization required high temperature (60 oC ) as well as
prolonged reaction time due to the increased number of phospine per palladium catalysts (Entry 2 and 3).
Moreover, the ratio of 3-93/3-94 decreased to 1.4 and 0.7, respectively. Because increased number of
phospine ligands per metal leads to retardation of the cyclization, we chose simple phosphine ligands such
as tributylphosphine and tri-tert-butylphosphine. For example, when we used tPBu3 as a ligand, the reaction
did not proceed at all at rt and all C-alkynyl-O-propagyl compound 3-92 decomposed at 60 oC (Entry 4).
Although the silastannylative cyclization proceed well with tributylphosphine in the presence of
Pd2(dba)3•CHCl3, we could not observe any improvement of the 3-93/3-94 ratio (>90% yield in NMR, 58%
In terms of either the reactivity of dialkynes or selectivity, all phosphine ligands we exaimined are
less effective than (C6F5)3P except for (2,4,6-trimethylphenyl)phospine. When we used (2,4,6-
bifunctionalization/cyclization proceeded at rt without any difficulty to afford 3-93/3-94 in 63% yield (95%
based on 1H NMR) with a ratio of 2.2/1.0. It has to be pointed out that the palladium catalyzed
silastannylation/ cyclization proceeds very efficiently even without any phospine ligans at rt, and the yield
Once we optimized the reaction conditions, we performed the palladium catalyzed silastanylation/
cyclization with 3-96 with/without phosphine ligands. Although the previous studies on the silastanylation/
209
Conditions Ratio
•CHCl3
2 Ph2P rt 3h NR
PPh2
N 60 oC 2.5h 59% 1.4 1.0 0.6
O OtBu
3 rt 3h NR
PPh2 60 oC 2.5 NR
PPh2
60 oC 24h 35% 0.7 1.0 1.3
60 oC 40h 1.0
4 P tBu3 rt 2h NR
60 oC 3h Decomp.
60 oC 2h 73%
7 P(p-MeO-C6H4)3 rt 2h NR
60 oC 10h 7% 1.0
8 PCy3 rt 2h NR
60 oC 3h Decomp.
Continued
210
Table 3. 2. continued
Conditions Ratio
10 P(OPh)3 rt 3h NR
60 oC 3.5h NR
11 Pd2(dba)3 rt 6h NR
O P
•CHCl3 3 60 oC 18h 56% 1.5 1.0
13 (o-MeO- 29%
C6H5)PPh2
14 DPPP Decomp.
15 DIPHOS Decomp.
16 (S,S)- Decomp.
CHIRAPHOS
211
cyclization with 3-92 implied that Pd2(dba)3•CHCl3 is a slightly more efficient catalyst than PdCl2(PhCN)2,
we used Pd (II) in this exploratory reaction. First, the reaction was examined with the standard phophine
ligand, (C6F5)3P, at 60 oC. As described in earlier (Table 3.1), the asymmetric diynes 3-96 might cyclize in
the presence of palladium catalyst to afford 3-97 and 3-98, which may further be dimerized to 3-99 by
heating (Eq. 13). The reaction could be easily followed by 1H NMR as well as TLC.
If the reaction is performed at rt without phosphine ligand, the formation of the dimeric compound
might be suppressed completely and only desired products 3-97 and 3-98 were observed by TLC analysis.
The isolated yield of the product was 67% and the ratio of 3-97/3-98 was 1.2/1.0 after column
chromatography. If the reaction mixture was stirred for the prolonged reaction time (5 h), the isolated yield
of 3-97/3-98 slightly decreased, while the ratio of 3-97/3-98 increased up to 1.5/1.0. Because we could
prepare the bifunctionalized product 3-97/3-98 in a gram scale, we did not further try to improve the
The configuration of the cyclized compounds was unambiguously assigned by 2D COSY and 1D
nOe experiments like described in the assignment of 3-93 and 3-94, and the results are shown in Figure 3.5
and 3.6. Two vinyl proton peaks of in 3-96 or 3-97 can be distinguished easily by observing the side bands
due to 117Sn/119Sn coupling, and all other protons are assigned based on coupling constant, coupling pattern,
chemical shift, and COSY NMR data. Once each proton was assigned without any doubt, the assignment
of the structure was refined by 1D nOe spectra. For example, if we irradiated frequency corresponding to
H9 of 3-96, a strong enhancement of H3 peak was observed. Irradiation of stannane substituted vinyl
212
OBn
6
H
O
BnO 5 2
O H
BnO 3 7
BnO
6.4% H H 9 H
8.3% nOe
H 2.3%
PhMe2Si 8
SnBu3
3-96
OBn
6
H
O
BnO 5 2
O
BnO H
3 7
BnO
7.3% H H 9 H nOe
8.9% 1.7%, 1.3%
Bu3Sn 8
H
SiMe2Ph
3-97
213
hydrogen (H8) might increase the H7a peak. Similar results were observed in the nOe experiment of 3-97.
We observed a strong enhancement of H3 peak by irradiation of H9 peak (or vice versa) as well as some
2 NO rt 5h 53 1.5 1.0
Although Pd (0) and Pd (II) are very efficient catalysts for the silastanylation/cyclization of diynes
3-92 with Bu3Sn-SiMe2Ph, it is still worth investigating the effects of other transition metals such as Ni or
Rh in this novel reaction. Thus, we decided to investigate the reaction with a series of Rh and Ni catalysts
under our optimized condition, and the results are summarized in Table 3.4. First, we chose NiCl2 to
explore the silastannylative cyclization without phosphine ligand. After the reaction mixture was heated at
60 oC for 24 h, no change was observed either on TLC or in NMR spectrum and all starting diyne 3-92 was
recovered quantitatively (Entry 1). Although the reaction was performed with a phospine ligand ((C6F5)3P)
at 60 oC, the ligand did not effect the reaction at all and all starting material was recovered quantitatively.
Next, we examined Ni(acac)2 as the transition metal catalyst with/without phosphine ligand (C6F5)3P in the
Sn-Si mediated bifucntionalization/cyclization, but the same results were obtained as the above. However,
we found that the starting material 3-92 smoothly converted to a new compound upon heating at 60 oC.
214
After 24 hr, we judged >36% of 3-92 was converted to the new product and all remaining was the starting
diynes.
Although the new product was isolated easily by column chromatography, the isolated compound
was a mixture of two isomers based on 1H NMR spectrum. The ratio of two product distribution (0.45/0.55)
may be judged by two different singlet peaks at δ 2.57 ppm and 2.52 ppm. These peaks may imply each
product have an sp3 hydrogen. The acetylene carbon is further proved by observing two peaks at δ 68.68
and δ 68.56 in 13C NMR and weak peak at ~2100 cm-1 in IR spectrum. Two doublet of doublets (δ 6.76
ppm, J = 7.7, 1.1 Hz and δ 6.72 ppm, J = 7.7, 1.4 Hz) with a different ratio (0.45/0.55) prove each product
may have at least one sp2 hydrogen with cis configuration. Because of heavy overlap between δ 3.6 and 5.2
ppm in 1H NMR spectrum, it is difficult to assign the exact configuration of the isomers. High resolution
mass spectrum shows M+ + Na is 1227.5149, which exactly matches the molecular weight of a dimmeric
product of the C-alkynyl-O-propargy substrate 3-92 within 7 ppm (calculated mass for M+ + Na is
1227.5234). Based on these information we postulate that the starting material 3-92 may have dimerized to
3-100 and/or 3-101 in the presence of (Ph3P)2NiCl2 (Entry 3). When we used another phospine bounded Ni
OBn
OBn
OBn
O
O O O BnO
OBn
BnO
BnO BnO O BnO O
BnO O BnO BnO
O
BnO OBn
OBn
OBn
3-100 3-101
215
Rh catalysts also were explored for the silastannylative cyclization of 1,6-diynes 3-92 with Bu3Sn-
SiMe2Ph. As shown in the previous Ni catalyzed reaction, only the formation of dimeric products was
observed in TLC and/or 1H NMR analysis. It has to be pointed out that the dimeric reaction in the presence
of Rh catalysts is much milder than in the presence of Ni catalysts. For example, if we used RhCl(PPh3)3 as
the transition metal catalyst in the reaction, all starting 1,6-diynes 3-92 was converted at rt within 24 h to
5 (Ph3P)2NiCl2 60 oC 24h 63 36
6 NICl2dppp 60 oC 24h 64 35
7 [Rh(COD)Cl]2 rt 24h 47
8 RhCl(PPh3)3 rt 24h 75
10 Rh(COD)(acac) 60 oC 24h 23
216
3. 5. Dynamic NMR Studies of Silastanylated 1,3-Dienes, 3-93 and 3-94
dienes, which exhibit an axial chirality due to restricted rotation around a single bond. RajanBabu and
Warren observed rapid equilibration between the two helical forms 3-102 and 3-103 at rt without regard to
the size of stannane and silane substitutents (Figure 3.8). However, the fluxional 3-102/3-103 can be
frozen at low temperature, and the rate of enantiomerization depends on the Si and Sn. At the low
temperature, the coalescence temperature and kinetic parameters such as ∆H‡, ∆S‡, and ∆G‡, can be
determined by line shape analysis with variable temperature NMR (VT NMR) techniques. They also
reported that the atropisomerism can be commonly observed in carbocyclic and heterocyclic silistanyl 1,3-
R R' Tc
MeO2C CO2Me MeO2C CO2Me
Bu Me 10
Tc
Bu Et 20
Bu t-BuMe2 20
R3Sn SiR'3 R3Sn SiR'3
Ph t-BuMe2 20
3-102 3-103
Ph i-Pr -10
X Tc
X X
Tc
N-Ts -40 oC
NCHPhMe -60 oC
217
OBn OBn
SnBu3 SnBu3
H H
O O
BnO Tc > ? BnO
BnO SiMe2Ph BnO SiMe2Ph
BnO BnO
O O
H H
H H
3-93a (RA) 3-93b (SA)
OBn OBn
SiMe2Ph SiMe2Ph
H H
O O
BnO Tc > ? BnO
BnO SnBu3 BnO SnBu3
BnO BnO
O O
H H
H H
3-94a (RA) 3-94b (SA)
OBn OBn
H H
O O
BnO BnO
O H Tc > ? O H
BnO BnO
BnO BnO
H H H H
Bu3Sn Bu3Sn
SiMe2Ph SiMe2Ph
3-97a (SA) 3-97b (RA)
OBn OBn
H H
O O
BnO BnO
O H Tc > ? O H
BnO BnO
BnO BnO
H H H H
PhMe2Si PhMe2Si
SnBu3 SnBu3
3-98a (SA) 3-98b (RA)
All possible atropisomeric isomers of Sn-Si mediated cyclic adducts are shown in Figure 3.9. Pairs
of 3-93a/3-94a and 3-93b/3-94b are regioisomeric so are 3-97a/3-98a and 3-97b/3-98b, while pairs of 3-
93a/3-93b, 3-94a/3-94b, 3-97a/3-97b, and 3-98a/3-98b are diastereomeric as a result of axial chirality.
Each of these regioisomers can be isolated relatively easily by column chromatography, but their
atropisomeric isomers, if it is possible, cannot be isolated at rt because (i) either the conversion between
218
two atropisomers are very fast at rt or (ii) only one isomer is formed, and no separation is needed. Previous
research on 1,4-disubstituted (Z,Z)-1,3-dienes in our laboratory demonstrates that the (Z,Z)-1,3-dienes can
be freely inter-converting above coalescence temperature (Tc) (see Figure 3.8). However, the axially chiral
diastereomers (for example, 3-102 and 3-103) may be frozen below the corresponding coalescence
To determined fluxional nature of 3-93, 3-94, 3-97, and 3-98, we investigated the variable
temperature NMR in the rage of +70 oC to -70 oC and the results are shown in Figure 3.9 - 3.16. First, the
spectra of 3-93 were taken from 20 oC to -60 oC in CD2Cl2, but surprisingly, we could not observe any new
peaks in the VT NMR spectra. The singlet peak of SiMe2Ph (δ 0.42 ppm in 1H NMR at 20 oC) split into
two singlet peaks at 0 oC; but the observation may not support atropisomerism of 3-93 because two methyl
groups in dimethylphenylsilane (DMPS) ether can be separated at rt in 1H NMR because they are
diastereotopic. Moreover, we could not observe any splitting of other hydrogen peaks. Two vinyl proton
peaks became broaden upon lowering the temperature, but splitting was not observed at the temperatures
we examined. To investigate the atropisomerizam at high temperature, we used C6D6 as the NMR solvent.
Interestingly, the chemical shifts of stannane substituted vinyl hydrogen H8 at high field (δ 5.94 ppm) and
silyl substituted vinyl hydrogen H9 at down field (δ 6.06 ppm) are reversed and they appears: δ 6.01 ppm
for H8 and at δ 5.92 ppm for H9. Even though careful VT NMR experiments were performed by heating
upon 70 oC, we could not find any evidence for the atropisomerism of 3-93. We have done the same
experiment with D-gluconosubstituted (Z,Z)-1,3-dienes 3-94, 3-97, and 3-98 in CD2Cl2 and C6D6 in the
range of -70 oC to +70 oC, but no atropisomerism was observed in the dynamic NMR spectra.
Based on the above dynamic NMR study results, we may conclude the silastanylated cyclic
adducts 3-93, 3-94, 3-97, and 3-98, are the first atropisomerically frozen diastereomers. At this point,
unfortunately, we could not determine the absolute configuration of those compounds by nOe experiments.
219
Figure 3. 10. Various Temperature NMR Spectrum I of 3-93.
220
Figure 3. 11. Various Temperature NMR Spectrum II of 3-93.
221
Figure 3. 12. Various Temperature NMR Spectrum I of 3-94.
222
Figure 3. 13. Various Temperature NMR Spectrum II of 3-94.
223
Figure 3. 14. Various Temperature NMR Spectrum I of 3-97.
224
Figure 3. 15. Various Temperature NMR Spectrum II of 3-97.
225
Figure 3. 16. Various Temperature NMR Spectrum I of 3-98.
226
Figure 3. 17. Various Temperature NMR Spectrum II of 3-98.
227
3. 6. Bromination and Destannylation of Silylstannylated D-gluconosubstituted (Z,Z)-1,3-Dienes
Tin-bromine exchange on vinylstanne has been studied before (Chapter 2.3, Eq. 25). The
bromination can be achieved easily by treating the tin substituted vinyl with slightly excess NBS in
dichloro- methane at rt. While iodine-substituted at Csp2 is unstable, the bromine-substituted olefins are
3-106 3-107
Because we obtained a gram scale of vinyl silastanne 3-93, 3-97, and 3-98, we decided to
investigate the bromine-tin exchange reaction. Pleasantly, the reaction proceeded smoothly at rt to afford
the corresponding brominated substrate 3-108 – 3-110 in excellent to good yield, and the results are
summarized in Table 3.5. Although relatively big functional groups, SiMe2Ph and SnBu3, are substituted
(Z,Z)-1,3-dienes are expected to freze the helical isomerization in the range of -70 to +70 oC, the Br and
SiMe2Ph substituted (Z,Z)-1,3-dienes may be fluxional at these temperature. However, at this time we have
On the other hand, we have also described destannylation of the silastannylative cyclic products 3-
111 to the corresponding vinyl silane 3-112 in the previous chapter (see Chapter 2.6). The destannylation
proceeds slowly but very cleanly in dichloromethane at rt (5.0 equivalent of HCO2H and dichloromethane
at rt), and the destannated vinyl silane can be isolated by flash column chromatography.
3-111 3-112
228
We applied the acidic conditions for destannylation to 1,4-disubstituted (Z,Z)-1,3dienes, 3-93, 3-94, 3-97,
and 3-98. All substrate underwent the reaction very smoothly to afford the corresponding vinyl substrate 3-
113 – 3-116 in excellent yield (>99%), even on a half gram scale reaction. Table 3.6 is a summary of the
destannylation of silastannylated adducts 3-93, 3-94, 3-97, and 3-98. The configurations of the vinylsilanes
are confirmed by nOe experiments and the representative results for 3-114 and 3-115 are shown in Figure
3.14. For example, if we irradiated H9a of 3-114, strong enhancements of H2 and H9b were observed. We
may also deduce of (Z,Z)-confifuration of 1,3-diene 3-94 by observing of SiMe2Ph peak enhancement
when H9b peak was irradiated. The assignment of 3-115 is also very obvious by observing nOe effect
between H9 and H3, H8a and SiMe2Ph, and H8a and H8b.
3-93 3-108
PhMe2Si H PhMe2Si H
SnBu3 Br
3-97 3-109
Bu3Sn H Br H
SiMe2Ph SiMe2Ph
3-98 3-110
229
Entry Conditions Product Yield
3-93 3-113
3-94 3-114
HH H HH H
PhMe2Si H PhMe2Si H
SnBu3 H
3-97 3-115
HH H HH H
Bu3Sn H H H
SiMe2Ph SiMe2Ph
3-98 3-116
230
18.3%
OBn
4.9% 17.6% 6
H
OBn H 9a 4
6 O
4 H 3.4% BnO 5 2
O H 9b O
BnO
BnO 5 2 BnO 7
BnO SiMe2Ph
BnO 9.3% HH 9
O 8 11.3%
H H 8b
7 H PhMe2Si
H H 8a
3.0%
3.3% 18.6%
3-114 3-115
Desilanylation of 1,4 –disubstituted (Z,Z)-1,3-diene 3-93 was performed with Bu4NF in DMF at
60 oC. Although the removal of Si at sp3 carbon mediated by tetra-butylammonium fluoride (TBAF) is
well-known, it was difficult to remove the silanes at the sp2 carbon of 3-93. Because of the harsh reaction
OBn H OBn H
H Bu4NF H
O SiMe2Ph O H
BnO BnO
BnO
BnO
SnBu3 X BnO
BnO
SnBu3 (15)
O DMF O
H H
H 60 oC H
H H
3-93 3-117
Next, we investigated desilylation of destannated vinylsilanes such as 3-114 and 3-115 under
various conditions, and the results are shown in Scheme 3.3. Hydroiodic acid is the most commonly used
in reagent for the desilylation of vinylsilanes to afford olefins, and a small amount of iodine and H2O may
be used for the reaction instead of the hydroiodic acid. The reaction proceeds via protonation to the
vinylsilanes to afford stabilized β-silicon attacked by iodide in the same pot. We explored the desilylation
of both vinylsilane 3-114 and 3-115 under the iodine/H2O system, but the reaction did not proceed at all
and all starting vinylsilane was recovered. We also investigated the desilylation with stochiometric amount
231
of p-TsOH in the mixture of CH3CN-THF-H2O (3:3:1). Unfortunately, the both starting materials
decomposed after 50 h refluxing without formation of the desired olefins like 3-118 or 3-119. Further
efforts were made to do the desilylation of 3-115 under two reported conditions. First, the vinylsilane 3-
119 was heated with excess amount of TBAF (5.0 equivalents) in a mixture of THF-DMSO (= 1:2) at 80
o
C. Second, the silane was treated with KOtBu (1.1 equivalent), TBAF (5.0 equivalents), and catalytic
amount of 18-crown-6 in DMSO at rt. Although those reaction conditions are effective for the desilylation
OBn H OBn H
H a or b H
O H O H
BnO BnO
BnO
BnO
SiMe2Ph X BnO
BnO
H
O H O H
H H
H H
3-114 3-118
OBn OBn
H a, b, c, or d H
O O
BnO O BnO O
BnO
BnO X BnO
BnO
HH HH
PhMe2Si H PhMe2Si H
H H
3-115 3-119
Scheme 3. 4. Failed Desilanation of Vinylsilanes 3-114 and 3-115: (a) I2, H2O, benzene, 45 h, SM
recovered; (b) pTsOH, CH3CN-THF-H2O = 3:3:1, reflux, 50 h, decomposed ; (c) TBAF in 1.0M THF,
THF-DMSO (= 1:2), 80 oC, 23 h, decomposed; KOtBu, TBAF, 18-crown-6, DMSO, rt→0 oC→rt, 24 h, SM
recovered.
232
3. 8. Diels-Alder Reaction of Vinylsilanes
Our initial plan for the synthesis of C-arylglycoside nucleus of Papulacandin D is shown in
Scheme 3.4. The destannylated vinylsilane 3-113 and/or 3-115 may react with dienophiles shown in the
box in the Scheme 3.4 via Diels-Alder reaction. The spiroketal 3-80 and/or 3-120 may further be
transferred to C-arylglycoside 3-79 or 3-121 via Tamao-Fleming oxidation and oxidative aromatization as
key steps. Because C-arylglycoside 3-79 is thermodynamically more stable than 3-121, the C-
arylglycoside 3-121 may be epimerized easily to 3-79 in the presence of PPTS. Two hydroxyl groups in
the aryl moiety of the 3-79 can originate from the vinylsilanes in dienes and ketone equivalents in the
respectively.
Ph
Me 2
OBn H OBn Si OBn HO
H
O SiMe2Ph O O
BnO X Y BnO Y BnO OH
BnO H BnO
BnO BnO BnO
Diels-Alder Reaction BnO X
O O O
nOe H 3-79
H
H 3-80
3-113
PPTS
PhMe2Si H
H
Y
X OH
3-115 3-120 3-121
Possible Dienophiles
O
CH3
AcO
Br CHO Br CN AcO CN AcO O CH3 NO2
O
Scheme 3. 5. Application of Silyl-Stannane Adducts for Synthesis of the Core Structure of Papulacandin
D.
233
Diels-Alder reactions of spiro[4.5]decane 3-113 were studied with a variety of dienophiles such as
propyl ester, or acetic acid 1-acetoxy-vinyl ester, and the results are summarized in Table 3.7. We
performed the reaction under various conditions with different solvent and at various temperatures as
limiting factors. Unfortunately, we could not find any evidence for the formation of the Diels-Alder adduct
3-80, and all starting vinylsilane 3-113 decomposed under the conditions we applied.
Becaue our all attempts failed to produce the Diels-Alder adduct like 3-122 or 3-124, we assumed
that the Diels-Alder adducts were formed and further transformations of the crude product ensued (Eq. 16
and 17). However, we also failed to isolate the desired product 3-123 or 3-125, and all starting material
Ph Ph
e2 e2
M M
OBn H OBn Si OBn Si
H H Br 2M KOH H
O SiMe2Ph O O
BnO Br CN BnO
BnO
BnO
H
tolouene
BnO
BnO CN
X BnO
BnO
BnO
O (16)
O THF/DMSO
O H O
(xyxlene, reflux)
H H H
H H H
Ph Ph
e2 e2
M M
OBn H OBn Si OBn Si
H H OAc 2M KOH H
O SiMe2Ph O O
BnO AcO CN BnO
BnO
BnO
H
tolouene
BnO
BnO CN
X BnO
BnO
BnO
O (17)
O O THF/DMSO
H O
(xyxlene, reflux)
H H H
H H H
It was known that nitroethylene is one of the strongest electrophiles and its global electrophilicity
power ω, which is unique on relative scale for dienes and dienophiles, is 2.61. The electrophilicity power
ω of nitroethylene is 1.73 times grater than methyl acrylate, which is one of the most widely used
dienophiles in Diels-Alder reaction. Thus, it is reasonable that the Diels-Alder reaction of the sterically
234
Entry Conditions
↑↓
235
OBn H OBn OBn NO2
H O
O H NO2 O
BnO BnO BnO
SiMe2Ph NO2
BnO BnO + BnO
BnO (18)
BnO BnO
O O O
H SiMe2Ph SiMe2Ph
nOe
H
H
Conditions
a. Isolated yield. The number in the parenthesis is yield based on the recovered 3-114.
236
We performed the Diels-Alder reaction of vinylsilane 3-144 with the nitroethylene under various
conditions, and the results are shown in Table 3.8. When the reaction was done with 5 equivalent of
dienophile for 3 d, we isolated the regioisomeric mixture 3-12 and 3-127 in 44% (68% based on recovered
starting material) as well as the starting diene 3-144 (entry 1). After heating the reaction mixture for the
prolonged time (6.5 d), all the starting material was consumed and the isolated yield of the product
increased up to 72%. Gratifyingly, we can optimize the reaction with 10 equivalents of nitroethylene in
benzene and refluxing condition (entry 4). Because the reaction is very slow, the reaction mixture has to be
allowed to stand under refluxing condition for a week. The reaction is independent of the solvent, but
dependant on the reaction temperature. It is probabely that the dienophile, nitroethylene, can decompose at
high temperature. For example, if the reaction temperature in creased to 110 oC (toluene refluxing
condition), the yield of the product was only 17% (Entry 5). When toluene was used as the solvent instead
of benzene, the yield of the Diels-Alder adducts 3-126 and 3-127 decreased as expected from the above
considerations.
Next, the Diels-Alder adducts 3-126 and 3-127 were subjected to oxidation under various
conditions. Because Nef reaction is the most broadly used for the transformation of primary or secondry
nitroalkanes to aldehydes or ketones, we applied this reaction and its modified procedures to our substrates.
Unfortunately, all nitroalkanes 3-126 and 3-127 decomposed under the harsh conditions with basic/acidic
reagents. Even though we applied Oxone® mediated Nef reactions, which is milder than conventional Nef
conditions, we failed to obtain the desired product 3-128 and 3-129. Because silica gel or basic silica gel
may be used for an alternative reagent for the conversion of nitroalkanes to ketones, we performed the
reaction in sealed tubes packed with silicagel/MeOH or basic silicagel at rt or 50 oC, respectively.
However, the desired reaction did not proceed and all starting material 3-126 or 3-127 was either recovered
or decomposed. We also examined the reaction with activated silica gel (KMnO4 /silicagel = 0.5 mmol/g),
the reaction did not proceed. Finally, we explored the transformation with either CAN/Et3N in pyridine or
TiCl3-NH4OAc in THF, but we failed to obtain the desired products 3-128 and 3-129 and all starting
237
OBn OBn NO2
a, b, c, d,e,
O O f, g, or h
BnO BnO
NO2
BnO
BnO
+ BnO
BnO X
O O
SiMe2Ph SiMe2Ph
3-126 3-127
OBn OBn O
OBn OH
O O
BnO O
BnO O BnO
BnO + BnO
BnO BnO BnO
BnO
O O O
SiMe2ph SiMe2Ph
OH
Scheme 3. 6. Failed Attempts to oxidize 3-126 and 3-127: (a) 1. NaOH (10% in EtOH), 2.6N HCl, 0
o
C→rt, decompose; (b) silicagel, MeOH, rt, 20 d, SM recovered; (c) 1. Na2HPO4, NaOH, MeOH, 2.
Oxone®, rt, 2h, decomposed; (d) KMnO4/silicagel (0.5 mmol/g), bezene, reflux, 24 h, decomposed; (e)
basic silicagel (Na/EtOH), 90 oC, 4.5 d, decompose; (f) CAN, Et3N, H2O, Pyr, 50 oC, 5 hdecompose; (g) 1.
NaOH/EtOH, 2. H2SO4, 0 oC, 2 h, decompose; (h) TiCl3-NH4OAc, THF, H2O, rt, 42 h, decomposed.
We studied Diels-Alder reaction with ethyl propiolate in toluene under refluxing conditions. The
reaction was not efficient and only 25% of desired product was isolated as a regioisomeric mixtures (Eq.
19). If we use tert-butyl acrylate as a dienophile, the isolated yield of the Diels-Alder adduct improved, but
it was still low (46%) and the two regioisomers 3-130 and 3-131 could not be isolated by column
O
OBn H OBn OBn
OEt
H H OEt H OEt
O SiMe2Ph O O
BnO H BnO BnO
BnO BnO O
+ BnO O
(19)
BnO tolouene BnO BnO
O H O O
(xylene, reflux)
H H H
H H H
25%
3-113 3-128/3-129 = 1.0/0.51 3-130 3-131
238
O O
OBn H OBn OBn OtBu
H OtBu H t
O Bu H
O SiMe2Ph O O
BnO H BnO BnO
BnO BnO O
+ BnO (20)
BnO tolouene BnO BnO
O O O
H (xylene, reflux)
H H H
H 46% H H
However, when we used methylvinyl ketone as a dienophile, the desire product was isolated up to
62% yield with two regioisomeric mixture (3-134/3-135 = 0.2/1.0) (Eq. 21). It is not surprising the latter
reaction gave better isolated yield than that of previous reaction because methyl vinyl ketone is known to
The next step was Bayer-Villiger oxidation of the Diels-Alder products under known conditions.
All starting material 3-134 and/or 3-135 were consumed within 20h and single product was isolated after
work-up and column chromatography. Unfortunately, the isolated product was not desired one, but an
epoxide of the Diels-Alder adduct (Eq. 21). We also run Diels-Alder reaction and Bayer-Villiger oxidation
in situ. Although we found the formation of Diels-Alder products in TLC analysis, we could not
find/isolate any significant product after oxidation with mCPBA under buffered condition (Eq. 22).
O O
OBn H OBn OBn CH3
CH3 H
H CH3 H
O SiMe2Ph O O
BnO H BnO BnO
BnO BnO + BnO
BnO tolouene BnO O BnO
O O O
H (xylene, reflux)
H H H
H H H
3-130/3-131 = 0.2/1.0
3-113 3-134 mCPBA 3-135
62%
NaHCO3
(21)
CH2Cl2
48%
OBn OAc
OBn H
H O
O BnO
O
BnO OAc BnO
O BnO
BnO
BnO O
O H
H H
H
3-136 3-137
239
O
OBn H OBn OBn
H CH3 H H
SiMe2Ph CH3 O
O O mCPBA BnO
BnO BnO OAc
BnO
BnO tolouene
BnO
BnO O X BnO
BnO (22)
O O NaHCO3 O
H (xylene, reflux)
H H CH2 Cl2 H
H H H
2-113 2-138
2-134
reagent Bu3Sn-SiMe2Ph. For the reaction ethyl acrylate and methyl vinyl ketone were examined as
electrophiles. Although we followed the reaction very carefully by 1H NMR spectroscopy, we could not
find any evidence for the tandem reaction. After 6h, all diyne 3-92 were consumed and silastannylated
spiroketal 3-139 was isolated in 71 and 63%, respectively. As we described earlier the silatannylated cyclic
compound 3-139 are two diastereomers with a ratio of 1.54/1.0 and 1.67/1.0.
OBn OBn H
O H
O Bu3SnSiMe2Ph O X
BnO BnO
BnO + OEt BnO Y
BnO PdCl2(PhCN)2 BnO
O O H
or H
H
3-92 O 3-139
CH3
X
O
X = Bu3, SiMe2Ph OBn OBn Z
Y =Bu3, SiMe2Ph H Z H
Z = OEt, CH3 O O
BnO BnO
BnO BnO
BnO O BnO
O Y O Y
H H
H H
3-140 3-141
240
3. 9. Conclusion
Palladium catalyzed silylstannylative cyclization of dienes and its application to the synthesis of
the core structure of Papulacandin D have been studied. The silylstannylative cyclizations were performed
with various Pd(0) and Pd(+2) catalysts in the presence of a series of chiral/achiral phosphine ligand. The
axial chiralities of the silylstanylatied 1,3-dienes have been investigated by various temperature NMR
spectroscopy at 70 oC to -70 oC, and atropisomeric isomers have not observed by line shape analysis of 1H
NMR spectra. This is the first example of the atropisomeric frozen silylstanylatied 1,3-dienes.
The silylstanylatied 1,3-dienes can be brominated by NBS and destannylated by formic acid in
CH2Cl2 to give diens, which might react with dienophiles such as nitroethane, methyl vinyl ketone, and
Further transformation of the Diels-Alder adducts has to be studied to complete the synthesis of
241
CHAPTER 4
EXPERIMENTAL SECTION
4. 1. General Procedures
NMR spectra were recorded on Bruker on AM-250 and 400 MHz and CDCl3 was used for the
solvent. For 1H NMR spectra the hydrogen of CDCl3 was used as the standard (δ= 7.260 ppm) unless
otherwise mentioned. The 13C NMR spectrometer was operated at 100 MHz or 62.5MHz and used the
central line of CDCl3 as the standard (δ= 77.00 ppm). Chemical shifts are reported in parts per million on
the δ scale, and Hz is used for the coupling constants. The multiplicity are expressed like following: s =
singlet, d = doublet, t = triplet, q = quartet. Infrared spectra were obtained on Perkin-Elmer 1600 Infrared
Spectrometer and are reported in reciprocal centimeters (cm-1). The relative intensity of IR spectra are
reported as follows: br = broad, s = strong, m = medium, w = weak. High resolution mass spectra were
measured by The Ohio State University’s Shared Analytical Instrumentation Laboratory (SAIL) and
recorded on the Micromass QTOF electrospray mass spectrometer. Optical rotations were measured on
Perkin-Elmer 241 MC polarimeter with a sodium lamp at 589 nm and 1 mm slit, and the concentration is
g/dL. All melting points were determined by Thomas-Hoover capillary melting point apparatus and are
uncorrected.
All solvents were purchased from Fisher Co. and fresh distilled according to the literatures before
the using. Other chemicals were purchased from Aldrich Chemcal Co. or Across Co. and used as received.
Reactions were performed in flame dried glassware under an atmosphere of nitrogen, and monitored by
thin layer chromatography (TLC) using EM Science precoated 60 F254 plates or gas chromatography
(Hewlett Packard 5890). The GC was equipped with HP-1 column and an FID
242
detector connected to an HP 3396 integrator. Products were isolated by column chromatography using 60-
200 mesh silica gel. Preparative TLC was performed on Merck 2 mm preparative TLC plates or common
N
SiMe3
Imidazole (6.81 g, 100 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (12.3 g, 76.1 mmol) were
charged into a flame three necked 100 mL flask connected to a condenser. The mixture was refluxed under
positive nitrogen pressure for 10h 30 min. The mixture was cooled to rt, and distilled under reduced
pressure (52-54 oC/ 0.7 mmHg). The product can be distilled under house vacuum, but high vacuum is
more efficient. Previously reported 1-(trimethylsilyl) imidazole (10.1 g, 94%) was collected as a colorless
liquid. Colorless liquid. bp: 115-117 oC/~30 mmHg, 80-82 oC/4 mmHg, or 52-54 oC/ 0.7 mmHg (lit108 97
o
C/12 mmHg). The reagent was redistilled before further reaction. 1H NMR (CDCl3, 400 MHz): δ 0.47-
Preparation of N,N’-thiocarbonyl-diimidazole109
S
C
N N
N N
1-(Trimethylsilyl) imidazole (7.7 g, 55mmol) of was placed along with 50 mL of dried benzene
(distilled from CaH2) in a flame dried flask fitted with an efficient condenser. The flask was charged with
nitrogen atmosphere, and cooled to a temperature of 0 oC. Thiophosgen (3.2 g, 28 mmol) was slowly added
to the flask by a syringe. After the addition, the mixture was stirred at 0 oC for another 1 h. The solvent
243
was removed under house vacuum to give yellow solid. This solid was dried under high vacuum for
several days. An yellow solid (4.81 g) obtained and the yield was 98%. Yellow Solid. Mp: 98-100 oC
Ph3P CHCO2Et
To a 250 mL of flask was added 26.3g (0.1 mol) of triphenylphophine and 50 mL of dried benzene
was charged. Ethyl bromoacetate (16.7 g, 0.1 mmol) was dropwise a rate that maintains the reaction
mixture at rt or slightly higher. The mixture was stirred at rt for 4 h to give colorless salts. The salts were
filtered, and washed with 60 mL of cold benzene and 40 mL of pentane, and then dissolved in 600mL of
water. To remove some organic impurities, the solution was extracted with diethyl ether. Small amount of
phenolphthalein was added to the aqueous phase, which was cooled down to 0 oC. Sodium hydroxude
solution (2.0 M) was slowly added until the color changed to pink. The solid phophorane was collected by
filtration, and washed with cold water. The wet product was dried under high vacuum for overnight. A
white solid (26.4 g, 76%) was obtained, and the melting point and 1H NMR data are identical to literatures.
Ph3P CHCO2But
To a 100 mL of flame-dried flask was added 13.11g (0.05 mol) of triphenylphophine and 30 mL
of dried benzene was charged. 1,1-dimethylethyl bromoacetate (9.75 g, 0.05 mmol) was dropwise a rate
that maintains the reaction mixture at rt or slightly higher (around 20 min). The mixture was stirred at rt for
4 h to give white salts. The salts were filtered, and washed with 30 mL of cold benzene and 20 mL of
pentane, and then dissolved in 300mL of water. To remove some organic impurities, the solution was
extracted with diethyl ether. Small amount of phenolphthalein was added to the aqueous phase, which was
244
cooled down to 0 oC. Sodium hydroxude solution (1.0 M) was slowly added until the color changed to pink.
The solid phophorane was collected by filtration, and washed with cold water. The wet product was dried
under high vacuum for overnight. A white solid (16.1g, 86%) was obtained, and the melting point and 1H
NMR data are identical to literatures. Mp: 143-145 oC (lit.110(b) 152-154 oC).
Preparation of (cyanomethylene)triphenylphosphine111
PPh3 CHCN
Chloroacetonitrile (4.77 g, 0.063 mol) and triphenyl phophine (12.46 g, 0.0475 mol) were
dissolved in 70 mL of nitromethane in a flame dried 25 mL flask. The mixture was refluxed for 9 h,
and then the reactor was cooled down to rt. The precipitates were filtered and washed with
chloride was suspended in 100 mL of dried dichloromethane. Triethyl amine (7.0 mL) was slowly
added over 15 min., and the mixture was stirred for another 30 min. Cold water (2 X 75 mL) was used
for washing the mixture, and the organic phase was dried over magnesium sulfate. After filtration, the
organic phase was concentrated under vacuum to give yellow solid. The crude ylide was recrystalyzed
by benzene (14 mL/g). Total yield was 23% from chloroacetonitrile. Pale yellow solid. Mp: 188-
n
BuSnH
Bis-tributyltinoixde (30 g, 0.05mol) and and 6 g of (MeSiHO)x were placed in a flame dried three
neck flask connected to a condenser. The mixture was refluxed in an oil bath at 120 oC until no more
bubbles were observed (around 30min. to 1h). A distill head was connected to the flask, and the product
245
was carefully distilled under reduced pressure. The product was collected as a colorless liquid (20.9 g,
H3PO2
N
An aqueous solution of H3PO2 acid (3.93 mL, 5.0 g, 37.9 mmol, 50% in H2O) was charged into a
25 mL of one necked flask. The water was removed completely under high vacuum with heating. To the
water free hypophosphorous acid was added 5.2 mL (37.9 mmol) of N-ethylpiperidine at 0 oC.
Immediately, a white solid was formed, and the mixture was stirred for 30 min. The crude salt was used for
NH
O CCl3
H3CO
diethyl ether at rt under nitrogen atmosphere was added 7.7 mg (1.6 mmol) of sodium hydride in 50%
mineral oil. The reaction mixture was stirred until the solid had dissolved and gas evolution had ceased.
The reaction mixture was cooled to 0 oC, and 1.61 mL (16.1 mmol) of tricloroacetonitrile was added
slowly. The mixture was stirred in an ice bath for 10 min., and then at rt for another 30 min. It was
transferred to a separatory funnel, washed with saturated sodium bicarbonate, and brine solution. The
organic phase was dried over magnesium sulfate, the solid was filtered off, and the solvent was removed on
246
the rotary evaporator to get a yellow oil. This crude product was used for the next experimental without
Preparation of (trimethylsilyl)tri-n-butylstannane
Bu3SnSiMe3
A solution of 0.80 mL (5.71 mmol) of di-iso-propylamine in 10 mL of THF was cooled to -78 oC.
After 10 min, 3.4 mL of n-butyl lithium (1.6 M in hexane, 5.5 mmol) was added over 5min. The reaction
mixture was stirred at 0 oC for 5 min and then at rt for another 5 min. To the mixture was added tri-n-
butyltinhydride (1.34 mL, 5.0 mmol) at 0 oC over 5 min and the cooling bath was removed to bring back
the temperature to rt followed stirring for 20 min. Trimethylsilylchloride (0.70 mL, 5.5 mmol) was then
added slowly to the solution at 0 oC. After 10 min, the solution became cloudy (formation of lithium
chloride). The resulting solution was further stirred at rt for 2h. All volatile materials were removed on a
rotary evaporator to give crude product. The crude product was purified by column chromatography
(CDCl3, 400 MHz): δ 0.02 (s, 9 H), 0.81-0.89 (m, 15H), 1.24-1.51 (m, 12H).
Preparation of (tert-butyldimethylsilyl)tri-phenylstannane
Ph3SnSiMe2tBu
A solution of 0.91mL (6.5 mmol) of di-iso-propylamine in 10 mL of THF was cooled to -78 oC.
After 10 min, 3.75 mL of n-butyl lithium (1.6 M in hexane, 6.0 mmol) was added over 5min. The reaction
mixture was stirred at -78 oC for 5 min and then at rt for another 10 min. To the mixture was added tri-
phenyltinhydride (1.28 mL, 5.0 mmol) at 0 oC over 5 min and the cooling bath was removed to bring back
the temperature to rt followed stirring for 30 min. Tert-butyldimethylsilylchloride (0.98 g, 6.5 mmol) was
then added slowly to the solution at 0 oC. After 5 min, the solution became cloudy (formation of lithium
247
chloride). The resulting solution was further stirred at rt for 3h. All volatile materials were removed on a
rotary evaporator to give crude product. The crude product was purified by column chromatography
eluting with hexane to give 2.2g of of (trimethylsilyl)tri-n-butylstannane (92%). White solid (column
chromatography with hexane only). 1H NMR (CDCl3, 500 MHz): δ 0.44 (s, 6H), 1.00 (s, 9H), 7.33-7.37
13
(m, 9H), 7.51-7.59 (m, 6H). C NMR (CDCl3, 125 MHz): δ -2.49, 19.03, 27.47, 128.13, 128.32, 137.50,
140.64.
Bu3SnSiMe2Ph
To a solution of 20.5mL (14.6 mmol) of di-iso-propylamine in 250 mL of THF was added slowly
91.3 mL of n-butyl lithium (1.6 M in hexane, 14.6 mmol) was added at -78 oC. The reaction mixture was
stirred at -78 oC for 5 min and then at rt for another 20 min. To the resulting mixture was added slowly
Bu3SnH (35.7 mL, 38.6g, 13.3 mmol) at 0 oC followed by stirring at rt for 30 min.
Dimethylphenylsilylchloride (24.6 mL, 25g, 13.3 mmol) was then added slowly to the solution at 0 oC.
After 10 min, the solution became cloudy (formation of lithium chloride). The solution was further stirred
at rt for 10h. All volatile materials were removed on a rotary evaporator to give crude product. The crude
product was purified by column chromatography eluting with hexane to give the desired
(column chromatography with hexane only). 1H NMR (CDCl3, 500 MHz): δ 0.51 (s, 6H), 0.85 (t, J = 7.3
Hz, 9H), 0.86 (t, J = 7.0 Hz, 6H), 1.25 (sex, J = 7.3 Hz, 6H), 1.42 (tt, J = 7.2, 7.0 Hz, 6H), 7.32-7.34 (m,
13
3H), 7.45-7.47 (m, 2H). C NMR (CDCl3, 125 MHz): δ -0.39, 8.14, 13.66, 27.51, 30.12, 127.77, 128.36,
133.55, 140.89. IR (NaCl, neat): υ 2956m, 2923m, 1463w, 1244w, 1109w, 834m, 731m, 697m.
248
Preparation of 2-bromoacrolein115
Br CHO
To a solution of dimethyl sulfide (0.40 mmol, 24.9g, 19.4 mL) in acetonitrile (300 mL) was added
bromine (0.22 mmol, 35.2g, 11.3 mL) in carbon tetrachloride (10 mL) at -40 oC under nitrogen atmosphere
to give yellow precipitates. Addition of slightly excess amount of acrolein (0.26 mmol, 14.8g, 17.9 mL) to
the mixture changed the color of the precipitates from yellow to white. The precipitates were collected by
filtration with diethyl ether (200 mL), and the filtrates were washed with additional diethyl ether (100 mL)
and dried under house vacuum. After the solid was dissolved in 5% sodium bicarbonate solution (200 mL)
and stirred at 35 oC for 15 min, the aqueous mixture was extracted by dichloromethane. Combined organic
phase was washed with H2O and brine solution, successively, dried over MgSO4, and concentrated with
small amount of hydroquinone on a rotary evaporator (evaporation of solvent without hydroquinone led
most product polymeric product and yield only 5% of the desired product after vacuum distialltion!). The
crude product was distilled with small amount of hydroquinone under house vacuum to give the desired
product as pale yellow liquid form in 23% yield. Pale yellow liquid. Vacuum distillation. Bp 68-69 oC/38
mmHg (lit.115 45 oC/25 mmHg). 1H NMR (CDCl3, 250 MHz): δ 6.88 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3
13
Hz, 1H), 9.25 (s, 1H). C NMR (CDCl3, 62.5 MHz): δ 132.51, 136.47, 185.65. IR (NaCl, neat): υ 3423Br
Preparation of 1,2-dibromopropionitrile116
Br CN
Br
A solution of bromine (28.8g, 0.18mol) in dichloromethane (36 mL) was added dropwise to a
solution of acrylontrile (9.6g, 0.18mol) in dichloromethane (20 mL) at 0 oC under indirect light (6 h). The
mixture was exposed to light and the color of the mixture changed from deep red to colorless while the
temperature smoothly increased from 0 oC to rt over 6 h. After the reaction mixture was concentrated on a
249
rotary evaporator, the crude desired 1,2-dibromopropionitrile was obtained as colorless liquid by vacuum
distillation (35.5g, 93%). Colorless liquid. Vacuum distillation; Bp 61-62 oC/0.6 mmHg (lit.116 46-48
o
C/0.25 mmHg). 1H NMR (CDCl3, 250 MHz): δ 3.76 (B of ABX, JAB = 10.5 Hz, JBX = 6.5 Hz 1H), 3.79 (A
13
of ABX, JAB = 10.5 Hz, JAX = 9.0 Hz 1H), 4.54 (X of ABX, JAX = 9.0 Hz, JBX = 6.5 Hz 1H). C NMR
(CDCl3, 62.5 MHz): δ 24.86, 29.69, 115.28. IR (NaCl, neat): υ 3040s, 2971s, 2250m, 1614w, 1434s,
1420m, 1298m, 1236s, 1173s, 1126s, 951s, 931s, 910s, 735s, 702m, 616s.
Preparation of 2-bromoacrylonitrile116
Br CN
Freshly dried quinole (over KOH) (21.8 g, 169 mmol) was added dropwise to 2,3-
atmosphere and darkness. After stirred at rt for 2h, the reaction mixture was fractionally distilled under
reduced pressure to give 2-bromoacrylonitrile as yellow liquid (19.6 g, 90%). Yellow liquid. Vacuum
distillation. Bp 33 oC/32 mmHg (lit.116 18 oC/20 mmHg). 1H NMR (CDCl3, 250 MHz): δ 6.40 (d, J = 2.5
13
Hz, 1H), 6.71 (t, J = 2.5 Hz, 1H). C NMR (CDCl3, 62.5 MHz): δ 93.35, 115.03, 135.90. IR (NaCl, neat):
υ 3382Br s, 2226m, 1723s, 1600s, 1416m, 1372s, 1266s, 1234m, 1147s, 1107m, 934m, 911m, 878w, 738s,
704s, 617s.
AcO CO2Me
A mixture of methyl pyruvate (0.2 mmol, 20.4 g, 18.1 mL) and acetic anhydride (0.4 mmol, 40.1
g, 37.8 mL) was refluxed for 24 h under nitrogen atmosphere in the presence of pTsOH•H2O (0.5 g). The
reaction mixture was subjected to vacuum distillation under reduced pressure to give the desired methyl α-
250
acetoxyacrylate as colorless liquid (13.3 g, 46%). Colorless liquid. Vacuum distillation; Bp 85 oC/27
mmHg (lit.117 67-69 oC/17 mmHg). 1H NMR (CDCl3, 250 MHz): δ 2.02 (s, 3H), 3.78 (s, 3H), 5.44-5.46
13
(m, 1H), 6.01-6.02 (m, 1H). C NMR (CDCl3, 62.5 MHz): δ 20.30, 52.50, 113.96, 144.49, 161.87, 168.84.
IR (NaCl, neat): υ 3562Br s, 3007w, 2958m, 1770s, 1738s, 1650s, 1440s, 1373s, 1307s, 1218s, 1148s,
Preparation of 3-(acyloxy)-3-butene-2-one118
H3COC OAc
To a stirred solution of 2,3-butanedione (0.2 mol, 17.2 g, 17.6 mL) and triethyl amine (0.2 mol,
20.2 g, 27.8 mL) in dried dichloromethane (200 mL) at 0 oC was added dropwise to a solution of acetyl
chloride (0.2 mol, 15.7 g, 14.2 mL) in 50 mL of dichloromethane. The reaction mixture was stirred
overnight. To the stirred solution was added 200 mL of hexane and the precipitates were filtered and the
collected organic phase was concentrated with small amount of hydroquinone on a rotary evaporator. The
crude mixture was purified by vacuum distillation under reduced pressure in the presence of catalytic
amount of hydroquinone. The distillated product was obtained as a yellow liquid form in 41% yield (10.54
g). Yellow liquid. Vacuum distillation; Bp 86 oC/27 mmHg (lit.118(b) 32 oC/5 mmHg). 1H NMR (CDCl3,
13
400 MHz): δ 5.89 (d, J = 2.4 Hz, 1H), 5.59 (d, J = 2.4 Hz, 1H), 2.32 (s, 3H), 2.20 (s, 3H). C NMR
(CDCl3, 100 MHz): δ 20.30, 25.31, 113.95, 151.60, 168.76, 191.54. IR (NaCl, neat): υ 1766s, 1698s,
1643m, 1432m, 1372s, 1300m, 1212s, 1127s, 1024s, 970m, 929m, 874m.
H OAc
Cl C C CN
H H
To a aqueous solution of sodium cyanide (100 g, 1.95 mol) in H2O (300 mL) was added dropwise
chloroacetaldehyde (~50% in H2O, 2.0 mol, 254 mL) at -10 oC to 0 oC over 20 min. After stirring for 5
251
min, the mixture was extracted with diethyl ether (4 X 150 mL), and the combined organic phase was dried
over MgSO4, filtered, and concentrated on a rotary evaporator. The crude mixture was purified by vacuum
distillation under reduced pressure, and yellow liquid was obtained as the major fraction in 39% yield (57.5
g). Pale yellow liquid. Vacuum distillation; Bp 67 oC/1.2 mmHg (lit.119 65 oC/1 mmHg). 1H NMR
13
(CDCl3, 250 MHz): δ 5.54 (t, J = 5.8 Hz, 1H), 3.79 (d, J = 5.9 Hz, 2H), 2.18 (s, 3H). C NMR (CDCl3,
62.5 MHz): δ 20.03, 41.72, 60.95, 114.45, 168.57. IR (NaCl, neat): υ 1774s, 1639m, 1431w, 1374s, 1190s,
Preparation of 2-(acetyoxy)-2-propenenitrile119
AcO CN
To a 2-chloro-1-cyanoethyl acetate (12.8 g, 86.7 mmol) in diethyl ether (90 mL) was added slowly
dried triethyl amine (8.8 g, 12 mL, 86.7 mmol) at 0 oC. The reaction mixture was stirred at that
temperature for 16 h, and then the resulting mixture was diluted with excess amount of diluted HCl
neutralizing as well as dissolving Et3N•HCl. The combined ether layer was concentrated with small
amount of bezoquinone, and the crude mixture was purified by vacuum distillation to give the desired 2-
(acetyoxy)-2-propenenitrile as colorless liquid in 72% yield (6.9 g). Colorless liquid. Vacuum distillation;
Bp 86-88 oC/27 mmHg (lit119 65 oC/12 mmHg). 1H NMR (CDCl3, 250 MHz): δ 5.74 (d, J = 2.8 Hz, 1H),
13
5.67 (d, J = 2.8 Hz, 1H), 2.21 (s, 3H). C NMR (CDCl3, 62.5 MHz): δ 20.21, 113.06, 119.21, 127.44,
167.19. IR (NaCl, neat): υ 3032w, 2946m, 1757s, 1431s, 1308w, 1222s, 1068s, 1038s, 979w, 938m, 901m,
4. 3. Preparation of Substrates
D-ribonic acid γ-lactone (7.50 g, 50.63 mmol) was dissolved in 180 mL of acetone dried over 4 Å.
Iodine (1.80 g, 7.08 mmol, 14 mol %) and anhydrous MgSO4 were added, and the mixture was stirred at rt
252
(20 oC) under nitrogen atmosphere for 12 h until no more starting material was detected by TLC. After the
reaction mixture was diluted with excess amount of chloroform, the solid was filtered off and washed with
additional chloroform. The organic phase was washed with 0.2 M sodium thiosulfate solution to give pale
yellow solution, and the aqueous phase was back-extracted with additional dichloromethane. The
combined organic phase was washed with brine solution, dried over MgSO4, and filtered under house
vacuum. After removed the solvent in vacuum, pale yellow solid was formed. The solid was recrystallized
from 95% ethyl alcohol to give white solid needles. More product was isolated from the residue by flash
OH
O O
O O
1-77
Rf =0.5 (hexane :EtOAc = 1:1). Mp: 134-136 oC [lit.120 134-136 oC]. 1H NMR (CDCl3, 250 MHz): δ 1.39
(s, 3 H), 1.48(s, 3 H), 1.55 (Br s, 1 H), 3.82 (dd, J = 12.1, 1.6 Hz, 1 H), 4.00 (dd, J = 11.1, 2.3 Hz, 1 H),
4.63 (app t, J = 2.1 Hz, 1 H), 4.77 (dd, J = 5.6 Hz, 1 H), 4.84 (dd, J = 5.6 Hz, 1 H).
lactone.
chloride (6. 47 g, 42.9 mmol), and imidazole (6.09 g, 89.4 mmol) were placed in a 100 mL of flame-dried
flask under nitrogen atmosphere. To the flask was 25 mL of DMF dried over 4 Å molecular sieves slowly
added at 0 oC, and the mixture was stirred at 0 oC for 1 h and at rt for 9 h 30 min. After the starting
material disappeared on TLC, the mixture was diluted with dichloromethane, and washed with H2O and
brine solution. The combined organic phase was dried over MgSO4, filtered, and the solvent was removed
in vacuo. The crude mixture may be used for the next experiment without further purification, or purified
253
by flash column chromatography eluting with hexane;EtOAc = 5:1 to 4:1solution. After column
OTBS
O O
O O
1-78
Rf = 0.63 (hexane:EtOAc = 3:1). Mp: 73-75 oC (lit.121 75-76 oC). 1H NMR (CDCl3, 250 MHz): δ 0.06(s, 3
H), 0.08 (s, 3 H), 0.89 (s, 9 H), 1.39 (s, 3 H), 1.48 (s, 3 H), 3.80 (dd, J = 11.3, 1.0 Hz, 1 H), 3.89 (dd, J =
11.3, 1.8 Hz, 1 H), 4.60 (app t, J = 1.5, Hz, 1 H), 4.70 (dd, J = 5.6 Hz, 1 H), 4.73 (dd, J = 5.6 Hz, 1 H).
To a flame dried 250 mL of flask was added 10.3 g (34.05 mmol) of 5-O-[(1,1-dimethylethyl)
Freshly dried diethyl ether (150 mL) was introduced into the flask, and the temperature of the flask was
lowered to -78 oC. Dibal-H (1. 5 equiv., 1.5 M in toluene) was slowly dropwise over 12 min., and the
mixture was stirred at the temperature for 2 h. After starting material disappeared on TLC, the excess
amount of Dibal-H was quenched by 15 mL of absolute methyl alcohol at -78 oC, and the mixture was
diluted with diethyl ether. The organic phase was washed by saturated sodium tartaric acid solution, water,
and brine solution. The combined organic phase was dried over MgSO4, filtered under house vacuum, and
the solvent was removed on a rotary evaporator. The crude mixture maybe used for the next experiment
without further purification, or purified by flash column chromatography eluting with hexane:EtOAc = 4:1.
Without column, 10.34 g (>99%) of colorless oil was obtained as the product, and the oil changed to white
solid on standing at rt for overnight. 1H NMR shows the product is α/β mixture in a ratio of 0.13/1.00.
254
OTBS
O OH
O O
1-79
Rf = 0.47 (hexane:EtOAc = 4:1). Mp: 52-53 oC (lit.121 52-54 oC). Major isomer, β; 1H NMR (CDCl3, 250
MHz): δ 0.13 (s, 3 H) 0.14 (s, 3 H), 0.92(s, 9 H), 1.32 (s, 3 H), 1.49 (s, 3 H), 3.72-3.77 (m, 2 H), 4.36 (s, 1
H), 4.50 (d, J = 5.9 Hz, 1 H), 4.70 (d, J = 5.9 Hz, 1 H), 4.77 (d, J = 11.9 Hz, 1 H), 5.28 (d, J = 11.8 Hz, 1
H). Minor isomer, α; 1H NMR (CDCl3, 250 MHz): δ 0.06(s, 6 H), 0.85(s, 9 H), 1.39 (s, 3 H), 1.55 (s, 3 H),
3.73-3.76 (m, 2 H), 4.15 (s, 1 H), and another 4 H overlap over β anomeric peaks.
To a 100 mL of flame-dried three neck round bottom flask connected to a condenser were added
Dimethoxyethane (35 mL) was added and the mixture was stirred at rt. for 4 h and then refluxed for another
4 h. After the solvent was removed under vacuum, E and Z mixture mixtures were isolated by flash column
chromatography eluting with hexane only to hexane:EtOAc = 95:5. E and Z mixtures were isolated as
colorless oil in a ratio of 0.24/1.0, and the combined isolated yield was 92%.
Major, (Z)-isomer
TBSO OH
CO2tBu
O O
(Z)-1-80, R = tBu
255
20
[α]
Colorless oil (column chromatography, hexane:EtOAc = 95:5). Rf = 0.38 (hexane:EtOAc = 9:1). D
= +69.3 (c 1.0 in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.07 (s, 6H), 0.90 (s, 3H), 1.36 (s, 3 H), 1.47 (s,
3 H), 1.47 (s, 9 H), 2.9 (br s, 1H, disappeared with D2O), 3.59 (ddd, J=8.4, 5.4, 3.0 Hz, 1 H), 3.69 (dd,
J=10.2, 5.4 Hz, 1 H), 3.78 (dd, J=10.2, 3.0 Hz, 1 H), 4.26 (dd, J=8.4, 6.3 Hz, 1 H), 5.69 (ddd, J=8.5, 6.3,
13
1.0 Hz, 1 H), 5.89 (dd, J=11.6, 1.0 Hz, 1 H), 6.18 (dd, J=11.6, 8.6 Hz, 1 H). C NMR (CDCl3, 75 MHz):
δ -5.16, -5.12, 18.6, 25.6, 28.2, 28.3, 64.6, 70.3, 74.1, 78.2, 81.4, 109.2, 124.3, 143.5, 165.9. IR (NaCl,
neat): υ 3477m, 2854s, 2933s, 2857s, 1716s, 1652s, 1463m, 1369s, 1254s, 1159s, 1058 s, 836s, 779s.
Minor, (E)-isomer
CO2tBu
TBSO OH
O O
(E)-1-80, R = tBu
20
[α]
Colorless oil (column chromatography, hexane:EtOAc = 95:5). Rf = 0.24 (hexane:EtOAc = 4:1). D
= -4.62 (c 1.19 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s 9 H), 1.36 (s,
3 H), 1.48 (s, 3 H), 1.48 (s, 9 H), 3.56 (ddd, J = 9.0, 5.6, 3.1 Hz, 1 H), 3.65 (dd, J = 10.0, 5.6 Hz, 1 H), 3.79
(dd, J = 10.0, 3.1 Hz, 1 H), 4.10 (dd, J = 9.3, 6.6 Hz, 1 H), 4.80 (app t, J = 5.1 Hz, 1 H), 6.06 (dd, J = 15.6,
1.5 Hz, 1 H), 7.00 (dd, J = 15.6, 5.2 Hz, 1 H). IR (NaCl, neat): υ 3496m, 2979m, 2950m, 2930m, 2885m,
2875m, 1717s, 1658m, 1472m, 1463m, 1368s, 1314m, 1256s, 1217m, 1153s, 1062m, 837s, 779m.
Cyclized byproduct:
OTBS
O
CO2tBu
O O
α/β = 1.0/0.56
256
Column; hexane:EtOAc = 95:5 to 9:1. Colorless oil. Rf = 0.32 (hexane:EtOAc = 9:1). Major isomer, α;
1
H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.88 (s, 9 H), 1.43 (s, 9 H), 2.53(d, J = 6.8 Hz, 2 H), 3.68 (d, J
= 3.6 Hz, 2 H), 4.04(dd, J = 7.0, 3.5 Hz, 1 H), 4.27 (ddd, J = 11.1, 6.8, 4.3 Hz, 1 H), 4.39-4.46 (m, 1 H),
13
4.63 (dd, J = 6.5, 3.2 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.49, -5.35, 18.32, 25.55, 25.83, 27.40,
28.05, 40.01, 63.85, 78.69, 81.49, 82.03, 83.08, 84.69, 113.60, 169.96. Minor isomer, β; 1H NMR (CDCl3,
400 MHz): δ 0.03 (s, 6 H), 0.88 (s, 9 H), 1.43 (s, 9 H), 2.59(d, J = 6.9 Hz, 1 H), 2.61 (d, J = 6.9 Hz, 1 H),
3.66 (d, J = 3.6 Hz, 2 H), 4.04(dd, J = 7.0, 3.5 Hz, 1 H), 4.39-4.46 (m, 1 H), 4.72 (dd, J = 6.1, 4.4 Hz, 1 H),
4.78 (dd, J = 6.2, 0.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.56, -5.55, 18.10, 24.97, 25.90, 26.21,
28.05, 36.37, 64.55, 80.41, 80.70, 81.91, 84.00, 84.81, 112.09, 170.41. IR (NaCl, neat): υ 2930s, 2857s,
1733s, 1472m, 1462m, 1381m, 1368s, 1256s, 1212m, 1157s, 1078s, 977m, 949m, 837s, 778s.
A 50 mL of flame-dried three neck round bottom flask was charged with 609 mg (2.0 mmol) of 5-
flask under nitrogen atmosphere. The mixture was stirred at 20 oC. Even stirring it for 102 h, small
amount of starting material was detected on TLC. The solvent was removed under vacuum, and the (E)
and (Z) products were isolated as well as 9.5% of starting material. Total isolated yield was 95% based on
An alternative procedure may be used for the olefination by stabilized Wittig reagent: To a 50 mL
of flame-dried three neck round bottom were charged 609 mg (2.0 mmol) of 5-O-[(1,1-
flask under nitrogen atmosphere. The mixture was stirred under reflux for 8h. After flash column
257
chromatography, 72% of (E)/(Z) mixture (1.27/1.0) and 15% of cyclized byproduct were isolated. The
Major, (Z)-isomer
TBSO OH
CO2Et
O O
(Z)-1-80, R = tBu
20
[α]
Rf = 0.45 (hxane:EtOAc = 6:1). D = +78.5 (c 2.33, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.04 (s, 3
H), 0.05 (s, 3 H), 0.87 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.31 (s, 3 H), 1.44 (s, 3 H), 2.54 (Br s, 1 H), 3.55-
3.59 (m, 1 H), 3.65 (dd, J = 10.1, 5.7 Hz, 1 H), 3.75 (dd, J = 10.1, 3.0 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H),
4.23 (dd, J = 8.5, 6.3 Hz, 1 H), 5.73 (ddd, J = 8.3, 6.3, 1.0 Hz, 1 H), 5.94 (dd, J = 11.6, 1.1 Hz, 1 H), 6.26
13
(dd, J = 11.6, 8.6 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.49, -5.44, 14.07, 18.27, 25.33, 25.81, 27.89,
60.44, 64.26, 69.92, 73.75, 77.94, 109.01, 122.13, 144.48, 166.01. IR (NaCl, neat): υ 3484m, 2985m,
2931s, 2857s, 2720s, 1649m, 1464m, 1419m, 1381m, 1371m, 1254m, 1221m, 1191s, 1164m, 1057s, 871m,
836s, 779m.
