Syntheses of Medicinally Important Enantiopure Compounds Using

Syntheses of Medicinally Important
Enantiopure Compounds Using (2S,3S) and

(2S,3R)-tetra hydro-3-hydroxy-5-oxo-2,3-
furandicarboxylic acids
A thesis submitted to
Mahatma Gandhi University
in partial fulfilment of the requirements
for the award of the degree of
DOCTOR OF PHILOSOPHY
inChemistry under the Faculty of Science
Submitted by
Zabeera K T
Under the supervision of
Prof. (Dr). I. Ibnusaud
Institute for Integrated Programmes and Research inBasic Sciences

Mahatma Gandhi University
Athirampuzha, Kottayam - 686 560
Kerala, India
January 2020
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DECLARATION
I hereby declare that the thesis entitled “Syntheses of Medicinally Important

Enantiopure Compounds Using (2S,3S) and (2S,3R)-tetra hydro-3-hydroxy-5-
oxo-2,3-furandicarboxylic acids” is an authentic record of the research work carried
out by me under the supervision and guidance of Prof. (Dr). I. Ibnusaud,
Director,Institute for Integrated Programmes and Research in Basic Sciences(IIRBS),
Mahatma Gandhi University, Kottayam. No part of this thesis has been presented for
the award of any other degree or diploma of any University or Institute earlier.
Kottayam Zabeera K T
31-01-2020
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CERTIFICATE
This is to certify that the thesis entitled “Syntheses of Medicinally Important

Enantiopure Compounds Using (2S,3S) and (2S,3R)-tetra hydro-3-hydroxy-5-
oxo-2,3-furandicarboxylic acids” is an authentic record of the research work carried
out by Mrs.Zabeera K T under my supervision and guidance. This is for the partial
fulfillment for the award of the degree of Doctor of Philosophy in Chemistry under the
faculty of Science of Mahatma Gandhi University, Kottayam. No part of the thesis has
been presented for the award of any other degree or diploma earlier.
Kottayam Prof. (Dr). I. Ibnusaud