Minor, (E)-isomer
CO2Et
TBSO OH
O O
(Z)-1-80, R = Et
Rf = 0.34 (hxane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H),
1.47(s, 3 H), 2.57 (app d, J = 4.9 Hz, 1 H), 3.47-3.59 (m, 1 H), 3.64 (dd, J = 9.9, 5.4 Hz, 1 H), 3.77 (dd, J =
9.9, 3.1 Hz, 1 H), 4.12 (dd, J = 9.3, 6.7 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 1 H), 4.86 (app td, J = 9.3, 2.1 Hz, 1
H), 6.13 (dd, J = 15.6, 1.5 Hz, 1 H), 7.11 (dd, J = 15.6, 4.9 Hz, 1 H).
258
Cyclized byproducts
OTBS
O
CO2Et
O O
20
[α]
Rf = 0.49 (hexane:EtOAc = 6:1). D = -12.0 (c 0.89, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 3
H), 0.05 (s, 3 H), 0.89 (s, 9 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.32(s, 3 H), 1.52(s, 3 H), 2.61 (d, J = 6.6 Hz, 2
H), 3.68 (d, J = 3.5 Hz, 2 H), 4.06 (dd, J = 6.7, 3.4 Hz, 1 H), 4.13 (qt, J = 7.1, 3.4 Hz, 2 H), 4.31 (ddd, J =
13
11.1, 6.7, 4.4 Hz, 1 H), 4.41 (dd, J = 6.4, 4.4 Hz, 1 H), 4.65 (dd, J = 6.4, 3.1 Hz, 1 H). C NMR (CDCl3,
100 MHz): δ -5.54, -5.38, 14.12, 18.30, 25.51, 25.88, 27.39, 38.82, 60.49, 63.78, 81.25, 82.01, 84.60,
84.85, 113.69, 170.65. IR (NaCl,neat): υ 2930s, 2857m, 1740s, 1472m, 1371m, 1256m, 1213m, 1159m,
OTBS
O
CO2Et
O O
Rf = 0.49 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 250 MHz): δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.24 (t, J = 7.1
Hz, 3 H), 1.32(s, 3 H), 1.46(s, 3 H), 2.67 (dd, J = 6.8, 2.7 Hz, 2 H), 3.62-3.74 (m, 2 H), 4.09-4.18 (m, 1 H),
4.14 (q, J = 7.2 Hz, 2 H), 4.49 (ddd, J = 10.9, 6.8, 4.1 Hz, 1 H), 4.71-4.81 (m, 2 H).
A flame-dried three necked round bottom flask was fitted with a double spaced condenser, and
1.00 g (2.45 mmol) of acrylic acid tert-butyl ester (Z)-1-80, R = tBu, 0.97g (4.90 mmol) of 1,1-
259
thiocarbonyldiimidazole, and 0.1g of DMAP were placed under nitrogen atmosphere. Dichloromethane
(dried over 4 Å MS, 20 mL) was added, and the mixture was refluxed for overnight (13 h 30 min.). The
reaction mixture was cooled to rt, and the solvent was removed by rotary evaporation under house vacuum.
The deep brown oil was purified by flash column chromatography eluting with hexane:EtOAc = 97:3 to
95:1mixture. Desired product (1.031 g) and starting material (86 mg) were obtained. The yield was 89%
N
N
S
O
TBSO
CO2tBu
O O
(Z)-1-81
20
Pale yellow oil (column chromatography, hexane:EtOAc = 97:3 to 95:5). [α] D = +88.5 (c 3.42 in CHCl3).
Rf = 0.23 (hexane:EtOAc = 9:1). 1H NMR (CDCl3, 250 MHz): δ -0.03 (s, 3 H), 0.00 (s, 3 H), 0.84 (s, 9 H),
1.40 (s, 9 H), 1.40 (s, 3 H), 1.51(s, 3 H), 3.92-4.04 (m, 2 H), 4.85 (dd J = 8.1, 6.3 Hz, 1 H), 5.53 (ddd J =
8.1, 4.0, 2.8 Hz, 1 H), 5.68 (dd, J = 11.6, 1.6 Hz, 1 H), 5.75 (ddd, J = 7.8, 6.4, 1.5 Hz, 1 H), 6.13 (dd J =
13
11.6, 7.8 Hz, 1 H), 6.98 (s, 1 H), 7.53 (s, 1 H), 8.25 (s, 1 H). C NMR (CDCl3, 75 MHz): δ -5.3, 18.3,
25.4, 25.9, 27.9, 28.2, 61.2, 74.1, 74.9, 81.3, 109.6, 118.0, 124.6, 130.7, 137.2, 142.3, 164.8, 183.3. IR
(NaCl, neat): υ 3125w, 2980m, 2953m, 2938m, 2884m, 2857m, 1713s, 1658w, 1650m, 1531w, 1463m,
1413m, 1391s, 1371s, 1345m, 1327s, 1282s, 1245s, 1156s, 1109m, 1066s, 1022m, 986m, 957m, 876m,
833s. Anal. Calcd. for C24H40O6N2SSi: C, 56.22; H, 7.87; N, 5.47; S, 6.24. Found: C, 56.42; H, 8.02; N,
5.38; S, 6.07.
The desired compound has been made by the same procedure with above. Acrylic acid tert-butyl
ester (E)-1-80, R = tBu (471 mg, 1.2mmol), 475 mg (2.4 mol) of 1,1-thiocarbonyldiimidazole, and 50 mg
260
of DMAP were placed into a flame dried 50 mL of three neck flask with a double spaced condenser.
Dichloromethane (dried over 4 Å MS, 15 mL) was added, and the mixture was stirred under refluxing for
10 h. The starting material was completely consumed (TLC), and excess amount of solvent was removed
under vacuum to give deep brown oil. The mixture was purified by flash column chromatography eluting
N
N
S
CO2tBu
O
TBSO
O O
(E)-1-81
20
[α]
Pale yellow oil. Column; hexane:EtOAc = 8:1 to 6:1. D = +3.5 (c 1.0, CHCl3). Rf = 0.24
(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ -0.04 (s, 3 H), 0.01 (s, 3 H), 0.85 (s, 9 H), 1.35 (s, 9
H), 1.41 (s, 3 H), 1.51(s, 3 H), 3.97 (dd J = 12.0, 2.9 Hz 1 H), 4.06 (dd J = 11.9, 2.3 Hz 1 H), 4.73 (dd J =
8.9, 6.2 Hz, 1 H), 4.86 (ddd J = 7.1, 6.0, 1.3 Hz, 1 H), 5.36 (app dt, J = 9.0, 2.5 Hz m, 1 H), 5.99 (dd J =
13
15.6, 1.4 Hz, 1 H), 6.64 (dd J = 15.6, 5.7 Hz, 1 H), 7.08 (s, 1 H), 7.58 (s, 1 H), 8.37 (s, 1 H). C NMR
(CDCl3, 100 MHz): δ -5.9, 17.9, 25.0, 27.5, 27.6, 60.0, 74.5, 75.8, 80.14 (d), 109.4, 117.4, 124.7, 130.6,
136.6, 138.6, 164.1, 182.0. IR (NaCl, neat): υ 3134m, 2980s, 1932s, 2857s, 1817m, 1713s, 1608m, 1532w,
This compound was made with pure acrylic acid ethyl ester or (E)/(Z) mixture because it is
difficult to separate the mixture. (Z)-Acrylic acid ethyl ester (Z)-1-80, R = Et (123 mg, 0.337 mmol), 1,1-
thiocarbonyldiimidazole (180 mg 1.012 mmol), and 19 mg of DMAP were used along with freshly dried
261
THF. After refluxing for 12 h, some starting material was detected on TLC. Additional 3.0 equivalents of
thiocarbonyldiimidazole was added to the flask, and refluxed for 5h 30min. The starting material was
completely consumed (TLC), and the mixture was cooled to rt. After removal of the solvent in vacuo,
brown mixture was isolated by flash column chromatography by hexane:EtOAc = 6:1 to 4:1. Desired
N
N
S
O
TBSO
CO2Et
O O
(Z)-1-82
20
[α]
Yellow oil. Column; hexane:EtOAc = 6:1 to 4:1. Rf = 0.30 (hexane:EtOAc = 4:1). D = +86.3 (c
0.76, CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.05 (s, 3 H), -0.01 (s, 3 H), 0.83 (s, 9 H), 1.19 (t, J = 7.1
Hz, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.93-4.07 (m, 4 H), 4.86(dd, J = 8.4, 6.4 Hz, 1 H), 5.47-5.50 (m, 1 H),
5.72-5.80 (m, 2 H), 6.22 (dd, J = 11.6, 7.7 Hz, 1 H), 6.98 (d, J = 0.7 Hz, 1 H), 7.52 (s, 1 H), 8.22(s, 1 H).
13
C NMR (CDCl3, 100 MHz): δ -5.6, 14.0, 18.1, 25.0, 25.7, 27.6, 60.6, 61.0, 74.0, 74.6, 81.1, 109.5, 117.8,
122.5, 130.5, 143.8, 165.2, 182.9. IR (NaCl, neat): υ 3132w, 2985s, 2930s, 2857s, 1716s, 1650m, 1532m,
1464m, 1389m, 1325m, 1283m, 1229m, 1194m, 1109m, 1066m, 1024m, 986m, 957m, 870m, 834s, 778m,
745m, 655m.
Because it is difficult to separate (E)/(Z) mixture of acrylic acid ethyl ester, the starting material
was used without further purification. Acrylic acid ethyl ester 1-80, R = Et (294 mg, 0.806 mmol, E/Z =
1.3/1.0) and 431 mg (2.42 mmol) of 1,1-thiocarbonyldiimidazole were dissolved in 10 mL of freshly dried
THF along with catalytic amount of DMAP. The mixture was refluxed under nitrogen atmosphere for 6 h.
Because some starting material was detected on TLC, another 3.0 equivalents of thiocarbonyldiimidazole
262
were added, and continually refluxed it for overnight (total 19 h). After confirming that all starting material
was consumed (TLC), the solvent was removed under reduced pressure. The brown mixture was purified
by flash chromatography eluting with hexane:EtOAc = 6:1 to 4:1 solution. E product (149 mg) and Z
product (127 mg) were isolated as yellow oil. Total isolated yield was 77% and the (E)/(Z) ratio was 1/1.2.
N
N
S
CO2Et
O
TBSO
O O
(E)-1-82
Yellow oil. Column; hexane:EtOAc = 6:1 to 4:1. Rf = 0.10 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400
MHz): δ -0.05 (s, 3 H), -0.00 (s, 3 H), 0.83 (s, 9 H), 1.13 (t, J = 7.1 Hz, 3 H), 1.39 (s, 3 H), 1.49 (s, 3 H),
3.93-4.08 (m, 4 H), 4.72 (dd, J = 8.8, 6.2 Hz, 1 H), 4.86 (ddd, J = 7.3, 6.1, 1.5 Hz, 1 H), 5.36 (app dt, J =
8.8, 2.6 Hz, 1 H), 6.05 (dd, J = 15.6, 1.5 Hz, 1 H), 6.73 (dd, J = 15.6, 5.5 Hz, 1 H), 7.26 (s, 1 H), 7.53 (t, J
13
= 1.1 Hz, 1 H), 8.25 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.7, 14.0, 18.2, 25.3, 25.7, 27.7, 60.3, 60.5,
74.9, 76.0, 80.4, 109.9, 117.6, 123.1, 130.9, 136.8, 140.1, 165.1, 182.3.
dimethyl[1, 3]dioxolan-4-yl}-acrylonitrile
To a 100 mL of flame-dried three necked round bottom flask was added 378 mg (1.241 mmol) of
acid under nitrogen atmosphere. Freshly dried toluene (40 mL) was introduced via a syringe, and the
mixture was refluxed. Two more 206 mg samples of (cyanomethylene)triphenyl-phosphorane were added
after 8 h and 12 h, respectively. After the solvent was removed in vacuo, the mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 10:1 to 8:1, to get 146 mg of (E)-1-83 (white solid),
263
CN
TBSO OH
O O
(E)-1-83
White solid (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.48 (hexane:EtOAc = 4:1). Mp:
20
68-70 oC. [α] D = -6.0 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.34
(s, 3H), 1.45 (s, 3H), 2.16 (br s, 1H), 3.45 (ddd, J = 9.4, 5.1, 3.1 Hz, 1H), 3.64 (dd, J = 10.1, 5.2 Hz, 1H),
3.78 (dd, J = 10.1, 3.1 Hz, 1H), 4.13 (dd, J = 9.5, 6.9 Hz, 1H), 4.80 (ddd, J = 6.7, 3.8, 2.1 Hz, 1H), 5.72
13
(dd, J = 16.2, 2.0 Hz, 1H), 7.00 (dd, J = 16.2, 3.8 Hz, 1H). C NMR (CDCl3, 100 MHz): δ -5.54, -5.41,
18.27, 24.99, 25.81, 27.38, 64.11, 69.77, 76.62, 77.19, 100.30, 109.87, 117.26, 151.19. IR (NaCl, neat):
υ 3498br s, 2989m, 2956s, 2930s, 2850s, 2227s, 1638m, 1432m, 1463m, 1383s, 1382s, 1257s, 1217s,
1165m, 1067s, 972w, 864m, 837s, 779s. Anal. Calcd. for C16H29O4NSi: C, 58.68; H, 8.93; N, 4.28. Found:
TBSO OH
CN
O O
(Z)-1-83
Yellow oil (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.35 (hexane:EtOAc = 4:1).
20
[α] D = -30.4 (c 1.15 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H),
1.37 (s, 3H), 1.48 (s, 3H), 2.62 (Br s, 1H), 3.54 (ddd, J = 9.2, 4.5, 3.5 Hz, 1H), 3.70 (dd, J = 10.1, 4.8 Hz,
1H), 4.18 (dd, J = 9.4, 6.4 Hz, 1H), 5.09 (ddd, J = 8.3, 6.4, 0.9 Hz, 1H), 5.52 (dd, J = 11.2, 1.0 Hz, 1H),
13
6.56 (dd, J = 11.2, 8.5 Hz, 1H). C NMR (CDCl3, 100 MHz): δ -5.51, -5.41, 18.29, 25.25, 25.82, 27.68,
63.91, 69.37, 76.10, 77.45, 101.76, 110.21, 115.36, 148.94. IR (NaCl, neat): υ 3498Br s, 3070w, 2989m,
2885s, 2857s, 2224m, 1723w, 1631w, 1472s, 1463m, 1383s, 1372s, 1255s, 1219s, 1164s, 1096s, 1063s,
937w, 869m, 837s, 779s, 736m, 670m. HRMS (Electrospray): Calcd. for C16H29O4NSNa (M++Na),
264
350.1764; Found (M++Na), 350.1760. Anal. Calcd. for C16H29O4NSi: C, 58.68; H, 8.93; N, 4.28. Found:
HO OTBS
CN
O O
(Z)-1-84
20
[α]
Compound (Z)-1-84 was isolated as yellow oil and 3% yield. Rf = 0.24 (hexane:EtOAc = 4:1), D =-
9.8 (c 0.83, CHCl3). 1H NMR (CDCl3, 250 MHz): δ 0.09 (s, 3 H), 0.89 (s, 9 H), 1.49 (s, 3 H), 1.52 (s, 3 H),
1.94 (t, J = 6.1 Hz, OH, disappeared with D2O), 3.68-3.71 (m, 2 H), 3.89-3.96 (m, 1 H), 4.34 (app t, J = 6.1
13
Hz, 1 H), 5.05 (dd, J = 9.1, 6.2 Hz, 1 H), 5.46 (d, J = 11.1 Hz, 1 H), 6.60 (dd, J = 11.0, 9.3 Hz, 1 H). C
NMR (CDCl3, 100 MHz): δ -3.9, -3.7, 18.5, 25.6, 26.3, 28.2, 65.0, 71.4, 75.7, 79.8, 101.7, 109.9, 115.6,
150.2. IR (NaCl, neat): υ 3498s, 2988s, 2931s, 2885s, 2857s, 2224m, 1727w, 1631w, 1472m, 1463m,
1382m, 1372m, 1254s, 1219s, 1164m, 1096m, 1063s, 937m, 869m, 837s, 779s, 670m.
CN
HO OTBS
O O
(E)-1-84
Compound (E)-1-84 was isolated as yellow oil and 1% yield. Rf = 0.24 (hexane:EtOAc = 4:1). 1H NMR
(CDCl3, 250 MHz): δ 0.15 (s, 3 H), 0.89 (s, 9 H), 1.39 (s, 3 H), 1.49 (s, 3 H), 1.93 (app t, J = 6.0 Hz 1 H),
3.64-3.83 (m, 3 H), 4.31 (app t, J = 6.7 Hz, 1 H), 4.75 (ddd, J = 6.3, 4.5, 1.0 Hz, 1 H), 5.70 (dd, J = 16.2,
OTBS
O
CN
O O
1-85
265
Compound trans-1-85 was isolated as colorless oil and 4% yield. Rf = 0.47 (hexane:EtOAc = 4:1). 1H
NMR (CDCl3, 250 MHz): δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H), 1.50(s, 3 H), 2.65(d, J = 6.7 Hz, 1 H),
3.70 (dd, J = 11.0, 2.8 Hz, 1 H), 3.78 (dd, J = 11.0, 2.9 Hz, 1 H), 4.15 (app t, J = 2.8 Hz, 1 H), 4.42 (app dt,
13
J = 6.7, 4.3 Hz, 1 H), 4.71 (dd, J = 5.9, 4.3 Hz, 1 H), 4.84 (d, J = 6.1 Hz, 1 H). C NMR (CDCl3, 100
MHz): δ -5.7, -5.6, 18.1, 18.9, 24.6, 25.8, 26.0, 65.4, 78.1, 81.3, 83.3, 84.7, 112.8, 117.6.
To a flame-dried 100 mL three necked flask fitted with a condenser were added 133 mg (0.406
mmol) of acrylonitrile (E)-1-84, 3.0 equivalents of 1,1-thiocarbonyldiimidazole (217 mg, 1.217 mmol), and
15 mg of DMAP. Freshly dried THF (40 mL) was added to the flask, and the mixture was stirred under
reflux condition. Another 217 mg of 1,1-thiocarbonyldiimidazole was added after 14 h, and refluxing was
continued for 8 h. All solvents were removed under reduced pressure to give crude brown mixtures. The
mixture was isolated by flash column chromatography eluting hexane:EtOAc = 5:1 to 2:1. The desired
product (E)-1-86 was obtained as pale yellow solid (102 mg, 88% based on recovered starting material) as
well as 46 mg of a mixture of (E)-1-86 and two isomers of cyclic byproducts 1-85 and in a ratio of 0.22/1.0
(cis/trans).
N
N
S
O CN
TBSO
O O
(E)-1-86
Pale yellow solid (column chromatography, hexane:EtOAc = 5:1 to 2:1) Rf = 0.25 (hexane:EtOAc = 3:1).
20
Mp: 51-53 oC. [α] D = -9.5 (c 0.61 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.03 (s, 3H), 0.01 (s, 3H),
0.85 (s, 9H), 1.40 (s, 3H), 1.50 (s, 3H), 3.94 (dd, J = 12.0, 3.1 Hz, 1H), 4.03 (dd, J = 12.0, 2.4 Hz, 1H),
4.75 (dd, J = 8.6, 6.5 Hz, 1H), 4.83 (ddd, J = 6.4, 4.7, 1.8 Hz, 1H), 5.39 (app dt, J = 8.5, 2.8 Hz, 1H), 5.68
266
(dd, J = 16.2, 1.8 Hz, 1H), 6.56 (dd, J = 16.1, 4.6 Hz, 1H), 7.05 (d, J = 0.7 Hz, 1H), 7.60 (s, 1H), 8.29 (s,
13
1H). C NMR (CDCl3, 100 MHz): δ -5.69, -5.62, 18.14, 25.09, 25.68, 27.47, 60.43, 74.85, 75.86, 80.46,
101.81, 110.22, 116.16, 117.97, 131.19, 136.40, 147.56, 182.24. IR (NaCl, neat): υ 3412Br s, 3131m,
3332m, 2988s, 2954s, 2931s, 2884s, 2857s, 2227s, 1704m, 1639m, 1533m, 1470s, 1392s, 1324s, 1283s,
1165m, 1108s, 1054m, 1023s, 957s, 837s, 813m, 779s, 744m, 673m, 655s. Anal. Calcd. for
OTBS
O
CN
O O
cis-1-85
1
H NMR (CDCl3, 400 MHz): δ 0.08 (s, 6 H), 0.90 (s, 3 H), 1.35 (s, 3 H), 1.53 (s, 3 H), 3.73 (d, J = 4.2 Hz,
1 H), 4.11-4.21 (m, 1 H), 4.44 (dd, J = 6.4, 4.2 Hz, 1 H), 4.70 (dd, J = 6.4, 2.7 Hz, 1 H). 13C NMR (CDCl3,
100 MHz): δ -5.51, -5.37, 18.37, 22.30, 25.04, 25.93, 27.43, 63.84, 80.47, 82.27, 84.22, 85.65, 114.16,
116.85.
OTBS
O
CN
O O
trans-1-85
Rf = 0.47 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 250 MHz): δ 0.05 (s, 6 H), 0.89 (s, 9 H), 1.35(s, 3 H),
1.50(s, 3 H), 2.65(d, J = 6.7 Hz, 1 H), 3.70 (dd, J = 11.0, 2.8 Hz, 1 H), 3.78 (dd, J = 11.0, 2.9 Hz, 1 H),
4.15 (app t, J = 2.8 Hz, 1 H), 4.42 (app dt, J = 6.7, 4.3 Hz, 1 H), 4.71 (dd, J = 5.9, 4.3 Hz, 1 H), 4.84 (d, J =
13
6.1 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.7, -5.6, 18.1, 18.9, 24.6, 25.8, 26.0, 65.4, 78.1, 81.3, 83.3,
267
Preparation of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-
The acrylonitrile (Z)-1-83 (143 mg, 0.45 mmol) and 161 mg (0.90 mmol) of 1,1-
was added 30 mg of DMAP, and the mixture was refluxed under nitrogen atmosphere. After 5 h, another
2.0 equivalents of 1,1-thiocarbonyldiimidazole were added, and refluxing was continued. The TLC showed
starting material still remained after 12 h. Finally, 2.0 equivalents more of 1,1-thiocarbonyldiimidazole, 32
mg of DMAP, and 20 mL of dichloromethane were added, and the mixture was refluxed for total 24 h.
After the mixture was cooled to rt, the solvent was removed under reduced pressure to give crude mixture.
The mixture was isolated by flash column chromatography eluting hexane:EtOAc = 4:1, and 62 mg
(26%)of desired product was obtained as yellow oil. TBDMS groups of some starting material migrated to
the nearby hydroxyl groups (1,3 TBS migration), and the resulting product reacted with 1,1-
N
N
S
O
TBSO
CN
O O
(Z)-1-86
20
Brown oil. Column chromatography; hexane:EtOAc = 4:1 to 2:1. Rf = 0.49 (hexane:EtOAc = 2:1). [α] D
= +22.9 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.01 (s, 3H), 0.01 (s, 3H), 0.88 (s, 9H), 1.46 (s,
3H), 1.55 (s, 3H), 3.98 (dd, J = 11.9, 3.1 Hz, 1H), 4.10 (dd, J = 11.9, 2.4 Hz, 1H), 4.87 (dd, J = 9.1, 6.3 Hz,
1H), 5.19 (ddd, J = 8.8, 6.3, 0.8 Hz, 1H), 5.40 (dd, J = 11.1, 0.9 Hz, 1H), 5.50 (app dt, J = 9.1, 2.8 Hz, 1H),
13
6.45 (dd, J = 11.1, 8.9 Hz, 1H), 7.07 (d, J = 0.7 Hz, 1H), 7.59 (s, 1H), 8.34 (s, 1H). C NMR (CDCl3, 100
MHz): δ -5.73, -5.69, 18.08, 25.08, 25.62, 27.52, 60.47, 74.55, 75.46, 80.28, 102.78, 110.71, 114.30,
117.52, 131.09, 137.17, 147.90, 182.59. IR (NaCl, neat): υ 3395Br s, 3164m, 3332m, 3120m, 2988m,
2955s, 2931s, 2883s, 2857s, 2224m, 1703m, 1533m, 1464s, 1391s, 1325s, 1284s, 1230s, 1163m, 1102s,
268
1075s, 1025s, 990s, 956s, 911s, 869s, 834s, 813m, 778s, 734s, 656m, 644m. Anal. Calcd. for
C20H31O4N3SiS; C, 54.89; H, 7.14; N, 9.60. Found; C, 54.40; H, 7.06; N, 9.32. HRMS (Electrospray): m/z
3]dioxolan-4-yl}-ethene
Dried methyltriphenylphosphonium bromide (3.55 g, 9.93 mmol) was suspended into a 250 mL of
flame-dried flask, which was charged with 40 mL of fresh THF under nitrogen. The flask was cooled to –
78oC, and 6.2 mL of nBuLi (1.6 M in hexane) was slowly added to give yellow color. The mixture was
stirred at -78 oC for 10 min. and at rt for 2h. The solution was cooled to -78 oC again, and 1.25 g (3.97
mmol) of 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-ribonofuranose in 25 mL
of dried THF was dropwised. After the addition, the mixture stirred at -78oC for 10 min. and at rt for 21h.
To quench excess phosphorane, 10 mL of acetone was added, and the mixture stirred for 10min. After
removed the solvent under vacuum, the mixture was purified by flash column chromatography eluting with
hexane:acetone = 10:1. The isolated product was 733.5 mg of 1-87 as colorless oil, and 170.7 mg of
starting material was recovered. The yield was 71% based on the recovered starting material.
TBSO OH
O O
1-87
20
[α]
Column; hexane:Acetone = 10:1. Rf = 0.32 (hexane:EtOAc = 9:1). D = -1.55 (c 0.58, CHCl3). 1H
NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.34 (s, 3 H), 1.45 (s, 3 H), 2.44 (Br s, 1 H), 3.60-
3.67 (m, 1 H), 3.66 (dd, J = 15.5, 5.7 Hz, 1 H), 3.79 (dd, J = 9.9, 3.6 Hz, 1 H), 4.04(dd, J = 8.9, 6.3 Hz, 1
H), 4.67 (app tt, J = 12.9, 1.0 Hz, 1 H), 5.26 (ddd, J = 11.7, 1.7, 1.3 Hz, 1 H), 5.40 (app dt, J = 17.1, 3.1 Hz,
13
1 H), 6.03 (ddd, J = 17.1, 10.4, 6.6 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.5, -5.5, 18.3, 25.4, 25.8,
269
27.8, 64.3, 69.5, 77.4, 78.7, 108.7, 117.4, 134.2. IR (NaCl, neat): υ 3561m, 2959s, 2930s, 2856m, 1643w,
1462m, 1370m, 1253m, 1216m, 1167m, 1114m, 1058s, 924m, 873m, 836s, 778m.
3]dioxolan-4-yl}-ethene; 1’-O-(1-imidazoyl)thione
4-yl}-ethene (153 mg, 0.506 mmol), 1,1-thiocarbonyldiimidazole (270 mg, 1.517 mmol), and 40 mg of
DMAP were dissolved in 20 mL of freshly dried THF. The mixture was refluxed under nitrogen
atmosphere for 8 h 30 min., and another 270 mg of 1,1-thiocarbonyldiimidazole was added. The mixture
was refluxed for another 12 h 30 min, and all starting material was consumed (TLC). After the reaction
mixture cooled to rt, the solvent was removed under reduced pressure to give brown oil. The oil was
purified by flash column chromatography with hexane:acetone = 15:1 solution. The product was obtained
N
N
S
TBSO O
O O
1-88
Yellow oil. Column; hexane:acetone = 15:1. Rf = 0.22 (hexane:Acetone = 9:1). 1H NMR (CDCl3, 400
MHz): δ -0.04 (s, 3 H), 0.01 (s, 3 H), 0.85 (s, 9 H), 1.39 (s, 3 H), 1.49 (s, 3 H), 3.97 (dd, J = 11.9, 3.4 Hz, 1
H), 4.08 (dd, J = 11.9, 2.5 Hz, 1 H), 4.68 (dd, J = 14.1, 6.3 Hz, 1 H), 4.71 (dd, J = 14.6, 6.3 Hz, 1 H), 5.12
(app dt, J = 10.3, 0.9 Hz, 1 H), 5.32 (app dt, J = 17.0, 1.2 Hz, 1 H), 5.45 (app dt, J = 7.5, 3.2 Hz, 1 H), 5.76
13
(ddd, J = 17.1, 10.3, 6.8 Hz, 1 H), 7.03 (s, 1 H), 7.58 (s, 1 H), 8.29 (s, 1 H). C NMR (CDCl3, 100 MHz):
δ -5.6, 18.2, 25.2, 25.7, 27.6, 60.5, 74.7, 78.3, 81.4, 109.2, 117.8, 118.9, 130.7, 132.2, 136.7, 182.8. IR
270
(NaCl, neat): υ 3179m, 2986s, 2953s, 2930s, 2884m, 2857s, 1646w, 1531w, 1464s, 1388s, 1325s, 1283s,
1247s, 1166m, 1109s, 1054m, 1009m, 958m, 874m, 835s, 778m, 744m, 654m.
A dried 100 mL three necked round bottom flask was equipped with a condenser and a magnetic
D-ribonofuranose 1-79 (305mg, 1.00 mmol) and 133 mg (1.50 mmol) of O-methylhydroxyl amine
hydrochloride under nitrogen. Methyl alcohol (50 mL) and 1 mL of pyridine were added, and the mixture
was refluxed under nitrogen for 5.5 h. The mixture was taken up water, and extracted with
dichloromethane. The combined organic phase was washed with brine and dried over MgSO4. After the
solid was filtered off, the collected organic phase was concentrated on a rotary evaporator and purified by
flash column chromatography eluting with hexane:EtOAc = 6:1. The isolated product (319 mg of colorless
oil) was obtained as a syn/anti mixture in a ratio of 1.0/0.25, and the yield was 96%.
TBSO OH
NOCH3
O O
1-89
(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 250 MHz): major isomer, syn, δ 0.05 (s, 6 H), 0.87 (s, 9 H), 1.32
(s, 3 H), 1.43 (s, 3 H), 2.62 (d, J = 4.8 Hz, 1 H), 3.50-3.70 (m, 3 H), 3.83 (s, 3 H), 4.09 (dd J = 8.5, 6.4 Hz 1
H), 4.72 (app t, J = 7.4 Hz 1 H), 7.16 (d, J = 7.7 Hz 1 H); minor isomer, anti; δ 0.05 (s, 6 H), 0.87 (s, 9 H),
1.11 (s, 3 H), 1.21 (s, 3 H), 2.70 (d, J = 3.8 Hz, 1 H), 3.71-3.83 (m, 3 H), 3.87 (s, 3 H), 4.20 (app t J = 6.7
13
Hz 1 H), 5.26 (app t, J = 6.3 Hz 1 H), 6.83 (d, J = 6.3 Hz 1 H). C NMR (CDCl3, 75 MHz): major isomer,
syn, δ -5.3, -5.1, 18.3, 26.0, 27.0, 28.0, 62.0, 64.3, 69.5, 75.4, 78.6, 109.9, 147.2; minor isomer, anti, δ -5.6,
-5.5, 18.4, 25.3, 25.7, 27.8, 62.4, 63.1, 70.7, 75.9, 82.4, 113.1, 149.1. IR (NaCl, neat): υ 3522Br, 2987s,
271
2956s, 2932s, 2884s, 2875s, 2819w, 1795w, 1741w, 1629w, 1471s, 1468s, 1382s, 1255s, 1219s, 1170s,
The reaction was performed with 173 mg (0.519 mmol) of O-methylhydroxyl amine 1-89 and 308
atmosphere. The mixture was refluxed in an oil bath for 9 h, and another 1.0 equivalent of 1,1-
thiocarbonyldiimidazole was added. After 1.5 h refluxing, all starting material was consumed (TLC). The
mixture was cooled to rt, and the crude mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 8:1 to 6:1. The isolated product was obtained as yellow oil (212 mg), and yield was 92%
(syn/anti = 1.00/0.32).
N
N
S
TBSO O
NOCH3
O O
1-90
Yellow oil (column chromatography, hexane:EtOAc = 8:1 to 6:1). Rf = 0.29 (hexane:EtOAc = 4:1). 1H
NMR (CDCl3, 400 MHz): major syn, δ 0.00(s, 3 H), 0.04 (s, 3 H), 0.88 (s 9 H), 1.39 (s, 3 H), 1.51 (s, 3 H),
3.57 (s, 3 H), 3.99 (dd, J = 11.7, 2.9 Hz, 1 H), 4.12 (dd, J = 11.9, 2.6 Hz, 1 H), 4.76-4.81 (m, 2 H), 5.49-
5.58(m, 1 H), 7.04 (s, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.61 (s, 1 H), 8.30 (s, 1 H); minor anti, δ 0.01 (s, 3
H), 0.03 (s, 3 H), 0.86 (s 9 H), 1.39 (s, 3 H), 1.52 (s, 3 H), 3.66 (s, 3 H), 3.95-4.03 (m, 2 H), 4.76-4.81 (m, 1
H), 5.31 (app t, J = 6.0 Hz, 1 H), 5.49-5.56 (m, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 7.04 (s, 1 H), 7.63 (s, 1 H),
13
8.30 (s, 1 H). C NMR (CDCl3, 125 MHz): major syn, δ -5.3, 18.4, 25.3, 25.9, 27.8, 60.7, 61.9, 74.2, 75.1,
80.6, 110.6, 118.1, 131.0, 137.0, 145.9, 182.0. IR (NaCl, neat): υ 3133w, 2989m, 2953m, 2935m, 2897m,
2856m, 1739w, 1626m, 1531w, 1463m, 1391s, 1344m, 1323s, 1283s, 1246s, 1229s, 1109m, 1076m, 1042s.
272
Anal. Calcd. for C19H33O5N2Ssi: C, 51.44; H, 7.50; N, 9.42; S, 7.23. Found: C, 51.57; H, 7.61; N, 9.23; S,
7.11.
dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone
A mixture of 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylehtyldiene)-D-
ribonofuranose 1-79 (222 mg, 0.73 mmol) and N,N-dimethyl hydrazine (6.6 mg, 1.10 mmol) was dissolved
in 10 mL of absolute methyl alcohol under nitrogen atmosphere. The mixture was refluxed in an oil bath
until no more starting material was detected on TLC (additional N,N-dimethyl hydrazine were added to the
reaction mixture, 2 X 3 equivalents). After the solvent was removed under vacuum, the crude mixture was
purified by flash column chromatography with hexane:EtOAc = 6:1 to 5:1. The product was obtained as
yellow oil (193 mg), which consisted of cyclic and acyclic compounds. The major portion was a syn/anti
mixture (1.0/0.17), and the minor portion was a cyclized α/β product (1.0/0.77). This mixture was used for
OTBS
TBSO OH O
NN(CH3)2 NHN(CH3)2
+
O O O O
1-91 1-92
Rf = 0.18 (hexane:EtOAc = 4:1). Major isomer 1-91, Syn,; 1H NMR (CDCl3, 400 MHz): δ 0.06 (s, 6 H),
0.88 (s, 9 H), 1.34 (s, 3 H), 1.45(s, 3 H), 2.81 (s, 6 H), 3.64-3.81(m, 4 H), 4.09 (dd, J = 8.8, 6.2 Hz, 1 H),
13
4.78 (dd, J = 6.5, 6.4 Hz, 1 H), 6.55 (d, J = 6.8 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.49, 19.29,
25.36, 25.83, 27.85, 42.54, 64.18, 69.70, 77.47, 78.37, 108.85, 131.77. anti, 1H NMR (CDCl3, 400 MHz):
δ 0.06(s, 6 H), 0.91 (s, 9 H), 1.39 (s, 3 H), 1.49(s, 3 H), 2.80 (s, 6 H), 3.64-3.81(m, 4 H, overlap over syn
compounds), 4.09 (m, 1 H, overlap over syn compounds), 4.67 (d, J = 6.1 Hz, 1 H), 6.45 (d, J = 5.6 Hz, 1
13
H). C NMR (CDCl3, 100 MHz): δ -5.49, 18.24, 24.45, 25.95, 27.85, 42.42, 64.08, 72.50, 77.19, 78.44,
273
109.07, 131.50. Minor isomer 1-92, α anomer; 1H NMR (CDCl3, 400 MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H),
0.88 (s, 9 H), 1.31 (s, 3 H), 1.39(s, 3 H), 2.46 (s, 3 H), 2.72-2.79(m, NH, disappeared with D2O), 3.94 (dd, J
= 7.8, 6.5 Hz, 1 H), 4.02 (t, J = 3.7 Hz, 1 H), 4.12-4.18 (m, 1 H), 4.54-4.58 (m, 2 H), 5.10 (d, J = 3.9 Hz, 1
13
H). C NMR (CDCl3, 100 MHz): δ -5.68, 18.24, 26.18, 27.0, 49.86, 64.88, 78.44, 80.48, 81.15, 84.49,
93.22, 111.91. β anomer; 1H NMR (CDCl3, 400 MHz) δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.87 (s, 9 H), 1.31 (s,
3 H), 1.39(s, 3 H), 2.50 (s, 3 H), 2.50 (s, 3 H), 2.72-2.79(m, NH, disappeared with D2O), 3.94 (m, overlap
over α anomer, 1 H), 4.02 (t, J = 3.7 Hz, overlap over α anomer, 1 H), 4.39 (dd, J = 6.2, 2.7 Hz, 1 H), 4.54-
13
4.58 (m, overlap over α anomer, 2 H), 4.92 (d, J = 2.6 Hz, 1 H). C NMR (CDCl3, 100 MHz) δ -5.43,
18.08, 25.94, 26.80, 49.61, 64.56, 79.31, 81.42, 81.75, 84.74, 98.55, 112.48.
was placed in a 25 mL of flame dried three neck flask, which was connected to a double spaced condensor.
Freshly dried THF (10 mL) was added to the flask, and the mixture was refluxed under nitrogen
atmosphere for 10 hr. Another 1.5 equivalent of thiocarbonyl-diimidazole was added and refluxing was
continued for 2 h. All solvents were removed under reduced pressure, and the dark brown mixture was
purified by column chromatography to give 133 mg of 1-93 as yellow oil. The product was a syn/anti
N
N
S
O
TBSO NN(CH3)2
O O
1-93
Yellow oil. Column; hexane:EtOAc = 7:1 to 5:1; Rf = 0.28 (hexane:EtOAc = 2:1). Major isomer, anti; 1H
NMR (CDCl3, 400 MHz): δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.84 (s, 9 H), 1.39(s, 3 H), 1.43(s, 3 H), 2.69 (s, 6
274
H), 3.96 (dd, J = 11.6, 5.1 Hz, 1 H), 4.02 (dd, J = 11.6, 3.6 Hz, 1 H), 4.32 (dd, J = 7.9, 6.7 Hz, 1 H), 4.60
(dd, J = 8.0, 6.4 Hz, 1 H), 5.82-5.84(m, 1 H), 6.29 (d, J = 6.3 Hz, 1 H), 6.99 (s, 1 H), 7.59 (s, 1 H), 8.26 (s,
1 H). Minor isomer, syn; 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3 H), 0.02 (s, 3 H), 0.85 (s, 9 H), 1.41(s,
3 H), 1.51(s, 3 H), 2.57 (s, 6 H), 4.10 (dd, J = 11.9, 3.8 Hz, 1 H), 4.13 (dd, J = 11.9, 2.3 Hz, 1 H), 4.72 (dd,
J = 9.3, 6.5 Hz, 1H), 4.86 (app t, J = 6.6 Hz, 1H), 5.50 (app dt, J = 9.2, 2.5 Hz 1H), 6.20 (d, J = 7.3 Hz, 1
H), 7.01 (t, J = 0.8 Hz, 1 H), 7.55(s, 1 H), 8.27 (s, 1 H).
TsNHNH2
0.73 mmol) and 143 mg (0.77 mmol) of p-toluenesulfonyl hydrazine were dissolved in 10 mL of dried
acetonitrile (dried over 4 Å MS). The mixture was refluxed for 2 h 30min, and another 1.05 equivalents of
p-toluenesulfonyl hydrazine were added. After refluxing for overnight, all starting material was consumed
(TLC). The mixture was concentrated under vacuum, and purified by flash column chromatography
eluting with hexane: EtOAc = 4:1. Very sticky colorless oil was obtained as the product and the isolated
yield was 80%. NMR spectrum shows the product is α/β mixture in a ratio of 1:2.
OTBS
O
NHNHTs
O O
1-94
Rf = 0.25 (hexane:EtOAc = 3:1). Major β anomer; 1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 3 H), 0.01 (s, 3
H), 0.79 (s 9 H), 1.25 (s, 3 H), 1.39 (s, 3 H), 2.38 (s, 3 H), 3.64 (dd, J = 11.5, 2.3 Hz, 1 H), 3.68 (dd, J =
11.3, 2.0 Hz, 1 H), 4.23 (d, J = 1.1 Hz, 1 H) 4.33 (dd, J = 6.0, 0.9 Hz, 1 H), 4.55-4.58 (m, 2 H), 4.74 (d, J =
13
10.3 Hz, 1 H), 6.53 (s, 1 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.78-7.82 (m, 2 H). C NMR (CDCl3, 100 MHz):
δ -5.9, -5.8, 18.1, 21.4, 24.9, 25.7, 26.6, 64.6, 81.6, 83.6, 85.7, 97.3, 112.2, 128.1, 129.3, 135.5, 143.5.
Minor α anomer; 1H NMR (CDCl3, 400 MHz): δ -0.04 (s, 3 H), -0.02 (s, 3 H), 0.79 (s 9 H), 1.27 (s, 3 H),
275
1.40 (s, 3H), 2.38 (s, 3H), 3.57 (dd, J = 11.0, 2.6 Hz, 1H), 3.61 (dd, J = 11.6, 2.3 Hz, 1H), 3.99 (app t, J =
2.4 Hz, 1 H), 4.38 (d J = 11.3 Hz, 1 H), 4.48 (dd, J = 6.0, 4.1 Hz, 1 H), 4.65 (d, J = 6.1 Hz, 1 H), 4.72 (dd, J
13
= 11.3, 4.0 Hz, 1 H), 6.49 (s, 1 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.78-7.82 (m, 2 H). C NMR (CDCl3, 100
MHz): δ -5.8, -5.7, 17.9, 21.4, 24.2, 25.7, 26.0, 65.1, 79.5, 82.1, 82.2, 92.1, 112.3, 128.1, 129.3, 135.5,
143.5. IR (NaCl, neat): υ 3240m, 2955s, 2930s, 2857s, 1599m, 1495w, 1462m, 1382m, 1334m, 1256m,
A mixture of 1-94 (233 mg, 0.609 mmol), 1,1-thiocarbonyl-diimidazole (375 mg, 1.892 mmol),
and DMAP (40 mg) was placed in a flame dried flask with a condenser. After 40 mL of dichloromethane
(dried over 4 Å MS) was added via a syringe, the mixture was refluxed under nitrogen for 2 h 30 min.
Another 1.892 mmol of 1,1-thiocarbonyldiimidazole and 40 mg of DMAP were added, and refluxing was
continued for 4 h 30 min. The mixture was cooled to rt and the solvent was removed under vacuum to get
the crude mixture of 1-95. The mixture was isolated by flash column chromatography with
hexane:EtOAc= 2:1 to 1:1 solution. The product (110.5 mg of brown solid) was obtained in an isolated
yield of 47%.
S N
OTBS N
O
NNH
O O
1-95
20
[α]
Pale yellow solid. Column: hexane:EtOAc = 2:1 to 1:1. Rf = 0.30 (hexane:EtOAc = 1:2). D = +78.5
(c 2.33, CHCl3). Mp: 100-102 oC. 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.87 (s, 9 H), 1.44 (s, 3
H), 1.63 (s, 3 H), 3.46-3.50 (m, 2 H, one H is disappeared with D2O), 3.72 (dd, J = 10.4, 4.4 Hz, 1 H), 3.79
(dd, J = 10.4, 2.5 Hz, 1 H), 4.55 (dd, J = 9.2, 6.5 Hz, 1 H), 5.61 (d, J = 6.5, 1 H), 7.19 (s, 1 H), 7.50 (s, 1
13
H), 8.13 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.5 -5.4, 18.3, 24.8, 25.8, 27.2, 64.2, 69.7, 75.3, 77.9,
111.3, 118.4, 131.5, 136.3, 159.6, 169.4. C18H30O4N4SSi 427.1835 (M+ + H), found 427.1825.
276
Preparation of 5-O-[(1,1-dimethyl)ethyl diphenylsilyl]-2, 3-O-(1-methyl ehtyldiene)-D- ribonic acid γ-
lactone.
dissolved in 36 mL of acetone dried over 4 Å. Iodine (0.36 g, 1.40 mmol, 14 mol %) and 0.75 g of
anhydrous MgSO4 were added, and the mixture was stirred at rt (20 oC) under nitrogen atmosphere for 12h.
All starting material was consumed and starting material was not detected on TLC. After the reaction
mixture was diluted with excess amount of chloroform, the reaction mixture was filtered and the filtrate
was washed with additional chloroform. The collected organic phase was washed with 0.2 M sodium
thiosulfate solution to give pale yellow solution, and the aqueous phase was back extracted with additional
dichloromethane. The combined organic phase was washed with brine solution and dried over MgSO4. the
solid was filtered off under house vacuum. After removal of the solvent in vacuum, pale yellow oil was
obtained. The crude mixture was purified by flash column chromatography eluting with hexane:EtOAc =
7:1 to 5:1 solution. The product was obtained as yellow oil (4.18 g, 98%).
OTBDPS
O O
O O
1-97
20
[α]
Pale yellow oil. Column; hexane:EtOAc = 7:1 to 5:1. Rf = 0.42 (hexane:EtOAc = 5:1). D = -13.1 (c
0.94, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.04(s, 9 H), 1.40 (s, 3 H), 1.49 (s, 3 H), 3.76 (dd, J = 11.5,
1.5 Hz, 1 H), 3.92 (dd, J = 11.5, 2.3 Hz, 1 H), 4.74 (d, J = 5.6 Hz, 1 H), 4.90 (d, J = 5.7Hz, 1 H), 7.37-7.49
13
(m, 6 H), 7.58-7.65 (m, 4 H). C NMR (CDCl3, 100 MHz): δ 19.1, 25.6, 26.7, 26.8, 63.5, 75.8, 78.4, 82.3,
113.1, 127.9, 128.0, 130.2, 131.5, 132.3, 135.4, 135.6, 174.1. IR (NaCl, neat): υ 3071w, 2991m, 2955m,
2933m, 2858m, 1789s, 1589w, 1472m, 1428m, 1384m, 1350m, 1272m, 1239m, 1216m, 1179m, 1152m,
1113s, 1082s, 1017m, 979m, 943m, 890w, 865m, 744m, 727m, 703s, 628m.
277
Preparation of 5-O-[(1,1-dimethyl)ethyl diphenylsilyl]-2, 3-O-(1-methyl ethyldiene)-D-ribonofuranose
diphemylsilyl] -2,3-O-(1-methyl ethyldiene)-D- ribonic acid γ-lactone and 30 mL of fresh dried diethyl
ether under positive nitrogen atmosphere. The temperature of the flask was lowered to -78 oC. Dibal-H
(1.5 equivalents, 1.5 M in toluene) was slowly dropwise over 10 min., and the mixture was stirred at the
temperature for 4 h. After the starting material was consumed (TLC), the excess amount of Dibal-H was
quenched by 10 mL of absolute methyl alcohol at -78 oC. The mixture was diluted with diethyl ether, and
the organic phase was washed by saturated sodium tartaric acid solution, water, and brine solution. The
combined organic phase was dried over MgSO4, filtered under house vacuum, and the solvent was removed
on a rotary evaporator. The crude mixture was subjected to column chromatography with eluting with
hexane:EtOAc = 9:1. 1H NMR shows the α/β ratio of the product is 0.24/1.00.
OTBDPS
O OH
O O
1-98
α/β = 0.24/1.0
Colorless oil. Column: hexane:EtOAc = 9:1. Rf = 0.27 (hexane:EtOAc = 7:1). Major isomer, β; 1H NMR
(CDCl3, 400 MHz): δ 1.00(s, 9 H), 1.31 (s, 3 H), 1.38 (s, 3 H), 3.58 (dd, J = 11.3, 2.8 Hz, 1 H), 3.73 (dd, J
= 11.3, 3.2 Hz, 1 H), 4.20 (app t, J = 2.7 Hz, 1 H), 4.43 (d, J = 10.2 Hz, 1 H), 4.52 (d, J = 5.9 Hz, 1 H), 4.63
13
(d, J = 5.9 Hz, 1 H), 5.27 (d, J = 9.7 Hz, 1 H), 7.16-7.37 (m, 6 H), 7.54-7.60 (m, 4 H). C NMR (CDCl3,
100 MHz): δ 19.0, 24.9, 26.4, 26.8, 65.4, 79,4, 81.6, 87.1, 103.2, 112.0, 127.8, 127.9, 129.8, 130.3, 131.6,
132.3, 135.4. Minor isomer, α; 1H NMR (CDCl3, 400 MHz): δ 0.97(s, 9 H), 1.31 (s, 3 H), 1.47 (s, 3 H),
3.64 (dd, J = 11.1, 2.4 Hz, 1 H), 3.72 (dd, J = 11.1, 2.8 Hz, 1 H), 3.89 (d, J = 11.2 Hz, 1 H), 4.07 (app t, J =
2.2 Hz, 1 H), 4.58 (dd, J = 6.2, 4.1 Hz, 1 H), 4.69 (dd, J = 6.3, 0.7 Hz, 1 H), 5.53 (dd, J = 10.9, 3.9 Hz, 1
13
H), 7.16-7.37 (m, 6 H), 7.54-7.60 (m, 4 H). C NMR (CDCl3, 100 MHz): δ 18.9, 24.6, 26.0, 26.8, 65.9,
81.1, 81.8, 86.9, 97.9, 112.9, 127.8, 129.9, 130.1, 131.7, 132.5, 135.6. IR (NaCl, neat): υ 3428s, 3074s,
278
3050s, 2934s, 2858s, 2358w, 2251w, 1962w, 1894w, 1827w, 1706m, 1589m, 1567w, 1472s, 1428s, 1382s,
1312m, 1267m, 1238m, 1160m, 1112s, 1074s, 999m, 937m, 911m, 871m, 823m, 777m, 738s, 702s, 614s.
dimethyl[1, 3]dioxolan-4-yl}-N,N-diphethylhydrazone
mixture was stirred with 45.4 mg of pyridine under nitrogen atmosphere at rt for 30min. The freshly
prepared diphenyl hydrazine solution was added dropwise into the flask containing D-ribonofuranose
solution. After stirring the mixture at rt for 21 5 h at rt, another 0.75 equiv. of freshly prepared diphenyl
hydrazine solution was added and the mixture was stirred for 3 h. All solvent was removed under reduced
pressure, and the crude mixture was purified by column chromatography eluting with hexane:EtOAc = 10:1
with 1% of Et3N. Reddish oil was obtained as the major portion, which contains the desired product 1-99
with some impurities. Because the impurities could not be removed even by Prep TLC, the mixture was
used for the next step without further purification. The approximate yield was 50%.
TBDPSO OH
NHNPh2
O O
1-99
Reddish oil. Column; hexane:EtOAc = 10:1 with 1% of Et3N. Rf = 0.33 (hexane:EtOAc = 7:1). 1H NMR
(CDCl3, 250 MHz): δ 0.09 (s, 9 H), 1.19 (s, 3 H), 1.27 (s, 3 H), 2.49(d, J = 5.2 Hz, 1 H), 3.46-3.49 (m, 1
H), 3.71-3.75 (m, 1 H), 4.17 (dd, J = 8.9, 6.3 Hz, 1 H), 4.90 (app t, J = 6.8 Hz, 1 H), 6.44 (d, J = 7.2 Hz, 1
13
H), Because of some impurities, phenyl signals are not assigned. C NMR (CDCl3, 100 MHz) δ 24.99,
26.79, 27.62, 29.22, 64.97, 69.76, 77.52, 78.15, 109.00, 121.02, 122.42, 122.64, 127.70, 128.85, 129.59,
279
Preparation of (1’R, 4S, 5R)-(E and Z)-3-{5-O-[2-(tert-butyldimeylsilanyloxy)-1-hydroxyethyl]-2, 2-
dimethyl[1, 3]dioxolan-4-yl}-N,N-diphethylhydrazone
of anhydrous methyl alcohol, and 139 mg of pyridine. The mixture was stirred under nitrogen atmosphere
at rt for 30 min. To another flame dried flask was taken 267 mg of 5-O-[(1,1-dimethylethyl) dimethylsilyl]
prepared diphenyl hydrazine solution was slowly added into the flask of D-ribonofuranose solution. After
stirring the mixture at rt for 24 h at rt, all starting material was consumed (TLC). The solvent was removed
under reduced pressure and the crude mixture was purified by column chromatography eluting with
TBSO OH
NNPh2
O O
1-100
Yellow oil. Column: hexane:EtOAc = 10:1 with 1% of Et3N. Rf = 0.38 (hexane:EtOAc = 7:1). 1H NMR
(CDCl3, 250 MHz): δ -0.04 (s, 6 H), 0.79 (s, 9 H), 1.25 (s, 6 H), 2.41 (Br s, 1 H), 3.37 (Br s, 1 H), 3.56 (dd,
J = 10.1, 5.1 Hz, 1 H), 3.64 (dd, J = 10.1, 3.4 Hz, 1 H), 4.02 (dd, J = 9.0, 6.1 Hz, 1 H), 4.84 (app t, J = 6.7
13
Hz, 1 H), 6.42 (d, J = 7.1 Hz, 1 H), 6.98-7.09 (m, 4 H), 7.12-7.19 (m, 2 H), 7.20-7.30 (m, 4 H). C NMR
(CDCl3, 100 MHz): δ -5.45, -5.41, 18.28, 25.35, 25.83, 27.72, 64.04, 69.48, 77.51, 78.18, 109.00, 122.43,
124.35, 129.58, 134.39, 143.51. IR (NaCl, neat): 3556m, 3065m, 3037m, 2986s, 2930s, 2856s, 2739w,
2711w, 1932w, 1784w, 1708w, 1591s, 1494s, 1471s, 1381s, 1320m, 901s, 836s.
To a flame dried flask fitted with a double spaced condenser were added 132 mg of N,N-
nitrogen pressure. Freshly distilled THF (20 mL) was added as the solvent, and the mixture was stirred
280
under reflux conditions. The reaction was followed by TLC analysis, and another 149.7 mg of thiocarbonyl
diimidazole was added after 4 h and 20 h respectively. All starting material was consumed after 24 h, and
the mixture was cooled to rt. Solvent was removed on the rotary evaporator, and the crude product was
purified by column chromatography eluting with hexane:EtOAc = 7:1 solution. The desired product 1-101
N
N
S
O
TBSO NNPh2
O O
1-101
Yellow oil. Column; hexane:EtOAc = 7:1. Rf = 0.21 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 250 MHz):
δ -0.05 (s, 3 H), 0.00 (s, 3 H), 0.85 (s, 9 H), 1.38 (s, 3 H), 1.41 (s, 3 H), 3.90 (dd, J = 11.9, 2.5 Hz, 1 H),
4.76 (dd, J = 8.7, 6.2 Hz, 1 H), 4.99 (dd, J = 7.2, 6.2 Hz, 1 H), 5.36 (app dt, J = 8.6, 2.7 Hz, 1 H), 6.32 (d, J
= 7.4 Hz, 1 H), 6.86-6.89 (m, 4 H), 6.99 (d, J = 0.4 Hz, 1 H), 7.09-7.14 (m, 2 H), 7.26-7.30 (m, 4 H), 7.49
13
(s, 1 H), 8.25 (s, 1 H). C NMR (CDCl3, 100 MHz) δ -5.04, 18.14, 25.31, 25.68, 27.64, 60.25, 74.01,
78.47, 81.05, 109.59, 117.67, 122.02, 124.60, 129.69, 130.63, 130.91, 136.91, 142.88, 182.36. IR (NaCl,
neat): υ 3132m, 3062m, 2953s, 2931s, 1704m, 1592s, 1532w, 1496s, 1463s, 1389s, 1346m, 1323s, 1283s,
1246s, 1218s, 1033s, 834s. C24H40O4N4SSi 581.2618 (M+ + H), found 581.2645.
To a flame dried flask fitted with a double spaced condenser were added D-ribonofuranose 1-79
(99 mg, 0.325 mmol), 1,1-thiocarbonyl diimidazole (116 mg, 0.650 mmol), and catalytic amount of DMAP
(10 mg) under positive nitrogen pressure. Freshly distilled THF (15 mL) was added as the solvent, and the
mixture was stirred under reflux conditions. The reaction was followed by TLC analysis, and another 116
mg of 1,1-thiocarbonyl diimidazole was added after 13 h. Most D-ribonofuranose 1-79 was consumed after
8 h, and the mixture was cooled to rt. Solvent was removed on the rotary evaporator, and the crude product
281
was purified by column chromatography eluting with hexane:EtOAc = 7:1 solution. The desired product 1-
103 (25 mg) and anomeric mixture (4 mg) were isolated along with the starting D-ribonofuranose 1-79 (18
mg).
OTBS N
O O N
S
O O
1-103
20
Yellow oil. Column; hexane:EtOAc = 7:1. [α] D = +124.7 (c 1.24 in CHCl3). Rf = 0.31 (hexane:EtOAc =
4:1). 1H NMR (CDCl3, 500 MHz): δ 3.73 (dd, J = 11.1, 3.4 Hz, 1 H), 3.77 (dd, J = 11.1, 3.9 Hz, 1 H), 4.26
(app td, J = 3.1, 0.9 Hz, 1 H), 4.85 (dd, J = 5.9, 0.9 Hz, 1 H), 5.01 (dd, J = 5.9, 1.6 Hz, 1 H), 5.31 (d, J =
1.6 Hz, 1 H), 7.12 (s, 1H), 7.74 s, 1H), 8.45 (s, 1H).
To a 10 mL of flame-dried flask was added 73 mg (0.179 mmol) of acrylic acid tert-butyl ester
(E)-1-81, R = tBu in 5 mL of benzene (dried over CaH2 and stored over 4 Å MS) under nitrogen
atmosphere. Triethyl amine (1.2 equiv.) and 2.0 equiv. of PhNCO were added to the above flask. The
mixture was stirred in an oil bath at 120 oC for 3 h 30 min. Another 2. 0 equivalents of PhNCO was added
and the mixture was refluxed for overnight (total refluxing time was 12 h 30 min.) After the solvent was
removed under vacuum, the mixture was purified by flash column chromatography with hexane:EtOAc =
282
NH
O
CO2tBu
O
TBSO
O O
(E)-1-104, R = tBu
Deep brown oil, Column; hexane:EtOAc = 8:1. Rf = 0.37 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400
MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.31 (s, 9 H), 1.35 (s, 3 H), 1.48 (s, 3 H), 3.86 (dd,
J=11.5, 3.6 Hz, 1 H), 3.93 (dd, J=11.5, 2.6 Hz, 1 H), 4.49 (dd, J=8.3, 6.2 Hz, 1 H), 4.75 (ddd, J=8.3, 3.4,
2.8 Hz, 1 H), 4.81 (ddd, J=7.5, 6.0, 1.4 Hz, 1 H), 6.01 (dd, J=15.6, 1.5 Hz, 1 H), 6.78 (Br s, 1 H), 6.86 (dd,
13
J=15.6, 2.8 Hz, 1 H), 7.03(t, J=7.4 Hz, 1 H), 7.25-7.28 (m, 2 H), 7.37 (d, J=8.1 Hz, 2 H). C NMR
(CDCl3, 100 MHz): δ -5.48, -5.44, 18.36, 25.44, 25.85, 27.78, 27.86, 29.24, 62.04, 72.61, 75.58, 76.36,
80.51, 109.26, 118.74, 123.35, 123.79, 128.87, 137.77, 140.88, 151.90, 165.35.
The reaction was performed by the same procedure for the (E)-1-81, R = tBu. 143 mg (0.392
mmol) of (Z)-1-81, R = Et, 187 mg (4.0 equiv.) of PhNCO, and 47.6 mg (1.2 equiv.) of triethylamine were
dissolved in 10 mL of dried benzene. The mixture was refluxed under nitrogen atmospere for 12 h 30 min.
The TLC analysis showed some starting material was remaining in the reaction mixture. To consume all
starting material another 4.0 equivalents of PhNCO and 1.2 equivalents of triethylamine were added, and
the mixture was refluxed until no more starting material was detected on TLC (total refluxing time was 22
h 30min.). The flask was cooled to rt and the excess benzene was removed on a rotary evaporator. The
desired compound was isolated by flash column chromatography eluting with hexane:EtOAc = 9:1 to 7:1 to
283
NH
O
O
TBSO
CO2Et
O O
(Z)-1-104, R = Et
Colorless oil. Column; hexane:EtOAc = 9:1 to 7:1. Rf = 0.28 (hexane:EtOAc = 7:1). 1H NMR (CDCl3,
400 MHz): δ 0.04 (s, 6 H), 0.88 (s, 9 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.84 (dd, J =
11.5, 4.7 Hz, 1 H), 3.92 (dd, J = 11.5, 2.5 Hz, 1 H), 3.95-4.18 (m, 2 H), 4.61 (dd, J = 8.6, 6.4 Hz, 1 H),
4.74-4.83 (m, 1 H), 5.80 (ddd, J = 7.9, 6.7, 1.2 Hz, 1 H), 5.89 (dd, J = 11.6, 1.1 Hz, 1 H), 6.26 (dd, J =
13
11.5, 8.4 Hz, 1 H), 6.57 (Br s, 1 H), 7.05 (tt, J = 7.0, 1.5 Hz, 1 H), 7.26-7.32 (m, 4 H). C NMR (CDCl3,
100 MHz) δ -5.5, -5.4, 6.3, 10.5, 14.0, 18.3, 25.3, 25.8, 25.9, 27.8, 60.4, 62.5, 73.0, 73.7, 75.4, 109.4,
Acrylic acid ethyl ester (Z)-1-81, R = Et (107 mg, 0.295 mmol) and (Bu3Sn)2O (185 mg, 0.310
mmol) were dissolved in 20 mL of freshly dried toluene. After the mixture was refluxed under nitrogen
atmosphere for 6 h 30 min., phenylisothiocyanate (2.1 equiv.) was added, and then the mixture was stirred
at 60oC for 23 h. After the solvent was removed under vacuum, the mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 6:1 solution. The product was obtained as a pale brown oil
TBSO O
O O
1-106
284
Pale brown oil. Column; hexane:EtOAc = 6:1. Rf = 0.26 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400
MHz): δ 0.09 (s, 6 H), 0.90 (s, 9 H), 1.36 (s, 3 H), 1.44 (s, 3 H), 3.92 (dd, J = 11.6, 5.3 Hz, 1 H), 4.01 (dd, J
= 11.6, 2.0 Hz, 1 H), 4.22 (ddd, J = 9.7, 5.3, 2.0 Hz, 1 H), 4.48 (dd, J = 9.7, 7.5 Hz, 1 H), 4.91 (app dt, J =
7.5, 2.0 Hz, 1 H), 5.95 (dd, J = 12.2, 1.9 Hz, 1 H), 6.43(dd, J = 12.2, 2.1 Hz, 1 H).13C NMR (CDCl3, 100
MHz) δ -5.3, 18.4, 24.5, 25.8, 26.9, 62.8, 75.0, 75.3, 78.5, 109.3, 119.7, 141.8, 166.7. IR (NaCl,neat): υ
3406m, 2930s, 2856s, 1731s, 1462w, 1382m, 1257m, 1214m, 1069m, 837m, 779m. C16H30O4Si 351.1604
To a flame dried 25 mL flask was added 189 mg of acrylic acid tert-butyl ester (Z)-1-81, R = tBu
in 10 mL of freshly dried pyridine. The flask was cooled at 0 oC, and 1.0 mL of benzoyl chloride was
slowly added. The mixture was stirred in an ice-bath for 30 min. and then at rt for 24 h. After the excess
pyridine was removed in vacuo over night, the crude product was diluted with dichloromethane. The
organic phase was washed with water (two times) and brine solution. The combined organic phase was
dried over MgSO4, the solid was filtered off, and the solvent was removed under reduced pressure. The
O
O
TBSO
CO2tBu
O O
1-108
Colorless oil. Preparative TLC; hexane:EtOAc = 7:1. Rf = 0.54 (hexane:EtOAc = 7:1). 1H NMR (CDCl3,
400 MHz): δ -0.05 (s, 3 H), -0.03 (s, 3 H), 0.83 (s, 9 H), 1.34 (s, 9 H), 1.39 (s, 3 H), 1.50 (s, 3 H), 3.89 (dd,
J = 11.4, 4.9 Hz, 1 H), 3.94 (dd, J = 12.6, 2.9 Hz, 1 H), 4.73 (dd, J = 8.7, 6.3 Hz, 1 H), 5.13 (ddd, J = 8.5,
4.8, 2.9 Hz, 1 H), 5.59 (dd, J = 11.6, 1.4 Hz, 1 H), 5.80 (ddd, J = 7.9, 6.3, 1.3 Hz, 1 H), 6.14 (dd, J = 11.6,
285
13
8.2 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.52 (tt, J = 7.4, 1.3 Hz, 1 H), 7.94-7.96 (m, 2 H). C NMR
(CDCl3, 100 MHz): δ -5.53, -5.48, 18.17, 25.37, 25.73, 27.88, 27.93, 62.31, 73.34, 73.64, 75.29, 80.58,
109.12, 124.11, 128.18, 129.72, 130.30, 132.76, 142.26, 164.55, 165.46. IR (NaCl, neat): υ 3064m, 2931s,
2857s, 2358w, 2255m, 1964w, 1911w, 1718s, 1648m, 1602m, 1585m, 1452s, 1414s, 1370s, 1343m, 1314m,
To a flame dried 30 mL flask were added 0.76 mmol (230 mg) of 1-87 and 4.56 mmol (617 mg) of
PhNCS dissolved 15 mL of dried THF at rt. Mineral oil free NaH (3.8 mmol, 91 mg) was added slowly,
and the mixture was stirred under nitrogen atmosphere at rt for 11 h. After all starting material was
consumed (TLC), 10 mL of water was added to quench the excess NaH. The reaction mixture was
extracted with dichloromethane, washed with brine, and dried over magnesium sulfate. The organic phase
was filtered through a filter paper and concentrated under reduced pressure to give brown oil. The mixture
was purified by column chromatography eluting with hexane:acetone = 15:1 to give 318 mg of product as a
NH
S
O
TBSO
O O
1-109
1
H NMR and 13C NMR spectra were complex after column chromatography and Prep TLC.
Yellow oil. Column; hexane:Acetone = 15:1. Rf = 0.26 (hexane:acetone = 9:1). 1H NMR (CDCl3, 250
MHz): δ 0.01 (s, 6 H minor), 0.05 (s, 3 H major), 0.88 (s, 9 H major), 0.89 (s, 9 H minor), 1.37 (s, 3 H),
1.48 (s, 3 H), 3.94 (dd, J = 11.7, 4.3 Hz, 1 H), 4.14(Br d, J = 11.4 Hz, 1 H), 4.43-4.72 (m, 2 H), 4.91-5.52
(m, 1 H), 5.41 (d, J = 8.4 Hz, 1 H), 5.68-6.02(m, 1 H), 7.15 (Br s, NH minor), 7.28-7.39 (m, 5 H), 8.53 (Br
286
13
s, NH minor). C NMR (CDCl3, 100 MHz): δ -5.48, 18.21, 25.29, 25.79, 27.68, 64.31, 77.43, 78.62,
108.93, 117.52, 118.57, 121.47, 125.27, 128.97, 133.06, 187.02. IR (NaCl, neat): υ 3241 Br, 3036m,
2986m, 2930s, 2884m, 2856m, 1949w, 1864w, 1704w, 1597s, 1540s, 1447m, 1381s, 1331m, 1289m, 1254s,
1194s, 1116m, 1061s, 1007m, 938m, 874m, 835s, 778m, 749m, 691m, 607m. C22H35O4NSSi 460.1954 (M+
A flame dried three neck round bottom flask was fitted with a double spaced condenser, and 192
mg (0.478 mmol) of acrylic acid tert-butyl ester (Z)-1-81 R = tBu, 258 mg (1.434 mmol) of 1,1-
thiocarbonylditriazole, and 10 mg of DMAP were placed under nitrogen atmosphere. Freshly distilled THF
(15 mL) was added, and the mixture was refluxed overnight (12h.). The reaction mixture was cooled to rt,
and the solvent was removed by rotary evaporation under house vacuum. The crude product was purified
by flash column chromatography eluting with hexane:EtOAc = 8:1 solution. Desired product (69 mg) and
starting material (115 mg) were obtained. The isolated yield of 1-110 is 28%, and 70% based on the
N N
N
S
O
TBSO
CO2tBu
O O
1-110
Colorless oil (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.31 (hexane:EtOAc = 6:1).
20
[α] D = +90.6 (c 0.58 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H),
1.39 (s, 9H), 1.40 (s, 3H), 1.51 (s, 3H), 4.00 (A of ABX, JAB = 11.8 Hz, JAX = 5.1 Hz, 1H), 4.02 (B of ABX,
JAB = 11.8 Hz, JBX = 2.5 Hz, 1H), 4.88 (dd, J = 7.3, 6.6 Hz, 1H), 5.63 (ddd, J = 7.5, 4.5, 3.1 Hz, 1H), 5.72
(dd, J = 11.6, 1.5 Hz, 1H), 5.78 (ddd, J = 7.9, 6.7, 1.5 Hz, 1H), 6.19 (dd, J = 11.6, 7.8 Hz, 1H), 8.02 (s,
287
13
1H), 8.85 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.56, 18.15, 25.09, 25.70, 27.56, 27.99, 61.29, 73.97,
75.04, 81.17, 82.38 (two peaks), 109.50, 124.57, 142.38, 153.61, 164.61, 180.69. IR (NaCl, neat): υ 2985s,
2951s, 2929s, 2860s, 1712s, 1643w, 1516w, 1472w, 1462s, 1388s, 1382s, 1321m, 1279s, 1239s, 1201s,
1157s, 1124s, 1066s, 966w, 943m, 835s, 778m, 666m, 651m. Anal. Calcd. for C23H39O6N3SSi: C, 53.77; H,
7.65; N, 8.18; S, 6.24. Found: C, 54.15; H, 7.62; N, 7.33; S, 6.25. HRMS (Electrospray): m/z Calcd for
To a flame dried three neck round bottom flask were placed acrylic acid tert-butyl ester (Z)-1-81
R = tBu (0.540 mmol, 217 mg), 1,1-thiocarbonylbenzimidazole (1.630 mmol, 451 mg), and dried DME (15
mL). Sodium hydride (60% in mineral oil, 0.594 mmol, 24 mg) was slowly added to the flask at rt in a dry
box, the reaction mixture was stirred for 2.5 h. After aqueous work-up (quenched by H2O, extracted with
CH2Cl2, washed with H2O and brine solution, dried over MgSO4, and filtered), the organic phase was
concentrated on a rotary evaporator under reduced pressure. The crude mixture was purified by column
chromatography with eluting hexane:EtOAc = 10:1 to 8:1 to give 35 mg of desired product 1-111 and 162
mg of starting material acrylic acid tert-butyl ester (Z)-1-81 R = tBu was recovered. The isolated yield was
12% and yield based on the recovered starting material was 46%.
Alternatively, we also used nucleophilic substitution at high temperature for the formation of 1’-
benzimidazole, and 1.3 mg of DMAP were placed. The mixture was heated in an oil bath at 130 oC with
stirring for 5 h. Another 25 mg of benzimidazole was added to it and continued the heating for additional
13 h. The deep brown crude mixture was purified by column chromatography eluting with hexane:EtOAc
= 10:1 to 8:1 solution to give 37 mg of pale yellow oil (isolated yield 62%).
288
N
N
S
O
TBSO
CO2tBu
O O
1-111
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1 to 8:1. Rf = 0.38 (hexane:EtOAc = 6:1).
1
H NMR (CDCl3, 250 MHz): δ -0.04 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.17 (s, 9H), 1.42 (s, 3H), 1.54 (s,
3H), 4.02 (A of ABX, JAB = 12.3 Hz, JAX = 1.1 Hz, 1H), 4.06 (B of ABX, JAB = 12.3 Hz, JBX = 2.9 Hz, 1H),
4.98 (dd, J = 8.1, 6.9 Hz, 1H), 5.62-5.72 (m, 2H), 5.81 (app t, J = 6.5 Hz, 1H), 6.19 (dd, J = 11.5, 7.9 Hz,
1H), 7.30-7.38 (m, 2H), 7.73-7.77 (m, 1H), 8.15-8.19 (m, 1H), 8.83 (s, 1H).
A mixture of O-methylhydroxyl amine 1-89 (131mg), 1,1-thiocarbonyl ditriazole (142 mg), and
10 mg of DMAP was placed in a 50 mL of flame dried three neck flask, which was connected to a double
spaced condenser. Freshly dried THF (20 mL) was added to the flask, and the mixture was refluxed under
nitrogen atmosphere for 6 hr. Another 2.0 equivalent of thiocarbonyl ditriazole was added and refluxing
was continued for 16 h. All solvents were removed under reduced pressure, and the dark brown mixture
was purified by column chromatography to give 79 mg of 1-115 as yellow oil along with 50 mg of starting
material. The product was a syn/anti mixture in a ratio of 1.69/1.00 based on 1H NMR spectrum.
N N
N
S
O
TBSO NOCH3
O O
1-115
289
Yellow oil (syn/anti = 1.69/1.0) (column chromatography, hexane:EtOAc = 10:1 to 8:1). Rf = 0.29
(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): syn (major), δ 0.00 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H),
1.40 (s, 3H), 1.50 (s, 3H), 3.59 (s, 3H), 4.00 (dd, J = 11.9, 3.8 Hz, 1H), 4.14 (dd, J = 11.9, 2.9 Hz, 1H),
4.76-4.83 (m, 2H), 5.61 (ddd, J = 11.0, 8.1, 4.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 8.92 (s,
1H); anti (minor), δ 0.00 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.38 (s, 3H), 1.50 (s, 3H), 3.70 (s, 3H), 3.98-
4.02 (m, 2H), 4.71-4.78(m, 1H), 5.32 (dd, J = 6.5, 5.5 Hz, 1H), 5.59-5.63 (m, 1H), 6.88 (d, J =5.4 Hz, 1H),
13
8.05 (s, 1H), 8.93 (s, 1H). C NMR (CDCl3, 100 MHz): syn (major), δ -5.60, -5.55, 18.21, 25.19, 25.73,
27.60, 61.05, 62.23, 74.16, 74.87, 81.40, 110.45, 144.43, 146.06, 153.64, 180.54; anti (minor), δ -5.53, -
5.35, 18.16, 24.82, 25.70, 27.21, 61.05, 62.23, 74.16, 74.87, 81.40, 109.76, 144.29, 147.27, 153.61, 180.80.
IR (NaCl, neat): υ 3123w, 2986w, 2952s, 2934s, 2857s, 1797w, 1723w, 1516m, 1466m, 1462m, 1392s,
1378s, 1345m, 1321s, 1279s, 1254s, 1199s, 1124s, 1082s, 1046s, 965s, 942m, 837s, 814m, 779s, 660s.
HRMS (Electrospray): Calcd. for C18H32O5N4SSiNa (M++Na), 467.1755; Found (M++Na), 467.1716.
After styrene oxide (17.5 g, 0.149 mmol) was dissolved in 150 mL of acetone, 0.5 mL of
concentrate sulfuric acid in 150 mL of H2O was added dropwise while the temperature of the mixture was
kept below 25 oC. The mixture was stirred for another 2 h, and then the acetone was removed under
vacuum at rt. After the solution was saturated by sodium chloride, the mixture was extracted with
diethylether. The organic phase was washed by sodium bicarbonate solution and brine, dried over
magnesium sulfate, and filtered. The excess solvent was removed in vacuo to give 17.5 g of pale yellow
solid. The yellow solid was recrystallized from hexane to give 16.9 g of white solid. The organic residue
was further purified by flash column chromatography eluting with hexane:EtOAc = 3:1 to get 0.12 g of
OH
OH
1-119
290
White solid. Recrystallization by hexane. Mp: 63-65 oC (lit.122 63-64 oC).
dried pyridine (over KOH), and the flask was cooled to –15 oC. After mesyl chloride (2.24 Equiv., 16.20 g,
10.9 mL, 141.46 mmol) was added slowly to the flask via a syringe for 30 min, the reaction mixture was
stirred at 0 oC for 4 h. The reaction mixture was mixed with ice at which time the dimesylate precipitated.
After the pH was adjusted to 3 with 6 N HCl, the solid was filtered off, and washed with ice water. The
product was transferred to a separator funnel, and extracted with dichloromethane. The organic phase was
dried over magnesium sulfate, and the solid was filtered off. Small amount of pentane was added to the
solution until crystallization just begun. After the mixture was cooled to -78 oC, the solid was collected by
filtration and washed with cold pentane. The solid was dried under vacuum to get the white solid (11.73 g).
The combined mother liquid was concentrated in a rotary evaporator, and purified by column
chromatography eluting with hexane:EtOAc = 3:1 solution to give addition 0.6 g of the dimesyl compound.
OMs
OMs
1-120
Preparation of 1-amino-2-phenylaziridine123
A 100 mL of round bottom flask was charged with 10 mL (0.1 mol) of hydrazine hydrate and 2.0
g (6.79 mmol) of finely powdered styrene glycol dimesylate. After the mixture was gently stirred at rt for
10 min., 60 mL of pentane was slowly added. The mixture was stirred at 25 oC until two clear phases were
291
observed upon stopping of stirring (24 h). The hydrazine hydrate was separated from the pentane, and
extracted with additional pentane. The combined pentane mixture was filtered through glass cotton, and
the solvent was removed on a rotary evaporator at rt. Quantitative amount of yellow oil was obtained, and
the 1H NMR spectrum shows the crude compound has >95% purity. This crude mixture was used for the
Ph
N NH2
1-121
Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 1.94 (d, J = 7.8 Hz, 1 H), 1.97(d, J = 4.7 Hz, 1 H), 2.54 (dd, J
= 7.8, 4.7 Hz, 1 H), 3.67 (Br s, 2 H), 7.09-7.24 (m, 5 H).
with 1-amino-2-phenyaziridine
D-Ribonofuranose 1-79 (477 mg, 1.57 mmol) and freshly prepared 1-amino-2-phenyaziridine (845
mg, 6.30mmol) in 20 mL of pentane were dissolved in 30 mL of ethyl alcohol at 0 oC. The mixture was
stirred at 0 oC to rt for 6 h. After removal of the solvent in vacuo, the mixture was purified and the product
was isolated by flash column chromatography eluting with hexane:EtOAc = 4:1 to 1:1. Starting material,
ribofuranose, was recovered (71%), and the only other product was 1-122.
CH3
Ph
N N
CH3
1-122
Yellow oil. Rf = 0.23 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 250 MHz): δ 1.82 (s, 3 H), 1.91 (s, 3 H),
2.16 (d, J = 4.6 Hz, 1 H), 2.28 (d, J = 7.6 Hz, 1 H), 2.72 (dd, J = 7.6, 4.6 Hz, 1 H), 7.12-7.20 (m, 5 H).
Preparation of 5(R)-O-{[(1,1-dimethylethyl)diphenylsilyl]oxy}methyltetrahydrofuranol
A flame dried 100 mL of one neck flask was charged with 2.46 g (6.94 mmol) of lactone 1-123
and Et2O (40 mL) under nitrogen atmosphere. Freshly distilled diethyl ether was added via a syringe to the
292
flask at rt and the temperature was decreased to -78 oC. Dibal-H (6.9 mL, 1.5M in toluene) was added
slowly, and the mixture was stirred at the temperature for 1 h. After all starting material was consumed
(TLC), 10 mL of absolute methyl alcohol was added to quench the excess Dibal-H at -78 oC. The mixture
was diluted with diethyl ether and washed with saturated disodium tartarate (0.5 M) and brine. The water
phase was extracted 3 or 4 times by diethyl ether, and combined ether was dried over magnesium sulfate.
After the solid was filtered off, the organic phase was concentrated in vacuo to give colorless oil as α/β
anomeric mixture of the lactols. The crude yield was almost quantities and it was used for the next
A double spaced condenser was connected to a flame dried 100 mL of three neck flask. Crude
lactol 1-124 (2.08 g, 5.82 mmol), (carbethoymethylene)triphenylphosphorane (3.04 g, 8.73 mmol), and
catalytic amount of benzoic acid (200 mg) were dissolved in 20 mL of freshly distilled DME under
nitrogen atmosphere, and the mixture was stirred at rt for 34 h. After the solvent was removed in vacuo,
the crude mixture was purified by flash column chromatography using hexane:EtOAc = 8:1 to get 1.55 g
(64%) of the desired product as pale yellow oil. Small amount of TBDPS group migrated product (76 mg,
OH
TBDPSO O
OEt
1-125
20
Pale yellow oil. Column; hexane:EtOAc = 8:1 to 6:1. Rf = 0.29 (hexane:EtOAc = 5:1). [α] D = +1.5 (c
0.89 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.07 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 1.48-1.62 (m, 2H),
2.21-2.29 (m, 1H), 2.31-2.39 (m, 1H), 2.47 (d, J = 2.9 Hz, OH), 3.50 (dd, J = 10.1, 7.2 Hz, 1H), 3.66 (dd, J
= 10.1, 3.5 Hz, 1H), 3.69-3.76 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.81 (dt, J = 15.6, 1.5 Hz, 1H), 6.94 (d, J
13
= 15.6, 6.9 Hz, 1H), 7.35-7.46 (m, 6H), 7.64-7.68 (m, 4H). C NMR (CDCl3, 125 MHz): δ 14.25, 19.22,
26.84, 28.19, 31.08, 60.15, 67.79, 71.04, 121.64, 127.80, 129.87, 133.00, 132.02, 135.52, 148.47, 166.60.
293
IR (NaCl, neat): υ 3084Br s, 3070m, 3050m, 2930s, 1961w, 1894w, 1825w, 1720s, 1652s, 1589m, 1472s,
1428s, 1390s, 1368s, 1302s, 1270s, 1198s, 1112s, 1045s, 985m, 939m, 882w, 823s, 744s, 704s, 614s.
HRMS (Electrospray): m/z Calcd for C25H34O4SiNa (M++Na), 449.2119; Found (M++Na), 449.2125.
thiocarboyloxy]-2-heptenoate
A mixture of 2-heptenoate 1-125 (166mg, 0.389 mmol), 1,1-thiocarbonyl diimidazole (104 mg,
0.584 mg), and 10 mg of DMAP were placed in a 50 mL of flame dried three neck flask, which was
connected to a double spaced condenser. Freshly dried THF (10 mL) was added to the flask, and the
mixture was refluxed under nitrogen atmosphere for 2 hr. Another 1,1-thiocarbonyl diimidazole (120 mg)
was added and refluxing was continued for 22 h. All solvents were removed under reduced pressure, and
the dark brown mixture was purified by column chromatography to give 174 mg of 1-127 as yellow oil
along with 26 mg of starting material. The isolated yield of the thiocarbamated product 1-127 is 83% (99%
O S
TBDPSO O
1-127 OEt
20
Pale yellow oil. Column; hexane:EtOAc = 5:1 to 4:1. Rf = 0.46 (hexane:EtOAc = 3:1). [α] D = +2.0 (c
0.77 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.04 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 2.02-2.06 (m, 1H),
2.07-2.04 (m, 1H), 2.16-2.33 (m, 2H), 3.87 (d, J = 11.6, 4.7 Hz, 1H), 3.94 (dd, J = 11.6, 3.7 Hz, 1H), 4.17
(q, J = 7.1 Hz, 2H), 5.69 (app dq, J = 8.7, 4.8 Hz, 1H), 5.82 (dt, J = 15.6, 1.5 Hz, 1H), 6.92 (d, J = 15.6, 6.8
13
Hz, 1H), 7.03 (s, 1H), 7.29-7.44 (m, 6H), 7.57-7.66 (m, 5H), 8.28 (s, 1H). C NMR (CDCl3, 100 MHz):
δ 14.18, 29.13, 26.69, 27.83, 28.52, 60.26, 63.63, 83.41, 117.80, 122.30, 127.76, 127.80, 129.92, 129.94,
130.73, 132.59, 132.65, 135.40, 135.43, 136.83, 146.72, 166.16, 183.59. IR (NaCl, neat): υ 3134m, 3072s,
294
3050s, 2956s, 2932s, 2859s, 2331m, 1960w, 1825w, 1760m, 1717s, 1655s, 1590w, 1532m, 1465s, 1428s,
1388s, 1326s, 1285s, 1230s, 1170s, 1113s, 1043s, 998s, 965s, 910s, 824s, 800s, 734s, 703s, 655s, 615s.
HRMS (Electrospray): m/z Calcd for C29H36N2O4SSiNa (M++Na), 559.2057; Found (M++Na), 559.2060.
Preparation of 3(S)-hydroxy-γ-butyrolactone124
To a 2 L of three neck flask connected to a condenser was added 8.58 g of sodium hydroxide in
1335 mL (~0.16M). Maltose monohydrate (90% purity, 27.3 g, 75 mmol) was poured into the flask, and
was dissolved at rt with stirring. After 11.25 mL (99 mmol, 30%) of hydrogen peroxide was added to the
mixture, the temperature of the mixture was increased to 80 oC and stirring was continued for 24 h. (Note.
The temperature control and concentration of the mixture is critical to get high yield!). The mixture was
cooled at rt, and small amount of concentrated sulfuric acid was added to adjust the pH to ~1. The mixture
was concentrated to a syrup on a rotary evaporator, then the pH was adjusted to ~7 by addition of some
sodium bicarbonate in an ice bath. Some ethyl acetate was added to the mixture to reduce bubbles. After
the pH of the mixture was adjusted to ~7, 500 mL of ethyl acetate was added and the mixture was stirred
vigorously for 20 min. The mixture was kept standing at rt and ethyl acetate layer was carefully separated.
The same procedure was repeated several times until no more ethyl acetate phase had brown color. The
combined organic phase was dried over magnesium sulfate and was concentrated on a rotary evaporator.
The desired product was isolated by flash column chromatography using hexane:EtOAc = 1:1 to 1:3. The
HO
1-129
Yellow liquid. Column; hexane:EtOAc = 1:1 to 1:3. Rf = 0.42 (hexane:EtOAc = 1:1). Vacuum
distillation; Bp: 122-123 oC/0.6 mm Hg (lit.124 98-100 oC/0.3 mm Hg). 1H NMR (CDCl3, 400 MHz): δ 2.53
(dd, J=17.9, 0.6 Hz, 1 H), 2.76 (dd, J=17.9, 6.1 Hz, 1 H), 2.66-3.10 (Br s, 1 H), 4.30 (d, J=10.3 Hz, 1 H),
295
Preparation of 3(S)-O-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-γ-butyrolactone125
To a flame dried 25 mL of one necked flask were added 2.30 g (22.5 mmol) of 2-39, 4.07 g (27
mmol) of TBSCl, and 3.63 g (56.3 mmol) of imidazole under nitrogen atmosphere. DMF (dried over 4 Å
MS, 5.0 mL) was slowly added to the flask with stirring in an ice bath. The mixture was stirred at the
temperature for 15 min. and at rt for 27 h. After all starting material was consumed (TLC), the mixture was
diluted with dichloromethane. The organic phase was washed with water and brine, dried over magnesium
sulfate, and filtered. The solvent was removed in vacuo. Almost 100% yield of crude product was
obtained as a white solid, and this was used for the next experiment without further purification. If pure
compounds are needed, they can be purified by recrystallization from petroleum ether or column
TBSO
1-130
White Solid. Recrystallization; Pet Ether. Column; hexane:EtOAc = 6:1 to 3:1. Mp: 61-62 oC. Rf = 0.3
(hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.87 (s, 9 H), 2.42 (dd, J=17.5, 2.7
Hz, 1 H), 2.68 (dd, J=17.5, 6.1 Hz, 1 H), 4.16 (dd, J=9.7, 2.3 Hz, 1 H), 4.36 (dd, J=9.7, 4.8 Hz, 1 H), 4.57-
13
4.61 (m, 1 H). C NMR (CDCl3, 100 MHz) δ -4.93, -4.87, 17.86, 25.57, 38.11, 68.05, 76.06, 175.65.
HRMS (electrospray) m/z calcd for C10H20O3Si 239.1079 (M+ + Na), found 239.1086.
A flame dried 100 mL of one neck flask was charged with 2.35 g (10.9 mmol) of 3(S)-O-{[(1,1-
ether was added via a syringe to the flask at rt and the temperature was decreased to -78 oC. Dibal-H (1.5
equiv., 1.5M in toluene) was added slowly, and the mixture was stirred at the temperature for 2 h. After all
296
starting material was consumed (TLC), 20 mL of absolute methyl alcohol was added to quench the excess
Dibal-H at -78 oC. The mixture was diluted with diethyl ether and washed with saturated disodium
tartarate (0.5 M) and brine. The water phase was extracted 3 or 4 times by diethyl ether, and combined
ether was dried over magnesium sulfate. After the solid was filtered off, the organic phase was
concentrated in vacuo to give colorless oil as α/β anomeric mixture of the lactols. The crude yield was
almost quantities and it was used for the next experiment without further purification. The mixture could
OH
TBSO
1-131
Colorless liquid. Column; hexane:EtOAc = 6:1. Rf = 0.36 (hexane:EtOAc = 3:1). Major epimer, β; 1H
NMR (CDCl3, 400 MHz): δ 0.10 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 1.96 (td, J=17.5, 4.5 Hz, 1 H), 2.05
(d, J=13.3 Hz, 1 H), 3.88 (dd, J=9.5, 3.8 Hz, 1 H), 3.94 (d, J=11.3 Hz, 1 H), 4.06 (d, J=9.5 Hz, 1 H), 4.46-
4.49 (m, 1 H), 5.41 (dd, J=10.6, 4.6 Hz, 1 H). Minor epimer, α; 1H NMR (CDCl3, 400 MHz) :δ 0.06 (Br s,
6 H), 0.88 (s, 9 H), 1.93-1.97 (m, 1 H), 2.03-2.19 (m, 1 H), 3.70 (dd, J=9.1, 2.5 Hz, 1 H), 3.86-3.95 (m, 1
H), 4.10 (dd, J=9.0, 5.0. Hz, 1 H), 4.54-4.62 (m, 1 H), 5.66 (dd, J=4.7, 2.7 Hz, 1 H).
isolated as a byproduct.
OH
OH
TBSO
297
White solid. Column; hexane:EtOAc = 3:1. Rf = 0.35 (hexane:EtOAc = 1:1). 1H NMR (CDCl3, 400
MHz): δ 0.04 (s, 3 H), 0.05 (s, 3 H), 0.85 (s, 9 H), 1.76 (app qd, J = 5.5, 1.5 Hz, 2 H), 3.43 (Br s, 2 H), 3.52
(dd, J = 5.1, 3.4 Hz, 2 H), 3.59-3.68 (m, 1 H), 3.68-3.79 (m, 1 H), 3.89 (app tt, J = 5.0 Hz, 1 H).
To a flame dried 250 mL one necked flask were added 4.216 g (19.3 mmol) of lactol and 7.396 g
(21.2 mmol) of (carbethoymethylene) triphenylphosphorane under nitrogen. Freshly distilled toluene (100
mL) was added, and the mixture was stirred under refluxing for 2 h 30 min. After the oslvent was removed
in vacuo, the mixture was purified by flash column chromatography eluting with hexane:EtOAc = 5:1 to
give colorless E/Z mixture. The isolated yield was 86% and E/Z ratio was 4.4/1.0.
OH
O
TBSO OEt
(E)-1-132
Yellow oil. Column; hexane:EtOAc = 9:1 to 5:1. Rf = 0.43 (hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400
MHz) δ 0.08 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H), 2.17 (s, 1 H), 2.32-2.44 (m, 2 H),
3.48 (dd, J=11.2, 5.0 Hz, 1 H), 3.57 (dd, J=11.2, 3.9 Hz, 1 H), 3.78-3.89 (m, 1 H), 4.19 (q, J=7.1 Hz, 2 H),
5.86 (ddd, J=15.6, 2.6, 1.3 Hz, 1 H), 6.92 (dt, J=15.6, 7.6 Hz, 1 H). 1H NMR (DMSO-d6, 400 MHz) δ 0.01
(s, 3 H), 0.03 (s, 3 H), 0.83 (s, 9 H), 1.18 (t, J=7.1 Hz, 3 H), 2.21-2.24 (m, 1 H), 2.38-2.48 (m, 1 H), 3.10-
3.39 (m, 2 H), 3.71-3.74 (m, 1 H), 4.10 (q, J=7.1 Hz, 2 H), 4.62-4.76 (m, 1 H), 5.86 (d, J=15.6 Hz, 1 H),
13
6.89 (dt, J=15.6, 7.5 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -4.61, 14.25, 18.05, 25.82, 36.88, 53.82,
60.22, 66.10, 123.84, 144.72, 166.65. IR (NaCl, neat): υ 3460s, 3056w, 2927s, 1724s, 1657s, 1471m.
HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found 311.1664.
EtO O
OH
TBSO
(Z)-1-132
298
20
[α]
Pale yellow oil. Column; hexane:EtOAc = 9:1 to 7:1. Rf = 0.52 (hexane:EtOAc = 3:1). D = +58.7 (c
1.16, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.88 (s, 9 H), 1.27 (t, J = 7.2 Hz,
3 H), 2.57 (Br s, 1 H), 2.72 (dddd, J = 14.5, 7.2, 7.2, 1.4 Hz, 1 H), 3.02 (dddd, J = 14.6, 8.7, 4.8, 1.2 Hz, 1
H), 3.38-3.52 (m, 2 H), 3.92 (app dt, J = 10.7, 5.4 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 5.88 (d, J = 11.6 Hz,
13
1 H), 6.30 (ddd, J = 11.6, 8.7, 7.3 Hz, 1 H). C NMR (CDCl3, 100 MHz), δ -4.7, 14.2, 18.0, 25.7, 33.1,
60.1, 65.5, 71.9, 121.7, 145.4, 166.8. IR (NaCl, neat): υ 3476s, 2954s, 2929s, 2886s, 2857s, 1721s, 1646m,
1474m, 1464m, 1415m, 1388m, 1362m, 1254s, 1178s, 1111s, 1040s, 837s, 777s.
When the reaction was performed for prolonged time (14 hrs) and with excess amount (3.0
OH OEt
TBSO
1-138
Yellow oil. Column; hexane:EtOAc = 9:1 to 5:1, Rf = 0.33 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400
MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H), 2.37 (td, J=7.5, 1.2 Hz, 2 H),
3.46 (dd, J=9.9, 6.7 Hz, 1 H), 3.63 (dd, J=10.0, 3.7 Hz, 1 H), 3.78-3.80 (m, 1 H), 4.19 (q, J=7.1 Hz, 2 H),
5.90 (dd, J=15.7, 1.3 Hz, 1 H), 6.98 (dt, J=15.6, 7.9 Hz, 1 H).
O
CO2Et
TBSO
Yellow oil. Column; hexane:EtOAc = 9:1 to 5:1. Rf = 0.56 (hexane:EtOAc = 6:1). 1H NMR (CDCl3, 400
MHz): δ 0.47(s, 3 H), 0.56 (s, 3 H), 0.88 (s, 9 H), 4.26 (t, J=7.1 Hz, 3 H), 1.68 (ddd, J=12.7, 7.7, 5.8 Hz, 1
H), 2.00 (ddd, 2.42 J=12.7, 5.5, 1.6 Hz, 1 H), 2.48(A of ABX, J=15.2, 5.9 Hz, 1 H), 2.59 (B of ABX,
13
J=15.2, 7.2 Hz, 1 H), 3.61 (dd, J=9.2, 4.6 Hz, 1 H), 4.16(qd, J=7.2, 1.1 Hz, 1 H), 4.43-4.47 (m, 2 H). C
299
NMR (CDCl3, 100 MHz) δ -4.83, -4.77, 14.19, 18.03, 25.78, 40.40, 41.80, 60.50, 72.59, 74.43, 76.05,
171.11.
thiocarbonyl) oxy]-2-hexenoate
To a flame dried flask were added 1.289g (4.47 mmol) of 1-132, 4.0 equivalents of 1,1’-
thiocarbonyl diimidazole, and 180 mg of DMAP along with 80 mL of dichlroethane (dried over 4 Å MS).
The mixture was refluxed for 3 h, and all starting material was consumed (TLC). After the solvent was
removed on a rotary evaporator, the product was isolated by flash column chromatography with
hexane:EtOAc = 6:1 to 5:1 to give 157 mg of Z product and 789 mg of E product. Total isolate yield was
N
O OEt
O S
TBSO
(Z)1-133
Yellow oil. Column; hexane:EtOAc = 6:1 to 5:1. Rf = 0.25 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 400
MHz): δ 0.00 (s, 3 H), 0.01 (s, 3 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.90-3.08 (m, 2 H), 4.16 (q, J =
7.2 Hz, 2 H), 4.28 (m, 1 H), 4.55 (dd, J = 11.1, 5.0 Hz, 1 H), 4.64 (dd, J = 11.1, 5.9 Hz, 1 H), 5.93 (dd, J =
13
11.5 Hz, 1 H), 6.36 (app dt, J = 11.5, 7.5 Hz, 1 H), 7.05 (s, 1 H), 7.67 (s, 1 H), 8.40 (s, 1 H). C NMR
(CDCl3, 100 MHz), δ -4.7, 14.2, 17.9, 25.6, 33.8, 60.1, 68.8, 75.9, 118.0, 122.3, 130.7, 137.0, 144.0, 166.1,
184.3.
300
N
O S
O
TBSO OEt
(E)-1-133
Yellow oil. Column; hexane:EtOAc = 6:1 to 5:1. Rf = 0.15 (hexane:EtOAc = 5:1). 1H NMR (CDCl3, 400
MHz): δ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H), 2.46 (dddd, J = 14.3, 7.5, 6.2,
1.2 Hz, 1 H), 2.53 (dddd, J = 14.5, 7.3, 5.9, 1.3 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.25 (quin, J = 5.8 Hz, 1
H), 4.57 (dd, J = 11.2, 4.7 Hz, 1 H), 4.64 (dd, J = 11.2, 5.7 Hz, 1 H), 5.91 (app dt, J = 15.7, 1.2 Hz, 1 H),
6.96 (app dt, J = 15.6, 7.9 Hz, 1 H), 7.06 (d, J = 0.7 Hz, 1 H), 7.62 (s, 1H), 8.35 (s, 1 H).
Preparation of 3(S)-O-{[(p-methoxyphenyl)methyl]oxy}-γ-butyrolactone126
camphorsulfonic acid (93 mg, 0.40 mmol). After the mixture was stirred at rt. for 16 h, it was diluted with
petroleum ether. The precipitate formed was removed by filtration, and the filtrate was washed by
saturated sodium bicarbonate. Combined organic phase was dried over magnesium sulfate, the solid was
filtered off, and then the solvent was removed in vacuo. The crude mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 3:1 to 2:1 to get 683 mg (39%) of a brown oil, identified as
shown below.
PMBO
1-134
Yellow oil. Column; hexane:EtOAc = 3:1 to 2:1. Rf = 0.21 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400
MHz): δ 2.53 (dd, J = 17.7, 1.6 Hz, 1 H), 2.62 (dd, J = 17.7, 5.3 Hz, 1 H), 3.75 (s, 3 H), 4.21-4.33 (m, 3 H),
301
13
4.41 (d, J = 1.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 2 H). C NMR (CDCl3, 100 MHz):
δ 34.6, 54.9, 70.4, 72.8, 73.4, 113.6, 128.8, 129.1, 159.1, 175.3.
Preparation of 3(S)-O-{[(p-methoxyphenyl)methyl)methyl]oxy}-γ-butyrolactol126
To 1-134 (642 mg, 2.89 mmol) in freshly distilled diethyl ether (15 mL) at -78 oC under nitrogen
atmosphere was added 4.34 mmol of 1.5 M Dibal-H in toluene. The mixture was stirred at -78 oC for 1.5 h,
at which time all starting material was consumed (TLC). Absolute methyl alcohol (10 mL) was added at -
78 oC to quench the excess Dibal-H. The mixture was diluted with diethyl ether, and washed with saturated
sodium tartaric acid solution and brine. The aqueous phase was back extracted 2 times with diethyl ether,
and then combined ether phase was dried over magnesium sulfate. The solid was filtered off, and the
solvent was removed under vacuum. The crude mixture (559 mg, 86%) was obtained, and the mixture used
OH
PMBO
1-135
A double spaced condenser was connected to a flame dried 100 mL of three neck flask. Crude 1-
135 (559 mg, 2.49mmol) and (carbethoymethylene)triphenylphosphorane (955 mg, 2.74 mmol) was
dissolved in 15 mL of freshly distilled toluene under nitrogen atmosphere, and the mixture was refluxed for
2 h. After the solvent was removed in vacuo, the crude mixture was purified by flash column
chromatography using hexane:EtOAc = 4:1 to 1:1 to get 446.4 mg of yellow oil, which was E/Z mixture
with 1.0/0.1 ratio. Because the Z compound decomposed being rapidly, only E compound was
characterized.
302
OPMB OEt
HO
(E)-1-136
Yellow oil. Column; hexane:EtOAc = 4:1 to 1:1. Rf = 0.37 (hexane:EtOAc = 1:1). 1H NMR (CDCl3, 400
MHz): δ 1.71 (t, J = 7.1 Hz, 3 H), 2.33 (app t, J = 6.3 Hz, 2 H), 2.76 (Br s, 1 H), 3.38-3.53 (m, 3 H), 3.66
(s, 3 H), 4.07 (q, J = 7.1 Hz, 2 H), 4.31-4.43 (m, 2 H), 5.77 (d, J = 15.7 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 2 H),
13
6.84 (app dt, J = 15.1, 7.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H). C NMR (CDCl3, 100 MHz): δ 13.9, 33.7,
54.9, 59.9, 63.4, 71.1, 77.7, 113.6, 123.3, 129.1, 129.9, 144.5, 159.0, 166.0.
EtO O
OH
PMBO
(Z)-1-136
Z compounds were isolated a mixture with the E-isomer. 1H NMR (CDCl3, 250 MHz): δ 1.69 (t, J = 7.1
Hz, 3 H), 2.36 (Br s, 1 H), 2.74-2.91 (m, 2 H), 3.38-3.59 (m, 3 H), 3.68 (s, 3 H), 4.06 (q, J = 7.1 Hz, 2 H),
4.38 (dd, J = 13.1 Hz, 1 H), 4.48 (dd, J = 11.3 Hz, 1 H), 5.77 (d, J = 11.6 Hz, 1 H), 6.18 (app dt, J = 11.5,
oxy}-2-hexenoate
A mixture of (E)-1-136 (309.5 mg, 1.05 mmol) and immidazole (179 mg, 2.63 mol) was dissolved
in 1 mL of DMF (dried over 4 Å MS). To the flask was added 189.9 mg (1.26 mmol) of TBSCl at 0 oC,
and the mixture was stirred at the temperature for 10 min, and at rt for 12 h under nitrogen. The mixture
was diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate.
Filtered organic phase was concentrated on a rotary evaporator, and purified by flash column
chromatography eluting with hexane:EtOAc = 9:1. The desired compound (295.3 mg) was isolated as
303
OPMB OEt
TBSO
1-137
Yellow oil. Column; hexane only to hexane:EtOAc = 9:1. Rf = 0.34 (hexane:EtOAc = 9:1). 1H NMR
(CDCl3, 400 MHz): δ 0.00 (s, 6 H), 0.85 (s, 9 H), 1.27 (t, J = 7.2 Hz, 3 H), 2.33 (app dt, J = 13.5, 6.4 Hz, 1
H), 2.45 (app dt, J = 11.6, 5.6 Hz, 1 H), 3.45-3.55 (m, 1 H), 3.58-3.67 (m, 1 H), 3.72 (s, 3 H), 4.13 (q, J =
7.1 Hz, 2 H), 4.45 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 5.81 (d, J = 15.7 Hz, 1 H), 6.80 (d, J =
13
8.5 Hz, 2 H), 6.93 (app dt, J = 15.1, 7.4 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 2 H). C NMR (CDCl3, 100 MHz):
δ -5.6, -5.5, 14.1, 18.1, 25.8, 34.5, 55.1, 59.9, 64.7, 78.0, 113.7, 123.3, 129.2, 144.3, 159.5, 166.5.
To 1-137 (284.7 mg, 0.70 mmol) in a mixture of dichloromethane/water (5 mL/0.5 mL), was
added DDQ (190.7 mg, 0.84 mmol) at rt. After the mixture was stirred for 1.5 h, the solvent was removed
in vacuo to get the crude mixture. The mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 4:1 solution. The desired product (81.3 mg, 43%) was obtained as pale yellow oil.
OH OEt
TBSO
1-138
To a 250 mL of one neck flask was added 2.30 g (7.98 mmol) of (E)-1-132 dissolved in 150 mL
of absolute methyl alcohol with 1.67 mL (1.5 equivalents) of triethylamine. After stirring for 48 h, the
mixture was washed with H2O and extracted with dichloromethane. The combined organic phase was
dried over magnesium sulfate, filtered, and concentrated under reduced pressure. After flash column
304
chromatography with hexane:EtOAc = 7:1 to 4:1, 1.32 g (86.6% based on recovered starting material) of
desired product (E)-1-138 was obtained. Cyclized compound (181 mg, 11.9% based on recovered starting
material) was isolated as a byproduct. Starting material (775.8 mg, 33.7%) was also recovered.
OH OEt
TBSO
1-138
20
[α]
Yellow oil. Column; hexane:EtOAc = 7:1 to 4:1. Rf = 0.33 (hexane:EtOAc = 6:1). D = -0.48 (c 1.45,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H),
2.37 (td, J=7.5, 1.2 Hz, 2 H), 3.46 (dd, J=9.9, 6.7 Hz, 1 H), 3.63 (dd, J=10.0, 3.7 Hz, 1 H), 3.78-3.80 (m, 1
H), 4.19 (q, J=7.1 Hz, 2 H), 5.90 (dd, J=15.7, 1.3 Hz, 1 H), 6.98 (dt, J=15.6, 7.9 Hz, 1 H). 1H NMR (C6D6,
400 MHz): δ 0.05 (s, 6 H), 0.90 (s, 9 H), 0.98 (t, J=7.1 Hz, 3 H), 1.91 (d, J=4.6 Hz, 1 H), 2.03-2.10 (m, 2
H), 3.17-3.31(m, 3 H), 3.46-3.56 (m, 1 H), 4.09 (q, J=7.1 Hz, 2 H), 5.96 (ddd, J=15.6, 2.9, 1.4 Hz, 1 H).
1
H NMR (DMSO-d6, 400 MHz): δ -0.05 (s, 6 H), 0.85 (s, 9 H), 1.21 (t, J=7.0 Hz, 3 H), 2.19-2.23 (m, 1 H),
2.37-2.42 (m, 1 H), 3.0-3.39 (m, 1 H), 3.49-3.56 (m, 1 H), 3.56-3.75 (m, 1 H), 4.10 (q, J=7.1 Hz, 2 H), 4.80
13
(d, J= 5.1 Hz, 1 H), 5.85 (d, J=15.3 Hz, 1 H), 6.91 (dt, J=15.6, 7.2 Hz, 1 H). C NMR (CDCl3, 100 MHz):
δ -5.42, -5.39, 14.25, 18.25, 25.84, 35.98, 60.24, 66.47, 70.52, 123.69, 144.65, 166.28. IR (NaCl, neat): υ
3478m, 2932s, 2859m, 1720s, 1654m, 1467m, 1367m, 1318m, 1258m, 1207m, 1167m, 1118m, 1045m,
982w, 839s, 770m. HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found 311.1652.
The same reaction was performed with isolated Z substrates. To a 250 mL of one neck flask was
179mg (0.621 mmol) of Z substrate dissolved in 100 mL of absolute methyl alcohol with 104 µL (0.745
mmol) of triethyl amine. After the mixture was stirred at rt for 72 h, and the solvent was removed under
reduced pressure. The mixture purified by flash column chromatography to give 111.6 mg (67.9% based
305
on recovered starting material) of TBS migrated compound (Z)-2-44 along with 14.9 mg (8.3%) of starting
material.
EtO O
OTBS
HO
(Z)-1-138
20
[α]
Pale yellow oil. Column; hexane:EtOAc = 6:1, Rf = 0.49 (hexane:EtOAc = 3:1). D = +6.1 (c 1.31,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.90 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.76 (dddd, J
= 15.4, 7.9, 7.9, 1.6 Hz, 1 H), 2.86 (dddd, J = 15.1, 7.6, 4.3, 1.6 Hz, 1 H), 3.49(dd, J = 10.0, 6.8 Hz, 1 H),
3.63 (dd, J = 10.0, 4.1 Hz, 1 H), 3.77 (ddd, J = 10.9, 7.1, 3.0 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 5.90 (app
dt, J = 11.5, 1.6 Hz, 1 H), 6.40 (app dt, J = 11.5, 7.5 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ -5.43, -5.40,
14.21, 18.25, 25.84, 32.59, 52.99, 66.86, 71.31, 121.53, 145.80, 166.62. IR (NaCl, neat): υ 3471s, 2955s,
2929s, 2857s, 1720s, 1644m, 1472m, 1464m, 1445w, 1415m, 1388m, 1362w, 1255m, 1176s, 1120s, 1036m,
1006w, 939w, 837s, 778m. HRMS (electrospray) m/z calcd for C14H28O4Si 311.1655 (M+ + Na), found
311.1647.
thiocarbonyl)oxy]-2-hexenoate
To a flame dried three neck flask were added 1.386 g (4.81 mmol) of 1-138, 1.43 g (7.22 mmol) of
MS). The mixture was refluxed under nitrogen atmosphere for 5 h, and another 0.5 equivalent of 1,1’-
thiocarbonyldiimidazole was added. Additional refluxing for 1 h consumed all starting material 1-138
(TLC), and the mixture was concentrated in vacuo to give brown oil. The crude product was purified by
flash column chromatography to give 1.72g (90%) of desired product 1-139 as a yellow oil.
306
N
O S OEt
TBSO
1-139
20
[α]
Yellow oil. Column; hexane:EtOAc = 5:1 to 4:1. Rf = 0.18 (hexane:EtOAc = 4:1). D = -18.7 (c 1.4,
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.05 (s, 3 H), 0.04 (s, 3 H), 0.88 (s, 9 H), 1.28 (t, J=7.1 Hz, 3 H),
2.80 (t, J= 6.4 Hz, 2 H), 3.88 (ddd, J=12.7, 12.0, 2.8 Hz, 1 H), 4.19 (q, J=7.1 Hz, 2 H), 5.68 (ddd, J=14.4,
8.0, 1.8 Hz, 1 H), 5.95 (ddd, J=15.6, 2.6, 1.3 Hz, 1 H), 6.92 (dt, J=15.6, 7.8 Hz, 1 H), 7.05 (s, 1H), 7.61 (s,
13
1 H), 8.33 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.51, 14.21, 18.13, 25.70, 32.69, 60.49, 62.43, 77.21,
82.14, 117.88, 125.05, 130.75, 141.82, 165.83, 183.40 IR (NaCl, neat): υ 3129w, 2932s, 2859m, 2361w,
1721s, 1657m, 1531w, 1467s, 1389s, 1322s, 1283s, 1234s, 1173m, 1103s, 1045m, 971s, 839s, 779m.
The reaction procedure was the same as with other Wittig reaction conditions. To a flame dried
100 mL of three neck flask were added 1.08 g (4.95 mol) of lactol 1-131, 2.98 g (9.89 mmol) of the Wittig
reagent, and 10 mol% of benzoic acid in 30 mL of flash dried toluene. The mixture was stirred under
refluxing for 6 h 30 min, and cooled at rt. The solvent was removed on a rotary evaporator, and the crude
mixture was purified by flash column chromatography to give yellow oil. Small amount of pure Z-
compound was isolated during the column, but most fractions were E/Z mixtures while some isolated E-
compound contained 5% of TBS migrated compound. These mixtures were used for the next experiment
without further purification to reduce product decomposition. Total isolated yield was 63%.
OH CN
TBSO
(Z)-1-140
307
Yellow oil. Column; hexane:EtOAc = 4:1 to 3:1. Rf = 0.50 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400
MHz): δ 0.08 (s, 6 H), 0.87 (s, 9 H), 2.58-2.70 (m, 2 H), 3.49 (dd, J = 11.2, 5.0 Hz, 1 H), 3.52 (dd, J = 11.2,
4.5 Hz, 1 H), 3.91 (app tt, J = 5.4 Hz, 1 H), 5.40 (app dt, J = 11.0, 1.3 Hz, 1 H), 6.56 (app dt, J = 11.0, 7.7
13
Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -4.8, -4.7, 17.9, 25.7, 36.4, 65.9, 71.2, 101.4, 115.8, 151.0. IR
(NaCl, neat): 3456s, 3072w, 2954s, 2930s, 2885m, 2857s, 2222m, 1722w, 1624m, 1472m, 1464m, 1389w,
1362m, 1255s, 1113s, 1048s, 1006m, 982w, 939w, 838s, 810m, 778s, 742m, 669m.
To a 100 mL of one neck flask was added 319 mg (1.32 mmol) of 1-140 (E/Z = 1.00/0.50 based on
1
H NMR) dissolved in 75 mL of absolute ethyl alcohol containing of 368 µL of triethyl amine. After
stirring at rt for 3 days, the product was isolated by flash column chromatography eluting with
hexane:EtOAc = 4:1 to give 213 mg (93% based on recovered starting material) of TBS group migrated
mixture (E/Z = 1.00/0.36 based on 1H NMR) as well as 90 mg of recovered starting material. The
recovered mixture was subjected to the same reaction again, which gave another 62 mg (68.9%, E/Z =
2.97/1.00 based on isolated compounds) of desired product and 15.6 mg (17%) of starting material. The
OH
CN
TBSO
1-145
Pale yellow oil. Column; hexane:EtOAc = 4:1, Rf = 0.56 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400
MHz): δ 0.08 (s, 6 H), 0.89 (s, 9 H), 2.36 (app dt, J = 7.0, 1.1 Hz, 1 H), 2.37 (app dt, J = 7.2, 1.6 Hz, 1 H),
2.50 (Br s, 1H), 3.44 (dd, J = 10.1, 6.4 Hz, 1H), 3.61 (dd, J = 10.0, 3.9 Hz, 1H), 3.77 (Br s, 1H), 5.43 (app
13
dt, J = 16.4, 1.6 Hz, 1 H), 6.78 (app dt, J = 16.2, 7.2 Hz, 1 H). C NMR (CDCl3, 100 MHz), δ -5.49, -5.45,
18.2, 25.8, 36.9, 66.3, 70.0, 101.8, 117.2, 151.9. IR (NaCl, neat): υ 3456s, 2955s, 2929s, 2858s, 2360w,
308
2225m, 1634m, 1472m, 1390w, 1362w, 1255m, 1124m, 970w, 939w, 838s, 778s. HRMS (electrospray) m/z
The γ-lactol 1-131 (185 mg, 2.22 mmol) and O-methylhydroxyl amine hydrochloride (216 mg,
2.44 mmol) were taken in a 50 mL flask. Dichloromethane (20 mL), 386 mg (4.89 mmol) of pyridine, and
0.5 mL of water were added to the flask. After refluxing the mixture for 25 h, another 1.0 equivalent of
pyridine and 0.5 equivalent of O-methylhydroxyl amine hydrochloride were added. The mixture was
refluxed until no more starting material was detected on TLC (total refluxing time was 43 h). After diluting
with dichloromethane, the mixture was washed with 10% hydrochloric acid solution, 5% of sodium
bicarbonate solution, and brine. The combined organic phase was dried over magnesium sulfate, filtered,
and concentrated in vacuum. The crude mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 6:1 to 5:1 solution. Desired product (195.8 mg, 35.7%, syn/anti = 1.16/1.0) was isolated
as colorless oil as well as 114.8 mg (20.9%) of a mixture of TBS migrated compound (syn/anti = 1.17/1.0)
OTBS
NOCH3
HO
1-141
syn/anti = 1.16/1.0
Colorless oil. Column; hexane:EtOAc = 6:1 to 5:1. Rf = 0.30 (hexane:EtOAc = 4:1). Syn; 1H NMR
(CDCl3, 400 MHz): δ 0.05 (s, 6 H), 0.85 (s, 9 H), 2.27 (Br s, 1 H), 2.37 (t, J = 6.2 Hz, 1 H), 3.39-3.56 (m, 2
13
H), 3.77 (s, 3 H), 3.85-4.0 (m, 1 H), 7.34(d, J = 6.4 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -4.7, 17.9,
25.7, 33.3, 61.2, 65.9, 70.8, 147.8. Anti; 1H NMR (CDCl3, 400 MHz): δ 0.06 (s, 6 H), 0.85 (s, 9 H), 2.27
(Br s, 1 H), 2.37 (t, J = 6.2 Hz, 1 H), 3.39-3.56 (m, 2 H), 3.83 (s, 3 H), 3.85-4.0 (m, 1 H), 6.72 (t, J = 5.7
13
Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -4.9, 17.9, 25.6, 30.2, 61.5, 66.0, 70.1, 147.8. IR (NaCl, neat): υ
309
3439s, 2954s, 2930s, 2898s, 2858s, 2359w, 1632w, 1472m, 1362m, 1256m, 1103s, 1052s, 1006m, 976m,
OH O
+ NHOCH3
NOCH3
TBSO TBSO
1-146 1-146'
1-146/1-146’ = 2.9/1.0
The isolated compounds were the mixture of 1-146 and 1-146’ in a ratio of 2.9 to 1.0. Major product, 2-55
exists as syn/anti mixtures with 2/1ratio. Yellow oil. Column; hexane:EtOAc = 4:1 to 3:1. Rf = 0.49
(hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 6 H, anti), 0.07 (s, 6 H, syn), 0.86(s, 9 H,
anti), 0.88 (s, 9 H, syn), 2.37-2.40 (m, 1 H), 2.43-2.62(m, 1 H), 3.39-3.59 (m, 2 H), 3.80 (s, 3 H, syn), 3.86
(s, 3 H, anti), 3.88-3.99 (m, 1 H), 6.74 (t, J = 5.7 Hz, 1 H, anti), 7.37 (t, J = 6.3 Hz, 1 H, syn).
Minor product, 1-141’, the cyclic products are α/β mixture in a ratio of 2.6 to 1. 1H NMR (CDCl3,
400 MHz): δ 0.03 (s, 6 H, β), 0.04 (s, 6 H, α), 0.88 (s, 9 H, β), 0.89 (s, 9 H, α), 1.92-2.13 (m, 2 H), 3.59-
3.77 (m, 3 H), 3.80 (s, 3 H, α), 3.85 (s, 3 H, β), 4.30-4.37 (m, 1 H, β), 4.50-4.57 (m, 1 H, α), 5.05 (dd, J =
5.8, 2.9 Hz,1 H, β), 5.22 (dd, J = 5.4, 2.5 Hz,1 H, α).
To a flask was added 177 mg (0.716 mmol) of 1-141 in 40 mL of absolute alcohol and 200 µL of
triethyl amine. After the mixture was stirred at rt for 40 h, it was concentrated in vacuo and the crude
product was purified by flash column chromatography eluting with hexane: EtOAc = 4:1 to get 73.2 mg
(51.2% based on recovered starting material) of 1-146 as colorless oil. The starting material was also
310
OH
NOCH3
TBSO
1-146
Colorless oil. Column; hexane:EtOAc = 4:1. Rf = 0,52 (Hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400
MHz): δ 0.08 (s, 6 H), 0.90 (s, 9 H), 2.30-2.42 (m, 2 H), 2.61 (d, J = 4.3 Hz, 1 H), 3.51 (dd, J = 10.0, 6.4
13
Hz, 1 H), 3.65(dd, J = 10.0, 4.1 Hz, 1 H), 3.83 (s, 3 H), 3.84-3.90 (m, 1 H), 7.46(d, J = 5.9 Hz, 1 H). C
NMR (CDCl3, 100 MHz): δ -5.43, -5.40, 18.3, 25.8, 33.3, 61.4, 66.4, 69.7, 148.0. IR (NaCl, neat):
υ 3415s, 2954s, 2929s, 2857s, 1472m, 1361w, 1255m, 1112m, 1055m, 940w, 837m, 778m. HRMS
(electrospray) m/z calcd for C11H25O2NSi 270.1501 (M+ + Na), found 270.1496.
To a 50 mL of three neck flask were added 450 mg (2.06 mmol) of lactol 1-131, 156 mg (2.27
mmol) of hydroxylamine hydrochloride, and 358 mg (4.53 mmol) of pyridine. To dissolve hydroxylamine
hydrochloride, 20 mL of dichloromethane and 0.5 mL of H2O were used as the solvent. After refluxing for
21 h 30 min, the mixture was diluted with dichloromethane, and washed by 5% sodium bicarbonate
solution and brine. The combined organic phase was dried over magnesium sulfate, the solid was filtered
off, and the product was concentrated in vacuo. The crude mixture was purified by flash column
chromatography eluting hexane:EtOAc = 3:1 to 2:1 to give 403 mg (84%) of colorless oil as syn/anti
mixture (0.86/1.00).
OTBS
NOH
HO
1-142
syn/anti = 0.86/1.0
Colorless oil. Column; hexane:EtOAc = 3:1 to 2:1. Rf = 0.21 (hexane:EtOAc = 2:1). Major isomer, anti;
1
H NMR (CDCl3, 400 MHz): δ 0.06 (s, 3 H), 0.07 (s, 3 H), 0.87 (s, 9 H), 2.51 (app dt, J = 15.2, 5.7 Hz, 1
311
H), 2.70 (app dt, J = 15.2, 5.8 Hz, 1 H), 2.88 (Br s, 1 H), 3.48 (dd, J = 11.2, 5.0 Hz, 1 H), 3.53 (dd, J =
13
11.3, 5.1 Hz, 1 H), 4.00 (app tt, J = 5.4 Hz, 1 H), 6.83 (t, J = 5.8 Hz, 1 H), 9.27 (Br s, 1 H). C NMR
(CDCl3, 100 MHz): δ -4.8, 18.0, 25.7, 29.7, 65.9, 70.8, 149.2. Minor isomer, syn; 1H NMR (CDCl3, 400
MHz): δ 0.06 (s, 3 H), 0.08 (s, 3 H), 0.87 (s, 9 H), 2.41 (app t, J = 6.1 Hz, 2 H), 2.88 (Br s, 1 H), 3.48 (dd, J
= 11.2, 5.0 Hz, 1 H), 3.53 (dd, J = 11.3, 5.1 Hz, 1 H), 3.92 (app tt, J = 5.4 Hz, 1 H), 7.43 (t, J = 6.4 Hz, 1
13
H), 9.71 (Br s, 1 H). C NMR (CDCl3, 100 MHz): δ -4.7, 18.0, 25.7, 38.8, 65.6, 70.1, 148.8. IR (NaCl,
neat): υ 3314s, 2954s, 2849s, 1658m, 1472s, 1389m, 1362s, 1311m, 1257s, 1098s, 1005m, 978m, 938m,
migration
A solution of 1-142 (113 mg, 0.484 mmol) in 27 mL of absolute methyl alcohol was stirred with
2.0 equivalents of triethyl amine at rt for 7 days. TLC showed the ratio of product/starting material was
6/4. After removed the solvent in vacuo, the mixture was purified by flash column chromatography to give
69.6 mg (80.3% based on recovered starting material) of colorless oil as well as 26.3 mg (23.3%) of
starting material.
OH
NOH
TBSO
1-147
syn/anti = 1.1/1.0
Colorless oil. Column; hexane:EtOAc = 2:1. Rf = 0.38 (hexane:EtOAc = 2:1). 1H NMR (CDCl3, 400
MHz): δ 0.07 (s, 6 H, syn), 0.08 (s, 6 H, anti), 0.89 (s, 9 H, syn), 0.89 (s, 9 H, anti), 2.43-2.32(m, 1 H),
2.46-2.62 (m, 1 H), 3.46-3.54 (m, 1 H), 3.61-3.66 (m, 1 H), 3.84-3.92 (m, 1 H), 6.93 (Br s, 1 H, anti), 7.52
13
(t, J = 6.0 Hz, 1 H, syn). C NMR (CDCl3, 100 MHz): δ -5.4, -5.4, 18.3, 25.8, 33.3, 66.5 (syn), 66.8
(anti), 69.3 (anti), 69.6 (syn), 149.4. IR (NaCl, neat): υ 2224s, 2954s, 2929s, 2857s, 1658w, 1472m,
312
1390w, 1362w, 1256m, 1115s, 1006w, 938w, 838s, 778s, 668w. HRMS (electrospray) m/z calcd for
A mixture of lactol 1-131 (0.530g, 2.43 mmol) and N,N’-dimethyl hydrazine (1.021g, 17.0 mmol)
was dissolved in 15 mL of absolute methyl alcohol, and the mixture was refluxed under nitrogen
atmosphere for 6 h. After removal of the solvent in vacuo, the mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 6:1 to 3:1. The desired product 1-143 (51.9 mg), migrated
product 1-148 (295. 9mg), and the mixture (1-143/1-148 = 0.88/1.00, 215.3mg) were isolated. After
dissolving in 10 mL of absolute methyl alcohol with 87 µL of triethyl amine, the mixture of 1-143 and 1-
148 was stirred at rt for 63 h. After all 1-143 was consumed (TLC), the mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 6:1 to 3:1. The isolated alcohol 1-148 was 98.6 mg
as yellow oil. The stereochemistry was assigned as anti based on the chemical shift (δ 6.61 ppm) and the
OTBS
NN(CH3)2
HO
1-143
anti
20
[α]
Yellow oil. Column; hexane:EtOAc = 6:1 to 3:1. Rf = 0.32 (hexane:EtOAc = 1:1). D = +10.8 (c 0.93,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 2.32 (Br s, 1 H), 2.45 (app t J = 5.6
Hz, 2 H), 2.72 (s, 6 H), 3.50 (dd, J = 11.1, 4.9 Hz, 1 H), 3.56 (dd, J = 11.1, 4.4 Hz, 1 H), 3.93 (app t, J = 4.9
13
Hz, 1 H), 6.61 (t, J = 5.4 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -4.63, -4.59, 18.0, 25.8, 37.5, 43.1,
66.2, 71.7, 134.5. IR (NaCl, neat): υ 3382s, 2954s, 2928s, 2884m, 2856s, 2785w, 1607w, 1472m, 1444m,
313
1361m, 1255s, 1103s, 1052s, 1006m, 938w, 832s, 776s. C12H28O2N2Si 283.1818 (M+ + Na), found
283.1792.