30-01-2020 (Supervising Teacher)
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Dedicated to my Family and Mentors.
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Acknowledgement
Working on this project has been extensive and difficult but I was so lucky to have wonderful
people around me who made this experience exciting and enlightening too. Without their
support and encouragement this research would not have been possible.
First and foremost, I offer my sincere gratitude to Professor I.Ibnusaud, IIRBS, Mahatma
Gandhi University, Kottayam, for his supervision, advice and guidance throughout my
research work. Words can’t express my respect and cordial gratitude to Prof.(Dr). I.Ibnusaud.
He gave valuable, inspiring and excellent supervision throughout the course of my research
program, which had been an indispensable factor in the successful completion of this work. I
am indebted to acknowledge him for the encouragement, concern and innovative suggestions.
Thank you sir for all the pains you took to teach me valuable lessons of life and the corrections
you made at my attempts will always remain etched in my memories for not just my research
period but many, many years to come and will motivate me to achieve great things in life.
Herein, I yield this opportunity to candidly acknowledge to Dr. Mohan Arumugam, Technical
Officer, IIT Madras, for his constant support, guidance, constructive criticism and extensive
discussions on my research work. His dedication towards research work is so much inspiring to
me.
I extend my wholehearted thanks to Prof. (Dr). PolavarapuPrasad Dept. of Chemistry,
Vandebilt University, U.S. for the Chiroptical studies on compound synthesizes from our
laboratory.
I wholeheartedly thank Prof(Dr). Irishi.I.N.Namboothiri, professor in the Department of
Chemistry, IIT Bombay who was member of my Doctoral committee. I humbly acknowledge
him for his valuable suggestions and guidance during the course of my research work.
I extend my gratitude to Prof(Dr). Bhakthansingaram,Prof(Dr). Subrahmanian, Prof. (Dr).
Samanth and Mrs.Samanth for their valuable advices during my course.
I extend my wholehearted thanks To P.K Basheer Sahib(Hon.MLA-Ernad), Justice.P.
Sadasivam(Hon.Ex.-Governor), Dr.RajanGurukkal(Hon. Vice Chairman,KSCSTE), Dr.K. T.
Jaleel(Hon.Higher education Minister) for all the support and help.
I express my sincere thanks to Hon.Minority Commission Kerala for all their support and help
during my hard period.
I express my deep sense of gratitude to Mr.Sharangadharan, Section Officer at IIRBS for his
timely help during my course.
I express my sincere thanks to Dr.P.V.Sasi, Dr.Susan Varughese, Dr. G. Krishnan,
Dr.SalaudinKunju,Dr.Sureshkumar T.N, Dr.Rajesh and Dr.Shine Joseph for their valuable
suggestions and guidance during the course.
I express my deep sense of gratitude to my senior Dr.Rani .R .Nair for her sincere help care and
concern during my research.
My special heartfelt thanks to Dr.Simimole,H.for her valuable advice, suggestions, corrections
heartfelt help and guidance during the course of this work.
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I owe my deepest gratitude to Mr. Bharath Krishna for his genuine help and support during my
research work. He assisted and motivated me all the time. I am thankful to him for his timely
interference, care, and concern. I really appreciate and respect for his timely effort. His involvement
in the crucial time of my work was so much encouraged.
Iexpress my sincere thanks to Mr.RitwikSarang for his help and suggestions. I also extend my
thanks to Mr.MahinK.I,Mrs.Mahima, Mrs.KeerthanaS. and Mrs.DivyaR.
Indeed, I am pleased to thank my colleagues Mr. Prasanth C. P, Mrs. Chithra Mohan, Mr.
Sarath. M for their heartfelt help and guidance during the course of this work.
Indeed, I am happy to thank my colleagues Dr. Tom Thomas, Dr. Divya S. Nair and Dr.
DeenammaHabel, Dr. Grace Thomas, Dr. Salini Thomas, Dr. Chithra, for their timely help on
various events.
I thank the whole MS students at IIRBS especially Mr. Sudheesh, Mr. Manish, Mr. Hemant,
Mrs.Moolya, Mr. Ajmal, Mr. Vysakh, Mr. Tharique, Mrs.Rameesa,Mr.Harry, Mrs. Pravia P
Nair, Mrs. Nihala, Mrs. Jeny Jose, Mr. Anand and Mr.Sivakumar.
I am delighted to thank my IIRBS colleagues Mrs. Athira, Mrs.Greeshma, Mrs.Sunu,
Mrs.Mini, Mrs.Savithri, Mrs. Selin, Mrs.Shiji, Mr.Syam, Mr.Akhilesh, Mrs.Suni, Mrs.Rama,
Mrs.Telsi and Mrs.Sindhufor their help on various occasions.
I am thankful to the Prof. SabuKuttan (Hon. Registrar, MG. University) and other office
staffs at IIRBS-Mr.Anilkumar, Mr.Dami and Mr.Tijo.Iam gratified to thank all the staffs of
the Mahatma Gandhi University for their sincere cooperation during the course of this work.
I express my deep heartfelt thanks to Mr. Shahjahan and family for all their help, support and
concern during my course
I thank my Parents Prof.K.T.Mohammed (Rtd.),Dr.M. Zuhrabi, parents in law
Mr.Mohammedali.K, Mrs.Ayisha K.T. and my brothers, sisters, brother in laws and sister in laws
for all their support, care and concern.
Indeed, I am proud to extend my gratitude to my husband Dr. YoonusSaleemKavanancheeri for his
non-judgmental attitude and endurance that strengthened and motivated me a lot to complete the
work successfully. Without his care and encouragement I would never have been able to finish this
work.
I will never find words enough to express my gratitude that I owe to my Little angel
AneeqaYoonusKavanancheeri for all her sufferings at IIRBS. She was with me for the past
five years of my research work. She was my inspiration in all my hard times and gave away her
childhood days for my research works at IIRBS. Finally, I dedicate my thesis and bestow a
bow before my daughter AneeqaYoonus.
Finally, above all I praise the Almighty for all the blessings showered upon me during the
period of my research work through my life.
Zabeera K T
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Abstract
This thesis concerns with the large scale isolation of (2S,3S) and (2S,3R)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylic acids (Garcinia and Hibiscus acids), from
inexpensive plant sources and their application for the synthesis of enantiopure chiral
and achiral molecules of biological interest. Thus value addition has been done to these
two chiral molecules isolated in the enantiopure forms from locally available plant
sources. A Chiroptical studies of(S)-(-)-crispine A analogue(1R,10bR)-1-((R)-1,2-
dihydroxyethyl)-1-hydroxy-8,9-dimethoxy-1,5,6,10b-tetrahydro pyrrolo[2,1-
a]isoquinolin-3(2H)-one derived from Garcinia acid have been carried out. The
experimental chiroptical tools are used to evaluate the absolute configuration (AC). In
the absence of such outside information, separate independent analysis of ORD, ECD,
and VCD does not entail a unique solution to the AC, and multiple diastereomers
present themselves as viable candidates for the AC of (-)-crispine A analogue.
Combined EDF and VDF spectral analysis, however, rules out the incorrect
diastereomers. Thus, the combined EDF and VDF spectral analysis are seen as a useful
diastereomer discrimination tool.
Molecules namely, furo[2,3-b]furanol, the (bis-THF) part of anti-HIV drug Darunavir.

A new metal-free, solvent-free route towards the construction of the privileged class of
indolizine frameworks has been developed.
There are four possible stereoisomers for non-racemic 2-hydroxy citric acid. Among
these, two of the isomers are extensively distributed in nature. The existence of the
other two isomers is yet to be known. To make available all optical isomers of 2-
hydroxycitric acid, attempts were made to invert the configurations of C-2 carbon
atoms of Garcinia and Hibiscus acids. Various known methods were attempted, which
includes Mitsunobu reaction, inversion using mono tosyl/mesityl derivatives, of the
triesters of Garcinia acid and Hibiscus acids, the isourea ether, trimethyl (1S, 2S)-1-
(((E)-N, N-dicyclohexylcarbamim-idoyl)oxy)-2-hydroxypropane- 1, 2, 3-tricarboxylate
and oxidation reduction strategy. The title acids were successfully converted to
(1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate and trimethyl (1S,2S)-2-
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hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate. Using these
electrophiles, the inversion was attempted with acetate anion in pyridine. Instead of the
inverted product, dimethyl (2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylates of Garcinia and Hibiscus acids were isolated. When the reaction was
carried out at an elevated temperature, surprisingly the trimethyl indolizine-1,2,3-
tricarboxylate was isolated as a crystalline solid. Thus, a new method for the
construction of indolizidine skeleton was developed. The epimerisation on C-2 carbons
of Garcinia and Hibiscus acid esters were failed due to anchimeric assistance which
leads to the retention of configuration to afford Garcinia acid diester exclusively on
hydrolysis. This may be the reason, why only two isomers are present in nature. When
(1S,2S)-trimethyl 2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate was refluxed in
toluene in the presence of triethylamine, without acetate anion, trimethyl 1-oxopropane-
1,2,3-tricarboxylate, an α-keto ester, a 1,2 rearranged product was isolated. The
triesters of Garcinia and Hibiscus acids were successfully converted to the tritosyl
derivatives for synthesizing a new class of chiral trisphosphine catalyst.
Through these studies, Garcinia and Hibiscus acids have been added to the existing
select list of naturally occurring Chirons.
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List of Publications
1. Johnson, Jordan.; Nair, S. Divya.; Pillai, M. Sarath.; Johnson, Didimos.;