OH
NN(CH3)2
TBSO
1-148
anti
20
[α]
Yellow oil. Column; hexane:EtOAc = 6:1 to 3:1. Rf = 0.35 (hexane:EtOAc = 1:1). D = -15.7 (c 1.62,
CHCl3). 1H NMR (CDCl3, 400 MHz), δ 0.02 (s, 6 H), 0.85 (s, 9 H), 2.26-2.45 (m, 2 H), 2.69 (s, 6 H), 3.15
(Br s, 1 H), 3.50 (dd, J = 9.9, 6.3 Hz, 1 H), 3.57 (dd, J = 10.0, 4.9 Hz, 1 H), 3.79-3.85 (m, 1 H), 6.68 (t, J =
13
4.7 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.5, 18.2, 25.8, 36.0, 43.0, 66.5, 70.5, 135.2. IR (NaCl,
neat): υ 3418s, 2954s, 2928s, 2856s, 2783w, 1611w, 1471m, 1444m, 1361w, 1253s, 1111s, 1006m, 939w,
hydrazone
To a flame dried flask were added 245 mg (1.12 mmol) of lactol 1-131 and small amount of 4 Å
molecular sieves under nitrogen atmosphere. Absolute methyl alcohol (10 mL) was used as the solvent.
To another flame dried flask was dissolved 372 mg (1.68 mmol) of N,N’-diphenyl hydrazine hydrochloride
in 10 mL of absolute methyl alcohol and 181 µL of pyridine under nitrogen stream. The mixture was
stirred at rt for 30min, and then slowly added to the mixture of lactol 1-131 via a syringe. After the mixture
was stirred at rt for 2 h, the solvent was removed under reduced pressure. The crude product was purified
by flash column chromatography eluting with hexane:EtOAc = 8:1 with 1% of Et3N. The desired product
1-144 was isolated as a yellow oil (218 mg), and TBS group migrated compound 1-149 was also obtained
as a yellow oil (62mg). The stereochemistry was assigned as anti based on the chemical shift (δ 6.53 ppm)
and the relatively small coupling constant (J = 5.6 Hz) of H-1 comparing of 1-141.
314
OTBS
NNPh2
HO
1-144
anti only
Yellow oil. Column; hexane:EtOAc = 8:1 with 1% of Et3N. Rf = 0.25 (hexane:EtOAc = 7:1). 1H NMR
(CDCl3, 400 MHz): δ 0.01 (s, 3 H), 0.06 (s, 3 H), 0.84 (s, 9 H), 2.52 (app t, J = 5.8 Hz, 2 H), 3.49 (dd, J =
11.2, 5.2 Hz, 1 H), 3.58 (dd, J = 11.2, 4.1 Hz, 1 H), 3.96 (ddd, J = 11.3, 10.3, 6.0 Hz, 1 H), 6.53 (t, J = 5.6
13
Hz, 1 H), 7.07-7.17 (m, 6 H), 7.34-7.39 (m, 4 H). C NMR (CDCl3, 100 MHz): δ -4.6, 17.9, 25.7, 37.2,
66.2, 71.5, 122.3, 124.0, 129.7, 135.9, 143.9. IR (NaCl, neat): υ 3406m, 3061w, 2953m, 2927m, 2856m,
1591s, 1496s, 1472m, 1377w, 1299m, 1253m, 1211m, 1092m, 1066m, 836m, 777m, 748m, 700m.
hydrazone
To a flame dried 25 mL flask were added 113.5 mg of 1-144 and 59.7 mg of triethyl amine in 16.8
mL of absolute methyl alcohol. The mixture was stirred at rt under nitrogen atmosphere for 36 h. After
removed the solvent in vaccuo, the crude mixture was purified by column chromatography (hexane:EtOAc
= 7:1 to 5:1) to give 74 mg of desired product along with 39 mg of the starting material. The isolated yield
OH
NNPh2
TBSO
1-149
Yellow oil. Column; hexane:EtOAc = 12:1. Rf = 0.41 (hexane:EtOAc = 7:1). 1H NMR (CDCl3, 250
MHz): δ 0.04 (s, 6 H), 0.89 (s, 9 H), 2.37-2.55 (m, 2 H), 3.55 (dd, J = 10.0, 6.3 Hz, 1 H), 3.66 (dd, J = 10.0,
4.5 Hz, 1 H), 3.93 (app tt, J = 11.5, 5.3 Hz, 1 H), 6.52 (t, J = 5.0 Hz, 1 H), 7.06-7.17 (m, 6 H), 7.33-7.41
315
13
(m, 4 H). C NMR (CDCl3, 100 MHz), δ -5.40, 18.29, 25.88, 36.01, 66.53, 70.23, 122.31, 124.09, 129.71,
thiocarbonyl) oxy]-hex-1-ene
To a flame dried three neck flask were added 257 mg (1.06 mmol, E/Z = 2.8/1.0) of 1-145, 569 mg
THF. The mixture was refluxed under nitrogen atmosphere for 13 h, and another 3.0 equivalents of 1,1’-
thiocarbonyldiimidazole were added. Continued refluxing for 8 h consumed all starting material (TLC).
The solvent was removed under reduced pressure to give deep brown oil. The mixture was purified by
flash column chromatography to give 252 mg (68%, E/Z = 3.5/1.0) of desired products as an E/Z mixture.
OTBS CN
(Z)-1-150
Pale yellow oil. Column; hexane:EtOAc = 4:1. Rf = 0.21 (hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400
MHz): δ 0.09 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 2.72-2.76 (m, 2 H), 4.30 (app tt, J = 5.5 Hz, 1 H), 4.53
(dd, J = 11.1, 5.3 Hz, 1 H), 4.67 (dd, J = 11.2, 5.6 Hz, 1 H), 5.50 (d, J = 11.0 Hz, 1 H), 6.61 (app dt, J =
13
10.9, 7.5 Hz, 1 H), 7.06 (s, 1 H), 7.65 (s, 1 H), 8.38 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -4.7, -4.8,
17.9, 25.6, 36.8, 67.9, 75.1, 102.7, 115.5, 117.8, 130.9, 137.3, 149.3, 183.8. IR (NaCl, neat): υ 2953m,
2929m, 2856m, 2220s, 1621s, 1531s, 1464m, 1389s, 1322m, 1286s, 1231s, 970w, 1114s, 998s, 838s, 778s.
316
N
S
CN
OTBS
(E)-1-150
1
H NMR (CDCl3, 400 MHz): δ 0.09 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 2.84 (dd, J = 7.5, 1.2 Hz, 1 H),
2.86 (dd, J = 7.5, 1.4 Hz, 1 H), 3.87 (dd, J = 11.4, 4.4 Hz, 1 H), 3.91 (dd, J = 11.5, 4.4 Hz, 1 H), 5.51 (app
dt, J = 16.3, 1.5 Hz, 1 H), 5.70 (app dt, J = 6.2, 4.4 Hz, 1 H), 5.74 (app dt, J = 16.3, 7.3 Hz, 1 H), 7.06 (s, 1
In a flame dried 50 mL flask fitted with a double spaced condensor were charged 103 mg of 4-
thiocarbonyl diimidazole, and 23 mg of DMAP in 20 mL of freshly distilled THF. The mixture was stirred
under nitrogen stream. Another 143 mg and 95 mg of thiocarbonyl diimidazole were added after 22 h and
44 h, and refluxing was conyinued. After total 55 h refluxing, the solvent was removed under reduced
pressure and the mixture was purified by column chromatography eluting with hexan:EtOAc solution.
NNPh2
OTBS
1-151
Yellow oil. Column; hexane:EtOAc = 7:1. Rf = 0.29 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400 MHz):
δ 0.02 (s, 6 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 2.81-2.85 (m, 2 H), 2.89 (dd, J = 11.4, 4.8 Hz, 1 H), 3.95 (dd, J
= 11.3, 4.0 Hz, 1 H), 5.86 (app tt, J = 10.8, 6.1 Hz, 1 H), 6.47 (t, J = 5.2 Hz, 1 H), 7.02 (s, 1 H), 7.03 (d, J =
13
7.9 Hz, 4 H), 7.11 (t, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 4 H), 7.54 (s, 1 H), 8.31 (s, 1 H). C NMR
317
(CDCl3, 100 MHz): δ -5.52, 18.13, 25.69, 33.19, 62.95, 83.30, 117.86, 122.21, 124.27, 129.71, 130.56,
132.83, 136.71,143.63, 183.59. IR (NaCl, neat): υ 3129w, 3060m, 3037m, 2952s, 2927s, 2856s, 1928w,
1704m, 1593s, 1531s, 1495s, 1463s, 1387s, 1323s, 1284s, 1231s, 1174m, 1095s, 1022m, 963s, 837s.
hexenoate
To a 25 mL of flame dried three neck flask was taken 215 mg (.0746 mmol) of (E)-ethyl 5(S)-
benzene. After addition of triethyl amine (1.2 equiv.) and PhNCO (1.1 equiv.) to the solution, the mixture
was refluxed under nitrogen atmosphere. After 5h, another 1.1 equivalents of PhNCO were added and
reflux was continued for 1h. The mixture was concentrated under reduced pressure, and the product was
purified by flash column chromatography eluting with hexane:EtOAc = 6:1 to 5:1 to get 292 mg of yellow
NHPh
O O OEt
TBSO
1-157
Yellow oil. Column; hexane:EtOAc = 6:1 to 5:1. Rf = 0.55 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 400
MHz), δ 0.06 (s, 6 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 2.53-2.67 (m, 2 H), 3.67 (dd, J = 10.8, 5.4
Hz, 1 H), 3.73 (dd, J = 10.7, 4.9 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.95 (app tt, J = 5.3 Hz, 1 H), 5.91 (d, J
= 15.6 Hz, 1 H), 6.64 (Br s, 1 H, the peak was disappeared with D2O), 6.95 (app dt, J = 15.6, 7.4 Hz, 1 H),
13
7.07 (t, J = 7.3 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.36-7.38 (m, 2 H). C NMR (CDCl3, 100 MHz): δ -
5.6, 14.1, 18.1, 25.6, 30.7, 33.4, 60.2, 63.4, 118.6, 123.3, 124.0, 128.8, 137.7, 143.6, 152.8, 166.1. IR
(NaCl, neat): 3330s, 3138w, 3059w, 2954s, 2929s, 2898m, 2857s, 2358w, 1938w, 1720s, 1656m, 1601s,
1540s, 1502m, 1472m, 1444s, 1390m, 1369m, 1313s, 1254s, 1219s, 1178s, 1108m, 1048m, 1028m, 979m,
318
The reaction of 2-44 with PhNCS and NaH inTHF
In a flame dried flask was taken 0.187 mmol (54 mg) of 1-138 dissolved in 10 mL of a flame-
dried flask. After mineral oil free NaH (0.225 mmol, 5.4 mg was added at rt, 0.281 mmol (38 mg) of
PhNCS were added slowly. The mixture was stirred under nitrogen atmosphere at rt for 3 h. It was
quenched with water and the product was extracted with dichloromethane. The organic phase was washed
with brine, dried over magnesium sulfate, and filtered through sintered funnel. The solvent was removed
under reduced pressure and purified it by flash column chromatography eluting hexane:EtOAc = 6:1 to get
OTBS
O
CO2Et
1-159
cis/trans = 0.75/1.0
Brown oil. Column; hexane:EtOAc = 6:1. Rf = 0.53 (hexane:EtOAc = 4:1). Major isomer, trans; 1H NMR
(CDCl3, 400 MHz): δ 0.04(s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.67 (ddd, J = 15.3,
9.5, 5.8 Hz, 1 H), 2.00 (ddd, J = 12.8, 5.6, 1.4 Hz, 1 H), 2.48 (dd, J = 15.2, 5.9 Hz, 1 H), 2.59 (dd, J = 15.2,
7.2 Hz, 1 H), 3.61 (ddd, J = 9.2, 2.5, 0.5 Hz, 1 H), 3.99 (dd, J = 9.2, 4.8 Hz, 1 H), 4.11-4.22 (m, 2 H), 4.40-
13
4.49 (m, 2 H). C NMR (CDCl3, 100 MHz): δ -4.9, 14.2, 18.0, 25.8, 40.4, 41.8, 60.5, 72.5, 74.4, 76.0,
171.1; minor isomer, cis, δ -4.8, -4.9, 14.2, 18.0, 25.8, 40.9, 41.1, 60.4, 72.6, 75.0, 75.6, 171.4. IR (NaCl,
neat): υ 2970s, 2930s, 2857m, 1737s, 1538w, 1472m, 1384m, 1302w, 1256m, 1157m, 1111m, 1078m,
1030m, 910m, 837m, 776m. Minor isomer, cis; δ 0.05(s, 6 H), 0.87 (s, 9 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.61-
1.65 (m 1 H), 2.26 (ddd, J = 13.3, 7.5, 6.3 Hz, 1 H), 2.58 (dd, J = 15.5, 6.5 Hz, 1 H), 2.76 (dd, J = 15.5, 7.2
Hz, 1 H), 3.73 (ddd, J = 9.2, 2.9, 0.8 Hz, 1 H), 3.78 (dd, J = 9.2, 4.8 Hz, 1 H), 4.11-4.22 (m, 2H), 4.35
(dddd, J = 1 3.8, 7.3, 5.8, 1.4 Hz, 1 H), 4.40-4.49 (m, 1 H).
319
Preparation of 4,6-O-benzylidene-D-glucopyranose127
Ph O
O
O
HO OH
OH
1-164
A mixture of D-glucose (10.0 g, 55.5 mmol), benzaldehyde dimethyl acetal (9.3 g, 61 mmol), and
catalytic amount of p-toluensulfonic acid (12 mg) in 40 mL of DMF (dried over 4 Å MS) was heated at 60
o
C under house vacuum with nitrogen bubbling to remove methyl alcohol formed during the reaction as a
byproduct. The heating was stopped after 3h and 0.3 mL of triethyl amine was added to the reaction
mixture at 0 oC, and the excess solvent was removed under high vacuum. The crude mixture was purified
by column chromatography eluting with EtOAc (with 1% of Et3N). The desired product was obtained as a
white solid (8.38 g), and the isolated yield was 56%.
(165/165’)
Sodium periodate (6.63g) in 65 mL of water and 8N sodium hydroxide solution (1.82 mL) were
bath (the temperature of reactants should be lower than 10 oC). The mixture was stirred at rt for additional
3 h, and to it was added about 1.8 mL of 8N sodium hydroxide solution to adjust the pH to 7 or little lower
than 7. After water was removed in a rotary evaporator, white solid was obtained. The crude product was
dissolved in excess amount of EtOAc, and filtered it under reduced pressure, and the filtrated was washed
several times with EtOAc. The combined organic phase was subjected to rotary evaporation to give
quantitative amount of 165’, which is equilibrium with its dimmer 165. This product was used for the next
experiment without further purification. The 1H NMR spectrum shows that the isolated compound is a
13
mixture of at least three compounds, but the C NMR spectrum and subsequent reactions imply that the
320
Ph O OH
O
Ph O OH O
O O
HO O Ph
CHO O
1-165 1-165'
White solid (column chromatography, hexane:EtOAc = 1:3). Rf = 0.43 (hexane:EtOAc = 1:1). Mp: 147-
149 oC. 1H NMR (DMSO-d6, 250 MHz) is complex. Three isomers were observed in 13C NMR spectrum,
and the major isomer shows δ 57.3, 66.4, 78.9, 84.6, 96.2, 122.5, 124.2, 124.8, 134.1 (Note: there is no
carbonyl carbon).
ester
toluene (10 mL) was added and the mixture was stirred under refluxing condition for 1 h 40 min. After the
solvent was removed under vacuum, the product as an E and Z mixture was isolated by flash column
chromatography eluting with hexane:EtOAc = 2:1. The E and Z compounds were isolated as a white solid
and a colorless oil respectively in a ratio of 1.0/1.89, and the combined isolated yield was 90%.
The same reaction was also performed in dimethoxyethane at rt. The mixture of 78 mg (estimated
as 0.310 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 221
nitrogen atmosphere for 26h, and all starting material was disappeared on TLC. After the solvent was
removed in a rotary evaporator, the crude mixture was purified by column chromatography eluting with
hexane:EtOAc = 2:1. The isolated yield was the same (90%), but the proportion of Z compound increased
to 2.4 to 1.
321
Ph O OH
O
CO2Et
(E)-1-166
White solid (column chromatography, hexane:EtOAc = 3:1). Rf = 0.33 (hexane:EtOAc = 2:1). Mp: 93-95
20
o
C. [α] D = -31.7 (c 0.71 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.30 ( t, J = 7.1 Hz, 3H), 2.71 (Br s,
1H), 3.67 (d, J = 7.5 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4.21-4.25 (m, 1H), 4.32 (d, J = 5.6 Hz, 1H), 5.56 (s,
1H), 6.22 (dd, J = 15.8, 1.7 Hz, 1H), 7.18 (dd, J = 15.8, 4.5 Hz, 1H), 7.34-7.41 (m, 3H), 7.49-7.51 (m, 2H).
13
C NMR (CDCl3, 100 MHz): δ 14.2, 60.7, 65.3, 71.1, 80.4, 100.8, 122.4, 126.1, 128.3, 129.1, 137.2,
143.4, 166.5. IR (NaCl, neat): υ 3476Br s, 2984m, 2924m, 2862m, 1702s, 1656m, 1453m, 1394m, 1370m,
1301s, 1274m, 1224m, 1189m, 1144m, 1082s, 1026s, 979m, 918w, 850w, 757m. Anal. Calcd. for
Ph O OH
O
EtO2C
(Z)-1-166
20
Colorless oil (column chromatography, hexane:EtOAc = 3:1). Rf = 0.42 (hexane:EtOAc = 2:1). [α] D = -
66.1 (c 0.61 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.33 ( t, J = 7.1 Hz, 3H), 3.62-3.73 (m, 1H), 3.83
(d, J = 6.7 Hz, 2H), 4.24 (qd, J = 7.1, 2.9 Hz, 2H), 4.41 (dd, J = 10.3, 4.5 Hz, 1H), 5.19 (app td, J = 9.1, 1.4
Hz, 1H), 5.55 (s, 1H), 6.09 (dd, J = 11.8, 1.2 Hz, 1H), 6.34 (dd, J = 11.7, 7.8 Hz, 1H), 7.35-7.37 (m, 3H),
13
7.47-7.50 (m, 2H). C NMR (CDCl3, 100 MHz): δ 14.1, 61.5, 65.6, 72.1, 78.5, 100.7, 122.4, 126.1, 128.3,
129.0, 137.3, 145.2, 168.1. IR (NaCl, neat): υ 3431Br s, 3037w, 2982m, 2930m, 2854m, 1722s, 1694s,
1658m, 1455m, 1422m, 1386s, 1302w, 1209s, 1090s, 1207s, 871w, 827m, 755m, 699s. Anal. Calcd. for
322
Preparation of (2R, 4S, 5R)-(E and Z)-3-(5-Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-buty
ester
A 100 mL of flame-dried three neck round bottom flask was charged with 708 mg (estimated as
3.10 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 1.40 g
introduced into the flask under nitrogen atmosphere. After the mixture was stirred under refluxing
condition for 4 h, the solvent was removed in a rotary evaporator to give crude mixture. The crude mixture
was purified by column chromatography eluting with hexane:EtOAc = 5:1 to 4:1. E and Z compounds
were isolated as white solid and combined yield was 82%. The ratio of E/Z was 1.0/5.5.
Ph O OH
O
CO2tBu
(E)-1-167
White solid. Column chromatography; hexane:EtOAc = 1 to 4:1. Rf = 0.42 (hexane:EtOAc = 2:1). Mp:
69-71 oC. 1H NMR (CDCl3, 400 MHz): δ 1.49 (s, 9H), 2.86 (Br s, 1H), 3.61-3.69 (m, 2H), 4.27-4.34 (m,
1H), 5.55 (s, 1H), 6.13 (dd, J = 15.8, 1.6 Hz, 1H), 7.05 (dd, J = 15.8, 4.7 Hz, 1H), 7.34-7.41 (m, 3H), 7.48-
13
7.52 (m, 2H). C NMR (CDCl3, 100 MHz): δ 28.04, 65.14, 71.12, 70.53, 80.95, 100.81, 124.20, 126.12,
128.24, 129.05, 137.27, 142.22, 165.92. IR (NaCl, neat): υ 3444 Br s, 3037w, 2978s, 2930s, 2855s, 1714s,
1694s, 1660s, 1455s, 1393s, 1369s, 1316s, 1257s, 1219s, 1155s, 1084s, 1029s, 980s, 917m, 858m, 759m,
698s. Anal. Calcd. for C17H22O5; C, 66.65; H, 7.24. Found; C, 65.45; H, 7.42.
Ph O OH
O
ButO2C
(Z)-1-167
White solid. Column chromatography; hexane:EtOAc = 5:1 to 4:1. Rf = 0.58 (hexane:EtOAc = 2:1). Mp:
20
93-94 oC. [α] D = -41.2 (c 1.16 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.51 (s, 9H), 3.64 (app td, J =
9.2, 4.4 Hz, 1H), 3.71 (app t, J = 10.3 Hz, 1H), 4.40 (dd, J = 10.5, 4.6 Hz, 1H), 5.16 (app td, J = 9.1, 1.2
323
Hz, 1H), 5.57 (s, 1H), 6.02 (dd, J = 11.8, 1.2 Hz, 1H), 6.25 (dd, J = 11.8, 7.8 Hz, 1H), 7.34-7.39 (m, 3H),
13
7.48-7.52 (m, 2H). C NMR (CDCl3, 100 MHz): δ 27.97, 65.51, 72.05, 78.30, 82.44, 100.62, 124.13,
126.08, 128.23, 128.98, 137.34, 143.96, 167.58. IR (NaCl, neat): υ 3420 Br s, 3036w, 2977s, 2930m,
1787w, 1766m, 1714s, 1683s, 1456s, 1393s, 1369s, 1316m, 1251s, 1158s, 1127s, 1090s, 1028s, 979s,
917m, 852m, 827m, 750m, 698s, 654m. Anal. Calcd. for C17H22O5; C, 66.65; H, 7.24. Found; C, 65.87; H,
7.47.
To a 100 mL of flame-dried three neck round bottom flask connected to a condenser were added
toluene (40 mL) was added and the mixture was stirred under refluxing condition for 12 h. Additional 206
nitrogen atmosphere for 2h. After the solvent was removed under vacuum, the crude mixture was purified
by column chromatography eluting with hexane:EtOAc = 3:1. The isolated E and Z compound were
yellowsh brown solid in both, and the ratio of E/Z was 1.0/2.3 (isolated yield 93%).
Ph O OH
O
CN
(E)-1-168
Yellowish brown solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.52 (hexane:EtOAc = 1:1).
20
Mp: 113-115 oC. [α] D = -35.2 (c 0.50 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.64 (Br s, 1H), 3.60-
3.63 (m, 1H), 3.65 (app t, J = 10.1 Hz, 1H), 4.22 (ddd, J = 8.9, 3.6, 2.2 Hz, 1H), 4.30 (dd, J = 9.9, 4.1 Hz,
1H), 5.55 (s, 1H), 5.78 (dd, J = 16.4, 2.0 Hz, 1H), 7.04 (dd, J = 16.4, 3.7 Hz, 1H), 7.37-7.42 (m, 3H), 7.45-
13
7.49 (m, 2H). C NMR (CDCl3, 100 MHz): δ 65.56, 71.61, 80.24, 100.85, 101.34, 115.41, 126.52, 128.81,
129.75, 137.30, 150.82. IR (NaCl, neat): υ 3603m, 3442s, 3055s, 2982m, 2920w, 2866m, 2306m, 2240s,
1639s, 1494w, 1452m, 1422m, 1391s, 1370m, 1323m, 1310m, 1265s, 1219m, 1142s, 1083s, 1027s, 967s,
324
921m, 896m, 739s, 706s, 667w, 632m. Anal. Calcd. for C13H13O3N; C, 67.52; H, 5.67; N, 6.06. Found; C,
Ph O OH
O
NC
(Z)-1-168
Yellowish brown solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.39 (hexane:EtOAc = 1:1).
20
Mp: 98-99 oC. [α] D = -156.1 (c 0.71 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.68 (Br s, 1H), 3.60-
3.65 (m, 1H), 3.69 (app t, J = 10.2 Hz, 1H), 4.31 (dd, J = 9.9, 4.2 Hz, 1H), 4.53 (app td, J = 7.9, 0.8 Hz,
1H), 5.58 (s, 1H), 5.59 (dd, J = 11.4, 1.0 Hz, 1H), 6.50 (dd, J = 11.4, 7.8 Hz, 1H), 7.36-7.42 (m, 3H), 7.50-
13
7.53 (m, 2H). C NMR (CDCl3, 100 MHz): δ 64.99, 70.81, 80.53, 100.80, 102.62, 115.50, 126.08, 129.18,
136.74, 148.88. IR (NaCl, neat): υ 3458Br s, 3068m, 2977m, 2926m, 2860s, 2225s, 1714w, 1634w, 1494w,
1455s, 1402s, 1385s, 1316w, 1295m, 1267m, 1216m, 1134s, 1086s, 1028s, 919m, 872w, 737s, 701s, 675m,
645m. Anal. Calcd. for C13H13O3N; C, 67.52; H, 5.67; N, 6.06. Found; C, 66.77; H, 5.87; N, 5.85.
To a 50 mL of flame dried flask were added 50 mg (0.180 mmol) of (2R, 4S, 5R)-(Z)-3-(5-
thiocarbony-ldiimidazole, and 7 mg of DMAP along with 20 mL of THF. After refluxing the mixture for 5
h, some starting material was detected on TLC. Another 180 mg of 1,1’-thiocarbony-ldiimidazoleand was
added and continued the refluxing for 28h. Additional 100 mg of of 1,1’-thiocarbony-ldiimidazole was
required to consume all starting material with refluxing 10h. After the solvent was removed on a rotary
evaporator, the product was isolated by flash column chromatography with hexane:EtOAc = 3:1 to give
66.9 mg of desired product as yellow solid. The isolated yield was 96%.
325
Ph O O Im
O
S
EtO2C
1-169
Yellow solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.33 (hexane:EtOAc = 2:1). Mp: 101-
20
103 oC. [α] D = -51.0 (c 2.06 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.26 ( t, J = 7.2 Hz, 3H), 3.92
(app t, J = 10.3 Hz, 1H), 4.18 (app tt, J = 7.1, 3.8 Hz, 2H), 4.67 (dd, J = 10.6, 5.2 Hz, 1H), 5.58 (app td, J =
9.8, 5.2 Hz, 1H), 5.70 (s, 1H), 5.99 (dd, J = 11.7, 0.8 Hz, 1H), 6.02 (app t, J = 9.4 Hz, 1H), 6.20 (dd, J =
11.7, 8.8 Hz, 1H), 7.03 (d, J = 0.8 Hz, 1H), 7.36-7.40 (m, 3H), 7.49-7.52 (m, 2H), 7.65 (s, 1H), 8.39 (s,
13
1H). C NMR (CDCl3, 100 MHz): δ 14.1, 60.8, 66.6, 73.0, 74.0, 101.2, 118.4, 124.4, 126.1, 128.3, 129.3,
130.2, 136.5, 136.9, 142.9, 165.4, 182.5. IR (NaCl, neat): υ 3133m, 3037w, 2982m, 2926m, 1715s, 1659m,
1532m, 1469s, 1392s, 1333s, 1295s, 1279s, 1231s, 1199s, 1126s, 1094s, 1005s, 947w, 919m, 872w, 828m,
752m, 698m. Anal. Calcd. for C19H20O5N2S; C, 58.75; H, 5.19; N, 7.21. Found; C, 58.05; H, 5.37; N, 7.13.
To a flame dried 50 mL flask were added 51 mg (0.183 mmol) of (2R, 4S, 5R)-(E)-3-(5-Hydroxy-
thiocarbonyldiimidazole, and 7 mg of DMAP along with 20 mL of fresh distilled THF. The mixture was
refluxed under nitrogen atmosphere for 14 h, and another 200 mg of 1,1’-thiocarbonyldiimidazole were
added. Continued refluxing for 5.5 h, but some starting material was detected on TLC. Finally, 150 mg of
1,1’-thiocarbonyldiimidazole and 18 h refluxing were required to consume all starting material. The
solvent was removed under reduced pressure to give deep brown oil as crude product. The mixture was
purified by flash column chromatography with hexane:EtOAc = 2:1, and 62.1 mg (89%) of desired product
326
Ph O O Im
O
S
CO2Et
1-170
Pale yellow solid. Column chromatography; hexane:EtOAc = 2:1. Rf = 0.17 (hexane:EtOAc = 2:1). Mp:
20
100-102 oC [α] D = -106.7 (c 0.45 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.26 ( t, J = 7.1 Hz, 3H),
3.84 (app t, J = 10.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.71 (dd, J = 10.8, 5.3 Hz, 1H), 4.74-4.69 (m, 1H),
5.54 (app td, J = 9.8, 5.2 Hz, 1H), 5.68 (s, 1H), 6.23 (dd, J = 15.7, 1.5 Hz, 1H), 6.96 (dd, J = 15.7, 4.9 Hz,
13
1H), 7.09 (s, 1H), 7.38-7.42 (m, 3H), 7.50-7.54 (m, 2H), 7.61 (s, 1H), 8.41 (s, 1H). C NMR (CDCl3, 100
MHz): δ 14.1, 60.8, 66.7, 73.4, 76.9, 101.2, 118.0, 124.0, 126.1, 128.4, 129.4, 130.8, 136.3, 136.7, 140.4,
165.6, 181.9. IR (NaCl, neat): υ 3416Br s, 3128m, 3038w, 2979m, 1728s, 1713s, 1666m, 1532m, 1470s,
1392s, 1334s, 1184s, 1139s, 1097s, 1004s, 920m, 852w, 748m, 699m, 653m. Anal. Calcd. for
To a flame dried 100 mL flask were added 472 mg (1.56 mmol) of (2R, 4S, 5R)-(E)-3-(5-
Hydroxy-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-butyl ester (Z)-1-167 and 832 mg (4.67 mmol) of
1,1’-thiocarbony-ldiimidazole and 7 mg of DMAP along with 50 mL of THF. The mixture was refluxed
under nitrogen atmosphere for 6 h. After removed all solvent in vaccuo, the crude mixture was purified by
column chromatography with hexane:EtOAc = 5:1 to give 278 mg of desired product along with 221 mg of
the starting material. The isolated yield was 81% based on recovered starting material.
Ph O O Im
O
S
BuO2tC
1-171
20
Yellow oil. Column chromatography; hexane:EtOAc 5:1. Rf = 0.37 (hexane:EtOAc 3:1). [α] D = -30.0 (c
1.17 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 9Η), 3.91 (app t, J = 10.3 Hz, 1H), 4.66 (dd, J =
327
10.6, 5.2 Hz, 1H), 5.53 (app td, J = 9.9, 5.2 Hz, 1H), 5.69 (s, 1H), 5.90 (d, J = 11.2 Hz, 1H), 6.03 (app t, J =
9.2 Hz, 1H), 6.11 (dd, J = 11.3, 8.9 Hz, 1H), 6.97 (dd, J = 1.6, 0.7 Hz, 1H), 7.34-7.39 (m, 3H), 7.48-7.52
13
(m, 2H), 7.64 (app t, J = 1.4 Hz, 1H), 8.34 (s, 1H). C NMR (CDCl3, 100 MHz): δ 27.94, 66.51, 72.82,
73.59, 82.27, 101.03, 118.15, 126.05, 128.20, 129.18, 130.63, 136.54, 137.06, 141.07, 164.61, 182.75. IR
(NaCl, neat): υ 3131s, 3037s, 2977s, 2931s, 2872s, 1954s, 1655m, 1602m, 1455s, 1392s, 1363s, 1314s,
1426s, 1157s, 1126s, 1092s, 1009s, 949m, 918m, 853m, 827m, 738s, 699s, 662m.
To a flame dried 50 mL flask were added 64 mg (0.211 mmol) (2R, 4S, 5R)-(E)-3-(5-Hydroxy-2-
phenyl-[1, 3]dioxin-4-yl)-acrylic acid tert-butyl ester (E)-1-167 and 113 mg (0.633 mmol) of 1,1’-
thiocarbony-ldiimidazole and 7 mg of DMAP along with 30 mL of THF. The mixture was refluxed under
nitrogen atmosphere for 13 h, and another 180 mg of 1,1’-thiocarbony-ldiimidazole was added. The
mixture was refluxed continually until no more starting material was detected on TLC (15 h). All solvent
was removed in vaccuo to give crude mixture, which was subject to column chromatography with
hexane:EtOAc = 2:1. The desired product was isolated as yellow oil (53 mg) and 1H NMR spectrum
implied the isolated compound is the mixture of two diastereomers with a ratio of 0.16/1.0.
Ph O O Im
O
S
CO2tBu
1-172
20
Yellow oil. Column chromatography; hexane:EtOAc = 2:1. Rf = 0.18 (hexane:EtOAc = 2:1). [α] D = -
81.0 (c 0.62 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 9H), 3.1 (app t, J = 10.3 Hz, 1H), 4.67
(ddd, J = 9.7, 4.9, 1.4 Hz, 1H), 4.72 (dd, J = 10.7, 5.2 Hz, 1H), 5.53 (app td, J = 9.8, 5.2 Hz, 1H), 5.67 (s,
1H), 6.14 (dd, J = 15.6, 1.5 Hz, 1H), 7.07 (s, 1H), 7.37-7.41 (m, 3H), 7.50-7.57 (m, 2H), 7.59 (s, 1H), 8.33
13
(s, 1H). C NMR (CDCl3, 100 MHz): δ 27.94, 66.74, 73.46, 77.11, 81.10, 101.46, 117.92, 125.89, 126.15,
328
128.37 (two peaks), 129.43, 131.07, 136.40, 139.23, 164.25, 182.06. IR (NaCl, neat): υ 3127w, 2977m,
2926w, 2871w, 1713s, 1661w, 1532w, 1469m, 1393s, 1368m, 1333s, 1296s, 1231s, 1155s, 1099s, 1004s,
acrylonitrile
and 17 mg of DMAP along with 20 mL of freshly distilled THF. The mixture was refluxed under nitrogen
atmosphere for 7 h, and another 217 mg of 1,1’-thiocarbonyldiimidazole was added. Refluxing was
continued for 5h at which time all starting material was consumed (TLC). The solvent was removed under
reduced pressure to give the crude mixture, which was purified by flash column chromatography eluting
with hexane:EtOAc = 4:1 to 1:1. The desired product was obtained as pale yellow solid (97 mg) in an
Ph O O Im
O
S
NC
1-173
Pale yellow solid (column chromatography, hexane:EtOAc = 4:1 to 1:1). Rf = 0.55 (hexane:EtOAc = 1:1).
20
Mp: 136-137 oC. [α] D = -90.0 (c 0.41 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.91 (app t, J = 10.4 Hz,
1H), 4.70 (dd, J = 10.8, 5.3 Hz, 1H), 5.10 (app t, J = 9.1 Hz, 1H), 5.58 (dd, J = 11.0, 0.6 Hz, 1H), 5.66 (app
td, J = 9.8, 5.3 Hz, 1H), 5.72 (s, 1H), 6.52 (dd, J = 11.1, 8.7 Hz, 1H), 7.07 (d, J = 0.9 Hz, 1H), 7.38-7.42
13
(m, 3H), 7.50-7.54 (m, 2H), 7.68 (app t, J = 1.3 Hz, 1H), 8.41 (s, 1H). C NMR (CDCl3, 100 MHz):
δ 66.52, 71.92, 77.38, 101.42, 104.42, 114.85, 117.77, 126.07, 128.37, 129.53, 131.31, 135.94, 137.55,
147.03, 182.43. IR (NaCl, neat): υ 3143Br s, 3110m, 3082m, 3039m, 2948m, 2872s, 2253m, 2223s,
1767w, 1713w, 1644w, 1534s, 1480s, 1467s, 1392s, 1330s, 1297s, 1276s, 1216s, 1131s, 1097s, 1069m,
329
1053m, 1006s, 971s, 910s, 871m, 834s, 759s, 735s, 702s, 653s. Anal. Calcd. for C17H15O3N3S: C, 59.81;
acrylonitrile
To a flame dried 25 mL flask were added 40 mg (0.172 mmol) of (2R, 4S, 5R)-(E)-3-(5-Hydroxy-
and 7 mg of DMAP along with 20 mL of freshly distilled THF. The mixture was refluxed under nitrogen
for 5 h consumed all starting material (TLC). The solvent was removed under reduced pressure to give
crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 4:1 to
1:1. The desired product was obtained as yellow oil (44 mg) and the isolated yield is 80%. The isolated
compound wasthe mixture of one major isomer and two minor diastereomers, and the ratio of major/two
minor was ratio 0.42/1.0 based on 1H NMR analysis. Further purification was not performed and only the
Ph O O Im
O
S
CN
1-174
20
Yellow oil. Column chromatography; hexane:EtOAc = 4:1 to 1:1. Rf = 0.26 (hexane:EtOAc = 1:1). [α] D
= -86.0 (c 0.25 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.84 (app t, J = 10.5 Hz, 1H), 4.23-4.27 (m,
1H), 5.56 (app td, J = 9.9, 5.2 Hz, 1H), 5.68 (s, 1H), 5.82 (dd, J = 16.2, 1.9 Hz, 1H), 6.79 (dd, J = 16.2, 4.0
Hz, 1H), 7.07-7.09 (m, 1H), 7.36-7.42 (m, 3H), 7.44-7.51 (m, 2H), 7.60 (app t, J = 1.5 Hz, 1H), 8.32 (s,
1H). IR (NaCl, neat): υ 3129Br s, 3068s, 2965m, 2863s, 2228s, 1770m, 1641w, 1534m, 1469s, 1393s,
1334s, 1291s, 1231s, 1175m, 1141s, 1094s, 1008s, 916s, 874w, 832m, 754s, 732s, 699s, 651s. HRMS
(Electrospray): m/z Calcd for C17H15O3N3SNa (M++Na), 364.0726; Found (M++Na), 364.0722.
330
Preparation of (2R, 4S, 5R)-5-Hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde; O-methyloxime
added 222 mg (estimated as 1.07 mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-
methyl alcohol and 1 mL of pyridine. After the mixture was refluxed under nitrogen atmosphere for 5.5h,
and all solvent was removed in a rotary evaporator to get the crude product. The crude mixture was
purified by column chromatography eluting with hexane:EtOAc = 4:1, and 216 mg of the desired product
was obtained as a white solid (isolated yield 91%). The isolated compound is a syn/ anti mixture with a
Ph O OH
O
NOCH3
1-175
White solid (syn/ anti = 1.0/0.18) (column chromatography, hexane:EtOAc = 4:1). Rf = 0.60
(hexane:EtOAc = 1:1). Mp: 105-108 oC. 1H NMR (CDCl3, 400 MHz): syn δ 3.70 (app t, J = 10.5 Hz, 1H),
3.90 (s, 3H), 3.99 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.25 (dd, J = 8.9, 3.9 Hz, 1H), 4.38 (dd, J = 10.9, 5.2 Hz,
1H), 5.54 (s, 1H), 7.23-7.42 (m, 3H), 7.47-7.52 (m, 3H); anti δ 3.67 (app t, J = 9.6 Hz, 1H), 3.80 (app td, J
= 9.9, 5.1 Hz, 1H), 3.96 (s, 3H), 4.38 (dd, J = 10.8, 5.0 Hz, 1H), 4.90 (dd, J = 9.5, 5.3 Hz, 1H), 5.51 (s,
13
1H), 6.91 (d, J = 5.3 Hz, 1H), 7.33-7.42 (m, 3H), 7.47-7.52 (m, 2H). C NMR (CDCl3, 100 MHz):
syn δ 62.19, 63.99, 70.15, 78.69, 101.35, 126.13, 128.33, 129.21, 137.04, 148.70, anti δ 62.51, 71.11,
75.62, 77.92, 100.71, 126.10, 128.33, 129.21, 136.94, 149.95. IR (NaCl, neat): υ 3489br s, 2978w, 3939w,
2252s, 1462m, 1390m, 1221w, 1086m, 1041m, 908s, 733s, 650m. Anal. Calcd. for C12H15O4N: C, 60.75;
331
Preparation of (2R, 4S, 5R)-5-Hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde; O-benzyloxime
(1-165) and 1.37 g (8.59 mmol) of O-benzylhydroxyl amine hydrochloride in 20 mL of methyl alcohol and
2 mL of pyridine. After the mixture was refluxed under nitrogen atmosphere for 5.5h, and all solvent was
removed in a rotary evaporator to get the crude product. The crude mixture was purified by column
chromatography eluting with hexane:EtOAc = 3:1, and 1.19 mg of the desired product was obtained as a
white solid (isolated yield 53%). The isolated compound is a syn/ anti mixture with a ratio of 1.0/0.14
Ph O OH
O
NOBn
1-176
Pale yellow solid. Recrystalization by hexane:EtOAc = 3:1 or Column; hexane:EtOAc = 3:1. Rf = 0.39
(hexane:EtOAc = 3:1). Mp: 139-140 oC. 1H NMR (CDCl3, 400 MHz): syn (major), δ 2.07 (Br s, OH), 3.67
(app t, J = 10.6 Hz, 1H), 3.96 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.24 (dd, J = 8.9, 3.9 Hz, 1H), 4.36 (dd, J =
10.9, 5.2 Hz, 1H), 5.12 (s, 2H), 5.52 (s, 1H), 7.30-7.40 (m, 8H), 7.46-7.50 (m, 2H); anti (minor), δ 2.07 (Br
s, OH), 3.65 (dd, J = 10.8, 10.1 Hz, 1H), 3.80 (app td, J = 9.8, 5.1 Hz, 1H), 4.33-4.38 (overlap with syn
isomer, 1H), 4.92 (dd, J = 9.5, 5.3 Hz, 1H), 5.16 (d, J = 11.9 Hz, 1H), 5.20 (d, J = 120.0 Hz, 1H), 5.50 (s,
13
1H), 6.95 (d, J = 5.3 Hz, 1H), 7.30-7.40 (m, 8H), 7.46-7.50 (m, 2H). C NMR (CDCl3, 100 MHz): syn
(major) δ 63.95, 70.10, 76.52, 78.76, 101.34, 126.12, 128.21, 128.32, 128.38, 128.70, 129.20, 136.85,
137.02, 149.21. IR (NaCl, neat): υ 3053w, 3031w, 2968m, 2924w, 2881m, 1635m, 1451s, 1396s, 1374s,
1336s, 1274w, 1226s, 1160w, 1110s, 1077s, 1019s, 998s, 950s, 923s, 897s, 870w, 748s, 695s, 654m, 618m.
HRMS (Electrospray): m/z Calcd for C18H19NO4Na (M++Na), 336.1206; Found (M++Na), 336.1296.
332
Preparation of (2R, 4S, 5R)-4-(Diphenylhydrazonomethyl)-2-phenyl-[1, 3]dioxane-5-ol
To a 100 mL of flame-dried one neck round bottom flask were added 780 mg (estimated as 3.10
mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 1.37 g (6.20
mmol) of N,N’-dimethyl hydrazine hydrochloride with 50 mL of methyl alcohol, 552 µL of pyridine (6.82
mmol), and small amount of 4 Å MS. The mixture was stirred at rt under nitrogen atmosphere for 17.5h.
After the solvent was removed in a rotary evaporator, the crude product was purified by column
chromatography eluting with hexane:EtOAc = 7:1 to give 993 mg of the desired product as white solid
(isolated yield 86%). The isolated compound is assigned as anti based on the chemical shift and coupling
constant of its characteristic hydrogen (6.63 ppm, d, J = 3.2 Hz) on 1H NMR spectrum.
Ph O OH
O
NNPh2
1-177
anti
White solid. Column chromatography; hexane:EtOAc = 7:1. Rf = 0.27 (hexane:EtOAc = 5:1). Mp: 119-
20
120 oC. [α] D = +58.8 (c 0.40 in CHCl3). 1
H NMR (CDCl3, 400 MHz): δ 3.42 (Br s, 1H), 3.75 (app t, J =
10.5 Hz, 1H), 4.14 (app td, J = 10.0, 5.3 Hz, 1H), 4.35 (dd, J = 8.9, 3.2 Hz, 1H), 4.43 (dd, J = 10.9, 5.2 Hz,
1H), 5.56(s, 1H), 6.63 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 7.35-7.43 (m, 7H), 7.47-7.50 (m, 2H).
13
C NMR (CDCl3, 100 MHz): δ 64.66, 70.20, 80.64, 101.43, 122.35, 124.86, 128.26, 129.91, 135.90,
137.26, 142.95. IR (NaCl, neat): υ 3453Br s, 3062m, 3036m, 2973m, 2927m, 2856m, 2358w, 2248m,
1955w, 1809w, 1703w, 1591s, 1495s, 1455s, 1395s, 1298s, 1215s, 1157s, 1074s, 1027s, 910s, 750s, 733s,
699s, 648s. Anal. Calcd. for C23H22O3N2; C, 73.78; H, 5.92; N, 7.48. Found; C, 72.89; H, 6.14; N, 7.42.
To a 100 mL of flame-dried three neck round bottom flask connected to a condenser were added
carbaldehyde (1-165) and 279 mg (1.498 mmol) of (p-toluene)sulfonyl hydrazine with 50 mL of methyl
333
alcohol and small amount of 4 Å MS. The mixture was stirred under reflux condition for 2.5 h, and all
solvent was removed in a rotary evaporator. The crude product was purified by column chromatography
eluting with hexane:EtOAc = 3:1 to 2:1 to give 354 mg of the desired product as white solid (isolated yield
75%). The isolated compound is assigned as anti based on the chemical shift and coupling constant of its
Ph O OH
O
NNHTs
1-178
White solid. Column chromatography; hexane:EtOAc = 3:1 to 2:1. Rf = 0.25 (hexane:EtOAc = 1:1). Mp:
143-144 oC. 1H NMR (acetone-d6, 400 MHz): δ 2.39 (s, 3H), 3.63(app t, J = 10.4 Hz, 1H), 3.73 (app dt, J
= 9.2, 5.1 Hz, 1H), 3.76 (s, 0.84 NH, disappeared with D2O), 3.77 (s, 0.16 NH, disappeared with D2O), 4.12
(dd, J = 9.2, 6.0 Hz, 1H), 4.21 (dd, J = 10.5, 5.1 Hz, 1H), 4.31 (d, J = 5.6 Hz, OH), 5.57 (s, 1H), 7.30 (d, J
= 6.0 Hz, 1H), 7.31-7.36 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.76 (dd, J = 6.6, 1.7 Hz,
13
2H). C NMR (acetone-d6, 100 MHz): δ 21.39, 63.91(d), 71.49, 81.91 (d), 101.28, 127.07, 128.44, 128.72,
129.48, 130.34, 137.32, 138.98, 144.61, 147.74 (d). IR (NaCl, neat): υ 3456Br s, 2924m, 2871m, 1698m,
1597m, 1455m, 1397m, 1328m, 1218w, 1164s, 1089s, 1028m, 915w, 814w. Anal. Calcd. for C18H20O5N2S;
C, 57.43; H, 5.36; N, 7.44. Found; C, 59.90; H, 6.66; N, 6.30. HRMS (Electrospray): m/z Calcd for
To a 100 mL of flame-dried one neck round bottom flask were added 208 mg (estimated as 1.0
mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and fresh prepared
1-amino-2-phenylaziridine (323 mg, 2.4 mmol) with 40 mL of ethyl alcohol and small amount of 4 Å MS.
The mixture was stirred at rt under nitrogen atmosphere for 5 h. The solid of the mixture was filtered off
and the organic phase was concentrated in a rotary evaporator. The crude product was purified by column
334
chromatography eluting with hexane:EtOAc = 6:1 to 4:1 to give 212 mg of the desired product as yellow
Ph O OH
O
Ph
N N
1-179
Yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.14 (hexane:EtOAc = 3:1).
Mp: 78-80 oC. 1H NMR (CDCl3, 400 MHz): δ 2.41 (app dt, J = 4.9, 1.1 Hz, 1H), 2.48 (ddd, J = 7.8, 5.2,
0.8 Hz, 1H), 3.08 (app dt, J = 7.8, 4.9 Hz, 1H), 3.43 (d, J = 1.7Hz, 1H), 3.71 (t, J = 10.6 Hz, 1H), 3.95-4.02
(m, 1H), 4.25 (dd, J = 8.9, 2.4 Hz, 1H), 4.37 (dd, J = 10.9, 5.2 Hz, 1H), 5.55 (s, 1H), 7.24-7.29 (m, 3H),
7.31-7.39 9m, 5H), 7.48-7.50 (m, 2H), 8.37 (app t, J = 2.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 40.44
(major), 40.51 (minor), 44.00 (major), 41.13 (minor), 64.26, 70.08, 79.36, 101.32, 126.08, 126.08, 127.46,
128.25, 18.39, 129.12, 137.05, 137.72, 161.30 (major), 161.37 (minor). IR (NaCl, neat): υ 3394Br s,
3065s, 3035s, 2976s, 2856s, 2248m, 1956w, 1884w, 1813w, 1703m, 1644w, 1606m, 1497m, 1455s, 1393s,
1315m, 1221m, 1086s, 1011s, 912m, 735m, 698s. Anal. Calcd. for C19H20O3N; C, 70.35; H, 6.21; N, 8.64.
To a 100 mL of flame-dried three neck round bottom flask connected to a condenser were added
(1-165) and 932 mg (15.5mmol, 1.18 mL) of N,N’-dimethyl hydrazine with 50 mL of methyl alcohol and
small amount of 4 Å MS. After the mixture was refluxed under nitrogen atmosphere for 17.5h, and all
solvent was removed in a rotary evaporator to give crude product. The crude mixture was purified by
column chromatography eluting with hexane:EtOAc = 6:1 to 4:1 to give 652 mg of the desired product as
pale yellow solid (isolated yield 84%). The isolated compound is assigned as anti based on the chemical
shift and coupling constant of its characteristic hydrogen (6.61ppm, d, J = 3.1 Hz) on 1H NMR spectrum.
335
Ph O OH
O
NN(CH3)2
1-180
anti
Pale yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.35 (hexane:EtOAc = 1:1).
20
Mp: 66-68 oC. [α] D = +8.3 (c 0.55 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.83 (s, 6H), 3.64 (Br s,
1H), 3.70 (app t, J = 10.6 Hz, 1H), 3.98 (ddd, J = 10.2, 9.1, 5.2 Hz, 1H), 4.24 (dd, J = 8.9, 3.2 Hz, 1H),
4.36 (dd, J = 10.8, 5.2 Hz, 1H), 5.57 (s, 1H), 6.61 (d, J = 3.1 Hz, 1H), 7.31-7.42 (m, 3H), 7.48-7.57 (m,
2H). 13C NMR (CDCl3, 100 MHz): δ 42.41, 65.09, 70.02, 80.54, 101.24, 126.12, 128.21, 128.95, 133.64,
137.46. IR (NaCl, neat): υ 3392Br s, 2966m, 2862s, 2778m, 2358w, 1597m, 1457s, 1396s, 1316w, 1264m,
1220m, 1085s, 1027s, 918m, 823m, 762s, 699s. Anal. Calcd. for C13H18O3N2; C, 62.38; H, 7.25; N, 11.19.
3]dioxin-5-yl} ester
To a flame dried 100 mL flask were added 163 mg (0.687 mmol) of (2R, 4S, 5R)-5-hydroxy-2-
thiocarbonyldiimidazole, and 20 mg of DMAP along with 50 mL of freshly distilled THF. The mixture
was refluxed under nitrogen atmosphere for 8.5 h, and another 200 mg of 1,1’-thiocarbonyldiimidazole was
added. Continued refluxing for 11 h consumed all starting material (TLC). The solvent was removed
under reduced pressure to give crude mixture, which was purified by flash column chromatography eluting
with hexane:EtOAc = 6:1. The desired product 1-181 was obtained as yellow solid (215 mg) and the
isolated yield is 90%. The isolated compound is syn/anti mixture with a ratio of 1.0/0.13 based on 1H
NMR spectrum.
336
Ph O O Im
O
S
NOCH3
1-181
syn/anti = 1.0/0.13
Yellow solid (syn/ anti = 1.0/0.13). Column chromatography; hexane:EtOAc = 6:1. Rf = 0.41
(hexane:EtOAc = 1:1). Mp: 85-88 oC. 1H NMR (CDCl3, 400 MHz): syn δ 3.78 (s, 3H), 3.87 (app t, J =
10.5 Hz, 1H), 4.68 (dd, J = 9.7, 6.7 Hz, 1H), 4.75 (dd, J = 10.7, 5.3 Hz, 1H), 5.66 (s, 1H), 5.69 (app td, J =
9.9, 5.3 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 7.37-7.41 (m, 4H), 7.49-7.52 (m, 2H), 7.61 (app t, J = 1.2 Hz,
1H), 8.31 (s, 1H), anti δ 3.82 (s, 3H), 3.90 (app t, J = 10.2 Hz, 1H), 4.69 (dd, J = 9.5, 5.0 Hz, 1H), 5.39 (dd,
J = 11.2, 4.4 Hz, 1H), 5.65 (s, 1H), 5.66 (app td, J = 9.9, 5.3 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 7.05 (d, J =
13
1.2 Hz, 1H ), 7.37-7.41 (m, 3H), 7.49-7.52 (m, 2H), 7.63 (app t, J = 1.2 Hz, 1H), 8.31 (s, 1H). C NMR
(CDCl3, 100 MHz): syn δ 62.14, 66.80, 71.49, 76.59, 101.58, 118.14, 126.12, 129.49, 131.07, 136.23,
145.08, 182.60, anti δ 62.31, 66.80, 71.01, 76.59, 101.31, 118.14, 126.12, 129.49, 130.97, 136.79, 145.90,
182.44. IR (NaCl, neat): υ 3412Br s, 3129m, 3037m, 2966m, 2938m, 2870m, 1631w, 1532m, 1469s,
1393s, 1355s, 1294s, 1233s, 1103s, 1039s, 1006s, 920m, 887m, 752m, 699m, 651m. Anal. Calcd. for
3]dioxin-5-yl} ester
To a flame dried 50 mL flask were added 1.32 g (4.21 mmol) of (2R, 4S, 5R)-5-hydroxy-2-phenyl-
and 50 mg of DMAP along with 20 mL of freshly distilled THF. The mixture was refluxed under nitrogen
atmosphere for 4.5 h, and another 300 mg of 1,1’-thiocarbonyldiimidazole was added. Continued refluxing
for 3 h consumed all starting material (TLC). The solvent was removed under reduced pressure to give
crude syn/anti mixture, which was isolated by flash column chromatography eluting with hexane:EtOAc =
3:1 and then recrylstalization over hexane. The pure syn isomer of 1-182 was obtained as white solid (1.17
337
g) and the pure anti isomer of 1-182 was obtained as brown oil (56 mg). The combined isolated yield is
69%.
Ph O O Im
O
S
NOBn
1-182
syn
White solid. Column; hexane:EtOAc = 3:1, then recrystalization over hexane. Rf = 0.16 (hexane:EtOAc =
20
3:1). [α] D = -85.2 (c 0.27 in CHCl3). Mp: 108-109 oC. 1H NMR (CDCl3, 500 MHz): δ 3.84 (app t, J =
10.4 Hz, 1H), 3.69 (dd, J = 9.6, 6.3 Hz, 1H), 4.72 (dd, J = 10.8, 5.4 Hz, 1H), 5.00 (s, 2H), 5.65 (s, 1H),
5.72 (app td, J = 9.9, 5.4 Hz, 1H), 7.04 (s, 1H), 7.19-7.25 (m, 5H), 7.38-7.41 (m, 3H), 7.48-7.52 (m, 4H),
13
8.29 (s, 1H). C NMR (CDCl3, 125 MHz): δ 66.71, 71.48, 76.38, 76.44, 101.61, 118.09, 127.97, 128.01,
128.30, 128.40, 130.43, 136.22, 136.75, 136.86, 145.72, 182.21. IR (KBr): υ 3118w, 3033w, 2952m,
2884m, 1651w, 1628m, 1531m, 1498m, 1463s, 1297s, 1373s, 1329s, 1308s, 1292s, 1277s, 1236s, 1213s,
1128s, 1098s, 1017s, 952m, 932s, 829m, 750s, 696s, 680m, 649s, 618m, 579w. HRMS (Electrospray): m/z
Calcd for C22H21N3O4SNa (M++Na), 446.1145; Found (M++Na), 446.1151; Calcd for C22H21N3O4SH
Ph O O Im
O
S
NOBn
1-182
anti
Brwon oil. Column; hexane:EtOAc = 4:1 to 3:1. Rf = 0.26 (hexane:EtOAc = 3:1). 1H NMR (CDCl3, 400
MHz): δ 3.88 (app t, J = 10.3 Hz, 1H), 4.65 (dd, J = 10.8, 5.1 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 5.07 (d, J
= 12.3 Hz, 1H), 5.43 (dd, J = 9.5, 6.7 Hz, 1H), 5.64 (s, 1H), 5.67 (app td, J = 9.7, 5.2 Hz, 1H), 6.88 (d, J =
13
6.7 Hz, 1H), 7.00 (s, 1H), 7.29-7.40 (m, 8H), 7.47-7.55 (m, 3H), 8.28 (s, 1H). C NMR (CDCl3, 100
MHz): δ 66.66, 70.90, 71.52, 16.97, 101.21, 118.12, 126.10, 127.95, 128.27, 128.36, 128.46, 128.50,
338
129.46, 130.81, 136.21, 136.46, 136.93, 146.16. IR (NaCl, neat): υ 2953s, 2857m, 1736s, 1498w, 1473w,
1428m, 1377w, 1243w, 1243w, 1185w, 1143w, 1112s, 1031m, 923w. HRMS (Electrospray): m/z Calcd for
C22H21N3O4SNa (M++Na), 446.1145; Found (M++Na), 446.1164; Calcd for C22H21N3O4SH (M++H),
[1,3]dioxan-5-yl] ester
To a flame dried 100 mL flask were added 716 mg (2.06 mmol) of (2R, 4S, 5R)-4-(diphenyl
and 80 mg of DMAP along with 60 mL of freshly distilled THF. After the mixture was refluxed under
nitrogen atmosphere for 17.5 h, another 1.10 g of 1,1’-thiocarbonyl diimidazole was added. After 9 h
refluxing, all starting material was disappeared on TLC. The solvent was removed under reduced pressure
to give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc =
6:1 to 4:1. The desired product 1-183 was obtained as yellow solid (833 mg) and 26 mg of the starting
material was recovered. The isolated yield is 90% (93% based on the recovered starting material). The
isolated compound is assigned as anti based on the chemical shift and coupling constant of its characteristic
Ph O O Im
O
S
NNPh2
1-183
anti
Yellow solid. Column chromatography; hexane:EtOAc = 6:1 to 4:1. Rf = 0.29 (hexane:EtOAc = 2:1).
20
Mp: 65-67 oC. [α] D = +26.0 (c 0.45 in CHCl3). 1
H NMR (CDCl3, 400 MHz): δ 3.93 (app t, J = 10.5 Hz,
1H), 4.68 (dd, J = 10.7, 5.4 Hz, 1H), 4.79 (dd, J = 9.5, 5.7 Hz, 1H), 5.68 (s, 1H), 5.83 (app td, J = 9.9, 5.4
Hz, 1H), 6.46 (d, J = 5.7 Hz, 1H), 6.98 (dd, J = 8.6, 1.2 Hz, 4H), 7.03 (d, J = 0.7 Hz, 1H), 7.15 (td, J = 7.4,
1.0 Hz, 2H), 7.30-7.33 (m, 4H), 7.36-7.40 (m, 3H), 7.49-7.52 (m, 2H), 7.64 (s, 1H), 8.37 (s, 1H). 13C NMR
339
(CDCl3, 100 MHz): δ 66.89, 72.14, 79.33, 101.64, 117.98, 122.21, 124.82, 126.19, 128.35, 129.38, 129.74,
130.92, 131.29, 136.55, 136.80, 142.84, 182.77. IR (NaCl, neat): υ 3129m, 3064m, 3038m, 2967m, 2246w,
1955w, 1767w, 1702w, 1592s, 1532w, 1495s, 1464m, 1392s, 1335s, 1300s, 1279s, 1232s, 1157m, 1098s,
1004s, 911s, 831s, 750s, 733s, 699s, 644m. Anal. Calcd. for C27H24O3N4S; C, 66.48; H, 4.99; N, 11.56.
methyl)-2-phenyl-[1,3]dioxan-5-yl} ester
To a flame dried 100 mL flask were added 174 mg (0.462 mmol) of (2R, 4S, 5R)-4-(p-
thiocarbonyldiimidazole, and 14 mg of DMAP along with 50 mL of freshly distilled THF. After the
mixture was refluxed under nitrogen atmosphere for 12 h, all starting material was disappeared on TLC.
The solvent was removed under reduced pressure to give crude mixture, which was purified by flash
column chromatography eluting with hexane:EtOAc = 1:1. The desired product 1-84 was obtained as
white solid (108 mg) and the isolated yield is 48%. This reaction was also performed with crude (2R, 4S,
column chromatography. In this case, the yield was 43% from 1-164 (total 3 steps). The isolated
compound is assigned as anti based on the chemical shift and coupling constant of its characteristic
Ph O O Im
O
S
NNHTs
1-184
anti
White solid. Column chromatography; hexane:EtOAc = 1:1. Rf = 0.39 (hexane:EtOAc = 1:2). Mp: 166-
167 oC. 1H NMR (acetone-d6, 400 MHz): δ 2.33 (s, 3H), 3.74 (s, NH), 4.02(app t, J = 10.8 Hz, 1H), 4.85
(dd, J = 9.6, 5.3 Hz, 1H), 5.67 (app td, J = 10.0, 5.4 Hz, 1H), 5.81 (s, 1H), 7.02 (dd, J = 1.6, 0.8 Hz, 1H),
340
7.18 (dd, J = 7.9, 0.4 Hz, 2H), 7.35-7.39 (m, 3H), 7.40 (d, J = 5.3 Hz, 1H), 7.47-7.50 (m, 2H), 7.60 (app t, J
13
= 1.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 8.20 (s, 1H). C NMR (acetone-d6, 100 MHz): δ 21.49, 66.83,
69.16, 72.26, 78.13, 101.99, 119.16, 127.17, 128.13, 128.92, 129.91, 130.23, 131.69, 136.99, 137.67,
138.14, 144.69, 145.09, 180.38. IR (NaCl, neat): υ 3053m, 2982m, 2362w, 2306w, 2229m, 2130w, 2066w,
1696s, 1598m, 1482w, 1459m, 1417m, 1388m, 1266s, 1153m, 1094m, 1052m, 894w, 815w, 738s, 699m.
HRMS (Electrospray) m/z calcd. For (M++Na); 209.0924. Found (M++Na); 209.0901. Anal. Calcd. for
To a flame dried 50 mL flask were added 104 mg (0.321 mmol) (2R, 4S, 5R)-4-[(2-Phenylaziridin-
12 mg of DMAP along with 30 mL of freshly distilled THF. After the mixture was refluxed under nitrogen
atmosphere for 5 h, another 171 mg of 1,1’-thiocarbonyldiimidazole was added and stirred it under reflux
condition for 17.5 h. The solvent was removed under reduced pressure to give crude mixture, which was
purified by flash column chromatography eluting with hexane:EtOAc = 4:1 to 1:1. The desired product 1-
185 was obtained as brown oil (64 mg) and the isolated yield is 49%.