Kallingathodi, Zabeera.; Ibnusaud, Ibrahim.; Polavarapu, Prasad.
"Dissymmetry Factor Spectral Analysis Can Provide Useful Diastereomer
Discrimination: Chiral Molecular Structure of an Analogue of (-)-Crispine A"
ACS.Omega, 2019, 4,6154.
2. Habel, Deenamma Nair, S. Divya.; Prakasan, C. Prasanth.; Pillai, M. Sarath.;

Kallingathodi, Zabeera.; Mohan, Chithra, Nair, V. Vysakh.; Ansari, N.
Tharique.; Syed, D. Rameeza.; Thomas, A. Annu.; Abdulrafoof, V. Rinshad.;
Nair, R. Rani.; Thomas, Grace.; Haleema, Simimole.; Gopinath, Chithra.;
Ibnusaud, Ibrahim. “Collective Synthesis of Structural Skeletons of Chiral
Pyrroloisoquinoline-Indolizinoindolone Alkaloids, Bis-Furan, Furopyrans and
Achiral Indolizines from Naturally Occurring Non-Racemic 2-Hydroxycitric Acid
Lactones” (Manuscript ready for submission).
List of Symposium / Conference Proceedings

1. Collective Synthesis of Structural Skeletals from Naturally Occurring Non-
Racemic 2-Hydroxycitric Acid Lactones. National Seminar on Green
approaches towards chemical synthesis, St. Gregorios of Arts and Science
College, Kottarakkara, 7th -8th November, 2019.
2. Skeletal Diversity from Naturally Occuring Non Racemic 2-Hydroxycitric

Acids National Organic Symposium Trust XV J-NOST Conference for
Research Scholars, University of Delhi, Delhi 18th -21st October, 2019.
Presented a paper
3. Syntheses of chiral intermediates using (2S,3S) and (2S,3R) - tetrahydro-3-

Hydroxy-5-oxo-2, 3-furandicarboxylic acids. International conference on
Emerging Frontiers in Chemical Sciences, EFCS, Farook college of Arts
and Science, 23th -25thSeptember-2017. Presented a paper
4. Synthesis of Biologically and Functionally Useful Enantiopure Molecules

Obtained from (2S,3S)- Tetrahydro-3-Hydroxy-5-Oxo-2,3-Furandicarboxylic
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Acids. International conference on tropical plants and molecular design,
TKM College of Arts and Science,14th -15th February- 2017.Presented a
paper.
5. Enantiopure Synthesis of Indolizinoindole, Pyrroloisoquinoline and Imidazole

Alkaloids from (2S,3R)- and (2S,3S)-Tetrahydro-3-Hydroxy-5-Oxo-2,3-
Furandicarboxylic Acids, National Seminar on Emerging Trends in
Chemistry, Madurai Kamaraj University, 14th-18th March-2016.
Presented a paper.
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Contents
Chapter 1
Studies on the isolation of non-racemic hydroxycitric acids, (2S,3S)
and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic
acids, and Chiroptical studies of(S)-(-)-crispine A analogue namely
(1R,10bR)-1-((R)-1,2-dihydroxyethyl)-1-hydroxy-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one derived
from Garcinia acid.
1.1. Introduction ......................................................................................................... 1
1.1a. Chirality and Organic Molecules ........................................................................ 1
1.1b. Context of the Thesis: Value addition to Indian natural
resources. 3
1.1.1. Enantioselective synthesis: General strategies for
Enantiomerically pure compound synthesis ..................................................... 4
1.1.1.1. Chiral resolution in racemates ........................................................... 5
1.1.1.2. The chiral pool approach ......................................................... 5
1.1.1.3. Asymmetric synthesis........................................................................ 6
1.1.1.4. Enantioconvergent synthesis ............................................................. 6
1.2. Medicinally pertinent non-racemic molecule ...................................................... 8
1.2.1. Significance of the chiral compounds ................................................... 8
1.2.2. Contemporary compact drug development ............................................ 9
1.3. Objective of the present study ........................................................................... 10
1.4. Results and Discussion.. .................................................................................... 15
1.4.1 Isolation and characterization of (2S,3S) tetrahydro-3-
hydroxy-5-oxo-2,3-furandicarboxylic acid .......................................... 15
1.4.2. Isolation and characterization of (2S,3R)-tetrahydro-3-
hydroxy-5-oxo-2,3-furandicarboxylic acid ........................................... 18
1.5. General Experimental Details ........................................................................... 20
1.6. Experimental Section .................................................................................................... 21
1.6.1 (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic
acid 21
1.6.2 (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic
acid 22
1.7. Chiroptical studies of(S)-(-)-crispine A analogue namely
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one related to
Garcinia acid. 23
1.7.1. ORD of the (1R,10bR,1′R) diastereomer ............................................... 24
1.7.2. ERD of the (1R,10bR,1′R) diastereomer ............................................... 25
1.7.3. VCD of the (1R,10bR,1′R) diastereomer. .............................................. 26
References ................................................................................................................. 29
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Chapter 2
Synthesis and application of Weinreb amides related to (2S,3S) and
(2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids
2.1. Introduction ....................................................................................................... 31