Ph O O Im
O
S
N N
Ph
1-185
Brown oil. Column chromatography; hexane:EtOAc = 4:1 to 2:1. Rf = 0.26 (hexane:EtOAc = 1:1). 1H
NMR (CDCl3, 400 MHz): δ 3.74 (d, J = 9.8 Hz, minor 1H), 3.76 (d, J = 10.0 Hz, major 1H), 3.92 (app t, J
= 10.4 Hz, major 1H), 3.93 (app t, J = 10.6 Hz, minor 1H), 4.69 (dd, J = 10.7, 5.3 Hz, 1H), 4.81-4.90 (m,
2H), 5.66 (s, major 1H), 5.67 (s, minor 1H), 5.79 (app tt, J = 10.0, 3.3 Hz, 1H), 7.05 (dd, J = 1.6, 0.9 Hz,
major 1H), 7.06 (dd, J = 1.5, 0.7 Hz, minor 1H), 7.35-7.41 (m, 8H), 7.47-7.51 (m, 3H), 7.58-7.60 (m, 1H),
8.31 (s, minor 1H), 8.33 (s, major 1H). 13C NMR (CDCl3, 100 MHz): δ 42.85, 53.66 (major), 53.77
341
(minor), 66.81, 71.61, 79.10, 101.52, 117.90, 126.09, 127.25 (minor), 127.44 (major), 128.39, 128.80
(minor), 128.84 (major), 129.19, 129.50, 131.23, 136.13 (major), 136.16 (minor), 137.26, 137.77 (major),
138.15 (minor). IR (NaCl, neat): υ 3401Br s, 3127m, 3060m, 3033m, 2966m, 2931m, 2872m, 2245w,
1760w, 1694s, 1652w, 1533w, 1495m, 1467s, 1393s, 1335s, 1283s, 1278s, 1231s, 1179s, 1154s, 1099s,
[1,3]dioxan-5-yl] ester
To a flame dried 100 mL flask were added 363 mg (1.45 mmol) of (2R, 4S, 5R)-(dimethyl
diimidazole, and 50 mg of DMAP along with 50 mL of freshly distilled THF. After the mixture was
refluxed under nitrogen atmosphere for 3 h, all starting material was consumed (TLC). The solvent was
removed under reduced pressure to give crude mixture, which was purified by flash column
chromatography eluting with hexane:EtOAc = 3:1. The desired product 1-186 was obtained as yellow solid
(215 mg) and the isolated yield is 90%. The isolated compound is assigned as anti based on the chemical
shift and coupling constant of its characteristic hydrogen (6.41ppm, d, J = 5.9 Hz) on 1H NMR spectrum.
Ph O O Im
O
S
NN(CH3)2
1-186
anti
Pale yellow solid. Column chromatography; hexane:EtOAc = 3:1. Rf = 0.28 (hexane:EtOAc = 1:1). Mp:
20
89-90 oC. [α] D = -92.7 (c 0.94 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.76 (s, 6H), 3.88 (app t, J =
10.4 Hz, 1H), 4.64 (dd, J = 9.7, 6.0 Hz, 1H), 4.69 (dd, J = 10.6, 5.3 Hz, 1H), 5.67 (s, 1H), 4.77 (app td, J =
9.9, 5.3 Hz, 1H), 6.41 (d, J = 5.9 Hz, 1H), 7.03 (d, J = 0.7 Hz, 1H), 7.26 (s, 1H), 7.33-7.41 (m, 3H), 7.51-
7.54 (m, 2H), 7.60 (s, 1H), 8.30 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 42.17, 66.97, 72.85, 79.85,
101.60, 126.19, 127.46, 128.28, 128.34, 129.28, 130.80, 136.77, 183.09. IR (NaCl, neat): υ 3431Br s,
342
3135w, 2958w, 2859m, 2790w, 1594m, 1531w, 1466s, 1392s, 1333s, 1292s, 1279s, 1232s, 1162w, 1101s,
1004s, 919m, 827w, 752m. Anal. Calcd. for C17H20O3N4S; C, 56.65; H, 5.59; N, 15.54. Found; C, 56.59;
H, 5.79; N, 15.19.
To a 50 mL of flame-dried one neck round bottom flask were added 437 mg (estimated as 2.10
mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 314 mg (2.31
mmol) of benzoylhydrazine with 10 mL of ethyl alcohol. White precipitates were formed by stirring the
mixture at rt, and the resulting mixture stand inder nitrogen atmosphere at rt for 20 h. The crude mixture
was purified by recrylstalization over 95% EtOH to give white solid. The product was further obtained
from the mother liquid by column chromatography eluting hexane:EtOAc = 1:3. The combined yield of the
product was 490 mg (72% yield). The isolated compound is assigned as anti based on the chemical shift
and coupling constant of its characteristic hydrogen (7.73 ppm, d, J = 6.3 Hz) on 1H NMR spectrum.
Ph O OH
O
NNHCPh
1-187 O
anti
White solid. Column; hexane:EtOAc = 1:3,then recrystalization with 95% EtOH. Rf = 0.40 (hexane:EtOAc
= 1:3). Mp: 207-209 oC. 1H NMR (DMSO-d6, 500 MHz): δ 3.61 (app t, J = 10.3 Hz, 1H), 3.68 (app td, J
= 9.3, 4.7 Hz, 1H), 4.18 (dd, J = 10.3, 4.8 Hz, 1H), 4.21 (app t, J = 8.3 Hz, 1H), 5.47 (d, J = 5.9 Hz, OH,
smaller up to 0.1H with D2O), 5.69 (s, 1H), 7.34-7.38 (m, 3H), 7.41-7.42 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H),
7.58 (t, J = 7.3 Hz, 1H), 7.73 (d, J = 6.3 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 11.5 (s, NH, disappeared with
13
D2O). C NMR (DMSO-d6, 125 MHz): δ 62.74, 70.70, 81.20, 100.01, 126.30, 127.66, 128.18, 128.65,
128.95, 132.02, 133.16, 137.82, 147.72, 163.46. IR (KBr): υ 3446Br s, 3194s, 3072s, 2917m, 2854m,
1659s, 1629m, 1601m, 1579m, 1559s, 1492w, 1451m, 1393m, 1366s, 1351s, 1306s, 1289s, 1280s, 1261m,
1227w, 1210w, 1176w, 1145s, 1107m, 1089s, 1074s, 1047s, 1033s, 1011s, 978m, 961m, 933w, 916w,
343
898w, 750s, 705s, 696s, 652m, 572m. HRMS (Electrospray): m/z Calcd for C18H18N2O4SNa (M++Na),
To a 50 mL of flame-dried one neck round bottom flask were added 455 mg (estimated as 2.19
mmol) of crude (2R, 4R, 5R)-5-hydroxy-2-phenyl-[1, 3]dioxane-4-carbaldehyde (1-165) and 198 mg (2.40
mmol) of acetylhydrazine with 10 mL of ethyl alcohol. White precipitates were formed by stirring the
mixture at rt, and the resulting mixture stand inder nitrogen atmosphere at rt for 20 h. The crude mixture
was purified by recrylstalization over 95% EtOH to give white solid. The product was further obtained
from the mother liquid by column chromatography eluting hexane:EtOAc = 1:3. The combined yield of the
product was 514 mg (89% yield). The isolated compound is syn/anti mixture with a ratio of 0.52/1.0.
Ph O OH
O
NNHCCH3
1-188 O
syn/anti = 0.52/1.0
White solid. Column; hexane:EtOAc = 1:1 to 1:3,then recrystalization with 95% EtOH. Rf = 0.14
(hexane:EtOAc = 1:3). Mp: 194-196 oC. 1H NMR (DMSO-d6, 400 MHz): syn (minor), δ 2.09 (s, 3H),
3.54-3.65 (m, 2H), 4.08-4.18 (m, 2H), 5.37 (d, J = 5.5 Hz, OH, disappeared with D2O), 5.60 (s, 1H), 7.25
(d, J = 6.7 Hz, 1H), 7.34-7.36 (m, 3H), 7.39-7.41 (m, 2H), 11.13 (s, NH, disappeared with D2O); anti
(major), δ 1.89 (s, 3H), 3.54-3.65 (m, 2H), 4.08-4.18 (m, 2H), 5.35 (d, J = 6.2 Hz, OH, disappeared with
13
D2O), 5.60 (s, 1H), 7.34-7.35 (m, 2H), 7.39-7.41 (m, 3H), 11.24 (s, NH, disappeared with D2O). C NMR
(DMSO-d6, 100 MHz): syn (minor), δ 20.10, 62.60, 70.56, 80.97, 99.79, 126.16, 128.00, 128.79, 137.73,
142.46, 171.87; anti (major), δ 21.46, 62.68, 70.64, 81.12, 97.79, 126.16, 128.00, 128.76, 137.73, 145.21,
165.66, 1.07, 62.15, 66.88, 70.10, 79.00, 99.73, 119.59, 125.82, 128.09, 128.50, 128.78, 137.36, 137.87,
160.04, 176.12. IR (KBr): υ 3450Br s, 3192s, 3064s, 2909m, 2850m, 1678s, 1570s, 1456s, 1401s, 1372s,
1315m, 1282s, 1257s, 1226m, 1216s, 1168s, 1092s, 1071s, 1020s, 991s, 970s, 949s, 929s, 873m, 755s,
344
698s, 682m, 640s, 600s, 571m, 499m. HRMS (Electrospray): m/z Calcd for C13H16N2O4Na (M++Na),
thiocarbonyl diimidazole
To a flame dried 50 mL flask were added 487 mg (1.49 mmol) of (2R, 4S, 5R)-
diimidazole, and 30 mg of DMAP along with 15 mL of freshly distilled THF. After the mixture was
refluxed under nitrogen atmosphere for 4h, another 320 mg of 1,1’-thiocarbonyl diimidazole. All starting
material was consumed (TLC) after 8 h refluxing. The solvent was removed under reduced pressure to
give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 3:1.
The desired product 1-189 was obtained as pale yellow solid (134 mg) and the isolated yield is 21%.
Ph O O
O Ph
N N OH
S Im
1-189
White solid. Column; hexane:EtOAc = 1:1, then recrystalization with hexane. Rf = 0.20 (hexane:EtOAc =
20
1:1). [α] D = -40.0 (c 0.17 in MeOH). Mp: 206-208 oC. 1H NMR (DMSO-d6, 500 MHz): δ 3.58-3.63 (m,
1H), 3.61 (app t, J = 10.5 Hz, 1H), 4.11 (dd, J = 10.8, 5.4 Hz, 1H), 4.56 (dd, J = 9.3, 5.5 Hz, 1H), 5.65 (d,
J = 5.3 Hz, 1H), 5.68 (s, 1H), 6.98 (s, 1H), 7.11 (d, J = 5.5 Hz, 1H), 7.35-7.38 (m, 5H), 7.55 (s, 1H), 7.60-
7.63 (m, 2H), 7.65-7.69 (m, 1H), 7.89-7.91 (m, 2H), 8.04 (s, 1H); 1H NMR (Acetone-d6, 500 MHz): δ 3.61
(app td, J = 9.3, 5.2 Hz, 1H), 3.70-3.75 (1H, overlap with Acetone-d6), 4.24 (dd, J = 10.4, 5.8 Hz, 1H),
4.65 (dd, J = 9.3, 5.2 Hz, 1H), 6.97 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.32-7.38 (m, 3H), 7.46-7.49 (m, 2H),
13
7.56 (s, 1H), 7.60-7.68 (m, 3H), 7.96-7.99 (m, 2H), 8.01 (s, 1H). C NMR (DMSO-d6, 125 MHz): δ 62.15,
67.27, 70.08, 79.14, 119.66, 121.79, 125.69, 126.29, 128.04, 128.58, 128.71, 129.53, 132.82, 137.38,
13
138.00, 158.56, 175.81; C NMR (Acetone-d6, 125 MHz): δ 60.49, 63.48, 68.43, 71.47, 80.82, 101.24,
345
120.46, 123.38, 126.79, 127.26, 128.84, 129.50, 129.73, 130.26, 133.52, 138.70, 138.85, 159.80, 177.50.
IR (KBr): υ 3446Br s, 3146s, 3064m, 2974s, 2928s, 2854s, 1638s, 1522m, 1500m, 1454s, 1413s, 1324s,
1312s, 1293s, 1257s, 1229s, 1147s, 1095s, 1072s, 1031m, 1014s, 998s, 920m, 902m, 832s, 816s, 748s,
723s, 710m, 696s, 671m, 654m, 632m, 602m, 602m, 516m. HRMS (Electrospray): m/z Calcd for
diimidazole
To a flame dried 50 mL flask were added 390 mg (1.48 mmol) of (2R, 4S, 5R)-
diimidazole, and 30 mg of DMAP along with 15 mL of freshly distilled THF. After the mixture was
refluxed under nitrogen atmosphere for 10h, another 320 mg of 1,1’-thiocarbonyl diimidazole. All starting
material was consumed (TLC) after 3 h refluxing. The solvent was removed under reduced pressure to
give crude mixture, which was purified by flash column chromatography eluting with hexane:EtOAc = 3:1.
The desired product 1-192 was obtained as pale yellow solid (175 mg) and the isolated yield is 32%.
Ph O O
O CH3
N N OH
S Im
1-192
White solid. Column; hexane:EtOAc = 1:1 to 1:3,then recrystalization with hexane. Rf = 0.40
20
(hexane:EtOAc = 1:3). [α] D = +70.4 (c 0.27 in MeOH). Mp: 205-206 oC. 1H NMR (DMSO-d6, 500
MHz): δ 2.39 (s, 3H), 3.39 (app td, J = 9.5, 5.4 Hz, 1H), 3.59 (app t, J = 10.4 Hz, 1H), 4.09 (dd, J = 10.8,
5.4 Hz, 1H), 4.47 (dd, J = 9.3, 5.3 Hz, 1H), 5.64 (s, 2H), 6.95 (s, 1H), 7.01 (d, J = 5.3 Hz, 1H), 7.31-7.37
(m, 5H), 7.45 (s, 1H), 7.94 (s, 1H); 1H NMR (Acetone-d6, 400 MHz): δ 2.42 (s, 3H), 3.56 (app td, J = 9.7,
5.3 Hz, 1H), 3.70 (app t, J = 10.5 Hz, 1H), 3.74 (Br s, NH), 4.21 (dd, J = 10.7, 5.3 Hz, 1H), 4.52 (dd, J =
9.2, 5.1 Hz, 1H), 5.67 (s, 2H), 6.95 (s, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.33-7.38 (m, 3H), 7.41-7.48 (m, 3H),
346
13
7.91 (s, 1H). C NMR (DMSO-d6, 100 MHz): δ 11.07, 62.15, 66.88, 70.10, 79.00, 99.73, 119.59, 125.82,
128.09, 128.50, 128.78, 137.36, 137.87, 160.04, 176.12; 13C NMR (Acetone-d6, 100 MHz): δ 11.37,
63.44,68.08, 72.33, 80.67, 101.35, 120.37, 126.85, 128.85, 129.52, 129.57, 131.44, 138.66, 138.75, 160.70,
177.95. IR (KBr): υ 3451Br s, 3147m, 3064m, 2975m, 2929m, 2854m, 2360w, 1949w, 1814w, 1742w,
1997w, 1676w, 1639s, 1582w, 1522m, 1500m, 1483m, 1454s, 1411s, 1390s, 1363m, 1394m, 1324s, 1312s,
1294s, 1258s, 1244m, 1229s, 1147s, 1096s, 1072s, 1032m, 1014s, 998s, 988s, 978s, 940w, 920m, 902m,
833s, 816s, 748s, 724s, 710m, 696s, 671m, 646m, 634m, 602m. HRMS (Electrospray): m/z Calcd for
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 302 mg of Ph3SnH (0.860 mmol) and 13.6 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 88 mg (0.172 mmol) of (1’R,
acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione (Z)-1-196 and 14 mg (0.086 mmol) of AIBN in 3.7
mL of benzene via a syringe pump during 2 h 15 min, and the mixture was stirred for another 0.5 h at 90 oC
(oil bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The concentrated mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as pale yellow oil (59.0 mg, 71%) with a
347
OTBS N OTBS N
O N O N
O O
O CO2tBu O CO2tBu
1-197-α 1-197-β
1-197-α/1-197-β = 0.1/1.0
Colorless oil. Column; hexane:EtOAc = 24:1, Rf = 0.63 (Hexane:EtOAc = 8:1). Major 1-197-β; 1H NMR
(CDCl3, 500 MHz): δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.87 (s, 9 H), 1.23 (s, 3 H), 1.36 (s, 9 H), 1.48 (s, 3 H),
1.98 (dd, J = 16.8, 5.8 Hz, 1 H), 2.21(dd, J = 16.8, 8.6 Hz 1 H), 2.84 (dddd, J = 8.9, 5.6, 3.6, 3.2 Hz, 1 H),
3.66-3.74 (m, 1 H), 3.76 (dd, J = 11.5, 4.4 Hz, 1 H), 3.87 (dd, J = 11.5, 2.0 Hz, 1 H), 4.21-4.26 (m, 2 H),
5.89 (d, J = 3.2 Hz, 1 H), 6.92 (s, 1 H), 7.04 (s, 1 H), 7.58 (s, 1 H). IR (NaCl, neat): υ 3118 Brm, 3002s,
2991s, 2980s, 2930s, 2851s, 1728s, 1461m, 1369s, 1254s, 1219s, 1154s, 1064s, 1000m, 941m, 906m, 838s,
779m, 739m, 662m. Minor 1-197-α was assigned by the characteristic peak is shown at δ 5.64 (d, J = 8.5
Hz, 1H).
An NOE experimental was performed on 1-197 by a 500MHz NMR, and the results are
3.3%
H OTBS CO2tBu
OTBS N
3.5%
N 4
O O N
5
H
N
O O 2
O CO2tBu 3 1
H 1.7% H
O 3.9% H
1-197-β
5.0%
348
The Reaction of (1’R, 4S, 5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 326 mg of Ph3SnH (0.928 mmol) and 14.6 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 92 mg (0.180 mmol) (1’R, 4S,
acrylic acid tert-butyl ester; 1’-O-(1-imidazoyl)thione (E)-1-196 and 15 mg (0.093 mmol) of AIBN in 3.9
mL of benzene via a syringe pump during 2 h 25 min, and the mixture was stirred for another 0.5 h at 90 oC
(oil bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The concentrated mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as pale yellow oil (53.0 mg, 61%) with a
The alllo compounds were not characterized, but their characteristic peak (anomeric hydrogen
O N O N O N O N
O O O O
O CO2tBu O CO2tBu O CO2tBu O CO2tBu
349
The Reaction of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-
temperature
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 157 mg of Bu3SnH (0.54 mmol) and 7 mL of toluene (freshly dried over Na) under nitrogen
atmosphere. To the flask was added a solution of 185 mg (0.36 mmol) of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-
ester; 1’-O-(1-imidazoyl)thione (Z)-1-196 and 12 mg (0.072 mmol) of AIBN in 3.5 mL of toluene under
reflux condition via a syringe pump during 2 h 20 min, and the mixture was refluxed for another 3 h. The
mixture was cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated
mixture was purified by flash column chromatography eluting with hexane:EtOAc = 5:1. The isolated
c]pyran-7-carboxylic acid tert-butyl ester obtained as pale yellow oil (53.7 mg, 33%).
OTBS
O S
O
O CO2tBu
1-202
Yellow oil. Preparative TLC; hexane:EtOAc = 5:1. Rf = 0.17 (hexane:EtOAc = 4:1). 1H NMR (CDCl3,
400 MHz): δ 0.11(s, 3 H), 1.12(s, 3 H), 0.90 (s, 9 H), 1.34 (s, 3 H), 1.46 (s, 9 H), 1.49 (s, 3 H), 2.74(dd, J =
16.4, 3.6 Hz, 1 H), 2.97 (dd, J = 16.4, 8.7 Hz, 1 H), 3.08 (ddd, J = 12.3, 8.7, 3.7 Hz, 1 H), 3.95 (dd, J =
13
12.1, 4.2 Hz, 1 H), 4.04 (dd, J = 8.9, 6.9 Hz, 1 H), 4.11 (dd, J = 11.9, 1.6 Hz, 1 H), 4.25-4.36 (m, 2 H). C
NMR (CDCl3, 100 MHz): δ -5.2, -5.3, 18.4, 24.7, 25.9, 26.9, 28.0, 37.1, 50.9, 62.0, 71.0, 74.9, 78.8, 82.6,
111.3, 170.7, 218.4. IR (NaCl, neat): υ 2957m, 2930s, 2857m, 1731s, 1472m, 1368m, 1338m, 1268s,
1212m, 1152s, 1076m, 836m. HRMS (electrospray) m/z calcd for C21H38O6SSi 469.2056 (M+ + Na), found
469.2057.
350
The Reaction of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2, 2-
addition
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen atmosphere.
The flask was immersed into an oil bath and the oil bath temperature was adjusted to be 90 oC. To the flask
was added a solution of 278 mg (0.791 mmol) of Ph3SnH and 13 mg (0.079 mmol) of AIBN in 3.4 mL of
benzene via a syringe pump during 2 h 15 min, and the mixture was stirred for another 0.5 h at 90 oC (oil
bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The concentrated mixture was purified by flash column chromatography eluting with
tetrahydro-[1,3]dioxolo[4,5,c]pyran-7-y]-acetic acid tert-butyl ester 1-197 (24.1 mg, 37%) as well as [4-
(tert-butyl-dimethyl-silanoyloxymethyl)-6-imidazol-1-yl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5,c]pyran-
OTBS
O
O
O CO2tBu
1-203
20
Colorless oil. Column chromatography; hexane:EtOAc 20:1 to 15:1. Rf = 0.40 (hexane:EtOAc 8:1). [α] D
1
= +24.4 (c 1.23 in CHCl3). H NMR (CDCl3, 500 MHz): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.35 (s,
3H), 1.44 (s, 9H), 1.49 (s, 3H), 2.29-2.35 (m, 1H), 2.44-2.50 (m, 2H), 3.32 (ddd, J = 8.4, 5.6, 2.1 Hz, 1H),
3.65 (dd, J = 11.5, 5.6 Hz, 2H), 3.76 (dd, J = 11.6, 2.3 Hz, 1H), 3.82 (dd, J = 11.5, 2.1 Hz, 1H), 3.90 (dd, J
13
= 8.9, 5.1 Hz, 1H), 4.09 (dd, J = 4.9, 1.3 Hz, 1H). C NMR (CDCl3, 125 MHz): δ -5.23, -5.26, 18.45,
26.00, 26.40, 28.07, 28.25, 33.90, 36.23, 63.81, 65.93, 69.79, 75.38, 79.18, 80.72, 108.84, 171.24. IR
351
(NaCl, neat): υ 2982m, 2948m, 2929s, 2858m, 1731s, 1462w, 1368m, 1278m, 1255m, 1219m, 1152s,
1087m, 1060s, 1004w, 938w, 861m, 836s, 778m. Anal. Calcd. for C21H40O6Si; C, 60.54; H, 9.68. Found;
C, 60.27; H, 10.12. HRMS (Electrospray) Calcd. (M++Na); 439.2486. Found (M++Na); 439.2505.
The configuration has been determined by nOe experiment and the result is shown in below.
1.4%
1.6, 1.3%
3.3%
OTBS
H 0.7%, 0.6%
CO2tBu
OTBS
2.5, 1.9%
O 4
5 O
H
H
O O 2
3 1
O CO2tBu H
0.5%
H
O H
1-203
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 315 mg of Ph3SnH (0.897 mmol) and 14.1 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 87 mg (0.179 mmol) of (1’R,
acrylic acid ethly ester; 1’-O-(1-imidazoyl)thione (Z)-1-208 and 15 mg (0.090 mmol) of AIBN in 3.8 mL
352
of benzene via a syringe pump during 2 h 16 min, and the mixture was stirred for another 0.5 h at 90 oC (oil
bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The ratio of α/β anomeric mixture of the crude mixture was 0.26/1.0 measured by 1H NMR
spectroscopy. The concentrated mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 3:1. The cyclized N-pyranoside was obtained as colorless oil (55.4 mg, 68%) with a ratio
of α/β = 0.24/1.0.
OTBS N OTBS N
O N O N
O O
O CO2Et O CO2Et
altro-1-209-β altro-1-209-α
Colorless oil. Column; hexane:EtOAc = 1:2. Rf = 0.33 (hexane:EtOAc = 1:3). Major altro-1-209-β; 1H
NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.37 (s, 3
H), 1.52 (s, 3 H), 2.12-2.27 (m, 1 H), 2.24-2.41 (m, 1 H), 2.94 (app dtd, J = 6.3, 3.4 Hz, 1 H), 3.66-3.72 (m,
1 H), 3.79 (dd, J = 11.4, 4.4 Hz, 1 H), 3.91 (dd, J = 11.4, 2.1 Hz, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.19-4.26
13
(m, 1 H), 4.26-4.33 (m, 1 H), 5.89 (d, J = 3.1 Hz, 1 H), 6.97 (s, 1 H), 7.11 (s, 1 H), 7.66 (s, 1 H). C NMR
(CDCl3, 100 MHz): δ -5.34, -5.29, 14.04, 18.34, 25.81, 25.91, 27.99, 30.31, 38.33, 61.03, 62.71, 68.60,
75.30, 79.45, 83.01, 109.87, 116.21, 129.13, 134.89, 171.23. IR (NaCl, neat): υ 3391Br, 2931s, 2857m,
2361w, 1733s, 1494m, 1471m, 1373m, 1255s, 1220s, 1153m, 1086s, 1064s, 838s, 779m, 663m. HRMS
(electrospray) m/z calcd for C22H38O6N2Si 455.2577 (M+ + H), found 455.2572. 2nd major altro-1-209-α;
1
H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3 H), 0.06 (s, 3 H), 0.87 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.36 (s, 3
H), 1.47 (s, 3 H), 2.12-2.27 (m, 1 H), 2.24-2.41 (m, 1 H), 2.66-2.80 (m, 1 H), 3.66-3.72 (m, 1 H), 3.71-3.84
(m, 1 H), 3.84-3.96 (m, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.19-4.26 (m, 1 H), 4.26-4.33 (m, 1 H), 5.70 (d, J =
13
8.9 Hz, 1 H), 7.11 (s, 1 H), 7.16 (s, 1 H), 7.72 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.44, 14.04, 18.27,
353
25.57, 25.81, 27.63, 29.16, 39.51, 60.94, 64.45, 71.86, 75.19, 77.45, 82.79, 109.90, 117.01, 129.33, 136.45,
170.88.
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 241 mg of Bu3SnH (0.828 mmol) and 13.0 mL of benzene (dried over CaH2 and stored over 4 Å MS
in nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil
bath temperature was adjusted to be 90 oC. To the flask was added a solution of 74 mg (0.153 mmol) of
yl}-acrylic acid ethly ester; 1’-O-(1-imidazoyl)thione (E)-1-208 and 14 mg (0.090 mmol) of AIBN in 5.0
mL of benzene via a syringe pump during 2 h min, and the mixture was stirred for another 0.5 h at 90 oC
(oil bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The concentrated mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 3:1. The major product was N-Pyranoside 1-209 (59%, altro-β/ altro-α/ allo-β/ allo-α =
0.13: 0.05:1.0:0.31) and the minor product was 1-210 (altro/allo = 1.0/0.11)
O N O N O N O N
O O O O
O CO2Et O CO2Et O CO2Et O CO2Et
The allo-1-209-β and allo-1-209-α could not be characterized fully, but the characteristic peaks
were shown at δ 5.31 (d, J = 10.3 Hz) and 5.98 (d, J = 7.0 Hz) respectively.
354
OTBS
O
O
O CO2Et
altro-1-210
Colorless oil. Column; hexane:EtOAc = 24:1. Rf = 0.63 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 400
MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.35 (s, 3 H), 1.50 (s, 3 H), 2.40 (d, J = 14.3,
5.1 Hz, 1 H), 2.55 (dd, J = 14.2 Hz, 1 H), 3.34 (ddd, J = 8.6, 5.6, 2.2 Hz, 1 H), 3.65 (dd, J = 11.4, 5.6 Hz, 1
H), 3.65-3.71 (m, 1 H), 3.78 (dd, J = 11.8, 2.8 Hz, 2 H), 3.82 (dd, J = 11.8, 2.8 Hz, 1 H), 3.92 (dd, J = 8.7,
5.1 Hz, 1 H), 4.10 (dd, J = 5.1, 2.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 1 H). IR (NaCl,neat): υ 3418Brs, 2982s,
2952s, 2929s, 2882s, 2842m, 1731s, 1463m, 1377m, 1258m, 1179m, 1114m, 1071m, 1029m, 976w, 869m,
837s.
3]dioxolan-4-yl}-ethene; 1’-O-(1-imidazoyl)thione
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 402 mg of Ph3SnH (1.145 mmol) and 18.2 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 95 mg (0.229 mmol) (1’R, 4S,
O-(1-imidazoyl)thione 1-234 and 19 mg (0.115 mmol) of AIBN in 5.0 mL of benzene via a syringe pump
during 3 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was
cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was
purified by flash column chromatography eluting with hexane:EtOAc = 2:1 to 1:2. The isolated products
were 7-endo-cyclized compound 1-236 (25.5 mg, 29%, α/β = 0.39/1.0) as well 6-exo-cyclized compound
1-235 (26.4 mg, 30%, 4 diastereomers with a ratio of altro-α/ altro-β/allo-α/ allo-β= 0.42/1.0/0.22/0.35).
355
OTBS N
O N
O CH3
O
1-235
This compound was isolated as four diastreomer mixture and only two of them were fully characterized.
Pale yellow oil. Column chromatography; hexane:EtOAc 2:1 to 1:2. Rf = 0.23 (hexane:EtOAc 1:3). IR
(NaCl, neat): υ 3118Br s, 2979s, 2932s, 2843s, 1727w, 1681w, 1592w, 1499m, 1473m, 1462m, 1382s,
1250s, 1220s, 1150s, 1105s, 1070s, 1004m, 938i, 879m, 837s, 778m, 735m, 661m. HRMS (Electrospray);
OTBS N
O N
O CH3
O
altro-1-235-β
1
H NMR (CDCl3, 500 MHz): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (d, J = 7.3 Hz, 1H), 0.90 (s, 9H), 1.38 (s,
3H), 1.53 (s, 3H), 2.48 (dqd, J = 11.6, 7.2, 2.6 Hz, 1H), 3.66 (ddd, J = 8.1, 3.8, 1.6 Hz, 1H), 3.80 (dd, J =
11.6, 4.3 Hz, 1H), 3.89 (dd, J = 11.7, 2.0 Hz, 1H), 4.23-4.27 (m, 1H), 5.77 (d, J = 2.7 Hz, 1H), 6.99 (s, 1H),
13
7.09 (s, 1H), 7.70 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.29, -5.32, 10.32, 18.35, 25.81, 16.11, 28.20,
36.56, 62.62, 68.65, 77.85, 79.91, 83.85, 109.51, 116.28, 128.73, 134.88.
The structure has been confirmed by nOe experiment and the key result is shown below.
OTBS
H
1.8% 2.8% CH
3
4
N O
OTBS 5
H N
O N
N
O 2
3 1
O CH3 H H
O O
3.5% H
6.0%
altro-1-235-β 4.0%
356
OTBS N
O N
O CH3
O
altro-1-235-α
1
H NMR (CDCl3, 500 MHz): δ 0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.02 (d, J = 6.7 Hz, 1H), 1.37 (s,
3H), 1.47 (s, 3H), 2.30-2.40 (m, 1H), 3.76 (app td, J = 11.5, 6.3 Hz, 1H), 3.84-3.91 (m, 2H), 4.03 (dd, J =
13
8.3, 6.7 Hz, 1H), 4.20 (app t, J = 6.8 Hz, 1H), 5.35 (d, J = 8.9 Hz, 1H), 7.09 (s, 2H), 7.46 (s, 1H). C
NMR (CDCl3, 125 MHz): δ -5.43, 14.73, 18.26, 25.37, 25.83, 27.67, 37.39, 64.52, 71.79, 74.42, 79.98,
OTBS N
O N
O CH3
O
allo-1-235-β
1
H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.89 (d, J = 7.5 Hz, 3H), 1.38 (s,
3H), 1.53 (s, 3H), 2.26-2.35 (m, 1H), 3.60 (ddd, J = 9.1, 5.1, 2.0 Hz, 1H), 3.72 (dd, J = 11.9, 5.0 Hz, 1H),
3.86 (dd, J = 11.7, 2.0 Hz, 1H), 4.08 (dd, J = 9.1, 4.9 Hz, 1H), 4.35-4.38 (m, 1H), 5.22 (d, J = 10.1 Hz, 1H),
13
7.03 (s, 1H), 7.10 (s, 1H), 7.67 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.24, 12.14, 18.39, 25.83, 26.20,
28.40, 37.74, 62.90, 70.51, 79.22, 85.31, 109.66, 116.60, 128.94, 136.17.
OTBS N
O N
O CH3
O
allo-1-235-α
1
H NMR (CDCl3, 400 MHz): δ -0.02 (s, 3H), 0.00 (s, 3H), 0.84 (s, 9H), 1.14 (d, J = 7.5 Hz, 3H), 1.40 (s,
3H), 1.53 (s, 3H), 2.71-2.78 (m, 1H), 3.14 (ddd, J = 9.7, 4.7, 2.2 Hz, 1H), 3.72-3.75(m, 1H), 3.86 (dd, J =
357
11.7, 2.0 Hz, 1H), 4.08 (dd, J = 9.7, 5.1 Hz, 1H), 4.35-4.38 (m, 1H), 5.78 (d, J = 6.7 Hz, 1H), 7.11 (s, 1H),
13
7.54 (s, 1H), 8.17 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.42, 12.73, 18.35, 26.24, 28.05, 34.14, 62.40,
OTBS
N
O N
1-236
Pale yellow oil. Column chromatography; hexane:EtOAc = 2:1 to 1:2. Rf = 0.10 (hexane:EtOAc = 1:3).
The isolated product was α/β mixture as a ratio of 0.37/1.0. IR (NaCl, neat): υ 3118 Br s, 2985w, 2954s,
2931s, 2882s, 2872s, 1749w, 1723w, 1495m, 1472m, 1462m, 1381s, 1252s, 1219s, 1150s, 1108s, 1075s,
1005m, 939m, 882m, 837s, 779m, 733m, 662m. HRMS (Electrospray); Calc. (M++Na) 405.2180, found
(M++Na) 405.2152.
5.6%
5.9%
OTBS
N H H
N N
O TBSO O N
2.5%
O H
O 2.2%
H
O O H
H H
1.7%
β -1-236 2.2%
1
H NMR (CDCl3, 500 MHz): δ -0.03 (s, 3H), -0.01 (s, 1H), 0.86 (s, 9H), 1.34 (s, 3H), 1.45 (s, 3H), 1.91-
2.02 (m, 2H), 2.04-2.15 (m, 1H), 2.22-2.27 (m, 1H), 3.60 (dd, J = 11.1, 7.6 Hz, 3H), 3.74 (ddd, J = 9.7, 7.6,
2.1 Hz, 1H), 3.87 (dd, J = 11.0, 2.1 Hz, 1H), 4.14 (dd, J = 9.8, 6.8 Hz, 1H), 4.36-4.41 9m, 1H), 5.35 (dd, J
13
= 9.2, 2.2 Hz, 1H), 7.05 (s, 1H), 7.06 (s, 1H), 7.69 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.52, -5.35,
18.29, 24.67, 25.82, 26.17, 27.55, 31.98, 63.83, 64.90, 76.12, 77.79, 80.09, 88.91, 108.86, 116.97, 128.85,
135.31. Anal. Calcd. for C19H34O4N2Si; C, 59.65; H, 8.96; N, 7.32. Found; C, 57.56; H, 8.34; N, 6.99.
The configuration has been determined by nOe experiment. And the result is shown in below.
358
OTBS
N
O N
α-1-236
1
H NMR (CDCl3, 500 MHz): δ 0.01 (s, 3H), 0.00 (s, 1H), 0.85 (s, 9H), 1.36 (s, 3H), 1.43 (s, 3H), 1.91-2.02
(m, 1H), 2.04-2.15 (m, 1H), 2.22-2.27 (m, 1H), 2.63 (app dt, J = 14.7, 11.0 Hz, 3H), 3.45 (ddd, J = 9.8, 5.0,
1.8 Hz, 1H), 3.68 (dd, J = 11.1, 1.6 Hz, 1H), 3.96 (dd, J = 10.1, 5.0 Hz, 1H), 4.36-4.41 (m, 1H), 5.61 (dd, J
13
= 10.7, 5.0 Hz, 1H), 7.08 (s, 1H), 7.18 (s, 1H), 7.85 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.41, -5.32,
18.54, 23.31, 24.13, 25.82, 27.16, 28.42, 63.83, 72.83, 74.55, 76.13, 84.30, 107.76, 117.84, 128.74, 135.48.
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 323 mg of Ph3SnH (0.920 mmol) and 14.5 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 94 mg (0.184 mmol) (1’R, 4S,
acrylic acid ethyl ester; 1’-O-(O-phenyl)thione (E)-1-193 and 15 mg (0.092 mmol) of AIBN in 3.9 mL of
benzene via a syringe pump during 2.5 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.
The concentrated mixture was purified by flash column chromatography eluting with hexane:EtOAc = 2:1
to 1:2. The isolated products were 1-195 (51 mg, 71%) and penyl group migrated compound 1-194 (3 mg,
3%).
359
OTBS
O
O
O CO2Et
altro-1-195
Colorless oil. Column; hexane:EtOAc = 24:1. Rf = 0.63 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 400
MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.35 (s, 3 H), 1.50 (s, 3 H), 2.40 (d, J = 14.3,
5.1 Hz, 1 H), 2.55 (dd, J = 14.2 Hz, 1 H), 3.34 (ddd, J = 8.6, 5.6, 2.2 Hz, 1 H), 3.65 (dd, J = 11.4, 5.6 Hz, 1
H), 3.65-3.71 (m, 1 H), 3.78 (dd, J = 11.8, 2.8 Hz, 2 H), 3.82 (dd, J = 11.8, 2.8 Hz, 1 H), 3.92 (dd, J = 8.7,
5.1 Hz, 1 H), 4.10 (dd, J = 5.1, 2.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 1 H). IR (NaCl,neat): υ 3418Brs, 2982s,
2952s, 2929s, 2882s, 2842m, 1731s, 1463m, 1377m, 1258m, 1179m, 1114m, 1071m, 1029m, 976w, 869m,
837s.
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 257 mg of Ph3SnH (0.732 mmol) and 11.6 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 60 mg (0.146 mmol) of (1’R,
via a syringe pump during 2 h 30 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.
The concentrated mixture was purified by flash column chromatography eluting with hexane:EtOAc = 3:1
to 1:1. The cyclized N-pyranoside was obtained as pale yellow oil (31.9 mg, 57%) with a ratio of altro-α/
360
N
OTBS
O N
O
O CN
1-252
The compound was isolated as a mixture of two (from Z substrates) or four (E substrates) diastereomers at
C-1 and C-2, and only two major compounds (altro-α and altro-β) have been assigned. Yellow oil.
Column chromatography; hexane:EtOAc = 3:1 to 1:1. Rf = 0.24 (hexane:EtOAc = 1:6). IR (NaCl, neat):
υ 3115 w, 2987m, 2955s, 2991s, 2892s, 2857m, 2253w, 1700w, 1494m, 1472m, 1424w, 1384m, 1370m,
1312w, 1285w, 1253s, 1221s, 1159s, 1077s, 939w, 906w, 838s, 780i, 661m. HRMS (Electrospray); Calcd.
(M++Na); 430.2133. Found (M++Na); 430.2116. Anal. Calcd. for C20H33O4N3Si; C, 58.94; H, 8.16; N,
N
OTBS
O N
O
O CN
altro-1-252-β
1
H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.41 (s, 3H), 1.54 (s, 3H), 2.06 (dd,
J = 17.3, 5.4 Hz, 1H), 2.38 (dd, J = 17.3, 9.7 Hz, 1H), 2.69-2.79 (m, 1H), 3.73 (ddd, J = 8.9, 4.3, 2.1 Hz,
1H), 3.82 (dd, J = 11.6, 4.4 Hz, 1H), 3.93 (dd, J = 11.6, 2.0 Hz, 1H), 4.33 (dd, J = 8.9, 5.4 Hz, 1H), 4.52
13
(dd, J = 5.4, 3.4 Hz, 1H), 5.90 (d, J = 2.9 Hz, 1H), 6.98 (s, 1H), 7.15 (s, 1H), 7.69 (s, 1H). C NMR
(CDCl3, 100 MHz): δ -5.35, -5.33, 14.06, 18.35, 25.80, 25.93, 29.23, 39.24, 65.58, 68.19, 74.43, 80.08,
N
OTBS
O N
O
O CN
altro-1-252-α
361
1
H NMR (CDCl3, 400 MHz): δ 0.00 (s, 6H), 0.89 (s, 9H), 1.39 (s, 3H), 1.50 (s, 3H), 2.10 (dd, J = 17.3, 4.5
Hz, 1H), 2.31 (dd, J = 17.2, 9.5 Hz, 1H), 2.69-2.76 (m, 1H), 3.82 (dd, J = 11.6, 4.4 Hz, 1H), 3.98 (dd, J =
11.5, 2.3 Hz, 1H), 4.10 (app td, J = 4.6, 2.3 Hz, 1H), 4.28-4.35 (m, 2H), 5.74 (d, J = 10.0 Hz, 1H), 7.09 (s,
13
1H), 7.15 (s, 1H), 7.78 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.41, -5.36, 16.36, 18.38, 25.33, 25.83,
27.71, 40.53, 68.20, 72.23, 73.90, 75.51, 80.15, 82.01, 110.18, 116.09, 116.44, 129.06, 136.13.
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 296 mg of Ph3SnH (0.842 mmol) and 13.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 69 mg (0.168 mmol) (1’R, 4S,
5R)-(E)-3-{5-O-[2-(tert-butyldimethylsilanyloxy)-1-hydroxyethyl]-2-2-dimethyl[1, 3]dioxolan-4-yl}-
via a syringe pump during 2 h 40 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.
The concentrated mixture was purified by flash column chromatography eluting with hexane:EtOAc = 3:1
to 1:1. The cyclized N-pyranoside was obtained as pale yellow oil (51.0 mg, 80%) with a ratio of altro-α/
N
OTBS
O N
O
O CN
1-252
362
400 MHz 1H NMR altro-α altro-β allo-α allo-β
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 215 mg of Ph3SnH (0.613 mmol) and 9.7 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 51 mg (0.123 mmol) of (1’R,
benzene via a syringe pump during 2 h 10 min, and the mixture was stirred for another 0.5 h at 90 oC (oil
bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The concentrated mixture was purified by flash column chromatography eluting with
hexane:EtOAc = 2:1 to 1:1. After column chromatography, 39.0 mg (83%) of 4-diastereomermixture was
isolated as yellow oil with a ratio of altro-α/ altro-β/ allo-α/ allo-α/ = 0.24/1.0/0.03/0.75, only the major
compound (altro-β) has been assigned. The configuration has been assigned by the comparing the
chemical shift and coupling constant with known configuration (vide infra 1-197).
N
OTBS
O N
O NHOCH3
O
1-253
363
Colorless oil. Column chromatography; hexane:EtOAc = 2:1 to 1:1. Rf = 0.16 (hexane:EtOAc = 1:3). IR
(NaCl, neat): υ 3168 Br s, 2981m, 2952s, 2932s, 2893s, 2856s, 2250w, 2211w, 1698w, 1494m, 1472s,
1458s, 1383s, 1251s, 1219s, 1146s, 1064s, 1033s, 1004m, 938w, 911w, 837s, 779s, 733s. HRMS
(Electrospray); Calcd. (M++Na): 436.2238, found (M++Na): 436.2259. Anal. Calcd. for C19H35O5N3Si; C,
N
OTBS
O N
O NHOCH3
O
altro-1-253-β
1
H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.24 (Br s, 1H), 1.37 (s, 3H), 1.52
(s, 3H), 3.46 (s, 3 H), 3.51-3.61 (m, 1H), 3.72 (ddd, J = 8.5, 4.3, 1.9 Hz, 1H), 3.78 (dd, J = 11.4, 4.4 Hz,
1H), 3.90 (dd, J = 11.5, 2.0 Hz, 1H), 4.31 (dd, J = 8.5, 6.2 Hz, 1H), 4.46 (dd, J = 6.0, 4.4 Hz, 1H), 5.80 (d,
13
J = 2.9 Hz, 1H), 7.09 (s, 1H), 7.17 (s, 1H), 7.88 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.37, -5.33,
18.39, 25.45, 25.83, 29.24, 59.89, 62.17, 63.06, 69.43, 73.05, 78.87, 81.83, 109.78, 117.69, 128.81, 136.19.
dimethyl[1, 3]dioxolan-4-yl}-N,N-dimethylhydrazone
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 269 mg of Ph3SnH (0.766 mmol) and 12.1 mL of benzene (dried over CaH2 and stored over 4 Å MS in
364
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 70 mg (0.153 mmol) of (1’R,
dimethylhydrazone 1-249 and 12 mg (0.077 mmol) of AIBN in 3.3 mL of benzene via a syringe pump
during 2 h 10 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The
mixture was cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated
mixture was purified by flash column chromatography eluting with hexane:EtOAc = 2:1 to 1:1. After
column chromatography, 41.2 mg (63%) of 3-diastereomermixture was isolated as yellow oil with a ratio of
N
OTBS
O N
O NHN(CH3)2
O
1-254
Pale yellow oil. Column chromatography; hexane:EtOAc = 2:1 to 1:1. Rf = 0.17 (hexane:EtOAc = 1:3).
IR (NaCl, neat): υ 2985w, 2956s, 2931s, 2856s, 2817m, 2772m, 1716w, 1679w, 4198m, 1472m, 1382m,
1472m, 1382m, 1372m, 1285m, 1248s, 1230s, 1152s, 1080s, 1056s, 963w, 906w, 838s, 780s, 732w, 661m.
HRMS (Electrospray); Calcd. (M++Na): 449.2555, found: (M++Na) 449.2558. Anal. Calcd. for
The product was isolated as three diastereomer mixture, and only allo-β was fully characterized. The
configuration of the structure was assigned based on comparing the chemical shift and coupling constant
365
N
OTBS
O N
O NHN(CH3)2
O
allo-1-254-β
1
H NMR (CDCl3, 500 MHz): δ -0.02 (s, 3H), -0.01 (s, 3H), 0.85 (s, 9H), 1.46 (s, 3H), 1.47 9s, 3H), 2.23 (s,
6H), 3.20 (dd, J = 10.4, 8.5 Hz, 1H), 3.55 (app t, J = 9.1 Hz, 1H), 3.69 (dd, J = 10.5, 9.1 Hz, 1H), 3.72-3.78
13
(m, 2H), 3.86-3.91 (m, 1H), 5.18 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 7.07 (s, 1H), 7.69 (s, 1H). C NMR
(CDCl3, 100 MHz): δ -5.35, 18.33, 25.80, 26.50, 26.79, 49.01, 62.89, 63.26, 74.38, 78.11, 78.28, 86.35,
Two other diastereomers have been assigned partially due to the lack of information.
N
OTBS
O N
O NHN(CH3)2
O
altro-1-254-β
13
C NMR (CDCl3, 100 MHz): δ -5.32, -5.27, 18.42, 25.46, 25.88, 27.76, 47.63, 57.89, 62.92, 73.59, 78.21,
366
The Reaction of (1’R, 4S, 5R)-3-{5-O-[2-(tert-butyldimethylsilanyl oxy)-1hydroxy ethyl]-2, 2-
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 384 mg of Bu3SnH (1.32 mmol) and 16.4 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 120.7 mg (0.264 mmol) (1’R,
dimethylhydrazone 1-249 and 21.7 mg (0.132 mmol) of AIBN in 10 mL of benzene via a syringe pump
during 4 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was
cooled to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was
purified by flash column chromatography eluting with hexane:EtOAc = 7:1 to 2:1. After column
OTBS
O NHN(CH3)2
O
1-255
20
[α]
Yellow oil. Column; hexane:EtOAc = 7:1 to 2:1. Rf = 0.56 (hexane:EtOAc = 4:1). D = +20.5 (c 0.64,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.03(s, 3 H), 0.04 (s, 3 H), 0.88 (s, 9 H), 1.40 (s, 3 H), 1.41 (s, 3
H), 1.76-1.84 (m, 2 H), 2.81 (s, 6 H), 3.69-3.78 (m, 2 H), 3.98 (ddd, J=12.3, 8.3, 3.9 Hz, 1 H), 4.18 (dd,
13
J=8.5, 6.7 Hz, 1 H), 6.33 (d, J=6.5 Hz, 1 H). C NMR (CDCl3, 100 MHz): δ -5.38, -5.35, 18.3, 25.9, 27.0,
27.2, 35.2, 42.5, 59.8, 76.0, 81.9, 108.6, 130.5. IR (NaCl, neat): υ 2984m, 2953s, 2856m, 2363w, 1802w,
1694w, 1598w, 1472m, 1378m, 1252m, 1167m, 1090s, 1022m, 940s, 883m, 836s, 776m. HRMS
(electrospray) m/z calcd for C16H34O3N2Si 353.2236 (M+ + Na), found 353.2234.
367
Reaction of (6R)-(E)-ethyl 7-{[(1,1-dimethylethyl)diphenylsilyl]oxy}-6-[O-(1-imidazoyl)
thiocarboyloxy]-2-heptenoate
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with Ph3SnH (253 mg, 0.720 mmol) and 11.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 6R)-(E)-ethyl 7-{[(1,1-
mmol) and AIBN (12 mg, 0.072 mmol)in 3.1 mL of benzene via a syringe pump during 2 h 10 min, and the
mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the
solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 1:1. After column chromatography, 40 mg of 1-258,
15 mg of 1-260, and 3.7 mg of three diastereomer mixtures were obtained, respectively (combined isolated
yield is 80%).
N N N
OTBS OTBS OTBS
O N O N O N
1
H NMR (400 MHz) CO2Et CO2Et CO2Et
1-258 1-259 1-260
N
OTBS
O N
CO2Et
1-258
20
Colorless oil. Column; hexane:EtOAc = 1:1. Rf = 0.26 (hexane:EtOAc = 1:2). [α] D = +2.7 (c 0.78 in
CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.02 (s, 9H), 1.21(t, J = 7.2 Hz, 3H), 1.49 (app qd, J = 12.7, 3.5
368
Hz, 1H), 1.58 (app ddt, J = 12.8, 6.9, 6.2 Hz, 1H), 1.79 (Br d, J = 12.2 Hz, 1H), 1.99 (dd, J = 15.7, 8.1 Hz,
1H), 2.07 (dd, J = 15.7, 4.4 Hz, 1H), 2.13 (app dtd, J = 12.7, 6.9, 3.8 Hz, 1H), 2.14-2.29 (m, 1H), 3.67 (app
t, J = 6.9 Hz, 1H), 3.71-3.73 (m, 2H), 4.05 (qd, J = 7.2, 1.9 Hz, 2H), 5.07 (d, J = 8.9 Hz, 1H), 7.01 (s, 1H),
13
7.08 (s, 1H), 7.30 (m, 4H), 7.38-7.42 (m, 2H), 7.57 (s, 1H), 7.60-7.63 (m, 4H). C NMR (CDCl3, 125
MHz): δ 14.12, 19.27, 26.77, 27.09, 28.61, 35.70, 38.62, 60.70, 66.46, 79.03, 87.52, 116.86, 127.59 (two
C), 127.65, 129.62 (two C), 133.38, 133.45, 133.58, 135.62, 132.43, 171.16. IR (NaCl, neat): υ 2976w,
2926w, 2286w, 1734w, 1379m, 1294m, 1261m, 1210w, 1194w, 1154m, 1083s, 1017s, 910w, 754w, 699m.
HRMS (Electrospray): m/z Calcd for C29H38N2O4SiNa (M++Na), 529.2493; Found (M++Na), 529.2417.
N
OTBS
O N
CO2Et
1-260
20
Colorless oil. Column; hexane:EtOAc = 1:1. Rf = 0.21 (hexane:EtOAc = 1:2). [α] D = -6.9 (c 0.26 in
CHCl3). 1H NMR (CDCl3, 500 MHz): δ 1.07 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H), 1.55 (app dt, J = 3.9, 1.9
Hz, 1H), 1.68-1.76 (m, 1H), 1.92 (app tt, J = 13.8, 4.3 Hz, 1H), 2.00 (app dtd, J = 14.2, 4.4, 2.1 Hz, 1H),
2.08 (dd, J = 16.1, 4.5 Hz, 1H), 2.41 (dd, J = 16.1, 9.7 Hz, 1H), 2.56-2.58 (m, 1H), 3.72-3.80 (m, 1H), 4.03
(q, J = 7.1 Hz, 2H), 5.45 (d, J = 2.5 Hz, 1H), 6.96 (s, 1H), 7.08 (s, 1H), 7.37-7.45 (m, 6H), 7.63 (s, 1H),
13
7.68 (dd, J = 8.4, 1.5 Hz, 2H), 7.69 (dd, J = 8.1, 1.3 Hz, 2H). C NMR (CDCl3, 125 MHz): δ 14.11, 19.28,
21.58, 25.94, 26.78, 30.02, 35.58, 60.61, 66.38, 79.72, 87.17, 115.84, 127.73, 127.74, 129.07, 129.77,
129.78, 133,36, 133.39, 134.51, 135.54, 135.56, 172.07. IR (NaCl, neat): υ 3070w, 2953s, 2931s, 2856s,
1733s, 1589w, 1492m, 1473m, 1428m, 1390w, 1308w, 1281m, 1228w, 1113s, 1073m, 1032m. HRMS
(Electrospray): m/z Calcd for C29H38N2O4SiNa (M++Na), 529.2493; Found (M++Na), 529.2445.
369
4.4%
2.4%
H5
H1
H H3a 2.8%
H TBDPSO
2.7%
TBDPSO
O H O Im
Im H6a H7b H
H4a 6b 15.1%
7a
CO2Et
H CO2Et
1-258 1.8% H 0.6%
H4b 3b 2.9%
7.5%
H2
6.0% 2.7%
2.1%
4.6%
2.0%
1.5%
H5 3.1% H1
H H 6.1% H3a
TBDPSO 5.2%
TBDPSO 4.2%
O O Im
Im H6a H
H H4a 6b
H2
CO2Et H
1-260 H4b 3b H7b
4.6%
H7a CO2Et
370
The Reaction of (E)-ethyl 5(S)-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-6-[(N-imidazolythio
carbonyl)oxy]-2-hexenoate
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 199 mg of Ph3SnH (0.567 mmol) and 8.9 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 55 mg (0.138 mmol) (E)-ethyl
9.4 mg (0.057 mmol) of AIBN in 2.4 mL of benzene via a syringe pump during 1 h, and the mixture was
stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent was
removed in vacuo to give crude product. The α/β ratio of the crude product was altro-α/ altro-β/ allo-α/
allo-α/ = 0.21/1.0/0.78/0.22. The concentrated mixture was purified by flash column chromatography
eluting with hexane:EtOAc = 2:1 to 1:1. After column chromatography, 40.1 mg (79%) of 4-
diastereomermixture was isolated as yellow oil with a ratio of altro-α/ altro-β/ allo-α/ allo-β/ =
O N
TBSO
CO2Et
allo-1-257-β
Pale yellow oil. Column chromatography; hexane:EtOAc = 2:1 to 1:1. Rf = 0.16 (hexane:EtOAc = 1:3).
1
H NMR (CDCl3, 500 MHz): δ 0.09 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H), 1.96 (app
dt, J = 13.7, 6.1 Hz, 1H), 2.04 (app dt, J = 14.1, 4.5 Hz, 1H), 2.10 (dd, J = 16.5, 5.2 Hz, 1H), 2.62-2.68 (m,
1H), 2.70 (dd, J = 16.5, 8.5 Hz, 1H), 3.72-3.79 (m, 2H), 3.87 (app tt, J = 8.6, 4.2 Hz, 1H), 4.03 (qd, J = 7.1,
13
1.7 Hz, 2H), 5.57 (d, J = 3.6 Hz, 1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.72 (s, 1H). C NMR (CDCl3, 100
MHz): δ -4.90, 14.07, 17.99, 25.72, 33.19, 33.83, 34.54, 60.55, 65.12, 70.97, 85.01, 117.33, 128.98,
135.96, 172.15. IR (NaCl, neat): υ 3113w, 2954s, 2938s, 2896s, 2857s, 1732s, 1494m, 1472m, 1390m,
1362m, 1284m, 1255s, 1227s, 1176s, 1096s, 1035s, 918m, 879m, 838s, 777s, 739m, 662m. HRMS
371
(Electrospray); Calc. (M++Na) 369.2209, found (M++Na) 369.2205. The structure has been confirmed by
1.0%
1.5%
H
H
N 4 H O N
5
O N TBSO
N
H 2
3 1
TBSO H 7.1%
H H
CO2Et EtO2C
12.3%
allo-1-257-β 4.8%
O N
TBSO
CO2Et
altro-1-257-β
Pale yellow oil. Column chromatography; hexane:EtOAc = 2:1 to 1:1. Rf = 0.18 (hexane:EtOAc = 1:3).
1
H NMR (CDCl3, 500 MHz): δ 0.06 (s, 6H), 0.88 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.83 (ddd, J = 14.1,
10.1, 4.4 Hz, 1H), 2.08-2.25 (m, 1H), 2.11 (dd, J = 15.7, 5.2 Hz, 1H), 2.38 (dd, J = 15.8, 9.5 Hz, 1H), 2.80
(ddd, J = 9.4, 7.6, 4.3 Hz, 1H), 3.43 (dd, J = 11.2, 9.3 Hz, 1H), 4.02 (app tt, J = 9.8, 4.8 Hz, 1H), 4.07-4.13
13
(m, 1H), 4.09 (q, J = 7.1 Hz, 2H), 5.48 (d, J = 3.0 Hz, 1H), 6.94 (s, 1H), 7.07 (s, 1H), 7.64 (s, 1H). C
NMR (CDCl3, 100 MHz): δ -4.88, -4.84, 14.10, 18.01, 25.68, 31.63, 35.53, 36.15, 60.78, 62.14, 72.47,
H
CO2Et
N
4 H O N
O N 5
TBSO
N
H 2
3
TBSO 3.4%H
1.5% 1
H 4.6%
CO2Et H H
1.5% 3.4%
altro-1-257-β 2.1%
4.3%
372
N N N N
O N O N O N O N
3]dioxolan-4-yl}-ethene; 1’-O-(1-imidazoyl)thione
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with Ph3SnH (569 mg, 1.62 mmol) and 25.7 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-{5-O-[2-(tert-
imidazoyl)thione 1-269 (142 mg, 0.324 mmol) and AIBN (27 mg, 0.162 mmol) in 7.1 mL of benzene via a
syringe pump over 4 h 40 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature).
The mixture was further stirred under refluxing condition for 8 h to consume all starting material 1-269.
After removed all solvent on a rotary eveaporator under reduced predure, the crude mixture was purified by
column chromatographyl eluting hexane:EtOAc = 12:1 to give colorless oil (49 mg, 50%). The isolated
373
TBSO OH
O O
1-270
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with Ph3SnH (233 mg, 0.663 mmol) and benzene (10.5 mL, dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-(Z)-3-{5-O-[2-
ester; 1’-O-(1-tridazoyl)thione 1-272 (68 mg, 0.113 mmol) and AIBN (11 mg, 0.066 mmol) in 2.8 mL of
benzene via a syringe pump during 3 h, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.
The α/β ratio of the crude product was 0.32/1.0. The concentrated mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 8:1 to 7:1. The α-altro and β-altro of as [4-(tert-butyl-
dimethyl-silanoyloxymethyl)-6-imidazol-1-yl-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5,c]pyran-7-yl]-
OTBS N
O N
N
O
O CO2tBu
altro-1-274-α
Pale yellow oil. Column chromatography; hexane:EtOAc = 8:1 to 7:1. Rf = 0.20 (hexane:EtOAc = 4:1).
20
[α] D = +20.7 (c 0.58 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.02 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),
1.36 (s, 3H), 1.39 (s, 9H), 1.48 (s, 3H), 2.32 (dd, J = 16.2, 4.9 Hz, 1H), 2.51 (dd, J = 16.2, 5.3 Hz, 1H),
374
2.30 (app dq, J = 9.6, 5.1 Hz, 1H), 3.75 (dd, J = 11.6, 5.4 Hz, 1H), 3.88 (dd, J = 11.6, 2.3 Hz, 1H), 4.10
(ddd, J = 7.7, 5.3, 2.3 Hz, 1H), 4.28 (app t, J = 7.3 Hz, 1H), 4.31 (dd, J = 9.3, 7.0 Hz, 1H), 5.90 (d, J = 9.4
13
Hz, 1H), 7.97 (s, 1H), 8.33 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.41, -5.36, 18.31, 25.29, 25.81,
27.46, 28.02, 35.56, 38.50, 72.05, 74.62, 74.92, 81.25, 84.41, 110.37, 136.13, 152.01, 170.33. IR (NaCl,
neat): υ 3122w, 2985s, 2954s, 2930s, 2857s, 1725s, 1507m, 1472m, 1401m, 1431m, 1369s, 1272s, 1256s,
The structure has been confirmed by nOe experiment and the key result is shown below.
1.7%
0.7%
H OTBS
CO2tBu
OTBS N 1.2%
4
N 5
O
O H
N
H
O 2
3 1
O H 3.6% H
O CO2tBu O N
4.5% N
N
altro-1-274-α
1.4%
OTBS N
O N
N
O
O CO2tBu
altro-1-274-β
Pale yellow oil. Column chromatography; hexane:EtOAc = 8:1 to 7:1. Rf = 0.28 (hexane:EtOAc = 4:1).
20
[α] D = -4.3 (c 1.25 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H),
1.36 (s, 3H), 1.40 (s, 9H), 1.48 (s, 3H), 1.97 (dd, J = 16.7, 7.8 Hz, 1H), 2.38 (dd, J = 16.7, 7.0 Hz, 1H),
3.01 (ddd, J = 13.7, 7.1, 4.1 Hz, 1H), 3.72 (dd, J = 9.1, 4.9, 1.7 Hz, 1H), 3.76 (dd, J = 11.4, 5.0 Hz, 1H),
3.91 (dd, J = 11.4, 1.7 Hz, 1H), 4.30 (dd, J = 9.2, 6.3 Hz, 1H), 4.42 (app t, J = 6.2 Hz, 1H), 6.41 (d, J = 4.0
13
Hz, 1H), 7.98 (s, 1H), 8.24 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.30, 18.37, 25.43, 25.84, 27.66,
375
27.98, 32.73, 37.56, 63.06, 69.71, 74.40, 77.83, 81.24, 84.39, 109.47, 143.11, 152.14, 170.55. IR (NaCl,
neat): υ 3122w, 2985s, 2954s, 2931s, 2857s, 1739w, 2236w, 1727s, 1506m, 1472m, 1461m, 1369s, 1272s,
1255s, 1214s, 1157s, 1066s, 1022m, 956m, 939m, 910m, 875m, 837s, 814m, 779s, 734s, 678m. HRMS
The structure has been confirmed by nOe experiment and the key result is shown below.
0.9%, 1.5%
2.5%, 2.5% 0.9%, 0.7%
N H OTBS CO2tBu
OTBS 1.5%, 2.0%
1.2%, 1.4%
O N 4
O N
N H
5
N N
O 2
O 3 1
O CO2tBu H H
2.8%
O H
3.8%
altro-1-274-β
3.7%
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with Ph3SnH (162 mg, 0.461 mmol) and 7.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (1’R, 4S, 5R)-(E and Z)-3-{5-
amine; 1’-O-(1-triazoyl)thione 1-273 (41 mg, 0.092 mmol) and of AIBN (7.6 mg, 0.046 mmol) in 2.0 mL
of benzene via a syringe pump during 1 h 20 min, and the mixture was stirred for another 0.5 h at 90 oC (oil
bath temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude
product. The ratio of altro-α/ altro-β of the crude mixture is 0.69/1.0. The concentrated mixture was
purified by flash column chromatography eluting with hexane:EtOAc = 6:1. After column
376
chromatography, 17.6 mg (46%) of 3-diastereomermixture was isolated as yellow oil The structure has
OTBS N
O N
N
O NHOCH3
O
altro-1-275-β
20
Pale yellow oil. Column chromatography; hexane:EtOAc = 6:1. Rf = 0.23 (hexane:EtOAc = 2:1). [α] D =
-7.4 (c. 0.42 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.37 (s,
3H), 1.51 (s, 3H), 3.46 (s, 3 H), 3.74 (ddd, J = 8.9, 4.5, 2.0 Hz, 1H), 3.77 (dd, J = 11.4, 4.4 Hz, 1H), 3.81
(dd, J = 5.6, 3.4 Hz, 1H), 3.91 (dd, J = 11.7, 2.0 Hz, 1H), 4.33 (dd, J = 8.7, 6.7 Hz, 1H), 4.44 (app t, J = 6.3
13
Hz, 1H), 6.11 (d, J = 3.4 Hz, 1H), 8.01 (s, 1H), 8.51 (s, 1H). C NMR (CDCl3, 100 MHz): δ -5.33, 18.43,
25.23, 25.87, 27.58, 59.76, 62.12, 63.03, 69.82, 72.50, 77.85, 82.81, 109.83, 144.08, 151.83. IR (NaCl,
neat): υ 3263 Br s, 3118w, 2985m, 2954s, 2931s, 2862s, 1752w, 1508m, 1472m, 1463m, 1382s, 1276s,
1252s, 1218s, 1134s, 1068s, 954m, 914w, 836s, 813m, 780s, 734m, 698w, 677m. HRMS (Electrospray);
377
1.2%
0.7%
H OTBS
OTBS N NHOCH3
4
N O N
O H
5
N
N N
O 2
O NHOCH3 3 1
H H
O O 3.0%H
2.3%
altro-1-275-β
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with Ph3SnH (109 mg, 0.311 mmol) and benzene (4.9 mL, dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 1’-O-(1-
benzylimidazoyl)thione 1-276 (35 mg, 0.062 mmol) and AIBN (5 mg, 0.031 mmol) in 1.3 mL of benzene
via a syringe pump during 50 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The crude 1H NMR spectrum implies that a a/b mixture of N-pyranosides 1-277 were formed
along with 1-278. After all solvent was removed on a rotary eveaporator, the crude mixture was subjected
378
N
OTBS
O N
O
O CO2tBu
1-277
thiocarbonyl)oxy]-2-hexenoate
A flame-dried three neck 100 mL flask was connected to a condenser, and the flask was charged
with 37 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen
atmosphere. The flask was immersed into an oil bath, and the bath temperature was adjusted to be 90 oC,
and Ph3SnH (2.35 mmol, 825 mg) was added to it. A solution of 0.47mmol (187 mg) of 1-281 and 0.235
mmol (38 mg) of AIBN in 10 mL of benzene was added dropwise with stirring via a syringe pump during 3
h 40 min, and the mixture was stirred for another one hour. The mixture was cooled to rt, and the solvent
was removed the solvent in vacuo. The concentrated mixture was purified by flash column
chromatography eluting hexane:EtOAc = 1:1 to 1:3. The isolated yield of N-furanoside was 88%.
379
N
TBSO
N
O
H H
CO2Et
1-282
N N N N
TBSO TBSO TBSO TBSO
N N N N
O O O O
H H H H H H H H
Colorless oil. Column; hexane:EtOAc = 1:1 to 1:3. Rf = 0.23 (hexane:EtOAc = 1:3). The stereochemistry
was assigned tentatively. Major 1-282-a; about 2 mg was isolated as a pure form. 1H NMR (CDCl3, 400
MHz): δ 0.08 (s, 6 H), 0.94 (s, 9 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.85 (dd, J = 17.4, 8.7 Hz, 1 H), 1.95 (ddd, J
= 12.8, 11.2, 11.2 Hz, 1 H), 2.03 (ddd, J = 12.8, 6.8, 5.4 Hz, 1 H), 2.17 (dd, J = 17.4, 7.5 Hz, 1 H), 3.02
(ddddd, J = 13.2, 13.2, 8.6, 6.6, 2.1 Hz, 1 H), 3.79 (dd, J = 11.5, 3.1 Hz, 1 H), 4.02 (dd, J = 11.4, 3.0 Hz, 1
H), 4.09 (qd, J = 7.2, 1.0 Hz, 2 H), 4.17 (app tt, J = 6.9, 3.5 Hz, 1 H), 6.05 (d, J = 6.8 Hz, 1 H), 7.04 (s, 1
13
H), 7.20 (s, 1 H), 7.68 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.5, -5.3, 14.1, 18.6, 26.0, 30.2, 33.2,
41.2, 60.8, 63.5, 81.0, 88.2, 117.5, 128.5, 136.0, 171.9. IR (NaCl,neat): υ 3116 Br s, 2956s, 2930s, 2859s,
1731s, 1493m, 1469m, 1419m, 1386m, 1343m, 1255s, 1183m, 1077s, 1026m, 920m, 838s, 779s, 663m.
HRMS (electrospray) m/z calcd for C18H32O4N2Si 369.2209 (M+ + H), found 369.2210. 2nd major 1-282-
b; 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.91 (s, 9 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.77
(dd, J = 12.8, 8.3 Hz, 1 H), 2.20-2.63 (m, 3 H), 2.85-2.97 (m, 1 H), 3.65 (dd, J = 11.0, 3.6 Hz, 1 H), 3.78
(dd, J = 11.1, 3.7 Hz, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 4.33 (app tt, J = 7.3, 3.6 Hz, 1 H), 5.55 (d, J = 5.5Hz,
13
1 H), 7.07 (s, 1 H), 7.09 (s, 1 H), 7.66 (s, 1 H). C NMR (CDCl3, 100 MHz), δ -5.40, -5.38, 14.11, 18.37,
25.91, 32.31, 36.71, 42.85, 60.91, 64.69, 79.89, 91.04, 116.49, 129.82, 136.00, 171.32. Minor 3-59; 1H
NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.91 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.74-1.89
(m, 1 H), 2.20-2.63 (m, 3 H), 2.85-2.97 (m, 1 H), 3.68 (dd, J = 11.0, 3.7 Hz, 1 H), 3.81 (dd, J = 11.1, 3.7
Hz, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 4.27 (app tt, J = 6.9, 3.5 Hz, 1 H), 5.53 (d, J = 5.0 Hz, 1 H), 7.07 (s, 1
380
13
H), 7.17 (s, 1 H), 7.85 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.38, -5.35, 14.11, 18.37, 26.00, 32.00,
36.13, 42.67, 60.86, 65.20, 79.93, 91.24, 116.49, 129.82, 136.00, 171.15.
The 1-282-c and 1-282-d could not be fully characterized because only small amount of the
product was made; but the characteristic peak was found at δ 6.10 (d, J = 6.2 Hz) and at δ 5.60 (d, J = 5.7
Compound 1-283 was isolated as a major product under refluxing condition (see Table 12 for
detail)
TBSO
O S
CO2Et
1-283
cis/trans = 2.1/1.0
Yellow oil. Column; hexane:EtOAc = 6:1 to 3:1. Rf = 0.13 (hexane:EtOAc = 4:1). Major, cis; 1H NMR
(CDCl3, 400 MHz): δ 0.08 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.93 (ddd, J =
12.6, 11.3, 9.6 Hz, 1 H), 2.43-2.62 (m, 2 H), 3.24 (dd, J = 17.0, 3.8 Hz, 1 H), 3.29-3.34 (m, 1 H), 3.79 (dd,
J = 11.5, 2.6 Hz, 1 H), 3.98 (dd, J = 11.5, 2.7 Hz, 1 H), 4.10-4.23 (m, 2 H), 4.83 (app dq, J = 6.7, 3.5 Hz, 1
13
H). C NMR (CDCl3, 100MHz): δ -.5.42, -5.36, 14.16, 18.32, 25.82, 30.19, 35.13, 37.20, 60.91, 64.02,
78.68, 171.31, 177.41. Minor, trans; 1H NMR (CDCl3, 400 MHz), δ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.89 (s, 9
H), 1.27 (t J = 7.1 Hz, 3 H), 2.07 (app dt, J = 8.4, 5.1 Hz, 1 H), 2.43-2.62 (m, 2 H), 3.15 (dd, J = 16.8, 4.0
Hz, 1 H), 3.47 (app dq, J = 9.4, 4.0 Hz, 1 H), 3.72 (dd, J = 11.8, 3.7 Hz, 1 H), 3.97 (dd, J = 11.7, 3.4 Hz, 1
13
H), 4.10-4.23 (m, 2 H), 4.92 (app dq, J = 8.8, 2.7 Hz, 1 H). C NMR (CDCl3, 100MHz): δ -.5.62, -5.31,
14.15, 18.32, 25.80, 30.14, 35.56, 36.18, 60.86, 65.08, 78.01, 171.31, 178.45. IR (NaCl, neat): υ 2956s,
2928s, 2853m, 2360m, 1776w, 1736s, 1463m, 1352m, 1254s, 1183m, 1125m, 1028m, 839s, 780m. HRMS
(electrospray) m/z calcd for C15H28O4SSi 355.1375 (M+ + Na), found 355.1372.
381
The Reaction of (E) and (Z)-1-cyano-5-{[(1,1-dimethyl)ethyl dimethylsilyl]oxy}-4(S)-[(N-imidazoly-
thiocarbonyl) oxy]-hex-1-ene
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 35 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen atmosphere) under nitrogen
atmosphere. The flask was immersed into an oil bath, and the bath temperature was adjusted to be 90 oC,
and Bu3SnH (1.73 mmol, 503 mg) was added to it. A solution of 0.345 mmol (121 mg) of 1-298 (E/Z =
1.0/0.25) and 0.173 mmol (28 mg) of AIBN in 10 mL of benzene was added dropwise with stirring via a
syringe pump during 3 h 40 min, and the mixture was stirred for another one hour. The mixture was cooled
to rt, and the solvent was removed the solvent in vacuo. The concentrated mixture was purified by flash
column chromatography eluting hexane:EtOAc = 1:3. The isolated yield of the product 1-299 and 1-300
N
TBSO
N
O
H H
CN
1-299
N N N N
TBSO TBSO TBSO TBSO
N N N N
O O O O
H H H H H H H H
CN CN CN CN
Yellow oil. Column; hexane:EtOAc = 1:3. Rf = 0.15 (hexane:EtOAc = 1:3). Major 1-299-a; 1H NMR
(CDCl3, 400 MHz): δ 0.13 (s, 6 H), 0.94 (s, 9 H), 1.98 (dd, J = 7.8, 2.2 Hz, 2 H), 2.55 (dd, J = 16.8, 7.6 Hz,
1 H), 2.67 (dd, J = 16.9, 6.2 Hz, 1 H), 2.92-3.02 (m, 1 H), 3.79 (dd, J = 11.8, 2.7 Hz, 1 H), 4.06 (dd, J =
11.7, 2.7 Hz, 1 H), 4.22 (dddd, J = 8.0, 5.4, 5.4, 2.7 Hz, 1 H), 5.97 (d, J = 6.6 Hz, 1 H), 7.10 (s, 1 H), 7.30
13
(s, 1 H), 7.88 (s, 1 H). C NMR (CDCl3, 100 MHz): δ -5.40, 14.11, 18.36, 25.91, 32.31, 36.71, 42.85,
382
60.91, 66.69, 79.89, 91.04, 116.49, 129.82, 135.20, 171.32. IR (NaCl, neat): υ 3123 Brs, 2956s, 2930s,
2859s, 2254m, 1693s, 1493m, 1469m, 1422m, 1391m, 1362m, 1256s, 1226m, 1181m, 1088s, 1011m, 982m,
838s, 664m. HRMS (electrospray) m/z calcd for C16H27O2N3Si 344.1770 (M+ + Na), found 344.1769. 2nd
major 1-299-b; 1H NMR (CDCl3, 400 MHz): δ 0.09 (s, 6 H), 0.92 (s, 9 H), 2.10-2.20 (m, 1 H), 2.59-2.67
(m, 1 H), 2.81-2.90 (m, 1 H), 3.65 (dd, J = 11.3, 3.1 Hz, 1 H), 3.85 (dd, J = 11.3, 3.2 Hz, 1 H), 4.37 (app tt,
13
J = 7.5, 3.1 Hz, 1 H), 5.62 (d, J = 4.8 Hz, 1 H), 7.03 (s, 1 H), 7.71 (s, 1 H), 7.78 (s, 1 H). C NMR
(CDCl3, 100 MHz): δ -5.48, 14.11, 18.36, 26.00, 32.00, 36.13, 42.68, 60.87, 65.20, 79.94, 91.04, 116.52,
The 1-299-c and 1-299-d could not be isolated in pure forms but the anomeric hydrogen observed
at 5.56 ppm ( J = 6.0 Hz) and 6.01 ppm ( J = 6.0 Hz) suggest diastereomeric structres.
TBSO
O
CN
1-300
3 diasteromers were isolated as a mixture in a ratio of 0.43/0.27/0.26 based on 13C NMR, and the
stereochemistry was not assigned. Only 1H NMR spctrum of two diasteromer have been assigned.
Major; 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.89 (s, 9 H), 1.49-1.62 (m, 2 H), 1.67-
1.85 (m, 1H), 2.44 (dd, J = 13.8, 7.8 Hz, 1 H), 2.45 (dd, J = 14.5, 6.8 Hz, 1 H), 2.56-2.66 (m, 1 H), 3.50-
3.66 (m, 2 H), 3.82-3.87 (m, 1 H), 3.99-4.04 (m, 1 H), 13C NMR (CDCl3, 100 MHz): δ -5.35, 18.32, 20.92,
25.96, 33.07, 36.01, 64.98, 72.36, 79.93, 118.43. HRMS (electrospray) m/z calcd for C24H42O6N2Si
483.2890 (M+ + H), found 483.2903. Minor; 1H NMR (CDCl3, 400 MHz): δ 0.05 (s, 3 H), 0.06 (s, 3 H),
0.91 (s, 9 H), 1.49-1.62 (m, 2 H), 2.08 (ddd, J = 13.0, 8.0, 6.3 Hz, 1 H), 2.21 (app dt, J = 12.7, 5.3 Hz, 1 H),
2.31-2.39 (m, 2 H), 3.47-3.52 (m, 1 H), 3.63-3.66 (m, 1 H), 3.74 (dd, J = 8.0, 3.7 Hz, 1 H), 4.09-4.15 (m, 1
H), 13C NMR (CDCl3, 100 MHz): δ -5.40, 18.43, 20.68, 25.89, 33.14, 36.33, 65.46, 72.25, 78.87, 118.65.
383
2nd minor; 13C NMR (CDCl3, 100 MHz): δ -4.78, 16.30, 20.68, 25.77, 29.68, 36.59, 64.25, 70.52, 72.89,
118.00.
To a flame-dried 50 mL of three neck flask connected to a condenser was added 4.69 mmol (840
mg) of EPHP dissolved in 37 mL of dried benzene under positive pressure of nitrogen. The temperature of
the flask was adjusted to be 90 oC, and added a mixture of 0.469 mmol (187 mg) of 1-281 and 0.469 mmol
(77 mg) of AIBN in 10 mL of benzene via a syringe pump at 26 µL/min. After addition, the mixture was
stirred at 90 oC for another one hour. The mixture was washed with water, and crude product was extracted
with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered, and the
solvent was removed under reduced pressure. The concentrated mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 1:1 to 3:1 to give the desired products. The isolated yield of
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 276 mg of Ph3SnH (0.785 mmol) and 12.5 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 60.9 mg (0.157 mmol) of (2R,
and 13 mg (0.079 mmol) of AIBN in 3.4 mL of benzene via a syringe pump over 2 h , and the mixture was
stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent was
removed in vacuo to give crude product. The concentrated mixture was purified by flash column
384
chromatography eluting with hexane only to hexane:EtOAc = 1:2. The cyclized N-pyranoside was
obtained as white solid (30.5 mg, 54%) with the ratio of α/β = 0.8/1.0).
Ph O
O
O
H
EtO2C
H Im
1-285-α
White solid. Column chromatography; hexane only to hexane:EtOAc = 1:2. Rf = 0.12 (hexane:EtOAc =
20
1:4). [α] D = +25.0 (c 0.62 in CHCl3). Mp: 126-129 oC. 1H NMR (CDCl3, 400 MHz): δ 1.11 (t, J = 7.2
Hz, 3H), 2.60 (dd, J = 15.5, 8.5 Hz, 1H), 2.84 (dd, J = 15.4, 4.9 Hz, 1H), 3.15 (dddd, J = 8.8, 8.3, 7.0, 4.9
Hz, 1H), 3.65 (dd, J = 10.6, 8.8 Hz, 1H), 3.88-4.05 (m, 4H), 4.54 (dd, J = 9.3, 3.9 Hz, 1H), 5.58 (s, 1H),
13
5.78 (d, J = 7.0 Hz, 1H), 7.14 (s, 1H), 7.35-7.41 (m, 4H), 7.49-7.52 (m, 2H), 7.71 (s, 1H). C NMR
(CDCl3, 100 MHz): δ 13.90, 34.21, 45.28, 61.17, 70.75, 73.10, 82.78, 88.93, 102.61, 117.08, 126.22,
128.40, 129.01, 129.43, 136.16, 136.42, 170.20. IR (NaCl, neat): υ 3394 Br m, 3119m, 2982m, 1731s,
1495w, 1455w, 1428w, 1370m, 1282m, 1228m, 1165m, 1094m, 1047s, 1028s, 970s, 913m, 756s, 699s,
661m. HRMS (Electrospray) Calcd. for (M++Na); 381.1421. Found (M++Na); 381.1447. Anal. Calcd. for
Ph O
O
O
Im
EtO2C
H H
1-285-β
White solid. Column chromatography; hexane only to hexane:EtOAc = 1:2. Rf = 0.22 (hexane:EtOAc =
20
1:4). [α] D = -84.0 (c 0.77 in CHCl3). Mp: 57-60 oC. 1H NMR (CDCl3, 400 MHz): δ 1.77 (t, J = 7.1 Hz,
3H), 1.80 (dd, J = 17.8, 11.4 Hz, 1H), 2.69 (dd, J = 17.8, 3.5 Hz, 1H), 3.11 (app tdd, J = 11.4, 7.6, 3.5 Hz,
1H), 3.62 (dd, J = 11.6, 9.0 Hz, 1H), 3.75 (ddd, J = 9.9, 9.0, 4.0 Hz, 1H), 4.03 (app t, J = 11.0 Hz, 1H),
4.05 (q, J = 7.1 Hz, 2H), 4.63 (dd, J = 9.8, 4.3 Hz, 1H), 5.62 (s, 1H), 6.29 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H),
13
7.11 (s, 1H), 7.35-7.41 (m, 3H), 7.48-7.59 (m, 2H), 7.60 (s, 1H). C NMR (CDCl3, 100 MHz): δ 14.04,
385
31.03, 43.25, 61.11, 70.97, 73.05, 81.42, 86.95, 102.84, 117.42, 126.25, 128.42, 128.99, 129.62, 136.15,
136.42, 171.60. IR (NaCl, neat): υ 3388 Br m, 3119m, 3061m, 2983m, 2928m, 1729s, 1494m, 1478m,
1428s, 1376s, 1324m, 1228s, 1212s, 1080s, 1027s, 996s, 972s, 914m, 699s, 662m. HRMS (Electrospray)
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 309 mg of Ph3SnH (0.880 mmol) and 14 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 72.8 mg (0.176 mmol) of (2R,
11, and 14.5 mg (0.088 mmol) of AIBN in 3.8 mL of benzene via a syringe pump during 2 h 25 min, and
the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and
the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane only to hexane:EtOAc = 1:2. The cyclized N-pyranoside was
obtained as white solid (31 mg, 46%) with the ratio of α/β = 0.66/1.0).
Ph O
O
O
t H
Bu O2C
H Im
1-286-α
White solid. Column chromatography; hexane only to hexane:EtOAc = 1:2. Rf = 0.16 (hexane:EtOAc =
20
1:2). [α] D = +34.9 (c 0.59 in CHCl3). Mp: 125-128 oC. 1H NMR (CDCl3, 500 MHz): δ 1.33 (s, 9H), 2.54
(dd, J = 15.1, 8.5 Hz, 1H), 2.82 (dd, J = 15.1, 4.7 Hz, 1H), 3.18 (dddd, J = 8.8, 8.5, 6.9, 4.8 Hz, 1H), 3.65
(dd, J = 10.4, 8.9 Hz, 1H), 3.94 (app t, J = 10.1 Hz, 1H), 4.00 (app td, J = 9.8, 4.1 Hz, 1H), 4.58 (dd, J =
9.5, 4.1 Hz, 1H), 5.62 (s, 1H), 5.82 (d, J = 6.9 Hz, 1H), 7.20 (s, 1H), 7.21 (s, 1H), 7.41-7.46 (m, 3H), 7.53-
13
7.58 (m, 2H), 7.81 (s, 1H). C NMR (CDCl3, 100 MHz): δ 27.72, 35.87, 45.26, 70.76, 72.92, 81.84, 83.04,
386
89.05, 102.67, 117.08, 126.25, 128.39, 129.43, 130.29, 136.43, 136.70, 169.43. IR (NaCl, neat): υ 3393 Br
m, 3119m, 2983m, 2931m, 2872m, 1716m, 1396w, 1369m, 1281m, 1225w, 1150s, 1089s, 1045s, 963s,
934m, 913m, 831w, 760m, 700m. HRMS (Electrospray) Calcd. for (M++Na); 387.1915. Found; (M++Na)
387.1944.
H7 2.6% H5a
H3 1.5%
O H5e
Ph 1.4%
Ph O 1.6, 1.2% O
O O
O 6
H H1
BuO2tC ButO2C
H4 1.8, 0.8%
H N 2.7% 0.5, 0.9%
H2 Im
2.6%
N
1-286-α
1.9, 0.8%
H1→ Imd1 0.8 H2→ Imd2 0.8 H3→H7 6.6 H7→H3 5.9
H2→H1 0.8
Ph O
O
O
t Im
Bu O2C
H H
1-286-β
White solid. Column chromatography; hexane only to hexane:EtOAc = 1:2. Rf = 0.29 (hexane:EtOAc =
20
1:2). [α] D = -129.6 (c 0.46 in CHCl3). Mp: 59-61 oC. 1H NMR (CDCl3, 500 MHz): δ 1.37 (s, 9H), 1.71
(dd, J = 17.9, 11.5 Hz, 1H), 2.64 (dd, J = 17.8, 3.3 Hz, 1H), 3.07 (app tdd, J = 11.3, 7.5, 3.3 Hz, 1H), 3.59
(dd, J = 11.7, 9.0 Hz, 1H), 3.74 (app td, J = 9.1, 4.4 Hz, 1H), 4.03 (app t, J = 10.0 Hz, 1H), 4.62 (dd, J =
9.8, 4.4 Hz, 1H), 5.61 (s, 1H), 6.30 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 7.11 (s, 1H), 7.37-7.40 (m, 3H), 7.47-
387
13
7.51 (m, 2H), 7.61 (s, 1H). C NMR (CDCl3, 100 MHz): δ 27.90, 32.17, 43.26, 70.97, 73.07, 81.30, 81.15,
87.14, 102.82, 117.63, 126.25, 128.40, 129.20, 130.14, 136.16, 136.46, 170.92. IR (NaCl, neat): υ 3388 Br
m, 3119m, 2978m, 2931m, 2872m, 1723s, 1494m, 1455m, 1369s, 1247m, 1227m, 1157s, 1080s, 1046s,
971s, 913m, 755s, 699s. HRMS (Electrospray) Calcd. for (M++Na); 387.1915. Found; (M++Na) 387.1902.
Anal. Calcd. for C21H26O5N2; C, 65.27; H, 6.78; N, 7.25. Found; C, 62.68; H, 6.93; N, 5.64.
H7 2.6% H5a
H3 1.9, 1.1%
O H5e
Ph O N Ph
O 1.1, 0.6% O
O O
N
RO2C Im
6
H ButO2C
H H4 1.2%
3.1%
1-286-β H2 H1
3.4%
1.2%
H1→ Imd1 1.4 H3→H5a 2.6 H3→ Imd2 1.1 H7→H5a 2.5
acrylonitrile
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with 295 mg of Ph3SnH (0.841 mmol) and 13.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 52.7 mg (0.168 mmol) of (2R,
mg (0.088 mmol) of AIBN in 3.6 mL of benzene via a syringe pump during 2 h 20 min, and the mixture
was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent
388
was removed in vacuo to give crude product. The concentrated mixture was purified by flash column
chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside was obtained as pale
yellow solid (38.5 mg, 81%) with the ratio of α/β = 0.79/1.0).
Ph O
O
O
Im
NC
H H
1-302
Pale yellow solid (α/β = 1.0/0.79). Column chromatography; hexane:EtOAc 1:1 to 1:2. Rf = 0.12 (EtOAc
only). Mp: 126-130 oC. 1H NMR (CDCl3, 400 MHz): α-anomer, δ 2.73 (dd, J = 17.5, 4.6 Hz, 1H), 2.88
(dd, J = 17.5, 5.2Hz, 1H), 2.96-3.06 (m, 1H), 3.75-3.81 (m, 1H), 3.95 (app t, J = 9.7 Hz, 1H), 4.01-4.07 (m,
1H), 4.57 (dd, J = 9.6, 4.2 Hz, 1H), 5.63 (s, 1H), 5.82 (d, J = 7.2 Hz, 1H), 7.13 (s, 1H), 7.19 (s, 1H), 7.37-
7.42 (m, 3H), 7.49-7.52 (m, 2H), 7.79 (s, 1H); β-anomer, δ 1.91 (dd, J = 17.2, 9.9 Hz, 1H), 2.51 (dd, J =
17.2, 4.9Hz, 1H), 2.96-3.06 (m, 1H), 3.68 (d, J = 11.2, 9.2 Hz, 1H), 3.75-3.81 (m, 1H), 4.01-4.07 (m, 1H),
4.64 (dd, J = 9.9, 4.3 Hz, 1H), 5.64 (s, 1H), 6.17 (d, J = 7.5 Hz, 1H), 7.06 (s, 1H), 7.20 (s, 1H), 7.37-7.42
13
(m, 3H), 7.49-7.52 (m, 2H), 7.76 (s, 1H). C NMR (CDCl3, 100 MHz): α-anomer, δ 16.15, 44.85, 70.56,
73.43, 81.15, 87.60, 102.75, 116.53, 116.60, 126.22, 128.46, 129.59, 131.13, 136.06, 136.48; β-anomer,
δ 14.57, 69.42, 70.07, 73.08, 81.34, 85.90, 102.84, 115.73, 117.38, 126.18, 128.44, 129.55, 130.49, 136.00,
136.21. IR (NaCl, neat): υ 3115 m, 2971s, 2879s, 2251m, 1698s, 1493s, 1455m, 1421m, 1380s, 1314m,
1285m, 1229s, 1168s, 1142m, 1080s, 1048s, 969s, 912s, 823w, 755s, 732s, 701s, 660s. HRMS
(Electrospray) Calcd. for (M++Na); 334.1162. Found (M++Na); 334.1180. Anal. Calcd. for C17H17O3N3;
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 407 mg of Ph3SnH (1.158 mmol) and 18.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
389
temperature was adjusted to be 90 oC. To the flask was added a solution of 74 mg (0.232 mmol) of (2R, 4S,
and 19 mg (0.16 mmol) of AIBN in 5.0 mL of benzene via a syringe pump during 3 h 15 min, and the
mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the
solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside 1-303 was
obtained as pale yellow solid (42.2 mg, 63%) with the ratio of α/β = 1.0/0.83) and dethiocarbamated
9%).
Ph O
O
O
H3COHN Im
H H
1-303
α/β = 1.0/0.83
Pale yellow oil (α/β = 1.0/0.83). Column chromatography; hexane:EtOAc = 1:1 to 1:2. Rf = 0.22
(hexane:EtOAc = 1:6). Mp: 96-99 oC. 1H NMR (CDCl3, 400 MHz): α- anomer, δ 3.58 (s, 3H), 3.72-3.81
(m, 1H), 3.91-3.97 (m, 2H), 4.00-4.11 (m, 2H), 4.55 (dd, J = 9.5, 4.2 Hz, 1H), 5.57 (s, 1H), 5.86 (d, J = 5.3
Hz, 1H), 7.14 (s, 2H), 7.36-7.41 (m, 3H), 7.47-7.50 (m, 2H), 7.75 (s, 1H); β- anomer, δ 3.07 (s, 3H), 3.72-
3.81 (m, 1H), 3.91-3.97 (m, 2H), 4.00-4.11 (m, 2H), 4.58 (dd, J = 9.8, 4.0 Hz, 1H), 5.59 (s, 1H), 6.06 (d, J
13
= 6.8 Hz, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.36-7.41 (m, 3H), 7.47-7.50 (m, 2H), 7.68 (s, 1H). C NMR
(CDCl3, 100 MHz): α-anomer, δ 61.36, 62.89, 69.00, 70.65, 72.38, 78.92, 87.65, 116.53, 126.24, 129.08,
129.44, 130.41, 136.05, 136.30; β-anomer, δ 53.82, 64.61, 69.41, 70.80, 71.06, 79.44, 85.94, 118.29,
126.25, 129.08, 128.37, 129.45, 136.23, 137.02; IR (NaCl, neat): υ 3112 Br m, 2940s, 2893s, 2802w,
2238w, 1701m, 1495s, 1458m, 1425w, 1379s, 1313m, 1283m, 1226s 1058s, 1078s, 1049s, 1229s, 975s,
911s, 822w, 792w, 733s, 700s, 660s. HRMS (Electrospray) Calcd. for (M++Na); 340.1268. Found
(M++Na); 340.1290. Anal. Calcd. for C16H19O4N3; C, 60.56; H, 6.04; N, 13.24. Found; C, 60.17; H, 6.45;
N, 11.19.
390
The Reaction of (2R, 4S, 5R)-(Z)-Imidazole-1-carbothionic acid {O-[4-(benzyloxyimino)methyl]-2-
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 543 mg of Ph3SnH (1.547 mmol) and 24.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 131 mg (0.309 mmol) of (2R,
ester (Z)-1-296 and 25 mg (0.155 mmol) of AIBN in 6.6 mL of benzene via a syringe pump during 4 h 30
min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled
to rt, and the solvent was removed in vacuo to give crude product. The concentrated mixture was purified
by flash column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The cyclized N-pyranoside 1-
305 was obtained as pale yellow solid (19.2 mg, 38%) with the ratio of α/β = 1.1/1.0).
Ph O
O
O
BnOHN Im
H H
1-305
α/β = 1.1/1.0
White solid. Column; hexane:EtOAc = 1:1 to 1:2. Rf = 0.34 (hexane:EtOAc = 1:4). Mp: 96-99 oC. 1H
NMR (CDCl3, 500 MHz): α anomer, δ 3.90 (app t, J = 9.0 Hz, 2H), 3.95-4.00 (m, 3H), 4.52 (dd, J = 9.5,
4.2 Hz, 1H), 4.69 (d, J = 11.9 Hz, 1H), 5.51 (s, 1H), 5.68 (d, J = 5.4 Hz, 1H), 6.00 (Br s, NH, disappeared
with D2O), 7.06 (s, 1H), 7.12 (s, 1H), 7.27-7.40 (m, 7H), 7.48-7.51 (m, 3H), 7.56 (s, 1H); β anomer, δ 3.72
(app t, J = 9.7 Hz, 2H), 3.77 (app td, J = 9.3, 4.3 Hz, 1H), 4.03 (d, J = 11.7 Hz, 1H), 4.10-4.15 (m, 1H0,
4.19 (d, J = 11.3 Hz, 1H), 4.57 (dd, J = 9.7, 4.0 Hz, 1H), 4.73 (dd, J = 12.0 Hz, 1H), 5.56 (s, 1H), 5.59 (Br
s, NH, disappeared with D2O), 6.06 (d, J = 6.9 Hz, 1H), 7.10 (s, 1H), 7.18 (s, 1H), 7.27-7.40 (m, 7H), 7.48-
13
7.51 (m, 3H), 7.71 (s, 1H). C NMR (CDCl3, 125 MHz): δ 64.45, 68.82, 70.58, 70.74, 70.96, 72.29, 75.69,
76.90, 78.80, 79.48, 79.68, 85.95, 87.40, 102.49, 102,72, 116.51, 118.56, 126.20, 127.96, 128.33, 128.47,
391
128.51, 128.59, 128.70, 128.97, 129.06, 129.38, 129.43, 130.28, 136.18, 136.20, 136.32, 136.67, 136.80,
137.19, 137.38, 139.00; Because of the overlap of some aromatic carbons, the number of peaks found is
smaller than expected. IR (KBr): υ 2922w, 2859w, 1640s, 1515m, 1496m, 1478m, 1453m, 1428m, 1384s,
1217m, 1273m, 1225s, 1168m, 1097s, 1082s, 1054s, 1028s, 1009m, 961s, 916m, 824m, 792m, 754s, 726s,
699s, 658s, 632m, 597m. HRMS (Electrospray): m/z Calcd for C22H23N3O4Na (M++Na), 416.1581; Found
(M++Na), 416.1580.
phenyl-[1,3]dioxan-5-yl] ester
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged with 618
mg of Ph3SnH (1.760 mmol) and 28.0 mL of benzene (dried over CaH2 and stored over 4 Å MS in nitrogen
atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 117 mg (0.352 mmol) of
2-phenyl-[1,3]dioxan-5-yl] ester 1-297 and 29 mg (0.176 mmol) of AIBN in 7.6 mL of benzene via a
syringe pump during 4 h 35 min, and the mixture was stirred for another 0.5 h at 90 oC (oil bath
temperature). The mixture was cooled to rt, and the solvent was removed in vacuo to give crude product.
The concentrated mixture was purified by flash column chromatography eluting with hexane:EtOAc = 1:2
to only EtOAC. The cyclized N-pyranoside was obtained as pale yellow solid (57.6 mg, 54%) with the
Ph O
O
O
(H3C)2NHN H
H Im
1-306-α
Pale yellow solid. Column chromatography; hexane:EtOAc = 1:1 to EtOAc only with 1% of Et3N. Rf =
0.10 (EtOAc only) or 0.67 (EtOAc:MeOH = 9:1). Mp: 120-123 oC 1H NMR (CDCl3, 400 MHz): δ 2.40 (s,
392
6H), 3.80-3.91 (m, 2H) 3.96 (app t, J = 10.1 Hz, 1H), 4.06 (app td, J = 9.7, 4.3 Hz, 1H), 4.56 (dd, J = 9.6,
4.3 Hz, 1H), 5.55 (s, 1H), 5.75 (d, J = 4.9 Hz, 1H), 7.11 (s, 1H), 7.18 (s, 1H), 7.35-7.42 (m, 3H), 7.47-7.50
(m, 2H), 7.75 (s 1H); NH peak is overlapped with 3 Hs between 3.80-4.09. The integration of this region
13
becomes smaller as much as 0.4 H with D2O. C NMR (CDCl3, 100 MHz): δ 48.26, 66.19, 70.80, 72.26,
81.71, 90.66, 102.58, 116.44, 126.22, 128.40, 129.44, 130.00, 136.04, 136.42. IR (NaCl, neat): υ 3209Br s,
3116s, 3039m, 2982s, 2948s, 2880s, 2857s, 2778s, 1698w, 1666w, 1494s, 1454s, 1428m, 1379s, 1313s,
1282s, 1224s, 1165s, 1078s, 1049s, 1027s, 991s, 966s, 912s, 813m, 792m, 761s, 735s, 700s, 660s. HRMS
(Electrospray); Calcd. (M++Na); 353.1584. Found (M++Na); 353.1581. Anal. Calcd. for C17H22O3N4; C,
phenyl-[1,3]dioxan-5-yl] ester
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 1.06 g of Ph3SnH (3.02 mmol) and 24.0 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 138 mg (0.302 mmol) (2R, 4S,
and 50 mg (0.302 mmol) of AIBN in 6.5 mL of benzene via a syringe pump during 4 h 30 min, and the
mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the
solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane to hexane:EtOAc = 1:2. The cyclized N-pyranoside was
obtained as pale yellow solid (25.7 mg, 20%) 1-307 with 72.4 mg (62%) of 1-308. The isolated N-
Ph O
O
O
Ph2NHN H
H Im
1-307-α
393
Pale yellow oil. Column chromatography; hexane only to hexane:EtOAc = 2:1. Rf = 0.34 (hexane:EtOAc
20
= 1:2). [α] D = -1.9 (c 0.43 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 3.95 (app t, J = 9.8 Hz, 1H), 3.98
(app t, J = 9.3 Hz, 1H), 4.08 (dd, J = 9.6, 4.2 Hz, 1H), 4.16 (ddd, J = 9.0, 5.4, 1.7 Hz, 1H), 4.53 (s, NH,
disappeared with D2O), 4.55 (dd, J = 9.7, .4.4 Hz, 1H), 5.53 (s, 1H), 5.89 (d, J = 5.4 Hz, 1H), 6.93 (dd, J =
8.5, 0.9 Hz, 4H), 7.00 (s, 1H), 7.05 (app td, J = 7.4, 0.8 Hz, 2H), 7.12 (s, 1H), 7.24-7.28 (m, 4H), 7.38-7.41
13
(m, 3H), 7.46-7.49 (m, 2H), 7.51 (s, 1H). C NMR (CDCl3, 100 MHz): δ 66.35, 69.49, 70.81, 72.35,
82.85, 89.84, 102.65, 116.78, 120.49, 123.57, 126.23 (two peaks), 128.45, 129.48, 129.99, 136.29, 148.05.
IR (NaCl, neat): υ 3059m, 2966m, 2926m, 2359w, 2320w, 1702m, 1666w, 1589s, 1494s, 1461m, 1379m,
1313m, 1266s, 1224m, 1175m, 1078s, 1049s, 1028s, 969m, 910m, 736s, 698s. HRMS (Electrospray);
Ph O
O
O
Ph2NHN
H
1-308
Pale yellow solid. Column chromatography; hexane only to hexane:EtOAc = 7:1. Rf = 0.53
20
(hexane:EtOAc = 4:1). Mp: 74-77 oC. [α] D = -54.6 (c 0.70 in CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 3.60 (app td, J = 9.6, 4.5 Hz, 1H), 3.78 (app t, J = 9.1 Hz, 1H), 3.92 (app t, J = 9.8 Hz, 1H), 3.95 (app t, J
= 8.0 Hz, 1H), 4.01 (dd, J = 9.0, 6.0 Hz, 1H), 4.16 (dd, J = 8.9, 8.1 Hz, 1H), 4.42 (Br s, NH), 4.51 (dd, J =
9.7, 4.5 Hz, 1H), 5.48 (s, 1H), 7.05 (app td, J = 7.3, 1.1 Hz, 2H), 7.14-7.18 (m, 4H), 7.29-7.34 (m, 4H),
13
7.36-7.40 (m, 3H), 7.46-7.49 (m, 2H). C NMR (CDCl3, 100 MHz): δ 59.09, 71.35, 71.75, 72.42, 84.35,
102.23, 102.57, 122.90, 126.25, 128.30, 129.17, 129.24, 136.96, 148.03. IR (NaCl, neat): υ 3271m, 3061s,
3035s, 2982s, 2880s, 2240w, 1952w, 1703w, 1588s, 1495s, 1455s, 1379s, 1311s, 1271s, 1214m, 1169s,
1079s, 1049s, 1028s, 964s, 911m, 885w, 826w, 751s, 697s. HRMS (Electrospray); Calcd. (M++Na):
411.1679, found (M++Na): 411.1689. Anal. Calcd. for C24H24O3N2; C, 74.21; H, 6.23; N, 7.21. Found; C,
394
The Reaction of (2R, 4S, 5R)-Imidazole-1-carbothioic acid O-[4-cyanomethyl-2-phenyl-[1,3] dioxan-5-
yl] ester
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with 409 mg of Ph3SnH (1.166 mmol) and 18.4 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 67 mg (0.233 mmol) (2R, 4S,
and 19 mg (0.117 mmol) of AIBN in 5.0 mL of benzene via a syringe pump during 3 h 15 min, and the
mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the
solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 1:1 to 1:2. The isolated product was only
Ph O OH
O
N
1-309
White solid. Column chromatography; hexane:EtOAc = 3:1 to 2:1. Rf = 0.62 (hexane:EtOAc = 1:1). Mp:
20
143-144 oC. [α] D = +6.8 (c 0.38 in CHCl3). 1H NMR (CDCl3, 400 MHz): δ 2.64 (Br s, 1H), 3.66 (dd, J =
11.4, 10.2 Hz, 1H), 4.12 (app td, J = 9.9, 5.3 Hz, 1H), 4.38 (dd, J = 11.4, 5.3 Hz, 1H), 4.45 (d, J = 9.5 Hz,
13
1H), 5.46 (s, 1H), 7.37-7.41 (m, 3H), 7.44-7.48 (m, 2H). C NMR (CDCl3, 100 MHz): δ 63.47, 70.53,
70.91, 101.54, 116.17, 126.12, 128.42, 129.64, 135.66. Anal. Calcd. for C11H11O3N; C, 64.38; H, 5.40; N,
395
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with TTMSH (610 mg, 2.456 mmol) and 19.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-(Z)-imidazole-1-
0.246 mmol) and AIBN (202 mg, 1.446 mmol) in 5.2 mL of benzene via a syringe pump during 3 h 5 min,
and the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt,
and the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by
flash column chromatography eluting with hexane:EtOAc = 40:1 to 20:1. 1,3-Migrated product 1-305 was
Ph O
O
OBn
N
(Z)-1-310
Pale yellow oil. Column; hexane:EtOAc = 40:1 to 20:1. Rf = 0.24 (hexane:EtOAc = 15:1). 1H NMR
(CDCl3, 400 MHz): δ 2.42-2.44 (m, 1H), 4.21 (dd, J = 11.5, 2.5 Hz, 2H), 4.25 (app t, J = 11.5 Hz, 2H),
13
5.11 (s, 2H), 5.56 (s, 1H), 7.30-7.40 (m, 8H), 7.46-7.48 (m, 2H), 8.03 (d, J = 7.4 Hz, 1H). C NMR
(CDCl3, 100 MHz): δ 35. 46, 69.85, 75.75, 102.03, 126.07, 127.81, 128.14, 128.29, 128.38, 129.06,
137.59, 138.07, 151.26. IR (NaCl, neat): υ 350m, 3034s, 2956s, 2924s, 2857s, 1497m, 1455s, 1379s,
1314w, 1234s, 1213m, 1165s, 1112s, 1082s, 1045s, 1027s, 1010s, 961m, 920m, 839m, 748s, 698s. HRMS
4.2% 0.3%
2.0%
H1 H2a 2.0%
1.8%
Ph O
O O H2b
Ph H3 0.3%
OBn O
N 0.5% 0.9%
syn-1-310 OCH2Ph
H4 N
396
nOe (%) nOe (%) nOe (%)
2.6%
2.1%
H1 H2a 1.8%
Ph O 1.3%
O O H2b
Ph H3
O
N
anti-1-310 OBn
H4 N
OCH2Ph
A Pyrex tube was charged with a mixture of (Z)-1-296 (85 mg, 0.20 mmol) and AIBN (66 mg,
0.40 mmol) in benzene (4 mL). The reaction mixture was degassed by nitrogen bubbling for 5 min. To the
tube was added TTMSH ( 225 mg, 0.90 mmol) and the mixture was irradiated with stirring under a
sunlamp for 48 h. After removed the solvent under reduced pressure, the mixture was purified by column
chromatography eluting hexane to hexane:EtOAc = 20:1. The major portion of the isolated product was the
starting material (43.1 mg, syn/anti = 1.0/0.09) and the the minor portion was 1-312 (5.2 mg, 6%).
397
Ph O O Im
O
S
NH
BnO
1-312
Pale yellow oil. Column; hexane to hexane:EtOAc = 20:1. Rf = 0.21 (hexane:EtOAc = 20:1). 1H NMR
(CDCl3, 400 MHz): δ 3.78 (app t, J = 10.5 Hz, 1H), 1.45-1.52 (m, 1H), 4.54 (dd, J = 9.6, 6.6 Hz, 1H), 4.59
(dd, J = 10.8, 5.4 Hz, 1H), 5.06 (s, 2H), 5.39 (d, J = 12.1 Hz, 1H), 5.44 (d, J = 12.1 Hz, 1H), 5.57 (s, 1H),
13
5.58 (app td, J = 9.7, 5.4 Hz, 1H), 7.25-7.32 (m, 3H), 7.35-7.39 (m, 8H), 7.47-7.50 (m, 3H). C NMR
(CDCl3, 100 MHz): δ 67.10, 71.20, 75.29, 76.46, 100.40, 126.19, 127.93, 128.19, 128.35, 128.39, 128.54,
A flame-dried three neck 50 mL flask was connected to a condenser, and the flask was charged
with TTMSH (246 mg, 0.991 mmol) and 15.6 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-imidazole-1-
mmol) and AIBN (16 mg, 0.099 mmol) in 4.2 mL of benzene via a syringe pump during 2 h 30 min, and
the mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and
the solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane to hexane:EtOAc = 20:1. The 1,3-migrated product 1-313
and dethiocarbamated product 1-314 were isolated as 38% and 18% yield, respectively.
Ph O
O
N
NPh2
anti-1-313
398
Pale yellow oil. Column; hexane to hexane:EtOAc = 20:1. Rf = 0.34 (hexane:EtOAc = 8:1). 1H NMR
(CDCl3, 500 MHz): δ 2.52 (app t, J = 2.6 Hz, 1H), 4.21 (dd, J = 11.6, 1.6 Hz, 2H), 4.31 (d, J = 11.0 Hz,
13
2H), 7.00 (d, J = 5.9 Hz, 1H), 7.13-7.15 (m, 6H), 7.31-7.39 (m, 9H). C NMR (CDCl3, 125 MHz):
δ 37.79, 70.10, 101.88, 122.39, 124.11, 126.13, 128.29, 128.98, 129.72, 138.36, 138.69, 144.07.
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with TTMSH (173 mg, 0.696 mmol) and 11.0 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of 6R)-(E)-ethyl 7-{[(1,1-
mmol) and AIBN (12 mg, 0.07 mmol) in 3.0 mL of benzene via a syringe pump during 2 h 15 min, and the
mixture was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the
solvent was removed in vacuo to give crude product. The concentrated mixture was purified by flash
column chromatography eluting with hexane:EtOAc = 40:1 to 12:1. After column chromatography, brown
OTBS
O S
CO2Et
1-315
cis/trans = 0.28/1.0
Brown oil. Column; hexane:EtOAc = 40:1 to 12:1. Rf = 0.20 (hexane:EtOAc = 10:1). 1H NMR (CDCl3,
500 MHz): cis (minor), δ 1.07 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 1.45-1.52 (m, 1H), 1.81-1.85 (m, 1H), 2.04-
2.09 (m, 2H), 2.84 (dd, J = 16.8, 7.3 Hz, 1H), 2.96-3.01 (m, 1H), 3.22 (dd, J = 16.8, 4.3 Hz, 1H), 3.86 (dd,
J = 11.0, 3.9 Hz, 1H), 3.69-3.76 (m, 1H), 3.90 (dd, J = 11.0, 5.0 Hz, 1H), 4.13-4.23 (m, 2H), 4.52 (app qd,
J = 10.7, 4.6 Hz, 1H), 7.38-7.48 (m, 3H), 7.66-7.70 (m, 2H); trans (major), δ 1.11 (s, 9H), 1.28 (t, J = 7.2
399
Hz, 3H), 1.45-1.52 (m, 1H), 1.81-1.85 (m, 1H), 2.04-2.09 (m, 2H), 2.46 (dd, J = 16.5, 6.7 Hz, 1H), 3.12
(app qd, J = 9.1, 4.7 Hz, 1H), 3.19 (dd, J = 16.4, 6.0 Hz, 1H), 3.82 (dd, J = 11.0, 5.3 Hz, 1H), 3.94 (dd, J =
11.0, 4.8 Hz, 1H), 4.13-4.23 (m, 2H), 4.60 (app qd, J = 9.1, 4.7 Hz, 1H), 7.38-7.48 (m, 3H), 7.66-7.70 (m,
13
2H). C NMR (CDCl3, 125 MHz): cis (minor), δ 14.19, 19.24, 23.39, 26.80, 31.91, 40.86, 45.90, 65.55,
68.19, 84.29, 127.79, 129.86, 132.76, 133.06, 135.67, 171.60, 223.78; trans (major), δ 114.19, 19.24,
23.91, 25.16, 26.80, 40.86, 44.02, 60.70, 65.15, 80.86, 127.79, 129.86, 132.93, 132.97, 135.60, 135.64,
171.68, 223.99. IR (NaCl, neat): υ 2929s, 2858s, 1734s, 1472w, 1428m, 1365w, 1279m, 1254m, 1185m,
1160m, 1133m, 1113s, 1030w, 824w, 742w, 703s. HRMS (Electrospray): m/z Calcd for C26H34O4SSiNa
A flame-dried three neck 25 mL flask was connected to a condenser, and the flask was charged
with TTMSH (288 mg, 1.158 mmol) and 18.3 mL of benzene (dried over CaH2 and stored over 4 Å MS in
nitrogen atmosphere) under nitrogen atmosphere. The flask was immersed into an oil bath and the oil bath
temperature was adjusted to be 90 oC. To the flask was added a solution of (2R, 4S, 5R)-(Z)-3-[(imidazole-
1-carbothioyloxy]-2-phenyl-[1, 3]dioxin-4-yl)-acrylic acid ethyl ester (Z)-1-283 (90 mg, 0.232 mmol) and
AIBN (19 mg, 0.116 mmol) in 5.0 mL of benzene via a syringe pump over 3 h 10 min , and the mixture
was stirred for another 0.5 h at 90 oC (oil bath temperature). The mixture was cooled to rt, and the solvent
was removed in vacuo to give crude product. The concentrated mixture was purified by flash column
chromatography eluting with hexane only to hexane:EtOAc = 20:1. The isolated product was obtained as
Ph O
O
O
EtO2C S
H
1-316
400
Brown oil. Column; hexane:EtOAc = 20:1. Rf = 0.34 (hexane:EtOAc = 9:1). 1H NMR (CDCl3, 400 MHz):
δ 1.25 (t, J = 7.1 Hz, 3H), 2.83 (dd, J = 16.7, 5.7 Hz, 1H), 3.00 (dd, J = 16.7, 5.8 Hz, 1H), 3.40 (app dt, J =
11.6, 5.7 Hz, 1H), 4.01 (dd, J = 11.7, 9.3 Hz, 1H), 4.10 (app t, J = 10.0 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),
4.36 (app td, J = 9.9, 4.4 Hz, 1H), 4.67 (dd, J = 9.7, 4.3 Hz, 1H), 5.64 (s, 1H), 7.38-7.40 (m, 3H), 7.47-7.50
13
(m, 2H). C NMR (CDCl3, 100 MHz): δ 14.12, 34.22, 53.97, 610.., 69.51, 77.43, 82.60, 102.96, 126.33,
128.40, 129.50, 136.07, 170.43, 218.50. IR (NaCl, neat): υ 2976w, 2926w, 2286w, 1734w, 1379m, 1294m,
1261m, 1210w, 1194w, 1154m, 1083s, 1017s, 910w, 754w, 699m. HRMS (Electrospray): m/z Calcd for
EtO2C
EtO2C H
To a solution of diethylpropargyl malonate (6.87 mmol) in CH3CN (15 mL) was added
paraformaldehyde (628 mg, 20.91 mmol), CuBr (938 mg, 6.54 mmol), and iPr2NH (1.59 g, 15.68 mL) and
the mixture was heated to reflux for 16 h. The solvent was evaporated on a rotary evaporator and the
residue was directly loaded on a silica gel eluting hexane:EtOAc = 15:1. The desired diethyl-2,3-
butandienyl malonate was isolated as colorless oil. The isolated yield was 28%.
EtO2C
EtO2C
2-40
401
To a solution of diethyl-2,3-butandienyl malonate (404 mg, 1.90 mmol) in THF (5.4 mL) was
added KH (99 mg, 2.47 mmol) portionwise. The mixture was stirred for 30 min at rt and propargyl
bromide (565 mg, 3.80 mmol) was added. The resulting mixture was stirred at rt for 11 h, and the
quenched with saturated NH4Cl solution (3 mL). Normal extractive work-up (extracted with Et2O, washed
with H2O and brine solution, dried over MgSO4, filtered, and concentrated on a rotary evaporator), the
crude mixture was purified by column chromatography eluting hexane:EtOAc = 15:1 to give colorless oil
quantatitatively.
Phosphine ligand (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol) were
dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the mixture
were added Bu3Sn-SiMe3 (1.1 equiv, 40 mg, 0.11 mmol) and diethyl (2,3-butandienyl-2-
propynyl)propanate (1.0 equiv, 0.10 mmol, 25 mg). The mixture was standed at rt or proper temperature
(60 oC or 80 oC), and the reaction was monitored by 1H NMR spectroscopy. After all starting material
disappeared in 1H NMR spectrua the mixture was concentrated on a rotary evaporator. The residue was
EtO2C
SiMe3
SnPh3
EtO2C
2-44
Colorless oil. Column; hexane with 1% of Et3N. Rf = 0.63 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.13 (s, 9H), 0.79 (t, J = 8.3 Hz, 6H), 0.87 (t, J = 7.3 Hz, 9H), 1.22 (app td, J = 7.2, 3.2 Hz, 6H),
1.27 (sex, J = 7.4 Hz, 6H), 1.39-1.45 (m, 6H), 1.99 (dd, J = 13.2, 6.0 Hz, 1H), 2.80 (dd, J = 13.1, 8.7 Hz,
1H), 2.83 (d, J = 15.7 Hz, 1H), 3.23 (app dt, J = 1.7, 2.0 Hz, 1H), 3.29 (t, J = 7.3, 1.4 Hz, 1H), 4.05-4.11
(m, 1H), 4.14-4.21 (m, 3H), 5.35 (dd, J = 2.1, 1.4 Hz, 1H), 5.67 (t, J = 2.1 Hz, 1H), 5.96 (s, J Sn-H = 61.7
13
Hz, 1H). C NMR (CDCl3, 125 MHz): δ -0.44, 9.85, 13.67, 13.94, 14.02, 27.35, 29.12, 40.88, 45.74,
49.61, 59.29, 61.34, 123.37, 124.68, 153.46, 158.70, 171.44, 171.60. IR (NaCl, neat): υ 2956s, 2926s,
402
2872m, 2854m, 2359w, 1735s, 1616w, 1464m, 1366m, 1267s, 1248s, 1190s, 1152s, 1066s, 1020m, 931m,
856s, 838s, 758m, 690m. HRMS (Electrospray): m/z Calcd for C17H27O4BrSiNa (M++Na), 425.0754;
Bromination of Silylstannanes
To a solution of silylstannylated product 2-42 (52 mg, 0.0727 mmol) in 1.5 mL of CH2Cl2 was
added 1. 24 equiv of NBS (16.2 mg, 0.0901 mmol) at rt, and the mixture was stirred ar rt over night. After
all solvent removed on a rotary evaporator, the residue was purified by column chromatography eluting
EtO2C
SiMe2Ph
Br
EtO2C
2-55
Colorless oil. Column; hexane with 1% of Et3N. Rf = 0.55 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.12 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 1.24 (t, J = 7.1 Hz, 6H), 1.91 (dd, J = 13.1, 7.6 Hz, 1H),
2.88 (dd, J = 13.0, 9.4 Hz, 1H), 2.96 (d, J = 15.6 Hz, 1H), 3.02 (dt, J = 15.6, 2.2 Hz, 1H), 3.54 (app t, J =
13
8.0 Hz, 1H), 4.10-4.21 (m, 4H), 5.39 (d, J = 2.0 Hz, 1H), 5.61 (s, 1H), 6.20 (s, 1H). C NMR (CDCl3, 125
MHz): δ -5.09, -4.73, 14.01, 26.94, 42.18, 42.77, 48.49, 59.66, 61.65, 100.57, 125.54, 147.27, 148.63,
170.70, 170.89. IR (NaCl, neat): υ 2985s, 2931s, 2856s, 1756s, 1643w, 1464m, 1390w, 1267s, 1248s,
1195s, 1097m, 1069s, 1017w, 932w, 862w, 825s, 769s. HRMS (Electrospray): m/z Calcd for
EtO2C
SiMe3
Br
EtO2C
2-56
Colorless oil. Column; hexane:EtOAc = 12:1. Rf = 0.39 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.15 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.90 (dd, J = 13.2, 7.9 Hz, 1H), 2.85
403
(ddd, J = 13.1, 8.6, 1.1 Hz, 1H), 2.98 (d, J = 15.6 Hz, 1H), 3.03 (app dt, J = 15.6, 2.2 Hz, 1H), 3.53 (app t, J
13
= 8.1 Hz, 1H), 4.11-4.22 (m, 4H), 5.37 (d, J = 2.1 Hz, 1H), 5.52 (app t, J = 1.4 Hz, 1H), 6.17 (s, 1H). C
NMR (CDCl3, 125 MHz): δ -0.10, 14.01, 41.87, 42.71, 61.64, 61.65, 100.60, 123.59, 147.21, 151.32,
170.68, 170.87. IR (NaCl, neat): υ 29858s, 2957s, 2894m, 1733s, 1644w, 1447m, 1367m, 1270s, 1248s,
1194s, 1096m, 1069s, 1019m, 929m, 856s, 839s, 758m, 692w. HRMS (Electrospray): m/z Calcd for
Phosphine ligand (C6F3) 3P (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol)
were dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the
mixture were added Ph3Sn-SiMe3 (1.1 equiv, 51 mg, 0.11 mmol) and diethyl (di-2,3-butandienyl) propanate
(1.0 equiv, 0.10 mmol, 26 mg). The mixture was standed at rt or proper temperature (60 oC or 80 oC), and
the reaction was monitored by 1H NMR spectroscopy. After all starting material disappeared in 1H NMR
spectra the mixture was concentrated on a rotary evaporator. The residue was purified by column
chromatography eluting hexane with 1% of Et3N. The major portion and the minor portion were assigned
EtO2C
SiMe2tBu
SnPh3
EtO2C
2-58
White solid. Column; hexane with 1% of Et3N. Rf = 0.47 (hexane:EtOAc = 9:1). Mp: 82-84 oC. 1H NMR
(CDCl3, 500 MHz): δ -0.05 (s, 3H), -0.01 (s, 3H), 0.79 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz,
3H), 2.32 (dd, J = 13.3, 7.9 Hz, 1H), 2.38 (dd, J = 13.1, 2.7 Hz, 1H), 2.40 (dd, J = 13.8, 7.4 Hz, 1H), 2.66
(dd, J = 13.8, 8.0 Hz, 1H), 3.02 (app dt, J = 7.7, 2.3 Hz, 1H), 3.34 (app q, J = 7.8 Hz, JSn-H = 66.8 Hz, 1H),
4.07-4.17 (m, 4H), 5.41 (d, J = 1.5 Hz, 1H), 5.45 (s, JSn-H = 81.0 Hz, 1H), 5.65 (s, 1H), 6.03 (s, JSn-H =
13
179.0 Hz, 1H), 7.33-7.37 (m, 9H), 7.49-7.59 (m, 6H). C NMR (CDCl3, 125 MHz): δ -6.03, -5.77, 13.97,
17.19, 26.71, 39.10, 41.14, 47.24, 49.78, 58.81, 61.29, 61.47, 128.17, 128.21, 128.86, 130.69, 137.23,
404
139.15, 148.17, 154.04, 171.39, 172.46. IR (NaCl, neat): υ 3064w , 2954s, 2929s, 2864s, 1731s, 1480m,
1463m, 1444m, 1429s, 1388w, 1366w, 1298m, 1253s, 1184s, 1095m, 1074m, 1053w, 1022w, 930w, 824s,
770m, 729s, 699s. HRMS (Electrospray): m/z Calcd for C29H50O4SiSnNa (M++Na), 753.2396; Found
(M++Na), 753.2356.
EtO2C
H
SnPh3
EtO2C
2-59
cis/trans = 0.35/1.0
Colorless oil. Column; hexane with 1% of Et3N. Rf = 0.44 (hexane:EtOAc = 9:1). 1H NMR (CDCl3, 500
MHz): major δ 1.22 (t, J = 7.1 Hz, 6H), 2.11 (dd, J = 14.1, 3.5 Hz, 1H), 2.38-2.47 (m, 3H), 2.66-2.69 (m,
1H), 3.14-3.16 (m, 1H), 4.15 (qd, J = 7.1, 1.9 Hz, 4H), 4.63 (app dt, J = 17.0, 1.2 Hz, 1H), 4.80 (dd, J =
10.4, 1.0 Hz, 1H), 5.51 (s, 1H), 5.58 (ddd, J = 17.0, 10.3, 8.8 Hz, 1H), 6.01(s, JSn-H = 175.8 Hz, 1H), 7.34-
7.38 (m, 8H), 7.46-7.56 (m, 7H); minor δ 1.19 (t, J = 7.2 Hz, 3H), 1.90 (dd, J = 13.2, 9.8 Hz, 1H), 1.92 (t, J
= 7.2 Hz, 3H), 2.01 (dd, J = 13.4, 12.2 Hz, 1H), 2.38-2.47 (m, 2H), 2.55 (dd, J = 13.4, 7.0 Hz, 1H), 2.66-
2.69 (m, 1H), 4.11-4.28 (m, 8H), 4.77-4.81 (m, 1H), 4.92 (dd, J = 10.4, 1.5 Hz, 1H), 5.43 (d, J = 1.7 Hz,
13
1H), 5.54-5.62 (m, 1H), 6.05 (s, 1H), 7.34-7.38 (m, 8H), 7.46-7.56 (m, 7H). C NMR (CDCl3, 125 MHz):
major δ 14.00, 36.88, 39.15, 45.94, 51.44, 58.36, 61.43, 61.50, 115.76, 128.47, 128.67, 128.96, 137.17,
138.54, 138.80, 151.14, 172.19, 172.61; minor δ 13.91, 39.52, 41.84, 49.06, 56.89, 57.99, 61.25, 115.62
[some peaks are overlap with the major compound], 137.16, 138.62, 139.34, 152.09, 171.67, 172.50. IR
(NaCl, neat): υ 3064w , 2979m, 1730s, 1480w, 1429m, 1366w, 1256s, 1180w, 1097m, 1074m, 997w, 920w,
860w, 729s, 699s. HRMS (Electrospray): m/z Calcd for C33H36O4SiSnNa (M++Na), 639.1528; Found
(M++Na), 639.1570.
The trans configuration of the 2-58 was further transferred to 2-58’by brominzation with NBS.
405
EtO2C EtO2C
SiMe2tBu CH2Cl2 SiMe2tBu
+ NBS
SnPh3 rt Br
EtO2C EtO2C
2-58 2-58'
1
H NMR (CDCl3, 500 MHz): δ 0.08 (s, 3H), -0.01 (s, 3H), 0.13 (s, 3H), 0.85 (s, 9H), 1.24 (t, J = 7.2 Hz,
3H), 1.25 (t, J = 7.2 Hz, 3H), 2.30 (dd, J = 13.2, 5.9 Hz, 1H), 2.56 (dd, J = 14.7, 5.4 Hz, 1H), 2.58 (app t,
J = 12.8 Hz, 1H), 2.69 (dd, J = 14.6, 8.4 Hz, 1H), 3.01 (app dt, J = 12.6, 6.1 Hz, 1H), 3.21 (app dt, J = 8.4,
5.7 Hz, 1H), 3.21 (app dt, J = 8.4, 5.7 Hz, 1H), 4.13-4.25 (m, 4H), 5.47 (d, J = 2.1 Hz, 1H), 5.52 (s, J = 1.7
Hz, 1H), 5.60 (d, J = 1.9 Hz, 1H), 5.87 (s, 1H).
Phosphine ligand (0.1 equiv) and Pd2(dba)3•CHCl3 (0.05 equiv, 2.6 mg, 0.005 mmol) were
dissolved in C6D6 (1.0 mL) in an NMR tube, and the mixture was standed at rt for 30 min. To the mixture
were added Ph3Sn-SiMe3 (1.1 equiv, 51 mg, 0.11 mmol) and dimethyl dipropargylmalonate (1.0 equiv, 0.10
mmol, 21 mg). The mixture was standed at rt or proper temperature (60 oC or 80 oC), and the reaction was
monitored by 1H NMR spectroscopy. After all starting material disappeared in 1H NMR spectra the
mixture was concentrated on a rotary evaporator. The residue was purified by column chromatography
MeO2C
SiMe2Ph
SnBu3
MeO2C
2-62
Colorless oil. Column; hexane:EtOAc = 20:1. Rf = 0.40 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.35 (s, 6H), 0.82-0.86 (m, 6H), 0.88 (t, J = 7.3 Hz, 9H), 1.27 (sex, J = 7.3 Hz, 6H), 1.37-1.42 (m,
6H), 2.97 (Br s, 4H), 3.70 (s, 6H), 5.45 (s, 1H), 5.70 (t, J = 1.5 Hz, JSn-H = 50.0 Hz, 1H), 7.31-7.33 (m, 3H),
13
7.47-7.50 (m, 2H). C NMR (CDCl3, 100 MHz): δ -0.66, 10.68, 13.66, 27.31, 28.96, 43.89, 44.26, 52.78,
54.98, 123.23, 127.08, 128.69, 133.66, 140.05, 155.13, 157.76, 172.07. IR (NaCl, neat): υ 254s, 2923s,
406
2849m, 1738s, 1600w, 1458w, 1434m, 1376w, 1248s, 1196m, 1167m, 1111w, 1061w, 850m, 825m. HRMS
(Electrospray): m/z Calcd for C31H50O4SiSnNa (M++Na), 657.2393; Found (M++Na), 657.2390.
SiMe2tBu
TsN
SnPh3
2-69
1
H NMR (CDCl3, 500 MHz): δ 0.62 (s, 9H), 2.48 (s, 3H), 3.91 (s, 2H), 4.10 (s, 2H), 5.26 (s, 2H), 6.30 (s,
JSn-H = 59.1 Hz, 1H), 7.34-7.36 (m, 2H), 7.39-7.43 (m, 3H), 7.79 (d, J = 8.2 Hz, 2H).
Destannylation of Csp2-stannanes
To the solution of silylstannylated 1,4-diene (1.0 equiv, 0.126 mmol) in CH2Cl2 (1 mL) was added
formic acid (5.0 equiv, 0.623 mmol). The mixture was stirred at rt until all 1,4-diene were consumed based
on judging TLC analysis. After removed solvent on a rotary evaporator under reduced pressure, the residue
EtO2C
SiMe3
EtO2C
2-67
1
H NMR (CDCl3, 500 MHz): δ 0.14 (s, 9H), 3.05 (s, 2H), 3.08 (d, J = 1.8 Hz, 2H), 3.73 (s, 6H), 5.30 (app t,
EtO2C
SiMe2Ph
EtO2C
2-68
Colorless oil. Column; hexane:EtOAc = 15:1. Rf = 0.40 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.37 (s, 6H), 3.02 (s, 2H), 3.15 (d, J = 1.8 Hz, 2H), 4.92 (app t, J = 1.8 Hz, 1H), 5.11 (app t, J =
13
2.2 Hz, 1H), 5.69 (app t, J = 1.8 Hz, 1H), 7.31-7.33 (m, 3H), 7.49-7.53 (m, 2H). C NMR (CDCl3, 125
MHz): δ -1.51, 42.00, 45.47, 52.80, 57.00, 112.04, 121.41, 127.77, 128.81, 133.69, 139.04, 144.43, 154.81,
171.75. IR (NaCl, neat): υ 2953m, 1737s, 1591w, 1428m, 1288m, 1251s, 1201m, 1158m, 1067m, 893w,
407
846m, 732m, 701m. HRMS (Electrospray): m/z Calcd for C19H24O4SiNa (M++Na), 367.1336; Found
(M++Na), 367.1346.
EtO2C
SiEt3
EtO2C
2-69
Colorless oil. Column; hexane:EtOAc = 15:1. Rf = 0.50 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.65 (q, J = 7.8 Hz, 6H), 0.91(t, J = 7.9 Hz, 9H), 3.05 (s, 2H), 3.09 (s, 2H), 3.72 (s, 6H), 5.01 (s,
13
1H), 5.33 (s, 1H), 5.43 (s, 1H). C NMR (CDCl3, 125 MHz): δ 4.20, 7.55, 41.92, 45.54, 52.69, 52.76,
57.00, 109.90, 120.61, 145.37, 154.14, 171.80. IR (NaCl, neat): υ 2953m, 2875m, 1739s, 1434w, 1288w,
1254m, 1201w, 1158w, 1067w, 1016w, 890w, 831w, 735m. HRMS (Electrospray): m/z Calcd for
EtO2C
SiMe2tBu
EtO2C
2-70
Colorless oil. Column; hexane:EtOAc = 15:1. Rf = 0.39 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 0.10 (s, 6H), 0.89 (s, 9H), 3.03 (s, 2H), 3.09 (d, J = 1.9 Hz, 2H), 3.72 (s, 6H), 5.03 (s, 1H), 5.33
13
(app t, J = 1.9 Hz, 1H), 5.53 (s, 1H). C NMR (CDCl3, 125 MHz): δ -5.14, 17.13, 26.32, 42.07, 45.48,
52.75, 56.85, 110.78, 121.14, 144.92, 154.06, 171.79. IR (NaCl, neat): υ 2953s, 2928m, 2884m, 2856s,
1734s, 1598s, 1463m, 1435m, 1362w, 1287s, 1252s, 1201s, 1159s, 1066m, 892m, 829s. HRMS
(Electrospray): m/z Calcd for C17H28O4SiNa (M++Na), 347.1649; Found (M++Na), 347.1649.
EtO2C
SiiPr
EtO2C
2-71
Colorless oil. Column; hexane:EtOAc = 15:1. Rf = 0.50 (hexane:EtOAc = 8:1). 1H NMR (CDCl3, 500
MHz): δ 1.07 (d, J = 7.2 Hz, 18H),.1.17 (hept, J = 7.3 Hz, 3H), 3.06 (d, J = 2.1 Hz, 2H), 3.12 (d, J = 1.5
408
13
Hz, 2H), 3.72 (s, 6H), 4.96 (s, 1H), 5.38 (s, 1H), 5.44 (s, 1H). C NMR (CDCl3, 125 MHz): δ 12.59,
19.00, 41.98, 46.26, 52.75, 56.85, 109.35, 119.17, 145.38, 154.49, 171.82. IR (NaCl, neat): υ 2949m,
2865m, 1740s, 1462w, 1286w, 1255m, 1201w, 1158w, 1071w, 883w. HRMS (Electrospray): m/z Calcd for
SiMe3
TsN
2-75
1
H NMR (CDCl3, 500 MHz): δ 0.11 (s, 9H), 2.42 (s, 3H), 3.93 (d, J = 1.9 Hz, 2H), 3.97 (app t, J = 2.1 Hz,
2H), 5.07 (s, 1H), 5.32 (app t, J = 2.2 Hz, 1H), 5.50 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.2 Hz,
13
2H). C NMR (CDCl3, 125 MHz): δ -0.84, 21.52, 54.04, 56.44, 110.64, 124.61, 127.96, 129.68, 132.75,
To a 3 mL ample were added vinyl silane 2-67 (59.5 mg, 0.211 mmol), ethyl acrylate (63.2 mg,
0.632 mmol) and catalytic amount of benzoquinone in toluene (2 mL). The ample was sealed tightly by
flame and immersed into an 150 mL one-necked flask filled with xylene (or toluene or xylene). After
assembled with a condenser, the flask was heated in an oil-bath for 48 h. The reaction mixture was
concentrated on a rotary evaporator under reduced pressure to give crude mixture, which was subjected to
Me3Si Me3Si O
EtO2C EtO2C
OEt
OEt
EtO2C EtO2C
O
2-89 2-90
Colorless oil. Column chromatography; hexane:EtOAc = 12:1. Rf = 0.31 (hexane:EtOAc = 8:1). The
isolated compound was 2-89/2-90 mixture with a ratio of 0.75/0.25. 1H NMR (CDCl3, 500 MHz): δ 0.18
(s, 0.25 X 9H), 0.33 (s, 075 X 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.77-1.82 (m, 0.25H), 1.86 (dd, J = 13.1, 6.6
409
Hz, 0.25H), 1.88 (dd, J = 13.1, 6.6 Hz, 0.75H), 1.95 (dd, J = 13.2, 3.4 Hz, 0.25H), 1.96 (dd, J = 13.2, 3.4
Hz, 0.75H), 2.06 (Br s, 0.25H), 2.14-2.24 (m, 1.75H), 2.52-2.58 (m, 0.75H), 2.63 (dt, J = 6.6, 4.4 Hz,
0.25H), 2.78-3.04 (m, 4H), 3.70 (s, 0.25 X 3H), 3.70 (s, 0.25 X 3H), 3.71 (s, 0.75 X 3H), 3.71 (s, 0.25 X
13
3H), 4.11 (q, J = 7.2 Hz, 2H). C NMR (CDCl3, 100 MHz): major δ -1.31, 14.17, 25.84, 27.51, 27.53,
38.45, 43.50, 44.12, 52.64, 52.69, 57.96, 60.25, 127.56, 132.90, 172.65, 172.85, 175.47; minor δ -1.50,
23.07, 24.71, 28.26, 40.75, 43.63, 44.28, 52.68, 52.73, 57.89, 60.35, 128.32, 131.51, 172.58, 172.94,
175.77. IR (NaCl, neat): υ 2954s, 2903s, 2848m, 1736s, 1435s, 1272m, 1252s, 1198s, 1167s, 1116m,
1074s, 1049s, 1031s, 998m, 962m, 838s, 756m, 690m. HRMS (Electrospray): Calcd. for C19H30O6SiNa
2.7%
Me3Si SiMe3
H 3.4%
1 H
MeO2C 2 MeO2C
H
2.6% OEt
OEt MeO2C
MeO2C 3
4 1.5%
H H
O H O
2-89
1.9%
H1 → H2a 2.2 H2a → SiMe3 3.4 H2b → H4b 1.6 SiMe3 → H2a 0.5
410
2.5%
Me3Si O Me3Si O
H6b H1 2.9%
EtO2C EtO2C
OEt OEt
1.8% H2
EtO2C EtO2C 2.0%
H
H5b H3a 3b
H4a H4b
2-90
Me3Si Me3Si O
EtO2C EtO2C
OMe
OMe
EtO2C EtO2C
O
2-95 2-96
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.38 (hexane:EtOAc = 6:1). The
isolated compound was 2-95/2-96 mixture with a ratio of 0.79/0.21. 1H NMR (CDCl3, 400 MHz): δ 0.02
(s, 0.21 X 9H), 0.04 (s, 0.79 X 9H), 1.60 (Br s, 0.79H), 1.65 (Br s, 0.21H), 1.86 (dd, J = 10.7, 6.1 Hz,
0.21H), 1.89 (dd, J = 10.7, 6.5 Hz, 0.79H), 1.97 (app dt, J = 13.2, 4.0 Hz, 1H), 2.03-2.09 (m, 0.21H), 2.11-
2.26 (m, 1.79H), 2.54-2.62 (m, 0.79H), 2.67(app dt, J = 6.4, 4.1 Hz, 0.21H), 2.79-2.90 (m, 1.21H), 2.95-
13
3.02 (m, 1.79H), 3.64 (s, 0.21 X 3H), 3.68 (s, 0.21 X 6H), 3.71 (s, 0.79 X 3H), 3.72 (s, 0.79 X 6H). C
NMR (CDCl3, 100 MHz): major δ -1.28, 25.88, 27.50, 27.55, 38.34, 43.47, 44.12, 52.72, 52.74, 57.95,
127.48, 132.92, 172.67, 172.87, 175.98; minor δ -1.50, 23.05, 24.61, 28.11, 40.59, 43.62, 44.23, 52.68,
52.70, 57.83, 128.38, 131.38, 170.60, 172.96, 176.27. IR (NaCl, neat): υ 2953s, 2844m, 1736s, 1435s,
1252s, 1199s, 1167s, 1073m, 1019w, 837s. HRMS (Electrospray): Calcd. for C18H28O6SiNa (M++Na),
411
Me3Si Me3Si O
EtO2C EtO2C
OtBu
t
O Bu
EtO2C EtO2C
O
2-97 2-98
Colorless oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.20 (hexane:EtOAc = 8:1). The
isolated compound was 2-97/2-98 mixture with a ratio of 0.60/0.28/0.12. 1H NMR (CDCl3, 400 MHz):
δ 0.01 (s, 040 X 9H), 0.03 (s, 060 X 9H), 1.41 (s, 0.12 X 9H), 1.42 (s, 0.60 X 9H), 1.44 (s, 0.12 X 9H),
1.53-1.52 (m, 1H), 1.74-1.98 (m, 2H), 1.98-2.21 (m, 2H), 2.28 (app dtd, J = 11.8, 5.3, 2.7 Hz, 0.12H), 2.47
(app dtd, J = 9.9, 6.3, 3.4 Hz, 0.6H), 2.56 (app dt, J = 6.6, 4.2 Hz, 0.28H), 2.79-3.06 (m, 4H), 3.70 (s, 0.28
13
X 6H), 3.71 (s, 0.12 X 6H), 3.72 (s, 0.60 X 6H). C NMR (CDCl3, 100 MHz): 1st major δ -1.32, 25.85,
27.56, 27.70, 28.04, 41.62, 43.70, 44.41, 52.67, 57.90, 128.17, 131.79, 172.66, 173.01, 175.10; 2nd major
δ -1.41, 23.14, 24.95, 27.99, 28.04, 41.62, 43.70, 44.41, 52.67, 57.90, 128.17, 13.79, 172.66, 173.01,
175.10. IR (NaCl, neat): υ 2953s, 2846m, 1736s, 1435s, 1392m, 1367s, 1251s, 1198s, 1152s, 1074m,
999w, 968m, 838s, 756w, 690w. HRMS (Electrospray): Calcd. for C21H34O6SiNa (M++Na), 433.2071;
Me3Si Me3Si O
EtO2C EtO2C
CH3
CH3
EtO2C EtO2C
O
2-99 2-100
Colorless oil. Column chromatography; hexane:EtOAc = 5:1. Rf = 0.50 (hexane:EtOAc = 5:1). The
isolated compound was 2-99/2-100 mixture with a ratio of 0.80/0.20. 1H NMR (CDCl3, 500 MHz): δ -0.01
(s, 0.2 X 9H), 0.05 (s, 0.8 X 9H), 1.60 (Br s, 0.8H), 1.73-1.83 (m, 1.2H), 1.95 (d, J = 12.9 Hz, 1H), 2.07-
2.19 (m, 2H), 2.14 (s, 0.2 X 3H), 2.15 (s, 0.8 X 3H), 2.56-2.62 (m, 0.8H), 2.65 (dd, J = 9.6, 4.9 Hz, 0.2H),
2.80 (dd, J = 16.1 Hz, 0.8H), 2.89 (d, J = 15.4 Hz, 1.4H), 2.99 (app t, J = 17.0 Hz, 1.8H), 3.71 (s, 0.2 X
13
6H), 3.72 (s, 0.8 X 6H). C NMR (CDCl3, 125 MHz): major δ -1.96, 26.10, 27.07, 27.80, 43.49, 44.08,
46.30, 52.73, 52.75, 57.96, 127.56, 133.07, 172.63, 172.85, 201.94; minor δ -1.37, 23.16, 24.27, 26.96,
412
28.00, 43.54, 44.34, 48.58, 52.68, 52.73, 57.87, 128.30, 131.66, 172.57, 172.92, 210.71. IR (NaCl, neat):
υ 2958s, 2849m, 1736s, 1713s, 1434m, 1358m, 1252s, 1199m, 1073m, 839s. HRMS (Electrospray): Calcd.
Me3Si Me3Si O
EtO2C EtO2C
H
H
EtO2C EtO2C
O
2-101 2-102
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.29 (hexane:EtOAc = 6:1). The
isolated compound was 2-101/2-102 mixture with a ratio of 0.65/0.75/0.20. 1H NMR (CDCl3, 400 MHz):
δ 0.38 (s, 9H), 1.58 (Br s, 1H), 1.68-1.97 (m, 2H), 2.00-2.23 (m, 1H), 2.49-2.52 (m, 1H), 2.77-3.06 (m,
13
4H), 3.71 (s, 6H), 9.51 (s, 0.20H), 9.60 (s, 0.75H), 9.74 (s, 0.05H). C NMR (CDCl3, 125 MHz): 1st major
δ -1.61, 24.67 (3 carbon peaks), 43.55, 44.09, 45.15, 52.73, 52.76, 57.89, 127.37, 133.75, 172.58, 204.12;
2nd major δ -1.22, 21.14, 22.00, 26.26, 43.55, 44.35, 46.93, 52.71, 52.73, 57.82, 129.38, 131.29, 172.47,
172.82, 205.82. IR (NaCl, neat): υ 3474Br s, 2953s, 2847m, 2723w, 1736s, 1435s, 1252s, 1120s, 1168s,
1074s, 964w, 839s, 757w, 734m, 691m. HRMS (Electrospray): Calcd. for C17H26O5SiNa (M++Na),
Me3Si Me3Si
EtO2C EtO2C CN
EtO2C CN EtO2C
2-103 2-104
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.25 (hexane:EtOAc = 6:1). The
isolated compound was 2-103/2-104 mixture with a ratio of 0.31/0.32/0.37. 1H NMR (CDCl3, 500 MHz):
δ 0.02 (s, 0.37 X 9H), 0.05 (s, 0.32 X 9H), 0.08 (s, 0.31 X 9H), 1.51-1.63 (m, 1H), 1.76-1.81 (m,1H), 1.95-
13
2.06 (m, 1H), 2.16-2.36 (m, 2H), 2.64-2.85 (m, 1H), 2.88-3.15 (m, 4H), 3.67-3.73 (m, 6H). C NMR
(CDCl3, 125 MHz): (three isomers) δ -2.30, -1.85, -1.32, 22.01, 23.88, 23.91, 24.51, 25.50, 25.76, 26.56,
27.86, 28.49, 28.96, 29.01, 30.79, 43.31, 43.41, 43.45, 43.79, 43.92, 44.07, 52.81 (three carbon peaks),
413
52.87 (three carbon peaks), 57.59, 57.72, 57.77, 122.07, 122.71, 122.72, 126.08, 127.32, 128.82, 129.82,
132.99, 133.50, 172.24, 172.46, 172.49, 172.75, 172.78. IR (NaCl, neat): υ 2952s, 2844m, 2237w, 1733s,
1731s, 1434s, 153s, 1200s, 1163s, 1074s, 962w, 840s, 755w, 691w. HRMS (Electrospray): Calcd. for
Me3Si Me3Si
EtO2C EtO2C Ph
EtO2C Ph EtO2C
2-105 2-106
Colorless oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.46 (hexane:EtOAc = 10:1). The
isolated compound was 2-105/2-106 mixture with a ratio of 0.20/0.63/0.10/0.07. 1H NMR (CDCl3, 400
MHz): δ -0.31 (s, 0.07 X 9H), -0.04 (s, 0.10 X 9H), 0.00 (s, 0.63 X 9H), 0.03 (s, 0.20 X 9H), 1.18-1.19 (m,
0.5H), 1.43-1.58 (m, 1.5H), 1.59-1.71 (m, 1H), 1.77-1.93 (m, 1H), 1.93-2.23 (m, 1H), 2.78-2.96 (m, 2H),
2.99-3.13 (m, 2H), 3.68 (s, 0.10 X 6H), 3.70 (s, 0.63 X 6H), 3.71 (s, 0.07 X 6H), 3.72 (s, 0.20 X 6H), 7.07-
13
7.26 (m, 5H). C NMR (CDCl3, 100 MHz): δ -0.96, 21.96, 29.29, 32.50, 39.78, 43.70, 44.53, 52.69,
52.72, 58.06, 125.69, 127.20, 128.14, 128.31, 129.71, 132.09, 172.94, 172.95. IR (NaCl, neat): υ 2952m,
2896w, 2837w, 1737s, 1493w, 1449w, 1434m, 1251s, 1198m, 1163m, 1073m, 838s, 758m, 700s. HRMS
Me3Si O
EtO2C
OMe
OMe
EtO2C
O
2-107
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.32 (hexane:EtOAc = 3:1). 1H NMR
(CDCl3, 500 MHz): δ 0.79 (s, 9H), 2.15 (Br s, 1H), 2.26 (dd, J = 17.7, 4.0 Hz, 1H), 2.41-2.48 (m, 1H), 2.66
(ddd, J = 10.4, 6.4, 3.6 Hz, 1H), 2.80 (dd, J = 15.4, 1.8 Hz, 1H), 2.86 (d, J = 15.4 Hz, 1H), 2.96 (d, J = 15.7
Hz, 1H), 2.99 (d, J = 15.2 Hz, 1H), 3.32 (dd, J = 3.4, 1.2 Hz, 1H), 3.60 (s, 3H0, 3.70 (s, 6H), 3.71 (s, 3H).
13
C NMR (CDCl3, 125 MHz): δ -1.28, 24.60, 29.69, 39.56, 41.87, 43.17, 43.90, 51.87, 51.83, 52.73, 52.75,
414
58.21, 127.73, 131.40, 172.30, 172.76, 173.95, 173.97. IR (NaCl, neat): υ 3002m, 2953m, 1738s, 1835s,
1435s, 1255s, 1201s, 1182s, 1111m, 1073m, 1020m, 880m, 839s. HRMS (Electrospray): Calcd. for
0.8%
Me3Si O Me3Si O
0.9% H H
EtO2C MeO2C
OMe OMe
O H HH O
2-107 1.9%
5.5%
Me3Si O
EtO2C
OMe
OMe
EtO2C
O
2-108
415
Pale yellow oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.16 (hexane:EtOAc = 5:1). 1H
NMR (CDCl3, 500 MHz): δ 0.02 (s, 9H), 2.13 (m 1H), 2.17 (s, 1H), 2.24-2.31 (m, 1H), 2.54 (app td, J =
11.0, 4.7 Hz, 1H), 2.75 (dd, J = 11.0, 9.5 Hz, 3H), 2.85 (d, J = 17.3 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 2.99
13
(d, J = 16.5 Hz, 1H), 3.08 (d, J = 17.3 Hz, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 3.73 (s, 3H). C NMR (CDCl3,
125 MHz): δ -1.98, 27.50, 28.47, 43.55, 43.92, 44.14, 45.11, 51.89, 51.95, 52.78, 52.84, 57.98, 127.39,
131.52, 172.54, 172.63, 175.02, 175.27. IR (NaCl, neat): υ 2952m, 2860w, 1737s, 1435m, 1348m, 1255s,
1199s, 1170m, 1117w, 1073m, 841s. HRMS (Electrospray): Calcd. for C20H30O8SiNa (M++Na), 449.1602;
Me3Si O
EtO2C
OEt
OEt
EtO2C
O
2-109
Colorless oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.16 (hexane:EtOAc = 5:1). 1H NMR
(CDCl3, 400 MHz): δ 0.02 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 2.11-2.28 (m, 3H),
2.51 (app td, J = 10.8, 5.1 Hz, 1H), 2.75 (dd, J = 11.0, 9.3 Hz, 1H), 2.87 (d, J = 16.9 Hz, 1H), 2.91 (d, J =
15.0 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 3.07 (d, J = 16.4 Hz, 1H), 3.72 (s, 3H), 3.73 (s, 3H), 4.00-4.23 (m,
13
4H). C NMR (CDCl3, 100 MHz): δ -1.88, 13.98, 14.10, 27.74, 28.41, 43.56, 43.94, 44.31, 44.91, 52.76,
52.82, 58.01, 60.67, 60.86, 127.37, 131.66, 172.49, 172.65, 174.62, 174.85. IR (NaCl, neat): υ 2954s,
2908m, 2849m, 1738s, 1735s, 1436m, 1370m, 1340m, 1254s, 1178s, 1114m, 1073m, 1035m, 841s. HRMS
Me3Si
MeO2C
MeO2C CO2Et
CH3
2-110
Colorless oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.16 (hexane:EtOAc = 2:1). 1H NMR
(CDCl3, 500 MHz): δ 0.02 (s, 9H), 1.21 (s, 3H), 1.55-1.64 (m, 2H), 1.22 (app t, J = 13.6 Hz, 1H), 1.55-1.64
416
(m, 1H), 1.77 (app dt, J = 16.5, 1.6 Hz, 1H), 2.14 (ddd, J = 13.4, 6.1, 2.4 Hz, 3H), 2.49 (d, J = 16.6 Hz,
13
1H), 2.77-2.85 (m, 2H), 2.91-2.96 (m, 2H), 3.60 (s, 3H), 3.70 (s, 3H), 3.72 (s, 3H). C NMR (CDCl3, 125
MHz): δ -2.35, 24.43, 26.94, 34.92, 35.31, 42.51, 42.63, 51.70, 52.66, 52.67, 58.30, 129.65, 132.28,
172.57, 172.94, 177.15. IR (NaCl, neat): υ 2952m, 2896w, 1736s, 1456m, 1434m, 1252s, 1201m, 1168m,
1093m, 1073m, 862m, 837s. HRMS (Electrospray): Calcd. for C19H30O6SiNa (M++Na), 405.1704; Found
(M++Na), 405.1716 .
1.5%
Me3Si H SiMe32.6%
H6a H6b 1
MeO2C H2a
MeO2C 17.7%
H2b
MeO2C CO2Et MeO2C CO2Me
CH3 H5a H5b CH3
H3a H3b
2-110 1.2%
14.7%
16.1% 4.5%
Me3Si
O
MeO2C
NPh
MeO2C
O
2-114
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.12 (hexane:EtOAc = 5:1). 1H NMR
(CDCl3, 500 MHz): δ 0.13 (s, 9H), 2.34 (Br s, 1H), 2.37-2.41 (m, 1H), 2.61 (d, J = 16.6 Hz, 1H), 2.88-2.96
(m, 2H), 3.01-3.08 (m, 2H), 3.22 (dd J = 9.0, 1.2 Hz, 1H), 3.32 (app td J = 8.8, 1.8 Hz, 1H), 3.66 (s, 3H),
13
3.73 (s, 3H), 7.22-7.24 (m, 2H), 7.34-7.38 (m, 1H), 7.42-7.46 (m, 2H). C NMR (CDCl3, 125 MHz): δ -
417
1.69, 24.63, 27.89, 39.67, 40.74, 43.60, 44.52, 52.78, 57.89, 126.43, 127.22, 128.49, 129.04, 132.01,
133.85, 172.47, 179.22, 179.73. IR (NaCl, neat): υ 2953s, 2895w, 2849w, 1732s, 1712s, 1598w, 1499s,
1435s, 1386s, 1337w, 1262s, 1197s, 1157s, 1109w, 1072m, 957w, 915w, 876m, 840s, 760m, 731m, 692m.
HRMS (Electrospray): Calcd. for C24H29O6NSiNa (M++Na), 478.1656; Found (M++Na), 478.1664.
1.9%
SiMe3 2.2%
Me3Si O
O H H
1
MeO2C 2 MeO2C
NPh NPh
MeO2C 3 MeO2C
4
O H H O
H
2-114 0.6%
1.7% 3.0%
2.5%
Me3Si Me3Si O
MeO2C CH3 MeO2C
H
H
MeO2C MeO2C CH3
O
2-115 2-116
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.35 (hexane:EtOAc = 6:1). The
isolated compound was 2-115/2-116 mixture with a ratio of 0.41/0.25/0.34. 1H NMR (CDCl3, 500 MHz):
δ 0.07 (s, 0.25 X 9H), -0.01 (s, 0.41 X 9H), 0.06 (s, 0.34 X 9H), 0.99 (d, J = 6.6 Hz, 0.34 X 3H), 1.02 (d, J
= 6.6 Hz, 0.25 X 3H), 1.09 (d, J = 6.8 Hz, 0.41 X 3H), 1.62-1.75 (m, 1H), 1.93-1.97 (m, 0.25H), 2.07-2.11
(m, 0.75H), 2.16-2.26 (m, 1.25H), 2.33 (d, J = 5.1, 3.2 Hz, 0.34H), 2.41 (app td, J = 5.2, 3.0 Hz, 0.41H),
2.82-2.91 (m, 3H), 3.00 (d, J = 14.0 Hz, 0.34H), 3.07 (d, J = 16.3 Hz, 0.41H), 3.11 (d, J = 14.7 Hz, 0.25H),
418
13
3.71-3.74 (m, 3H), 9.54 (d, J = 2.6 Hz, 0.41H), 9.55 (d, J = 1.5 Hz, 0.25H), 9.70 (d, J = 3.1 Hz, 0.34H. C
NMR (CDCl3, 100 MHz): 1st major δ 0.18, 19.09, 27.82, 29.23, 31.17, 43.35, 44.04, 52.79, 55.01, 57.82,
129.49, 131.09, 172.50, 172.71, 204.76; 1.64, 14.15, 21.47, 24.17, 25.23, 27.03, 37.89, 57.00, 57.19, 60.47,
125.83, 127.41, 129.70, 131.23, 134.18, 143.35, 174.77; 2nd major δ -1.08, 19.61, 27.90, 30.88, 43.70,
43.77, 52.78, 55.27, 58.25, 129.36, 130.73, 172.66, 172.75, 205.81; 3rd major δ -1.43, 19.66, 25.19, 29.95,
32.82, 44.00, 44.04, 52.51, 52.74, 57.90, 129.49, 130.68, 172.68, 172.80, 204.45. IR (NaCl, neat): υ 2954s,
2856s, 2362w, 1737s, 1435s, 1252s, 1200m, 1163m, 1073m, 840s. HRMS (Electrospray): Calcd. for
Me3Si Me3Si
CN
MeO2C MeO2C
CN OAc
MeO2C MeO2C
OAc
2-117 2-118
Pale yellow oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.20 (hexane:EtOAc = 5:1). The
isolated compound was 2-117/2-118 mixture with a ratio of 0.83/0.17. 1H NMR (CDCl3, 500 MHz): δ 0.40
(s, 0.83 X 3H), 0.41 (s, 0.17 X 6H), 0.43 (s, 0.83 X 3H), 1.61-1.67 (m, 1H), 2.02-2.06 (m, 1H), 2.17 (s,
3H), 2.11-2.21 (m, 1H), 2.27-2.30 (m, 1H), 2.72-2.76 (m, 0.17H), 2.79-2.84 (m, 1.17H), 2.89-2.90 (m,
13
0.83H), 2.93-2.99 (m, 2H), 3.71 (s, 3H), 3.72 (s, 3H), 7.30-7.40 (m, 3H), 7.46-7.49 (m, 2H). C NMR
(CDCl3, 125 MHz): 1st major δ -1.68, -1.16, 20.91, 22.71, 30.91, 42.94, 44.02, 52.80, 52.88, 58.31, 74.76,
Me2PhSi Me2PhSi O
EtO2C EtO2C
OEt
OEt
EtO2C EtO2C
O
2-123 2-124
Colorless oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.20 (hexane:EtOAc = 8:1). The
isolated compound was a 2-123/2-124 mixture with a ratio of 0.70/0.30. 1H NMR (CDCl3, 400 MHz):
δ 0.28 (s, 0.3 X 3H), 0.03 (s, 0.7 X 3H), 0.35 (s, 0.3 X 3H), 0.36 (s, 0.7 X 3H), 1.15-1.20 (m, 3H), 1.78-
419
1.90 (m, 2H), 1.91-2.03 (m, 1H), 2.08-2.23 (m, 2H), 2.37 (Br s,0.3H), 2.48-2.53 9m, 0.7H), 2.58-2.66 (m,
0.3H), 2.63-2.76 (m, 1H), 2.87-2.97 (m, 3.7H), 3.69 (s, 0.3 X 3H), 3.70 (s, 0.7 X 3H), 3.72 (s, 0.7 X 3H),
3.73 (s, 0.3 X 3H), 3.90-4.03 (m, 0.3 X 2H), 4.09-4.19 (m, 0.7 X 2H), 7.33-7.35 (m, 3H), 7.48-7.50 (m,
13
2H). C NMR (CDCl3, 100 MHz): major δ -2.91, -2.85, 14.18, 25.71, 27.47, 27.57, 38.26, 43.74, 44.10,
52.71, 52.89, 60.23, 127.84, 128.36, 129.11, 132.41, 133.74, 183.17, 172.69, 172.86, 175.43; minor δ -
3.21, -2.88, 14.12, 22.96, 24.37, 27.82, 39.83, 40.68, 43.78, 44.27, 52.70, 57.75, 60.36, 127.81, 129.00,
129.15, 131.12, 133.87, 137.90, 172.61, 172.97, 175.53. IR (NaCl, neat): υ 2954m, 2849w, 1732s, 1435m,
1259s, 1199m, 1173m, 1114w, 1074w, 911s, 817w, 733s. HRMS (Electrospray): Calcd. for C24H32O6SiNa
Me2PhSi Me2PhSi O
EtO2C EtO2C
OtBu
OtBu
EtO2C EtO2C
O
2-125 2-126
Colorless oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.32 (hexane:EtOAc = 8:1). The
isolated compound was 2-125/2-126 mixture with a ratio of 0.22/0.49/0.29. 1H NMR (CDCl3, 500 MHz):
δ 0.27 (s, 0.22 X 3H), 0.28 (s, 0.29 X 3H), 0.31 (s, 0.49 X 3H), 0.32 (s, 0.22 X 3H), 0.33 (s, 0.29 X 3H),
0.57 (s, 0.49 X 3H), 1.37 (s, 0.29 X 9H), 1.40 (s, 0.49 X 9H), 1.44 (s, 0.22 X 9H), 1.62-1.68 (m, 0.5H),
1.72-1.92 (m, 2H), 2.06 (d, J = 16.7 Hz, 0.5H), 2.11-2.18 (m, 1H), 2.28 (Br s, 0.25H), 2.38 (m, 0.75H),
2.57 (app dt, J = 9.5, 3.9 Hz, 0.25H), 2.72 (d, J = 16.6 Hz, 0.75H), 2.79-3.00 (m, 4H), 3.68 (s, 0.29 X 3H),
3.70 (s, 0.49 X 3H), 3.71 (s, 0.22 X 3H), 3.72 (s, 0.49 X 6H), 3.73 (s, 0.29 X 3H), 7.32-7.35 (m, 3H), 7.48-
13
7.51 (m, 2H). C NMR (CDCl3, 125 MHz): 1st major δ -3.01, -2.81, 25.67, 27.44, 27.75, 28.03, 43.68,
44.10, 52.69, 52.77, 57.90, 127.83, 128.59, 129.06, 132.29, 133.75, 138.29, 172.72, 172.91, 174.74; 2nd
major δ -3.16, -2.70, 25.43, 27.86, 27.96, 28.06, 41.59, 43.76, 44.38, 52.64, 52.70, 57.77, 128.80, 129.10,
130.24, 133.81, 138.16, 172.65, 172.99, 174.81. IR (NaCl, neat): υ 2978m, 2952m, 2849m, 1736s, 1434m,
1392w, 1367m, 1255s, 1198m, 1152s, 1115m, 1073m, 833m, 817m. HRMS (Electrospray): Calcd. for
420
Me2PhSi Me2PhSi O
EtO2C EtO2C
CH3
CH3
EtO2C EtO2C
O
2-127 2-128
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.24 (hexane:EtOAc = 6:1). The
isolated compound was 2-127/2-128 mixture with a ratio of 0.71/0.29. 1H NMR (CDCl3, 500 MHz): δ 0.27
(s, 0.29 X 3H), 0.34 (s, 0.71 X 3H), 0.37 (s, 0.29 X 3H), 0.38 (s, 0.71 X 3H), 1.64-1.73 (m, 1H), 1.84-2.01
(m,3H), 2.09-2.14 (m, 1H), 2.42 (app dtd, J = 14.6, 5.9, 2.4 Hz, 0.71H), 2.60(app dt, J = 6.4, 4.4 Hz,
0.21H), 2.74-2.97 (m, 4H), 3.70 (s, 0.29 X 3H), 3.71 (s, 0.71 X 3H), 3.72 (s, 0.29 X 3H), 3.74 (s, 0.71 X
13
3H), 7.31-7.37 (m, 3H), 7.45-7.51 (m, 2H). C NMR (CDCl3, 125 MHz): major δ -2.82, -2.51, 26.15,
26.57, 27.17, 27.98, 43.59, 45.12, 15.85, 52.74, 52.76, 97.93, 127.95, 128.46, 129.26, 132.46, 133.75,
138.01, 172.66, 172.89, 210.90; minor δ -3.63, -2.51, 22.64, 23.22, 26.76, 27.53, 43.67, 44.21, 48.53,
52.69, 52.74, 57.82, 127.89, 128.98, 129.26, 131.31, 133.98, 137.83, 172.58, 172.95, 201.53. IR (NaCl,
neat): υ 2952s, 2919m, 2849m, 1736s, 1711s, 1434m, 1358m, 1254s, 1199m, 1167m, 1114m, 1073m, 833m,
816m, 775m, 737m, 703m. HRMS (Electrospray): Calcd. for C23H30O5SiNa (M++Na), 437.1755; Found
(M++Na), 437.1757.
Me2PhSi Me2PhSi O
EtO2C EtO2C
H
H
EtO2C EtO2C
O
2-129 2-130
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.32 (hexane:EtOAc = 6:1). The
1
isolated compound was 2-129/2-130 mixture with a ratio of 0.63/0.37. H NMR (CDCl3, 500 MHz):
δ 0.32 (s, 3H), 0.36 (s, 0.63 X 3H), 0.40 (s, 0.37 X 3H), 1.61-1.68 (m, 0.63H), 1.77-1.89 (m, 2.37H), 1.98-
2.02 (m, 0.37H), 2.07-2.11 (m, 0.63H), 2.10-2.21 (m, 0.73H), 2.28 (Br s, 0.37H), 2.37-2.44 (m, 1H), 2.72
(d, J = 15.2 Hz, 0.73H), 2.80 (d J = 16.3 Hz, 0.37H), 2.86-2.91 (m, 3H), 3.70 (s, 0.37 X 3H), 3.71 (s, 0.63
X 3H), 3.73 (s, 0.63 X 3H), 3.72 (s, 0.37 X 3H), 7.33-7.38 (m, 2H), 7.47-7.49 (m, 2H), 9.43 (s, 0.37H),
421
13
9.52 (s, 0.63H). C NMR (CDCl3, 125 MHz): major δ -3.11, 24.56, 24.65, 24.73, 43.67, 44.10, 45.02,
52.74, 52.77, 57.82, 127.94, 128.01, 129.25, 129.39, 133.70, 137.85, 172.59, 172.77, 203.89; minor δ -
2.52, 20.86, 21.96, 26.05, 43.64, 44.31, 46.92, 52.74, 52.77, 57.72, 128.01, 128.09, 130.05, 130.82, 133.23,
137.53, 172.47, 172.85, 204.77. IR (NaCl, neat): υ 2953s, 2861m, 2719m, 1735s, 1434m, 1256s, 1199m,
1163m, 1114m, 1073m, 832m, 818m, 736m, 702m. HRMS (Electrospray): Calcd. for C22H28O5SiNa
Me2PhSi O
EtO2C
OMe
OMe
EtO2C
2-131 O
Colorless oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.15 (hexane:EtOAc = 5:1). 1H NMR
(CDCl3, 500 MHz): δ 0.24 (s, 3H), 0.32 (s, 3H), 2.18-2.25 (m, 1H), 2.43 (d, J = 10.0 Hz, 1H), 2.50 (dd, J =
11.1, 4.9 Hz, 1H), 2.71 (d, J = 16.7 Hz, 1H), 2.80 (dd, J = 11.1, 9.5 Hz, 1H), 2.86 (d, J = 15.1 Hz, 1H), 2.91
(d, J = 15.8 Hz, 1H), 2.99 (d, J = 15.8 Hz, 1H), 3.38 (s, 3H), 3.62 (s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 7.31-
13
7.35 (m, 3H), 2.47-2.49 (m, 2H). C NMR (CDCl3, 125 MHz): δ -3.84, -3.77, 27.54, 28.06, 43.63, 43.86,
44.18, 45.21, 51.80, 52.86, 52.70, 52.82, 57.87, 127.74, 127.82, 129.28, 131.35, 134.09, 137.18, 172.49,
172.59, 174.93, 174.00. IR (NaCl, neat): υ 2952m, 2849w, 1736s, 1434m, 1349m, 1257s, 1200s, 1171m,
1115m, 1073w. HRMS (Electrospray): Calcd. for C25H32O8SiNa (M++Na), 511.1759; Found (M++Na),
511.1748.
1.5%
1.1%
1.3%
0.9%
PhMe2Si H1 O
PhMe2Si O
H6a H6b
1 MeO2C H2
MeO2C 2
OMe
OMe
0.9%
MeO2C OMe OMe
3 MeO2C
4 J5b H3
O H5a
2-131 H4a H4b O
422
nOe(%) nOe(%) nOe(%)
H1 → H2 0.7 H2 → H3 0.9
Me2PhSi O Me2PhSi O
EtO2C EtO2C
OEt OEt
OEt OEt
EtO2C EtO2C
2-132 O 2-133 O
Pale yellow oil. Column chromatography; hexane:EtOAc = 5:1. Rf = 0.16 (hexane:EtOAc = 5:1). The
isolated compound was 2-132/2-133 mixture with a ratio of 0.68/0.32. 1H NMR (CDCl3, 500 MHz): major
δ 0.26 (s, 3H), 0.33 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 2.11-2.20 (m, 1H), 2.17 (s,
1H), 2.43-2.48 (m, 1H), 2.48 (app td, J = 13.8, 3.9 Hz, 1H), 2.69 (d, J = 16.1 Hz, 1H), 2.83 (dd, J = 11.2,
9.3 Hz, 1H), 2.80-2.93 (m, 2H), 2.99 (d, J = 17.5 Hz, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 3.75-3.83 (m, 2H),
7.18-7.41 (m, 2H), 7.30-7.34 (m, 3H), 7.46-7.50 (m, 2H); minor δ 0.26 (s, 3H), 0.33 (s, 3H), 1.25 (t, J = 6.5
Hz, 6H), 2.11-2.20 (m, 2H), 2.36 (d, J = 17.7 Hz, 1H), 2.62-2.63 (m,1H), 2.72 (d, J = 16.1 Hz, 1H), 2.99-
2.81 (m, 2H), 2.99 (d, J = 17.5 Hz, 1H), 3.70 (s, 3H), 3.73 (s, 3H), 3.85-3.92 (m, 2H), 3.99-4.04 (m, 2H),
13
7.30-7.34 (m, 3H), 7.46-7.50 (m, 2H). C NMR (CDCl3, 125 MHz): major δ -3.99, -3.44, 13.86, 14.09,
27.78, 27.94, 43.64, 43.88, 44.40, 44.91, 52.72, 52.80, 57.88, 60.66, 127.73, 127.79, 130.24, 131.49,
134.02, 137.40, 172.52, 172.62, 174.57, 174.60. IR (NaCl, neat): υ 2955m, 1732s, 1434m, 1371m, 1256s,
1196s, 1114m, 1072m, 1035m, 823w, 737w. HRMS (Electrospray): Calcd. for C27H36O8SiNa (M++Na),
423
PhMe2Si
O
MeO2C
NPh
MeO2C
O
2-134
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.14 (hexane:EtOAc = 3:1). 1H NMR
(CDCl3, 500 MHz): δ 0.42 (s, 3H), 0.51 (s, 3H), 1.72-1.77 (m, 1H), 2.33 (d, J = 17.0 Hz, 1H), 2.61 (s, 1H),
2.85-2.99 (m, 4H), 3.04 (app td, J = 9.0, 1.5 Hz, 1H), 3.20 (dd, J = 9.1,1.1 Hz, 1H), 3.66 (s, 3H), 3.75 (s,
3H), 7.20 (dd, J = 8.6, 2.3 Hz, 2H), 7.33-7.38 (m, 3H), 7.40-7.44 (m, 3H), 7.53 (dd, J = 7.9, 1.4 Hz, 2H).
13
C NMR (CDCl3, 125 MHz): δ -3.58, -3.35, 24.51, 27.65, 39.42, 40.86, 43.67, 44.56, 52.78, 52.80, 57.75,
128.42, 128.13, 128.16, 128.49, 129.03, 129.84, 132.10, 133.98, 133.74, 133.85, 136.45, 172.05, 172.55,
179.33, 179.59. IR (NaCl, neat): υ 2952w, 2872w, 1732s, 1712s, 1598w, 1499m, 1434w, 1385m, 1262m,
1197m, 1157m, 1115w, 1072w, 833w, 736w, 702w. HRMS (Electrospray): Calcd. for C29H31O6SiNa
Me2PhSi Me2PhSi
OAc
EtO2C EtO2C
OAc COCH3
EtO2C EtO2C
COCH3
2-135 2-136
Colorless oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.19 (hexane:EtOAc = 3:1). The
isolated compound was 2-135/2-136 mixture with a ratio of 0.76/0.24. 1H NMR (CDCl3, 500 MHz): δ 0.29
(s, 0.24 X 3H), 0.31 (s, 0.76 X 3H), 0.34 (s, 0.24 X 3H), 0.35 (s, 0.24 X 3H), 0.76 (Br s, 1H), 1.84 (dd, J =
13.0, 10.2 Hz, 1H), 1.96 (dd, J = 14.1, 5.7 Hz, 1H), 2.04 (s, 0.76 X 3H), 2.06 (s, 0.76 X 3H), 2.07 (s, 0.24 X
3H), 2.09 (s, 0.24 X 3H), 2.13-2.18 (m, 1H), 2.51-2.57 (m, 0.76H), 2.69 (app t, J = 15.3 Hz, 1H), 2.78-2.90
(m, 2H), 2.98 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 14.5 Hz, 0.24H), 3.69 (s, 0.24 X 3H), 3.70 (s, 0.76 X 3H),
13
3.71 (s, 0.76 X 3H), 3.76 (s, 0.24 X 3H), 7.34-7.37 (m, 3H), 7.46-7.49 (m, 2H). C NMR (CDCl3, 125
MHz): 1st major δ -4.02, -3.71, 21.02, 23.16, 24.36, 32.10, 32.81, 43.16, 43.37, 52.77, 52.81, 58.26, 84.07,
424
PhMe2Si PhMe2Si
MeO2C MeO2C
CN CN
MeO2C MeO2C
OAc OAc
2-137 2-138
Pale yellow oil. Column chromatography; hexane:EtOAc = 15:1. Rf = 0.20 (hexane:EtOAc = 5:1). The
isolated compound was 2-137/2-138 mixture with a ratio of 0.83/0.17. 1H NMR (CDCl3, 500 MHz): δ 0.40
(s, 0.83 X 3H), 0.41 (s, 0.17 X 6H), 0.43 (s, 0.83 X 3H), 1.61-1.67 (m, 1H), 2.02-2.06 (m, 1H), 2.17 (s,
3H), 2.11-2.21 (m, 1H), 2.27-2.30 (m, 1H), 2.72-2.76 (m, 0.17H), 2.79-2.84 (m, 1.17H), 2.89-2.90 (m,
13
0.83H), 2.93-2.99 (m, 2H), 3.71 (s, 3H), 3.72 (s, 3H), 7.30-7.40 (m, 3H), 7.46-7.49 (m, 2H). C NMR
(CDCl3, 125 MHz): 1st major δ -1.68, -1.16, 20.91, 22.71, 30.91, 42.94, 44.02, 52.80, 52.88, 58.31, 74.76,
Me3Si Me3Si O
OEt
TsN TsN
OEt
O
2-91 2-92
Colorless oil. Column chromatography; hexane:EtOAc = 7:1. Rf = 0.31 (hexane:EtOAc = 5:1). The
isolated compound was 2-91/2-92 mixture with a ratio of 0.66/0.34. 1H NMR (CDCl3, 500 MHz): δ -0.06
(s, 0.34 X 9H), -0.03 (s, 066 X 9H), 1.17 (t, J = 7.1 Hz, 0.34 X 3H), 1.20 (t, J = 7.1 Hz, 0.66 X 3H), 1.53
(Br s, 1H), 2.01 (Br s, 0.34H), 2.10 (Br d, J = 12.9 Hz, 0.66H), 2.16-2.22 (m, 1H), 2.42 (s, 3H), 2.53-2.57
(m, 0.66H), 2.61-2.63 (0.34H), 3.87-3.99 (m, 2H), 4.01-4.07 (m, 2H), 4.05 (q, J = 7.1 Hz, 0.34 X 2H), 4.09
13
(q, J = 7.1 Hz, 0.66 X 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.2, 3.2 Hz, 1H). C NMR (CDCl3, 100
MHz): major δ -1.64, 14.15, 21.47, 24.17, 25.23, 27.03, 37.89, 57.00, 57.19, 60.47, 125.83, 127.41, 129.70,
131.23, 134.18, 143.35, 174.77; minor δ -1.74, 14.09, 20.84, 22.63, 24.17, 26.34, 40.25, 57.14, 57.39,
60.56, 126.33, 127.41, 129.69, 130.03, 134.22, 143.30, 175.23. IR (NaCl, neat): υ 2954s, 2856m, 1731s,
1598w, 1455m, 1251s, 1165s, 1099s, 1033m, 838s, 664s, 597s. HRMS (Electrospray): Calcd. for
425
Me3Si Me3Si O
CH3
TsN TsN
CH3
O
2-139 2-140
Colorless oil. Column chromatography; hexane:EtOAc = 5:1 to 4:1. Rf = 0.29 (hexane:EtOAc = 3:1). The
isolated compound was 2-139/2-140 mixture with a ratio of 0.10/0.09/0.69/0.12. 1H NMR (CDCl3, 500
MHz): δ -0.06 (s, 0.22 X 9H), -0.02 (s, 0.78 X 9H), 1.54 (Br s, 1H), 1.57-1.67 (m, 1H), 1.72-1.82 (m, 1H),
1.87-1.95 (m, 1H), 1.98-2.06 (m, 1H), 2.12 (s, 0.12 X 3H), 2.13 (s, 0.69 X 3H), 2.13 (s, 0.09 X 3H), 2.22
(s, 0.10 X 3H), 2.42 (s, 3H), 2.63-2.49 (m, 1H), 3.83-3.90 (m, 1H), 4.01-4.07 (m, 3H), 7.29-7.32 (m, 2H),
13
7.68-7.71 (m, 2H). C NMR (CDCl3, 125 MHz): major δ -1.50, 21.48, 24.21, 24.34, 26.66, 27.97, 45.64,
57.04, 57.15, 116.13, 125.87, 127.40, 129.73, 134.15, 143.41, 209.96. IR (NaCl, neat): υ 2951s, 2861s,
1711s, 1598w, 1513w, 1455w, 1344s, 1250m, 1164s, 1099m, 839s, 667s. HRMS (Electrospray): Calcd. for
Me3Si Me3Si
CN
TsN TsN
CN
2-141 2-142
Brown oil. Column chromatography; hexane:EtOAc = 5:1. Rf = 0.27 (hexane:EtOAc = 3:1). The isolated
compound was a/b/c/d mixture with a ratio of 0.23/0.16/0.04. 1H NMR (CDCl3, 400 MHz): δ -0.02 (s, 0.04
X 9H), -0.01 (s, 0.16 X 9H), 0.02 (s, 0.57 X 9H), 0.13 (s, 0.23 X 9H), 1.62-1.72 (m, 1.27H), 1.81 (Br s,
0.73H), 1.96-2.03 (m, 2H), 2.18-2.29 (m, 1H), 2.43 (s, 3H), 2.92-2.94 (m, 0.16H), 2.97-3.02 (m, 0.57H),
3.01-3.04 (m, 0.23H), 3.11-3.13 (m, 0.04H), 3.89-4.82 (m, 4H), 7.33 (d, J = 8.0 Hz, 3H), 7.71 (d, J = 8.2
13
Hz, 3H). C NMR (CDCl3, 125 MHz): 1st major δ -1.50, 19.89, 21.50, 23.52, 26.17, 29.15, 56.92, 57.12,
116.16, 172.33, 128.35, 129.86, 134.08, 136.54, 143.63; 2nd major δ -1.42 (SiMe3); 3rd major δ -2.18
(SiMe3); 4th major δ -2.66 (SiMe3). IR (NaCl, neat): υ 2953s, 2919s, 2861m, 2238w, 1731w, 1598w,
426
1454m, 1345s, 1253s, 1164s, 1099m, 1069m, 842s, 666s. HRMS (Electrospray): Calcd. for
Preparation of 3,4,5-Tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-one128
n-Butyllithium (1.6M in hexane, 226 mL, 141mL) was added dropwise to a stirred solution of
propagyl alcohol (102 mmol, 5.74g, 5.96 mL) in 300 mL of THF at -78 oC under nitrogen atmosphere.
After 30 min, chlorotrimethylsilane (307 mmol, 39 mL), was added dropwise to the solution at -78 oC and
followed increasing the temperature to rt. Aqueous solution of hydrochloric acid (2M, 200mL) wad added
slowly and stirred it over night (about 8h). After separation of organic phases from the mixture, the
aqueous phase was extracted with diethyl ether (2 X 200 mL). Combined organic phase was dried over
MgSO4, filtered, concentrated in a rotary evaporator to give a crude mixture. The crude mixture was flash
column chromatography eluting with hexane. After evaporation of the hexane, the residue was distillated
TMS
OH
Yellow liquid. Column chromatography; hexane and then hexane:Et2O = 1:1. Rf = 0.17 (hexane:Et2O =
1:1). Vacuum distillation; Bp 102-104 oC/30 mmHg (lit128 95-96 oC/22 mmHg). 1H NMR (CDCl3, 500
13
MHz): δ 0.15 (s, 9H), 2.52 (Br s, 1H), 4.22 (s, 2H). C NMR (CDCl3, 125 MHz): δ -0.24, 51.66, 90.71,
103.79. IR (NaCl, neat): υ 3340Br s, 2961s, 2896w, 2177m, 1674w, 1652w, 1410w, 1251s, 1043s, 984m,
843s, 760m.
3,4,5-Tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-one
To a flame dried three neck 500 mL flask connected with a 100 mL dropping funnel were added
dichloromethane was slowly added at -78 oC (the inner temperature of the flask was between -75 oC and -
427
73 oC ) under nitrogen atmosphere. The dropping funnel was washed by 10 mL of dichloromethane and
added to the reaction mixture followed by stirring at -78 oC for 20min. 2,3,4,6-tetra-O-benzyl-D-
gluconopyranose 3-83 (40 mmol, 21.6g) dissolved in 40 mL of DMSO and 40 mL of dichloromethane was
added to the 500 mL flask at -78 oC (the inner temperature of the flask was <-70 oC ) through a dropping
funnel and the dropping funnel was washed by additional 420 mL of dichloromethane, which was added to
the flask. Then, the temperature increased to -40 oC and the mixture was stirred for 1h. After addition of
diisopropylethyl amine (102 mmol, 18.1 mL) at -40 oC, the temperature increased to rt and stirred the
mixture for 2h. The mixture was washed with saturated Na2HPO4 (100 mL), saturated NaHCO3 (100 mL),
and brine solution (100 mL). Combined organic phase was dried over MgSO4, filtered through a filter
paper, and concentrated in a rotary evaporator to give a crude mixture. The crude mixture was purified by
OBn
O
BnO
BnO
BnO
O
3-88
Colorless oil. Column chromatography; hexane:EtOAc = 8:1 to 7:1. Rf = 0.29 (hexane:EtOAc = 5:1). 1H
NMR (CDCl3, 500 MHz): δ 3.69 (dd, J = 11.0, 3.3 Hz, 1H), 3.76 (dd, J = 11.0, 2.3 Hz, 1H), 3.93 (app t, J =
6.7 Hz, 1H), 3.98 (dd, J = 8.3, 6.9 Hz, 1H), 4.15 (d, J = 6.6 Hz, 1H), 4.48 (app dt, J = 8.5, 2.7 Hz, 1H), 4.50
(d, J = 12.1 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H), 4.67
(d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 5.02 (d, J = 11.4 Hz, 1H), 7.18-
13
7.23 (m, 2H), 7.27-7.43 (m, 16H), 7.39-7.43 (m, 2H). C NMR (CDCl3, 125 MHz): δ 68.18, 73.50, 73.68,
73.89, 75.99, 77.34, 78.10, 80.89, 127.78, 127.90, 127.96, 128.07, 128.35, 128.40, 128.43, 136.88, 137.44,
137.47, 137.53, 169.30. IR (NaCl, neat): υ 3063m, 3030s, 2919s, 2868s, 1954w, 1878w, 1755s, 1496m,
1454s, 1363m, 1210m, 1164m, 1097s, 1073s, 1028m, 912w, 737s, 697s.
428
3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-tetrahydro-pyran-2-ol
A flame-dried 25 mL of flask was charged with trimethylsilyl acetylene (2.03 mmol, 199 mg) in
10 mL of THF. To the solution was added slowly n-butyllithium (1.6M in hexane, 1.27 mL) at -78 oC for
mmol, 729 mg) in 5 mL of THF was added slowly, the reaction mixture was stirred at -78 oC for 2h and
allowed to warm to rt for 1h. After all starting material was consumed (TLC), the mixture was diluted with
diethyl ether (50 mL). The diluted mixture was washed with saturated ammonium chloride (2 × 20 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was used for the next step
without further purification. If it was necessary, the crude mixture was purified by column chromatography
OBn
TMS
O
BnO
BnO
BnO
OH
3-89
Colorless oil (The compounds was isolated as a mixture of three diastereomers). Column chromatography;
hexane:EtOAc = 20:1 to 12:1. Rf = 0.31 (hexane:EtOAc = 4:1). 1H NMR (CDCl3, 500 MHz): major
isomer, δ 0.23 (s, 9H), 3.76-3.77 (m, 1H), 3.79-3.84 (m, 1H), 3.94-3.97 (m, 1H), 4.01-4.04 (m, 1H), 4.09-
4.15 (m, 2H), 4.57 (d, J = 12.2 Hz, 1H), 4.64 (d, J = 10.2 Hz, 6H), 4.73 (d, J = 11.4 Hz, 1H), 4.74 (d, J =
12.1 Hz, 1H), 4.79 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.92 (d, J = 10.7 Hz, 1H), 5.16 (d, J =
13
11.4 Hz, 1H), 7.17-7.52 (m, 20H). C NMR (CDCl3, 125 MHz): major (Because of overlap of peaks in
aromatic region, the peaks are not assigned), δ -0.38, 68.74, 72.96, 73.46, 74.26, 74.49, 75.18, 75.35, 75.18,
75.35, 80.30, 81.53, 91.85, 93.61, 99.46; minor (Because of overlap of peaks in aromatic region, the peaks
are not assigned), δ -0.45, 69.36, 71.77, 73.22, 73.24, 74.49, 74.98, 75.07, 78.21, 80.14, 88.72, 92.54,
103.43. IR (NaCl, neat): υ 3420 Br s, 3063s, 3031s, 2949s, 2927s, 2873s, 1951w, 1870w, 1805w, 1644m,
1496m, 1454s, 1395w, 1361m, 1251s, 1210m, 1070s, 1028s, 845s, 735s, 697s.
429
3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-trimethylsilanylethynyl-2-[trimethylsilanylprop-2-
ynyloxy]-tetrahydro-pyran
Montmorillonite A (300 mg) and 4 Å MS (450 mg) were placed into a 50 mL of flask. After dried
by flame under reduced pressure, the flask was cooled at rt under a stream of nitrogen. Dichloromethane (7
mL) was added to the flask and stirred it for 1min. To the suspension was added a mixture of 3,4,5-tris-
mg) and 3-Trimethylsilyl-2-propyn-1-ol (1.102 mmol, 141 mg) in 5 mL of dichloromethane. After stirring
at rt for 1.5h under nitrogen atmosphere, all starting material was consumed. The resulting mixture was
filtered through Celite® pad followed by addition of 10 mL of dichloromethane to the pad. All solvent was
removed under reduced pressure to give crude product. This crude product was used for the next step
without further purification. If it was necessary, the crude product was purified by column chromatography
OBn
TMS
O
BnO
BnO TMS
BnO
O
3-90
Colorless oil. Column chromatography; hexane:EtOAc = 50:1 to 20:1. Rf = 0.42 (hexane:EtOAc = 9:1).
1
Only α anomer was isolated as pure compounds. H NMR (CDCl3, 500 MHz): δ 0.16 (s, 9H), 0.20 (s,
9H), 3.72-3.80 (m, 3H), 3.97 (app t, J = 9.3 Hz, 1H), 4.02 (d, J = 3.0 Hz, 1H), 4.07 (dd, J = 9.5, 2.9 Hz,
1H), 4.28 (d, J = 15.3 Hz, 1H), 4.47 (d, J = 15.3 Hz, 1H), 4.53 (d, J = 10.7 Hz, 1H), 4.57 (d, J = 12.1 Hz,
1H), 4.46 (s, 2H), 4.67 (d, J = 12.0 Hz, 1H), 4.84 (d, J = 10.7 Hz, 1H), 4.91 (d, J = 11.4 Hz, 1H), 4.97 (d, J
13
= 11.4 Hz, 1H), 7.15-7.18 (m, 2H), 7.25-7.31 (m, 11H), 7.32-7.36 (m, 5H), 7.44 –7.46 (m, 2H). C NMR
(CDCl3, 125 MHz): δ -0.43, -0.19, 52.02, 68.93, 72.32, 73.22, 73.57, 74.32, 75.19, 74.32, 75.19, 75.27,
78.38, 80.41, 91.07, 91.09, 96.88, 99.84, 101.05, 127.32, 127.38, 127.44, 127.47, 127.64, 127.86, 128.02,
128.16, 128.24, 128.31, 138.23, 138.50, 138.52, 138.54. β (major) was isolated as a mixture of α/β with a
ratio of 0.17/1.0. 1H NMR (CDCl3, 400 MHz): δ 0.00 (s, 9H), 0.02 (s, 9H), 3.51-3.65 (m, 3H), 3.74 (ddd, J
= 10.1, 3.6, 1.8 Hz, 1H), 3.85 (app t, J = 9.3 Hz, 1H), 4.28 (d, J = 13.5 Hz, 2H), 4.35 (d, J = 111.8 Hz, 1H),
430
4.37 (d, J = 10.6 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.66 (d, J = 10.7 Hz, 1H),
4.67 (d, J = 11.9 Hz, 1H), 4.74 (d, J = 11.1 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 6.97-.7.01 (m, 2H), 7.27-
13
7.28 (m, 23H). C NMR (CDCl3, 125 MHz): δ -0.45, -0.19, 52.84, 68.20, 71.96, 73.37, 75.50, 75.60,
75.92, 77.75, 82.07, 84.25, 90.78, 91.95, 96.06, 100.29, 101.45, 127.52, 127.62, 127.67, 127.69, 127.93,
128.18, 128.20, 128.30, 128.33, 128.35, 138.09, 138.14, 138.82. IR (NaCl, neat): υ 3288s, 3062s, 3030s,
2958s, 2905s, 2182m, 1951m, 1872w, 1809w, 1606m, 1586w, 1496s, 1454s, 1402s, 1360s, 1308s, 1250s,
2,3,5-Tris-benzyloxy-6-benzylmethyl-2-ethynyl-tetrahydro-pyran-2-ol
To a flame-dried flask was added lithium acetylide ethylene diamine complex (19.8 mmol, 2.02g)
gluconolactone 3-88 (9.9 mmol, 5.33g) in 60 mL of THF was added slowly to the mixture at -78 oC, the
mixture was sirred at -78 oC for 3h. (a small amount of 2,3,4,6-tetra-O-benzyl-D-gluconolactone was
detected on TLC). To consume all starting material additional lithium acetylide ethylene diamine complex
(118mg) was added and continued stirring for another 1h at -78 oC. To the reaction mixture was added
saturated ammonium chloride solution (70 mL) -78 oC with stirring. The mixture was diluted by diethyl
ether and separated the organic phase by a separation funnel. All combined organic phase was washed with
water abd brine solution, dried over MgSO4, filtered, and concentrated in a rotary evaporator. The crude
mixture was purified by column chromatogramphy eluting with hexane:EtOAc = 20:1 to 7:1. Colorless oil
OBn
O
BnO
BnO
BnO
OH
3-91
Colorless oil. Column chromatography; hexane:EtOAc = 20:1 to 7:1. Rf = 0.27 (hexane:EtOAc = 5:1). 1H
NMR (CDCl3, 500 MHz): major: δ 2.73 (s, 1H), 3.62-3.76 (m, 4H), 3.90 (app t, J = 9.3 Hz, 1H), 3.96 (app
dt, J = 10.0, 3.2 Hz, 1H), 4.50-4.58 (m, 2H), 4.63 (d, J = 12.2 Hz, 1H), 4.78-4.86 (m, 2H), 4.90 (d, J = 12.1
431
Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 5.04 (d, J = 11.3 Hz, 1H), 7.12-7.21 (m, 2H), 7.25-7.36 (m, 18H);
minor: δ 2.59 (s, 1H) 3.53 (d, J = 9.6 Hz, 1H), 3.62-3.76 (m, 3H), 3.83 (app t, J = 9.3 Hz, 1H), 4.04 (ddd, J
= 11.1, 4.2, 2.1 Hz, 1H), 4.50-4.58 (m, 2H), 4.65 (d, J = 12.2 Hz, 1H), 4.78-4.86 (m, 3H), 4.90 (d, J = 12.1
13
Hz, 1H), 5.03 (d, J = 10.3 Hz, 1H), 7.12-7.21 (m, 2H), 7.25-7.36 (m, 18H). C NMR (CDCl3, 125 MHz):
major: δ (aromatic peaks are omitted) 68.43, 71.96, 73.40, 74.80, 74.96, 75.74, 75.84, 77.57, 82.40, 83.56,
82.40, 83.56, 83.72, 91.82; minor: δ (aromatic peaks are omitted) 68.46, 72.19, 73.40, 74.54, 75.29, 75.74,
76.42, 80.17, 82.86, 83.97, 95.27. IR (NaCl, neat): υ 3380Br s, 3292s, 3088m, 3062s, 3030s, 2919s, 2869s,
2116w, 1953w, 1877w, 1809w, 1746w, 1605w, 1496s, 1454s, 1398m, 1361s, 1266m, 1210s, 1070Br s,
Trimethyl-[3-(3,4,5-tri-benzyloxy-6-benzyloxymethyl-2-ethynyl-tetrahydro-pyran-2-yloxyl)-prop-1-
ynyl]-silane
After Montmorillonite K 10 (5g) and 4 Å MS were placed into a 250 mL flask, the flask was dried
by flame under reduced pressure. Once the flask cooled completely at rt dichloromethane (80 mL) was
added. To the suspension was added a mixture of 3-trimethylsilyl-2-propyn-1-ol (13.4 mmol, 1.72g) and
dichloromethane (80 mL) at rt. After stirred at rt under nitrogen atmosphere for 2h, the resulting mixture
was filtered through a Celite® pad. The pad was washed with additional dichloromethane (50 mL).
Combined organic mixture was concentrated under reduced pressure to give crude product, which used for
the next step without further purification. If it was necessary to purify it, the crude mixture was subjected
OBn
O
BnO
BnO TMS
BnO
O
3-92
432
Colorless oil. Column chromatography; hexane:EtOAc = 20:1 to 7:1. Rf = 0.28 (hexane:EtOAc = 6:1).
The compound was isolated as α/β mixture with a ratio of 0.68/0.32. 1H NMR (CDCl3, 500 MHz): δ 2.63
(s, 0.68H), 2.83 (s, 0.32H), 3.64 (d, J = 9.5 Hz, 0.32H), 3.71 (t, J = 9.3 Hz, 0.32H), 3.75-3.87 (m, 2.68H),
3.90 (t, J = 9.2 Hz, 1H), 3.94 (ddd, J = 8.0, 4.0, 2.0 Hz, 0.32H), 4.04-4.09 (m, 2H), 4.15 (dd, J = 9.5, 2.8
Hz, 0.68H), 4.36 (d, J = 15.3 Hz, 0.68H), 4.52 (d, J = 17.9 Hz, 0.68H), 4.54 (d, J = 15.4 Hz, 0.32H), 4.52-
4.57 (m, 2H), 4.66 (d, J = 15.1 Hz, 0.32H), 4.68 (d, J = 12.2 Hz, 0.32H), 4.73 (s, 0.32H), 4.76 (s, 2H), 4.84
(dd, J = 11.3, 7.9 Hz, 0.68H), 4.89 (d, J = 9.0 Hz, 0.32H), 4.91 (d, J = 10.6 Hz, 0.68H), 4.98 (s, 0.68 X 2H),
5.02 (d, J = 10.9 Hz, 0.32H), 5.12 (d, J = 11.3 Hz, 0.32H), 7.20-7.25 (m, 2H), 7.23-7.41 (m, 16H), 7.45-
13
7.53 (m, 2H). C NMR (CDCl3, 125 MHz): major: δ (aromatic peaks are omitted) 100.76, 96.93, 91.31,
83.44, 80.42, 77.25, 75.21, 74.29, 74.24, 73.72, 73.32, 72.48, 68.93, 52.19, -0.23; minor: δ (aromatic peaks
are omitted) 101.34, 99.15, 91.04, 83.40, 79.18, 78.87, 76.47, 75.74, 75.07, 74.57, 73.35, 72.48, 68.46,
53.66, -0.23.
3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2(S)-ethynyl-2-prop-2-ynyloxy-tetrahydro-pyran
Crude trimethyl-[3-(3,4,5-tri-benzyloxy-6-benzyloxymethyl-2-ethynyl-tetrahydro-pyran-2-
yloxyl)-prop-1-ynyl]-silane 3-92 (8.96 mmol estimated from 3-91) and 408 mg of benzyltriethyl
ammonium chloride were dissolved in a mixture of acetonitril/dichloro methane (100 mL, 1:1 mixture).
After treated by 50% sodium hydroxide solution (1.2 mL) at 0 oC, the mixture was stirred at at 0 oC for
5min and at rt for 30min. The mixture was diluted with diethyl ether, washed with water and brine
solution, dried over MgSO4, filtered, and concentrated in a rotary evaporator. The crude mixture was
purified column chromatography eluting with hexane:EtOAc = 20:1 to 15:1. The major product, α anomer,
was isolated as pure compound, but the minor product, β anomer, was contaminated <5% with unknown
compounds.
A similar procedure (except for using double volume of 50% sodium hydroxide solution) was
methylsilanylprop-2-ynyloxy]-tetrahydro-pyran to 3,4,5-tris-benzyloxy-6-benzyloxymethylethynyl-2-prop-
2-ynyloxy-tetrahydro-pyran 3-89.
433
OBn
O
BnO
BnO
BnO
O
3-82-α
White solid. Column chromatography; hexane:EtOAc = 20:1 to 15:1. Rf = 0.25 (hexane:EtOAc = 6:1).
20
[α] D = +21.0 (c 0.61 in CHCl3). 1H NMR (CDCl3, 500 MHz): δ 2.43 (app t, J = 2.5 Hz, 9H), 2.64 (s, 1H),
3.73 (dd, J = 11.0, 1.8 Hz, 6H), 3.77 (app t, J = 10.3 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.81 (dd, J = 11.0,
3.9 Hz, 1H), 3.95 (ddd, J = 10.1, 3.7, 1.8 Hz, 1H), 4.07 (app t, J = 10.3 Hz, 1H), 4.48 (B of ABX, JAB= 15.5
Hz, JBX= 2.5 Hz, 1H), 4.51 (A of ABX, JAB= 15.5 Hz, JAX= 2.6 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.58 (d,
J = 10.7 Hz, 1H), 4.69 (d, J = 12.1 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 4.87 (d, J = 10.7 Hz, 1H), 4.91 (d, J
= 10.9 Hz, 1H), 4.95 (d, J = 11.0 Hz, 1H), 5.02 (d, J = 10.9 Hz, 1H), 7.18-7.20 (m, 2H), 7.28-7.43 (m,
13
18H). C NMR (CDCl3, 125 MHz): δ 52.22, 68.13, 72.25, 73.36, 74.39, 74.98, 75.07, 75.68, 75.84, 77.67,
79.04, 79.35, 83.72, 96.14, 127.51, 127.57, 127.68, 127.71, 127.80, 127.90, 128.18, 128.30, 128.32,
128.37, 137.90, 138.03, 138.07, 138.59. IR (NaCl, neat): υ 3286s, 3060m, 3030s, 2923s, 2246m, 2121m,
1954w, 1878w, 1807w, 1606w, 1496m, 1450s, 1361s, 1212m, 1149s, 1087s, 910m, 734s, 698s. HRMS
OBn
O
BnO O
BnO
BnO
3-82-β
Colorless oil. Column chromatography; hexane:EtOAc = 20:1 to 15:1. Rf = 0.27 (hexane:EtOAc = 6:1).
1
H NMR (CDCl3, 500 MHz): δ 2.49 (app t, J = 2.3 Hz, 9H), 2.82 (s, 1H), 3.63 (d, J = 9.5 Hz, 6H), 3.69-
3.80 (m, 3H), 3.88 (app t, J = 9.3 Hz, 1H), 3.90-3.92 (m, 1H), 4.56-4.51(m, 4H), 4.66 (d, J = 12.3 Hz, 1H),
4.80 (d, J = 11.2 Hz, 1H), 4.87 (d, J = 10.7 Hz, 1H), 4.99 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 11.3 Hz, 1H),
13
7.18-7.21 (m, 2H), 7.26-7.45 (m, 23H). C NMR (CDCl3, 125 MHz): δ 52.93, 68.40, 73.32, 74.03, 74.14,
74.70, 75.04, 75.61, 75.71, 75.78, 76.38, 77.17, 79.19, 79.59, 83.36, 83.67, 99.29, 127.48, 127.51, 127.55,
434
127.63, 127.70, 127.78, 127.90, 127.94, 128.08, 128.17, 128.21, 128.26, 128.30, 128.33, 128.34, 128.38,
138.06, 138.13, 138.31, 138.61. IR (NaCl, neat): υ 3285s, 3088m, 3063s, 3031s, 2866s, 2359m, 2109m,
1952w, 1875w, 1810w, 1605w, 1586w, 1496s, 1454s, 1397m, 1361s, 1295s, 1210s, 1074 Br s, 911m, 735s,
697s.
(S)-8, 9, 10-tris-benzyloxy-7-benzyloxymethyl-4-[(dimethylphenylsilanyl)-methylene]-1,6-dioxa-3-
[(tri-butylstannanyl)-methylene]- spiro[4.5]decane
2(S)-3, 4 ,5-Tris-benzyloxy-6-benzyloxymethyl-2-ethynyl-2-prop-2-ynyloxy-tetrahydro-pyran 3-
82-α (50 µmol, 30.1mg), (C6F5)3P (5 µmol, 2.7 mg), Bu3SnSiMe2Ph (55 µmol, 23.4 mg), and
Pd2(dba)3•CHCl3 (2.5 µmol, 1.3 mg) were placed into an NMR tube. After 1 mL of C6D6 was added to the
tube, it was shaken vigorous and stand at rt. The reaction was followed by 1H NMR and TLC. After all
starting material was disappeared in 1H NMR spectrum and/or TLCanalysis, the solvent was removed
under reduced pressure. The crude mixture was purified by column chromatography eluting with
hexane:EtOAc = 40:1.
The same reaction was successful in a large scale (3.75 mmol) using PdCl2(PhCN)2 and benzene,
and a similar procedure was used for thepalladium catalyzed silylstannylative cyclization of 3-82-β.
OBn H
6
4 H 9
O SiMe2Ph
BnO 2
BnO SnBu3
BnO
O 8
H
7 H
H
3-93
NMR (CDCl3, 500 MHz): δ 0.40 (s, 3H), 0.42 (s, 3H), 0.83 (t, J = 7.3 Hz, 9H), 0.81-0.87 (m, 6H), 1.22
(sex, J = 7.3 Hz, 6H), 1.26-1.39 (m, 6H), 3.61 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 9.3 Hz, 1H), 3.75 (dd, J =
9.6 Hz, 1H), 3.82 (dd, J = 11.2, 3.6 Hz, 1H), 3.93 (ddd, J = 10.0, 3.4, 1.4 Hz, 1H), 4.03 (app t, J = 9.3 Hz,
1H), 4.39-4.43 (m, 3H), 4.51 (dd, J = 10.8, 1.0 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.64 (d, J = 10.8 Hz,
1H), 4.65 (d, J = 11.3 Hz, 1H), 4.73 (d, J = 10.3 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.83 (d, J = 10.9 Hz,
435
1H), 5.92 (s, 1H), 6.01 (s, JSn-H = 37.5 Hz, 1H), 7.17-7.30 (m, 23H), 7.47 (d, J = 6.7 Hz, 2H) . 1H NMR
(C6D6, 500 MHz): δ 0.49 (s, 3H), 0.51 (s, 3H), 0.94 (t, J = 7.3 Hz, 9H), 0.98-1.09 (m, 6H), 1.36 (sex, J =
7.3 Hz, 6H), 1.48-1.61 (m, 6H), 3.67 (dd, J = 11.1, 1.3 Hz, 1H), 3.79 (d, J = 9.3 Hz, 1H), 3.88 (dd, J = 11.0,
3.4 Hz, 1H), 4.02 (app t, J = 9.6 Hz, 1H), 4.23-4.25 (m, 1H), 4.38 (d, J = 12.3 Hz, 1H), 4.39 (app t, J = 9.3
Hz, 1H), 4.42 (d, J = 10.2 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 11.8 Hz,
1H), 4.74 (d, J = 11.7 Hz, 1H), 4.77 (d, J = 11.7 Hz, 1H), 4.84 (d, J = 11.8 Hz, 1H), 4.85 (d, J = 10.9 Hz,
1H), 4.97 (d, J = 11.3 Hz, 1H), 5.94 (s, JSn-H = 39.5 Hz, 1H), 6.06 (s, 1H), 6.99-7.08 (m, 6H), 7.12-7.19 (m,
11H), 7.18-7.26 (m, 4H), 7.34 (d, J = 7.5 Hz, 2H), 7.53-7.56 (m, 2H). 1H NMR (CD2Cl2, 500 MHz): δ 0.42
(s, 6H), 0.78-0.92 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H), 1.24 (sex, J = 7.3 Hz, 6H), 1.34-1.48 (m, 6H), 3.61 (dd,
J = 11.1, 1.6 Hz, 1H), 3.71 (app t, J = 9.6 Hz, 1H), 3.72 (d, J = 11.9 Hz, 1H), 3.81 (dd, J = 11.1, 3.6 Hz,
1H), 3.88 (ddd, J = 11.6, 3.4, 1.6 Hz, 1H), 3.96 (app t, J = 9.3 Hz, 1H), 4.37-4.42 (m, 2H), 4.4- (d, J = 11.8
Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.4, Hz, 1H), 4.65 (d, J = 12.6 Hz, 1H), 4.71 (d, J = 10.9
Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.82 (d, J = 11.1 Hz, 1H), 5.95 (s. 1H), 6.04 (s, JSn-H = 39.5 Hz, 1H),
13
7.04-7.09 (m, 2H), 7.17-7.38 (m, 21H), 7.50 (d, J = 6.7 Hz, 2H). C NMR (C6D6, 100 MHz): δ -0.84, -
0.27, 11.31, 13.92, 27.74, 29.38, 69.80, 73.02, 73.95, 74.24, 74.88, 75.55, 78/71, 81.40, 84.71, 106.37,
126.75, (the peaks of benzene rings are omitted because of overlap), 134.10 139.18, 139.28, 139.41,
13
139.55, 139.71, 154.39, 156.84. C NMR (CDCl3, 100 MHz): δ -1.34, -0.23, 10.98, 13.64, 27.27, 28.89,
69.41, 72.36, 73.73, 73.94, 74.07, 74.77, 74.59, 75.59, 78.28, 80.93, 84.24, 124.07, 126.86, 127.03, 127.38,
127.40, 127.53, 127.60, 127.72, 127.76, 127.81, 127.99, 128.23, 128.24, 128.30, 128.86, 129.26, 133.62,
138.54, 138.63, 138.65, 138.74, 138.99, 153.22, 155.99. IR (NaCl, neat): υ 3064m, 3029m, 2954s, 1606w,
1454m, 1427w, 1362m, 1248m, 1208m, 1146m, 1095s, 1028s, 820m, 732s, 697s. HRMS (Electrospray):
4.1%
nOe
OBn H
6
4 H 9
O SiMe2Ph
BnO 2
BnO SnBu3
BnO 8
O
nOe H
7 H
H nOe
436
nOe(%) nOe(%) nOe(%) nOe(%)
OBn H
6
4 H
O 9 SnBu3
BnO 2
BnO SiMe2Ph
BnO
8
O H
7 H
H
3-94
NMR (C6D6, 500 MHz): δ 0.48 (s, 3H), 0.54 (s, 3H), 0.89 (t, J = 7.3 Hz, 9H), 0.96-1.0 (m, 6H), 1.27-1.35
(m, 6H), 1.48-1.54 (m, 6H), 3.69 (dd, J = 11.1, 1.7 Hz, 1H), 3.86 (dd, J = 11.1, 3.5 Hz, 1H), 3.88 (d, J = 9.5
Hz, 1H), 4.02 (app t, J = 9.6 Hz, 1H), 4.25 (ddd, J = 10.0, 3.4, 1.7 Hz, 1H), 4.36 (d, J = 10.6 Hz, 1H), 4.43
(app t, J = 9.3 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 10.2 Hz, 1H), 4.58 (d, J = 12.1 Hz, 1H), 4.70
(d, J = 11.8 Hz, 1H), 4.77 (d, J = 11.3 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.89 (d, J = 11.3 Hz, 1H), 4.98
(d, J = 11.3 Hz, 1H), 5.05 (d, J = 11.8 Hz, 1H), 5.56 (s, 1H), 6.38 (s, JSn-H = 40.1 Hz, 1H), 6.99-7.35 (m,
23H), 7.55-7.57 (m, 2H). NMR (CD2Cl2, 500 MHz): δ 0.38 (s, 3H), 0.40 (s, 3H), 0.82 (t, J = 7.3 Hz, 9H),
0.79-0.88 (m, 6H), 1.17-1.27 (m, 6H), 1.35-1.48 (m, 6H), 3.63 (d, J = 11.0 Hz, 1H), 3.74 (app t, J = 9.6 Hz,
1H), 3.79-3.83 (m, 2H), 3.89 (d, J = 10.0 Hz, 1H), 4.02 (app t, J = 9.3 Hz, 1H), 4.38 (d J = 10.2 Hz, 1H),
4.49 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.58 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H),
4.77 (d, J = 11.0 Hz, 1H), 4.85 (d, J = 11.1 Hz, 1H), 4.86 (d, J = 11.0 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H),
13
5.71 (s, 1H), 6.30 (s, JSn-H = 38.4 Hz, 1H), 7.17-7.36 (m, 23H), 7.48-7.51 (m, 2H). C NMR (C6D6, 125
MHz): δ -0.75, -0.20, 11.16, 13.88, 27.71, 29.32, 69.65, 73.09, 73.89, 74.14, 74.91, 75.57, 78.86, 81.05,
84.81, 106.05, 123.76, 126.69, 139.23, 139.39, 139.55, 139.64, 139.88, 154.68, 156.30. IR (NaCl, neat):
υ 3088m, 3053m, 3031m, 2955s, 2922s, 2852s, 1731w, 1607w, 1496m, 1454m, 1427w, 1361m, 1248m,
437
1143m, 1094s, 1028s, 821m, 731s. HRMS (Electrospray): Calcd. for C59H76O6SiSnNa (M++Na),
4.5%
nOe
OBn H
6 9
4 H
O SnBu3
BnO 2
BnO SiMe2Ph
BnO 8
O H
nOe
H
H nOe
OBn
6 H
O
BnO 5 2
O
BnO H
3 BnO 7
HH 9 H
8
PhMe2Si H
SnBu3
3-97
NMR (CDCl3, 500 MHz): δ 0.42 (s, 3H), 0.53 (s, 3H), 0.84-1.10 (m, 6H), 0.97 (t, J = 7.3 Hz, 9H), 1.37
(sex, J = 7.4 Hz, 6H), 1.45-1.61 (m, 6H), 3.56 (d, J = 9.7 Hz, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.85 (dd, J =
10.5, 3.0 Hz, 1H), 3.92 (app t, J = 9.7 Hz, 1H), 3.96 (d, J = 9.9 Hz, 1H), 4.18 (app t, J = 9.3 Hz, 1H), 4.47
(d, J = 10.6 Hz, 1H), 4.50 (d, J = 11.0 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.68 (d, J = 10.7 Hz, 1H), 4.76
(d, J = 12.2 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.90 (d, J = 10.6 Hz, 1H), 4.91
(d, J = 11.3 Hz, 1H), 5.01 (d, J = 11.0 Hz, 1H), 6.03 (s, JSn-H = 38.5 Hz, 1H), 6.23 (s, 1H), 7.21-7.24 (m,
2H), 7.30-7.41 (m, 21H), 7.56 (d, J = 7.0 Hz, 2H) . ). 1H NMR (C6D6, 500 MHz): δ 0.45 (s, 3H), 0.53 (s,
3H), 1.37 (t, J = 7.5 Hz, 9H), 0.99-1.14 (m, 6H), 1.36 (sex, J = 7.4 Hz, 6H), 1.48-1.63 (m, 6H), 3.78 (d, J =
9.2 Hz, 2H), 3.94 (dd, J = 11.0, 4.0 Hz, 1H), 4.04 (app t, J = 9.2 Hz, 1H), 4.13 (d, J = 9.8 Hz, 1H), 4.32
438
(app t, J = 9.4 Hz, 1H), 4.37-4.43 (m, 3H), 4.57 (d, J = 12.2 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.76 (d, J =
10.8 Hz, 1H), 4.78 (d, J = 10.5 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 4.99 (d, J =
11.4 Hz, 1H), 5.85 (s, JSn-H = 41.2 Hz, 1H), 6.49 (s, 1H), 7.03-7.14 (m, 15H), 7.16-7.18 (m, 2H), 7.27-7.29
13
(m, 6H), 7.59 (dd, J = 7.3, 1.3 Hz, 2H) . C NMR (CDCl3, 125 MHz): δ -0.60, -0.54, 10.91, 13.68, 27.28,
28.94, 68.83, 71.68, 71.91, 72.58, 73.50, 74.89, 75.04, 75.32, 78.18, 83.44, 83.50, 106.19, 127.22, 127.41,
127.49, 127.57, 127.73, 127.86, 127.89, 127.96, 128.06, 128.18, 128.27, 128.76, 129.57, 132.99, 133.74,
138.12, 138.34, 138.61, 138.74, 138.89, 152.97. IR (NaCl, neat): υ 3088m, 3065s, 3029s, 2955s, 2923s,
2861s, 2247w, 1948w, 1877w, 1807w, 1743w, 1606m, 1496s, 1454s, 1427s, 1399m, 1359s, 1247s, 1208s,
1108s, 1067s, 1028s, 909s, 824s, 776m, 732s, 697s, 596m. HRMS (Electrospray): Calcd. for
OBn
6
H
O
BnO 5 2
O H
BnO 3 7
BnO
6.4% H H 9 H
8.3% nOe
H 2.3%
PhMe2Si 8
SnBu3
3-96
OBn
6
H
O
BnO 5 2
O H
BnO 3 BnO 7
HH 9 H
8
Bu3Sn H
SiMe2Ph
3-98
439
Colorless oil. Column chromatography; hexane:EtOAc = 40:1. Rf = 0.29 (hexane:EtOAc = 10:1). 1H
NMR (CDCl3, 500 MHz): δ 0.36 (s, 3H), 0.52 (s, 3H), 0.84-0.95 (m, 6H), 0.89 (t, J = 7.3 Hz, 9H), 1.23-
1.33 (m, 6H), 1.38-1.52 (m, 6H), 3.62 (d, J = 9.8 Hz, 2H), 3.76 (dd, J = 10.9, 4.2 Hz, 1H), 3.79 (app t, J =
9.5 Hz, 1H), 3.94 (d, J = 10.0 Hz, 1H), 4.17 (app t, J = 9.6 Hz, 1H), 4.50 (d, J = 12.5 Hz, 1H), 4.51 (d, J =
11.1 Hz, 1H), 4.57 (dd, J = 11.0, 1.6 Hz, 1H), 4.61 (d, J = 10.4 Hz, 1H), 4.65 (d, J = 12.5 Hz, 1H), 4.77 (d,
J = 11.2 Hz, 1H), 4.87 (d, J = 10.8 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.90 (d, J = 11.7 Hz, 1H), 5.06 (d, J
= 10.9 Hz, 1H), 5.72 (s, 1H), 6.54 (s, JSn-H = 40.5 Hz, 1H), 7.17-7.19 (m, 2H), 7.30-7.40 (m, 21H), 7.59
(dd, J = 7.7, 1,7 Hz, 2H) . 1H NMR (CD2Cl2, 500 MHz): δ 0.31 (s, 3H), 0.46 (s, 3H), 0.82 (t, J = 7.3 Hz,
9H), 0.85-0.79 (m, 6H), 1.19-1.27 (m, 6H), 1.37-1.43 (m, 6H), 3.49 (ddd, J = 10.1, 3.5, 1.7 Hz, 1H), 3.53
(dd, J = 10.4, 1.9 Hz, 1H), 3.67 (app t, J = 9.5 Hz, 1H), 3.68 (dd, J = 10.2, 3.6 Hz, 1H), 3.79 (d, J = 9.9 Hz,
1H), 4.07 (app t, J = 9.7 Hz, 1H), 4.40 (dd, J = 11.1, 1.2 Hz, 1H), 4.43 (d J = 12.1 Hz, 1H), 4.51 (dd, J =
11.1, 1.9 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 10.6 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.80 (d, J
= 10.6 Hz, 1H), 4.81 (d, J = 11.1 Hz, 2H), 4.98 (d, J = 11.1 Hz, 1H), 5.67 (s, 1H), 6.50 (s, JSn-H = 40.4 Hz,
13
1H), 7.13-7.16 (m, 2H), 7.21-7.35 (m, 21H), 7.52-7.55 (m, 2H) . C NMR (CDCl3, 125 MHz): δ -0.16,
0.09, 10.69, 13.65, 27.28, 28.85, 68.79, 71.67, 72.61, 73.30, 74.95, 75.31, 75.60, 78.42, 83.28, 83.90,
106.35, 123.44, 127.25, 127.43, 127.56, 127.79, 127.83, 127.85, 127.90, 128.03, 128.09, 128.25, 128.28,
128.36, 128.42, 128.87, 133.66, 134.47, 138.01, 138.24, 138.73, 138.83, 139.70, 149.50, 155.41. IR (NaCl,
neat): υ 3065m, 3030m, 2943s, 2924s, 2861s, 1048w, 1878w, 1813w, 1737w, 1623m, 1496m, 1454s,
1428m, 1359m, 1248m, 1209m, 1068s, 907m, 842s, 792m, 731s, 697s. HRMS (Electrospray): Calcd. for
OBn
6
H
O
BnO 5 2
O
BnO H
3 7
BnO
7.3% H H 9 H nOe
8.9% 1.7%, 1.3%
Bu3Sn 8
H
SiMe2Ph
3-97
440
H3 → H6 4.8 H5 → H6 8.6 H8 → H7 1.7, 1.3
mL of NBS (20 µmol, 3.6mg) at rt. The mixture was stirred at rt until no more starting material was
detected on TLC (16h). After all solvent was removed in a rotary evaporator, the crude mixture was
OBn H
H
O SiMe2Ph
BnO
BnO Br
BnO
O H
nOe
H
H
3-108
Yellow oil. Column chromatography; hexane:EtOAc = 20:1. Rf = 0.11 (hexane:EtOAc = 10:1). 1H NMR
(CDCl3, 500 MHz): δ 0.51 (s, 3H), 0.56 (s, 3H), 3.74 (d, J = 9.6 Hz, 2H), 3.80 (app t, J = 9.6 Hz, 1H), 3.85
(dd, J = 11.5, 3.8 Hz, 1H), 3.99 (ddd, J = 10.0, 3.6, 1.7 Hz, 1H), 4.02 (app t, J = 9.3 Hz, 1H), 4.53-4.56 (m,
2H), 4.56 (d, J = 10.2 Hz, 1H), 4.66 (d, J = 12.4 Hz, 1H), 4.67 (s, 2H), 4.69 (d, J = 11.0 Hz, 1H), 4.88 (d, J
= 10.7 Hz, 1H), 4.90 (d, J = 10.3 Hz, 1H), 4.92 (d, J = 11.3 Hz, 1H), 6.26 (s, 1H), 6.36 (s, 1H), 7.27-7.35
13
(m, 23H), 7.58 (d, J = 6.8 Hz, 2H). C NMR (CDCl3, 125 MHz): δ -2.24, -1.04, 68.87, 71.71, 73.45,
73.51, 74.95, 74.98, 75.58, 78.09, 82.40, 83.32, 101.94, 106.55, 127.40, 127.49, 127.54, 127.58, 127.62,
127.90, 128.07, 128.12, 128.29, 128.34, 128.83, 129.70, 133.83, 138.04, 138.41, 138.64, 138.86, 140.91,
151.09. IR (NaCl, neat): υ 3062m, 3030m, 2922s, 2854s, 1730w, 1623w, 1496w, 1454m, 1427w, 1362m,
1428m, 1209w, 1144m, 1092s, 1028s, 839m, 733s, 697s. HRMS (Electrospray): Calcd. for
441
OBn
H
O
BnO O
BnO H
BnO
HH H
PhMe2Si H
Br
3-109
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1. Rf = 0.17 (hexane:EtOAc = 10:1). 1H
NMR (CDCl3, 400 MHz): δ 0.38 (s, 6H), 3.51 (app dt, J = 10.1, 1.8 Hz, 1H), 3.56 (dd, J = 10.9, 1.7 Hz,
1H), 3.64 (d, J = 11.0 Hz, 1H), 3.69-3.64 (m, 1H), 3.79 (d, J = 9.3 Hz, 1H), 4.02 (app t, J = 8.9 Hz, 1H),
4.23 (dd, J = 10.6, 1.7 Hz, 1H), 4.38 (d, J = 9.7 Hz, 1H), 4.39 (d, J = 12.5 Hz, 1H), 4.47 (d, J = 10.7 Hz,
1H), 4.56 (d, J = 12.2 Hz, 1H), 4.63 (d, J = 11.4 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.4 Hz,
1H), 4.74 (d, J = 11.0 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 5.99 (s, 1H), 6.27 (s,
13
1H), 7.07-7.11 (m, 3H), 7.14-7.25 (m, 20H), 7.41 (d, J = 6.8 Hz, 2H). C NMR (CDCl3, 100 MHz): δ -
2.32, -1.95, 68.78, 69.16, 72.81, 73.25, 74.89, 75.05, 75.17, 78.28, 82.83, 83.56, 127.34, 127.40, 127.42,
127.60, 127.71, 127.76, 128.05, 128.17, 128.21, 128.33, 128.38, 128.81, 132.12, 133.98, 138.12, 138.33,
OBn
H
O
BnO O
BnO H
BnO
HH H
Br H
SiMe2Ph
3-110
NMR (CDCl3, 400 MHz): δ 0.38 (s, 3H), 0.52 (s, 3H), 3.48 (ddd, J = 10.0, 4.2, 1.9 Hz, 1H), 3.66 (dd, J =
10.6, 1.8 Hz, 1H), 3-68-3.72 (m, 2H), 3.81(app t, J = 9.5 Hz, 1H), 3.93 (d, J = 9.7 Hz, 1H), 4.52 (d, J =
12.4 Hz, 1H), 4.56 (d, J = 10.6 Hz, 1H), 4.58 (s, 2H), 4.62 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H),
4.79 (d, J = 11.0 Hz, 1H), 4.82 (d, J = 10.7 Hz, 1H), 4.87 (d, J = 11.3 Hz, 1H), 4.93 (d, J = 11.9 Hz, 1H),
13
5.93 (s, 1H), 6.84 (s, 1H), 7.14-7.16 (m, 2H), 7.26-7.36 (m, 21H), 7.55 (dd, J = 7.2, 1.7 Hz, 2H). C NMR
(CDCl3, 100 MHz): δ -3.24, -0.76, 68.64, 71.63, 72.93, 73.38, 74.50, 75.20, 75.67, 77.96, 82.26, 84.14,
442
107.63, 108.57, 126.64, 127.49, 127.53, 127.63, 127.76, 127.82, 127.86, 127.92, 128.12, 128.24, 128.30,
128.35, 128.43, 128.81, 137.89, 138.12, 138.38, 138.44, 138.53, 139.20, 148.35.
To a mixture of (S)-8,9,10-tris-benzyloxy-7-benzyloxymethyl-4-[(dimethylphenylsilanyl)-
mL of dichloromethane was added formic acid (0.839 mmol, 32 µL) at rt. The mixture was stirred at rt
until no more starting material was detected on TLC (24h). After all solvent was removed in a rotary
evaporator, the crude mixture was purified by column chromatography eluting with hexane:EtOAc = 20:1.
OBn H
H
O SiMe2Ph
BnO
BnO H
BnO
O H
nOe
H
H
3-113
NMR (CDCl3, 400 MHz): δ 0.26 (s, 3H), 0.27 (s, 3H), 3.51 (dd, J = 11.3, 1.8 Hz, 1H), 3.56-3.63 (m, 3H),
3.78 (ddd, J = 10.1, 3.8, 1.8 Hz, 1H), 3.86 (app t, J = 9.3 Hz, 1H), 4.36-4.41 (m, 4H), 4.45-4.48 (m, 2H),
4.56 (d, J = 10.7 Hz, 1H), 4.68 (d, J = 9.3 Hz, 1H), 4.70 (s, 2H), 4.82 (s, 1H), 5.11 (app t, J = 2.2 Hz, 1H),
13
5.90 (s, 1H), 7.03-7.05 (m, 2H), 7.07-7.14 (m, 21H), 7.31-7.32 (m, 2H). C NMR (CDCl3, 100 MHz): δ -
2.34, -1.54, 68.68, 71.54, 72.99, 73.21, 74.87, 75.52, 75.56, 78.30, 82.88, 83.79, 123.46, 127.43, 127.46,
127.48, 127.59, 127.65, 127.76, 127.85, 127.97, 128.16, 128.29, 128.34, 129.14, 133.65, 137.87, 138.21,
138.43, 138.57, 138.88, 143.35, 154.53. IR (NaCl, neat): υ 3062m, 3031m, 2921s, 2855s, 1731w, 1605w,
1497m, 1454m, 1428w, 1362m, 1250w, 1208w, 1149m, 1092s, 1028m, 837m, 732s, 697s. HRMS
443
OBn H
H H
O
BnO
BnO SiMe2Ph
BnO
O H
H
H
3-114
Colorless oil. Column chromatography; hexane:EtOAc = 30:1 to 20:1. Rf = 0.26 (hexane:EtOAc = 10:1).
1
H NMR (CDCl3, 500 MHz): δ 0.45 (s, 3H), 0.46 (s, 3H), 3.67 (d J = 9.5 Hz, 1H), 3.73 (dd, J = 11.1, 1.7
Hz, 1H), 3.78 (app t J = 9.7 Hz, 1H),, 3.82 (dd, J = 11.2, 4.0 Hz, 1H), 4.02 (ddd, J = 10.0, 3.8, 1.7 Hz, 1H),
4.09 (app t, J = 9.3 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 4.65 (d, J = 12.7 Hz, 1H),
4.66 (d, J = 10.7 Hz, 1H), 4.75 (d, J = 12.6 Hz, 1H), 4.73 (s, 2H), 4.88-4.93 (m, 3H), 7.24-7.27 (m, 4H),
13
7.29-7.38 (m, 19H), 7.58 (dd, J = 7.7, 1.2 Hz, 2H),. C NMR (CDCl3, 125 MHz): δ -1.96, -1.81, 68.80,
72.72, 73.26, 74.29, 74.84, 75.09, 75.64, 78.23, 82.49, 83.72, 127.44, 127.49, 127.58, 127.64, 127.74,
127.78, 127.84, 127.94, 128.15, 128.27, 128.33, 129.12, 133.68, 138.15, 138.21, 138.41, 138.27, 138.77,
145.63, 152.67. IR (NaCl, neat): υ 3064m, 3030m, 2922s, 2861s, 1951w, 1881w, 1807w, 1731w, 1604w,
1496m, 1453s, 1428m, 1361m, 1249m, 1208m, 1154s, 1093s, 1048s, 909m, 860w, 835m, 733s, 698s.
HRMS (Electrospray): Calcd. for C47H50O6SiNa (M++Na), 761.3269; Found (M++Na), 761.3291.
18.3%
4.9% 17.6%
OBn H 9a
6
4 H 3.4%
O H 9b
BnO 5 2
BnO SiMe2Ph
BnO
O 8
H
7 H
H
3.0%
3-114
OBn
H
O
BnO O
BnO H
BnO
HH H
PhMe2Si H
H
3-115
444
Colorless oil. Column chromatography; hexane:EtOAc = 40:1 to 20:1. Rf = 0.16 (hexane:EtOAc = 10:1).
1
H NMR (CDCl3, 500 MHz): δ 0.50 (s, 3H), 0.53 (s, 3H), 3.76-3.84 (m, 4H), 4.00 (d J = 9.1 Hz, 1H), 4.20
(app t J = 8.8 Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 10.7 Hz, 1H), 4.69
(d, J = 12.3 Hz, 1H), 4.71 (d, J = 12.9 Hz, 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.91
(d, J = 11.6 Hz, 1H), 4.92 (d, J = 10.6 Hz, 1H), 5.01 (d, J = 12.9 Hz, 1H), 5.02 (s, 1H), 5.32 (s, 1H), 6.16
13
(s, 1H), 7.27-7.28 (m, 2H), 7.30-7.40 (m, 21H), 7.58 (dd, J = 7.8, 1.1 Hz, 2H),. C NMR (CDCl3, 125
MHz): δ -2.11, -0.97, 69.08, 69.52, 72.50, 73.20, 73.90, 75.09, 75.11, 78.23, 82.69, 83.65, 108.13, 110.29,
126.01, 127.22, 127.41, 127.57, 127.70, 127.77, 127.88, 128.06, 128.10, 128.45, 128.21, 128.31, 128.39,
128.99, 133.68, 138.20, 138.17, 138.43, 138.54, 138.94, 143.50, 150.01. IR (NaCl, neat): υ 3087m, 3064s,
3029s, 2912s, 2872s, 2246w, 1952w, 1879w, 1810w, 1650w, 1604w, 1586s, 1496s, 1453s, 1427m, 1396w,
1360m, 1249m, 1209m, 1072s, 1028s, 908m, 833s, 732s, 697s. HRMS (Electrospray): Calcd. for
OBn
6
4 H
O
BnO 5 2
O
BnO
BnO 7
9.3% HH 9
11.3%
PhMe2Si H 8b
H 8a
3.3% 18.6%
3-115
Vinylsilane 3-113 (90 mg, 0.122 mmol) and ethyl propiolate (36 mg, 0.365 mmol) in toluene (122
µL) were placed into an 1 mL ample. To the mixture catalytic amount of benzoquinone was added, and the
ample was sealed tightly by flame. The reaction mixture was immersed into an 100 mL one necked-flask
filled with xylene. The flask was heated in an oil-bath under refluxing condition for 2 d. After removed
the solvent on a rotary evaporator under reduce pressure, the resulting mixture was purified by column
chromatography eluting hexane:EtOAc = 10:1 to 8:1. The Diels-Alder product was obtained as a mixture
of 3-130 and 3-131 (pale yellow oil) with a ratio of 1.0/0.2. The isolated yield is 14% (14 mg).
445
Ph Ph
e2 e2
M M
OBn Si OBn Si
H OEt H OEt
O O
BnO BnO
BnO O BnO O
BnO BnO
O O
H H
H H
3-130 3-131
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1 to 7:1. Rf = 0.39 (hexane:EtOAc = 3:1).
1
H NMR (CDCl3, 400 MHz): major δ 0.65 (s, 3H), 0.69 (s, 3H), 1.39 (t J = 7.1 Hz, 3H), 3.30 (d, J = 9.0
Hz, 1H), 3.50 (d, J = 10.7 Hz, 1H), 3.70 (dd, J = 10.5, 1.4 Hz, 1H), 3.83 (app t, J = 9.6 Hz, 1H), 3.87 (dd, J
= 10.6, 3.5 Hz, 1H), 3.97 (app t, J = 9.2 Hz, 1H), 4.02 (d, J = 10.7 Hz, 1H), 4.13 (dd, J = 10.2, 1.9 Hz, 1H),
4.38 (q, J = 7.1 Hz, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 10.9 Hz, 1H),
4.77 (s, 2H), 4.82 (d, J = 10.9 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H), 6.60 (d, J = 6.9
13
Hz, 2H), 6.99-7.42 (m, 23H), 7.56-7.58 (m, 2H), 7.90 (s, 1H), 9.26 (d, J = 1.0 Hz, 1H). C NMR (CDCl3,
100 MHz): mixture δ -0.65, 0.26, 14.26, 61.77, 73.72, 73.93, 74.06, 75.10, 75.44 , 75.45, 84.27, 84.55,
111.66, 120.30, 123.72, 127.75, 127.78, 127.99, 128.22, 128.30, 128.32, 128.42, 128.58, 128.67, 128.76,
128.79, 128.95, 128.97, 130.11, 131.13, 134.92, 135.56, 137.77, 138.65, 139.05, 139.23, 139.97, 142.20,
142.58, 167.07. IR (NaCl, neat): υ 3060m, 3030m, 2924m, 2860m, 1717s, 1647w, 1602w, 1497m, 1454m,
1428w, 1365w, 1289m, 1236w, 1217w, 1181w, 1108s, 1089s, 1028m, 838m, 817m, 780w, 736m, 698s.
HRMS (Electrospray): Calcd. for C52H56O8SiNa (M++Na), 859.3637; Found (M++Na), 859.3640.
Vinylsilane 3-113 (101 mg, 0.137 mmol) and methyl vinylketone (29 mg, 0.410 mmol) in toluene
(137 µL) were placed into an 1 mL ample. To the mixture catalytic amount of benzoquinone was added,
and the ample was sealed tightly by flame. The reaction mixture was immersed into an 100 mL one
necked-flask filled with xylene. The flask was heated in an oil-bath under refluxing condition for 2 d.
After removed the solvent on a rotary evaporator under reduce pressure, the resulting mixture was purified
by column chromatography eluting hexane:EtOAc = 10:1 to 8:1. The Diels-Alder product was obtained as
a mixture of 3-134 and 3-135 (pale yellow oil) with a ratio of 1.0/0.2. The isolated yield is 62% (68 mg).
446
Ph O
e2
M CH3
OBn Si OBn Si
H CH3 H
O O
BnO BnO
BnO BnO
BnO O BnO
O O
H H
H H
3-134 3-135
Pale yellow oil. Column chromatography; hexane:EtOAc = 10:1 to 8:1. Rf = 0.29 (hexane:EtOAc = 3:1).
1
H NMR (CDCl3, 400 MHz): major δ 0.19 (s, 3H), 0.27 (s, 3H), 1.26 (Br s, 1H), 1.40 (app td J = 12.8, 5.1
Hz, 1H), 1.81 (s, 3H), 1.80-1.90 (m, 1H), 2.46 (dd J = 4.9, 1.9 Hz, 1H), 2.54-2.62 (m, 2H), 2.64-2.74 (m,
1H), 3.30 (dd, J = 5.9, 3.0 Hz, 1H), 3.58 (dd, J = 9.7, 6.1 Hz, 1H), 3.62 (dd, J = 9.8, 4.4 Hz, 1H), 4.12 (d, J
= 10.4, 5.7 Hz, 1H), 4.17 (dd, J = 7.0, 3.1 Hz, 1H), 4.20 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 11.8 Hz, 1H),
4.41 (d, J = 11.1 Hz, 1H), 4.49 (d, J = 4.2 Hz, 1H), 4.50-4.56 (m, 1H), 4.61-4.71 (m, 3H), 4.84 (d, J = 7.2
13
Hz, 1H), 4.86 (d, J = 11.3 Hz, 1H), 7.19-7.39 (m, 25H). C NMR (CDCl3, 100 MHz): mixture δ -2.80, -
2.51, -2.28, -1.96, 19.61, 20.19, 20.41, 20.53, 27.87, 28,05, 28.40, 28.87, 29.69, 30.90, 45.45, 45.55, 70.21,
70.41, 70.67, 71.l44, 71.91, 72.01, 72.08, 72.39, 73.36, 73.39, 74.22, 75.13, 75.32,l 76.05, 78.33, 80.63,
80.72, 84.42, 85.73, 119.88, 120.56, 122.60, 122.81, [over lap in aromatic region], 210.28, 210.39. IR
(NaCl, neat): υ 3065m, 3028m, 2918m, 2854m, 1710s, 1496w, 1453m, 1426w, 1364w, 1303w, 1250w,
1208w, 1111s, 1028m, 815m, 736s, 698s. HRMS (Electrospray): Calcd. for C51H56O7SiNa (M++Na),
To the mixture of 3-134 and 3-135 (72 mg, 89 µmol) in CH2Cl2 (10 mL) were added mCPBA (70-
75%, 31 mg, 0.173 mmol) and NaHCO3 (60 mg, 0.714 mmol) at rt, and the resulting mixture was stirred at
rt for 2 h. All starting material 3-134 and 3-135 was consumed (judged by TLC analysis). The mixture
was diluted with CH2Cl2, washed with H2O and brine solution, dried over MgSO4, filtered, and
concentrated on a evaporator under reduced pressure. The residue was purified by column chromatography
eluting hexane:EtOAc = 10:1 to 8:1. The major portion was obtained as colorless oil (27 mg, 48%), which
447
Ph
e2 OBn Si OAc
M
OBn Si H
H O
O BnO
O
BnO OAc BnO
O BnO
BnO
BnO O
O H
H H
H
3-136 3-137
Colorless oil. Column chromatography; hexane:EtOAc = 10:1 to 8:1. Rf = 0.24 (hexane:EtOAc = 2:1).
13
C NMR (CDCl3, 100 MHz): δ -3.52, -1.26, 16.74, 22.29, 25.46, 27.71, 43.75, 60.74, 68.43, 68.97, 71.28,
71.50, 73.54, 73.59, 74.37, 77.20, 77.47, 82.13, 97.78, 104.19, 127.10, 127.53, 127.64, 127.76, 127.99,
128.06, 128.20, 128.28, 128.39, 129.61, 134.09, 138.39, 138.49, 139.02, 139.08, 211.48. HRMS
448
Bibliography
1. For three leading reviews in this area, see: (a) Barton, D.H.R. Pure Appl. Chem. 1981, 53, 15; (b)
Hartwig, W. Tetrahedron 1983, 39, 2609; (c) Crich, D.; Quintero, L. Chem. Rev. 1989, 89,1413.
2. (a) Barton, D. H. R. Pure Appl. Chem. 1977, 49, 1241; (b) Copeland, C.; Stick, R. V. Aus. J.
Chem. 1977, 30, 1269; (c) Patroni, J. J.; Stick, S. V. J. Chem. Soc., Chem. Comm. 1978, 449.
3. (a) Tatsuta, K.; Akimoto, K.; Kinoshita, M. J. Am. Chem. Soc. 1979, 101, 6116; Barton D.H.R.;
Stick, R. V. J. Chem. Soc., Perkin Trans 1. 1975, 1773; (c) Brrrett, A. G. M.; Prokopiou, P. A.;
4. (a) Wiberg, K. B.; Lowary, B. R.; Colby, T. H. J. Am. Chem. Soc. 1961, 83, 3998; (b) Eaton,
6. There are a large number of examples for secondary alcohol deoxygenation via the Barton-
McCombie reaction. See for examples, (a) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem.
Soc. 1983, 105, 4059; (b) Esmond, R.; Fraser-Reid, B.; Jaruis, B. B. J. Org. Chem. 1982, 47,
3360; (c) Beale, M. H.; Gaskin, P.; McMillan, J. J. Chem. Soc., Perkin trans 1. 1980, 885.
7. Primary alcohol deoxygenation has also been reported under vigorous conditions. Barton, D. H.
8. (a) Kim, S.; Yi, K. Y. J. Org. Chem. 1986, 51, 2615; (b) Refence 2.
9. (a) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983, 105, 4059; (b) Prisbe, E. J.;
10. (a) Bachi, M. D.; Bosch, E.; Denemark, K. D.; Girsh, D. J. Org. Chem. 1992, 57, 6803; (b)
Reference 2.
449
11. (a) Hayashi, T.; Iwaoko, T.; Takeda, N.; Ohki, E. Chem. Pharm. Bull. 1978, 26, 1786; (b) Barton,
D. H. R.; Crich, D.; Löbberding, A.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 646.
13. (a) Oba, M.; Mishiyama, K. Tetrahedron 1994, 50, 10193; (b) Oba, M.; Mishiyama, K. Synthesis
1994, 624; (c) Mishiyama, K.; Oba, M. Tetrahedron Lett. 1993, 34, 3745.
14. Togo, H.; Matsubayashi, S.; Yamazaki, O.; Yokoyama, M. J. Org. Chem. 2000, 65, 2816.
15. (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1992, 33, 5709; (b) Barton,
16. (a) Barton, D. H. R.; Crich, D.; Löbberding, A.; Zard, S. Z. Tetrahedron 1986, 42, 2329; (b)
Forrest, D.; Ingold, K. U.; Barton, D. H. R. J. Phys. Chem. 1977, 81, 915.
18. In this thesis we will not discuss the Barton-MaCombie deoxygenation of secondary hydroxyl
group, but will cover extensively new carbon-carbon bond formation reaction.
20. Barton’s radical means the initial radical intermediate, which is generated by attack of tributyltin
21. In earlier studies, the Barton-McCombie reaction had been only considered as a method for
23. Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 6127.
24. Bachi, M. D.; Bosch, E. J. Chem. Soc., Perkin Trans 1. 1988, 1571.
26. Yamamoto, M.; Utuma, T.; Iwasa, S.; Kohmoto, S.; Yamada, K. J. Chem. Soc., Chem.Commun.
1989, 1265.
28. (a) Bachi, M. D.; Melman, A. Synlett 1996, 60; (b) Bachi, M. D.; Bar-Ner, N.; Melman, A. J. Org.
Chem. 1996, 61, 7116. Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896.
450
29. Reading, M. T.; Fukuyama, T. Org. Lett. 1999, 1, 973.
30. (a) Tokuyama, H.; Yamashita, T.; Reading, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc.
1999, 121, 3791; (b) For another example of imidoyl radical mediated ring closure and its
32. Reynold, A. J.; Scott, A. J.; Turner, C. I.; Sherburn, M. S. J. Am. Chem. Soc. 203, 125, 12108.
33. Hart, D. J.; Tsai, Y.-M. J. Org. Chem. 1982, 47, 4403.
34. Paquette, L. A.; Colapret, J. A.; Andrews, D. R. J. Org. Chem. 1985, 50, 201.
35. Hashimoto, H.; Furucichi, K.; Miwa, T. J. Chem. Soc., Chem.Commun. 1987, 1002.
36. Kulkarni, Y. S.; Niwa, M.; Ron, E.; Snider, B. B. J. Org. Chem. 1987, 52, 609.
37. Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. Can. J. Chem. 1987, 65, 1859.
38. An excellent review of stereochemistry of intramolecular free radical cyclization by the Barton-
McCombie deoxygenation, see: RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139.
40. For the general reference of the stereochemistry for radical ring closure, see: (a) Beckwith, A. L. J.
Tetrahedron 1981, 37, 3073; (b) Beckwith, A. L. J.; Easton, J. C.; Lawrence, T.; Serelies, A. K.;
42. RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J. Am. Chem. Soc. 1989, 111, 1759.
43. RajanBabu, T. V.; Fukunaga, T. J. Am. Chem. Soc. 1989, 111, 296.
44. Houk, K.N.; Paddon-Row, M.N.; Spellmeyer, D. C.; Rondan, N. G.; Nagase, S. J. Org. Chem.
45. Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M. J. Am. Chem. Soc.
46. (a) Collins, P. W. J. Med. Chem., 1986, 29, 437; (b) Corey, E. J. Currenrt Trends in Organic
47. Clive, D. L. J.; Beaulieu, P.; Set, L. J. Org. Chem. 1984, 49, 1313.
451
48. Suzuki, M.; Koyano, H.; Noyori, R. J. Org. Chem. 1987, 52, 5583.
49. Harling, J. D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1988, 1380.
51. Giese, B.; Conzález-Gómez, J. A.; Witzel, T. Angew. Chem. Int. Ed. Engl. 1984, 23, 69.
52. Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J. Tetrahedron Lett. 1987, 28, 5833.
53. Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J. Tetrahedron Lett. 1988, 29, 351.
56. (a) Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett. 1984, 25, 1867; (b) Barton. D.
H. R.; Crich, D. Tetrahedro Lett. 1984, 25, 2787; (c) Baldwin, J. E.; Adlington, R. M.; Basak, A.
57. (a) Feldman, K. S.; Romanell, A. L.; Ruckle, R. E., Jr.; Miller, R. F. J. Am. Chem. Soc. 1988, 110,
3300; (b) Feldoman, K. S.; Burns, C. J. Org. Chem. 1991, 56, 4601; (c) Feldman, K. S.; Bervens,
60. Bartlett, P. A.; Mclaren, K. L.; Ting, P. C. J. Am. Chem. Soc. 1988, 110, 1633.
61. (a) Bachi, M. D.; Denenmark, D. J. Am. Chem. Soc. 1989, 111, 1886; (b) Bachi, M. D.; Balanov,
A.; Bar-Ner, N.; Bosch, E.; Denenmark, D.; Mizhiritsk, M. Pure Appl. Chem. 1993, 65, 595; (c)
Imidoyl radical mediated ring closure was reported as an alternative mechanism for the Fukuyama
62. (a) Gutierrez, C. G.; Stringham, R. A.; Nitasaka, T.; Glasscock, K. C. J. Org. Chem. 1980 45,
3393; (b) Gutierrez, C. G.; Summerbay, L. R. J. Org. Chem. 1984, 49, 5206.
63. Chang, S.-Y.; Shao, Y.-F.; Chu, S.-F.; Fan, G.-T.; Tsai, Y.-M. Org. Lett. 1999, 1, 945.
65. Wilcox, C.S.; Gaudio, J. J. J. Am. Chem. Soc. 1996, 108, 3102.
452
66. (a) Mulzer, J.; Schöllhorn, B. Angew. Chem. Int. Ed. Engl. 1990, 29, 431; (b) Torisawa, Y.;
Shibasaki, M.; Ikegami. S. Tetrahedron Lett. 1979, 21, 1865; (c) Molander, G. A.; Swallow, S. J.
Org. Chem. 1994, 59, 7148; (d) Jones, S. S.; Reese, C. B.; J. Chem. Soc., Perkin Trans 1 1979,
2767; (e) Halmos, T.; Montserret, R.; Filippi, J.; Antonakis, K. Carbohydrate Res., 1987, 170, 57.
67. (a) Linker, T.; Sommermann, T.; Kahlenberg, F. J. Am. Chem. Soc. 1997, 119, 9377; (b) Beyer, J.;
Madsen, R. J. Am. Chem. Soc. 1998, 120, 12137; (c) An excellent chapter for glycoside chemistry;
Collins, P.; Ferrier, R. Monosaccharides: Their Chemistry and Their Roles in Natural Products,
Compounds; 5th Ed.; John Wiley & Sons, New York, 1991, p. 161.
70. (a) Nicolaou, K. C.; Sato, M.; Theodorakis, E. A.; Miller, N. D. J. Chem. Soc., Chem. Commun.
1995, 1583; (b) Baldwin, J. E.; Adlington, R. M.; Kang, T. W.; King, L. g.; Patel, V. K.
71. Breitmaier, E.; Voelter, W. 13C NMR Spectroscopy: Methods and Applications in Organic
Chemistry; Ebel, H. F. Ed.; 2nd Ed.; Verlag Chemie, New York, 1978, pp. 379-393.
72. (a) Trost, B. M.; Krische, M. J. Synlett 1988, 1; (b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. –Y.;
Liu, F. Chem Rev. 1996, 96, 365; (c) Ojima, I.; Tzamarioudak, M.; Li, Z.; Donovan, R. J. Chem
73. (a) Mori, M,; Hirose, T.; Wakamatsu, H.; Imakuni, N.; Sato, Y. Organometallics 2001, 20, 1907;
74. (a) Gréau, S.; Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 2000, 122, 8579; (b) Warren, S.;
Chow, A.; Fraenkel, G.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 15402.
75. Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 8007.
76. Kang, S. -K.; Baik, T.-G.; Kulak, A. N.; Ha, Y. -Y.; Lim, Y.; Park, J. J. Am. Chem. Soc. 2000,
122, 11529.
77. Shin, S.; RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416.
453
78. Kang, S. -K.; Ha, Y. -Y.; Ko, B. –S.; Lim, Y.; Jung. J. Angew. Chem. Int. Ed. 2002, 41, 343..
79. (a) Sugimoto, M.; Nakamura, H.; Ito, Y. J. Chem. Soc., Chem. Comm. 1996, 2777; (b) Sugimoto,
M.; Matsuda, T.; Nakamura, H.; Ito, H. Tetrahedron 1999, 55, 8787.
80. Lautens, M.; Smith, N. D.; Ostrovsky, D. J. Org. Chem. 1997, 62, 8970.
81. (a) Chenard, B. L.; Laganis, E. D.; Davidson, F.; RajanBabu, T. V. J. Org. Chem. 1985, 50, 3666;
(b) Mitchell, T. N.; Killing, H.; Dicke, R.; Wickenkamp, R. J. J. Chem. Soc., Chem. Comm. 1985,
354.
82. (a) Chenard, B. L.; Van Zyl, C. M.; Sanderson, D. R. Tetrahedron Lett. 1986, 27, 2801; (b)
83. Ikenaga, K.; Hiramatsu, K.; Nasaka, N.; Matsumoto, S. J. Org. Chem. 1993, 58, 5045.
84. (a) Norley, M. C.; Kocieński, P. J.; Faller, A. Synlett. 1994, 77; (b) Casson, S.; Kocieński, P. J.;
Reid, G.; Smith, N.; Street, J. M.; Webster, M. Synthesis 1994, 1301.
85. Mitchell, T. N.; Wickenkamp, R. J.; Amamaria, A.; Dicke, R.; Schneider, U. J. Org. Chem. 1987,
52, 4868.
86. Murakami, M.; Amii, H.; Takizawa, N.; Ito, Y. Organometallics 1993, 12, 4223.
88. Hada, M.; Tanaka, Y.; Ito, M.; Murakami, M.; Amii, H.; Ito, Y.; Nakatsuji, H. J. Am. Chem. Soc.
89. Obora, Y.; Tsuji, Y.; Asayama, M.; Kawamura, T. Organometallics 1993, 12, 4697.
90. Tsuji, T.; Obora, Y. J. Am. Chem. Soc. 1991, 113, 9368.
91. (a) Mitchell, T. N.; Schneider, U. J. Orgmet. Chem. 1991, 407, 319; (b) Reference 82(b).
92. Koerber, K.; Gore, J.; Vatele, J. -M. Tetrahedron Lett. 1991, 32, 1187.
93. Jeganmohan, M.; Shanmugasundaram, M.; Chang, K. -J.; Cheng, C. -H. J. Chem. Soc., Chem.
94. For review on the synthesis of spiroketals see: (a) Perron, F.; Albizati, K. F. Chem Rev. 1989,
89,1617; (b) Kluge, A. F. Heterocycles 1986, 24, 1699; (c) Bovin, T. L. B. Tetrahedron 1987, 24,
3309.
454
95. (a) Traxler, P.; Fritz, H.; Richter, W. F. Helv. Chim. Acta 1977, 60, 578; (b) Traxler, P.; Fuhrer,
H.; Richter, W. F. J. Antibiot. 1983, 36, 967; (c) Traxler, P.; Tosch, W.; Zak, O. J. Antibiot. 1987,
40, 1146.
96. Hacksell, U.; Daves, G. D., Jr. Prog. Med. Chem. 1985, 22, 1.
97. Danishefsky, S.; Phillips, G.; Ciufolini, M. Carbohydrate Res, 1987, 171, 317.
98. (a) Dubois, E. D.; Beau, J. -M. Tetrahedron Lett. 1990, 31, 5165; (b) Dubois, E. D.; Beau, J. -M.
99. (a) Friesen, R.; Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133; (b) Friesen, R.; Sturino, C. F.
100. Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc. 1990, 112, 2746.
102. Carretero, J. C.; Eugenio de Diego, J.; Hamdouchi, C. Tetrahedron 1999, 55, 15159.
103. (a) Brimble, M. A.; Horner, G. M.; Stevenson, R. J. Aust. J. Chem. Soc. 1996, 49, 189; (b)
Brimble, M. A.; Robinson, S. G. tetrahedron Lett. 1996, 52, 9553; (c) Brimble, M. A.; Caprio, V.;
105. (a) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863; (b) Balachari, D.; O’Doherty, G. A.
106. (a) Barrett, A. G. M.; Penñ, M.; Willardsen, J. A. J. Chem. Soc., Chem. Comm. 1995, 1145; (b)
Barrett, A. G. M.; Penñ, M.; Willardsen, J. A. J. Chem. Soc., Chem. Comm. 1995, 1145; (c)
Barrett, A. G. M.; Penñ, M.; Willardsen, J. J. Org. Chem. 1996, 61, 1082.
107. (a) Rebock, J.; McCready, R.; Wolf, S.; Mossman, A. J. Org. Chem., 1979, 44, 1485. (b) Begtrup,
108. (a) Pulluket, J. J.; Urry, G. . Tetrahedron Lett., 1967, 21, 1953. (b) Staab, H. A.; Walter, G. Ann.,
109. (a) Lang, R. W.; Hansen, J. -J. Org. Synth., 1984, 62, 202. (b) Nader, F. W.; Brecht, A.; Kreisz, S.
455
111. (a) Wasserman, H. H.; Petersen, A. K. Tetrahedron. Lett., 1997, 38, 953. (b) Kukhar, V. P.;
112. (a) Hayashi, K.; Iyoda, J.; Shiihara, I. J. Orgnometal.Chem., 1967, 10, 81. (b) Sawyer, A. K.
113. Barton. D. H. R.; Jang, D. O; Jaszberenyi, J. C. Tetrahedron Lett., 1992, 33, 5709.
114. (a) Walkup, R. D.; Kahl, J. D.; Kane, R. R. J. Org. Chem., 1998, 63, 9113. (b) Gilbert, A. M.;
116. Sainz-Díaz. C. I.; Gálvez-Ruano, E.; Hernández-Laguna, A.; Bellanato, J. J. Org. Chem., 1995,
60, 74.
117. Wolinsky, J.; Novak, R.; Vasileff, R. J. Org. Chem., 1964, 29, 3596
118. (a) Ardecky, R. J.; Dominguez, D.; Cava, M. P. J. Org. Chem., 1982, 47, 409. (b) Tamariz, J.;
121. Voss, J. J. D.; Hanegland, J. J.; Townsend, C. A. J. Org. Chem., 1994, 59, 2715.
122. (a)Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschnmoser, A. Helv. Chim. Acta.,
1972, 55, 1276; (b) Mann, J,; Kane, P. D. . J. Chem. Soc., Perkin Trans 1., 1984, 657; (c) Wilcox,
123. Müller, R. K.; Joos, R.; Felix, D.; Horn, U.; Schreiber, J.; Winter, C.; Eschnmoser, A. J. Org.
125. Yamada, H.; Sugiyama, H.; Kajiwara, M. Heterocycles, 1987, 26, 2841.
126. Critcher, D. J.; Conolly, S.; Willis, M. J. Org. Chem., 1997, 62, 6638.
127. Barili, P. L.; Berti, G.; Catelani, G.; Cini, C.; D’Andrea, F.; Mastrorilli, E. Carbohydr. Res. 1995,
278, 43.
128. Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron, 1996, 52, 11601.
456