2.2. General synthesis of Weinreb amines ............................................................... 35
2.3 Synthesis of N-methoxy-N-methyl amides ......................................................... 36
2.3.1. Synthesis of Weinreb amides from the carboxylic acids ...................... 36
2.3.2. Synthesis of Weinreb amides from Acid Chloride ................................ 43
2.3.3. Synthesis of Weinreb amides from lactones, esters, acetate
and amides ............................................................................................. 45
2.3.4. Synthesis of Weinreb amide from anhydride ........................................ 47
2.3.5. Synthesis of Weinreb amide from aldehyde ......................................... 48
2.3.6. Synthesis ofWeinreb amide of α, β-unsaturated compound.................. 48
2.3.7. Synthesis of Weinreb amides from aryl halides .................................... 49
2.3.8. Synthesis ofWeinreb amide from Acetatate derivative ......................... 49
2.3.9. Synthesis from ketone and aldehydes ................................................... 50
2.3.10. Synthesis of Weinreb amide by Mitsunobu
reaction 51
2.4. Objective and strategy ....................................................................................... 52
2.5. Results and discussion ....................................................................................... 52
2.5.1. Synthesis of Weinreb amide from Acid Chloride of Garcinia
acid 53
2.5.2. Synthesis of Weinreb amide from anhydride of Garcinia
acid 53
2.5.3. Synthesis of (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-
3,3a(6aH)-diol, the bis furan part of anti HIV drug
Darunavir starting from Weinreb amide ............................................... 54
2.5.3.1 Synthesis of (3aS,6aS)-2,4,6-
trioxotetrahydrofuro[3,4-b]furan-3a(4H)-yl acetate
starting from Garcinia acid ..................................................... 55
2.5.3.2. Synthesis of sodium (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylate starting
from Garcinia acid .................................................................. 57
2.5.3.3 Synthesis of (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarbonyl dichloride
starting from disodium salt of Garcinia acid .......................... 58
2.5.3.4 Synthesis of (2S,3S)-3-hydroxy-2-
(methoxy(methyl)carbamoyl)-5-
oxotetrahydrofuran-3-carboxylic acid ................................... 59
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2.5.3.5. Synthesis of (2S,3S)-3-acetoxy-2-
(ethoxycarbonyl)-5-oxotetrahydrofuran-3-
carboxylic acid ....................................................................... 63
2.5.3.6. Synthesis of ethyl (2S,3S)-3-acetoxy-3-
(methoxy(methyl)carbamoyl)-5-oxotetra-
hydrofuran-2-carboxylate ....................................................... 65
2.6. Conclusion ......................................................................................................... 69
2.7. General Experimental Details ........................................................................... 69
2.7.1. Experimental Details ............................................................................... 70
2.7.1.1. Synthesis of (3aS,6aS)-2,4,6-
trioxotetrahydrofuro[3,4-b]furan-3a(4H)-yl acetate
................................................................................................ 70
2.7.1.2. Synthesis of disodium (2S,3S)-tetrahydro-3-hydroxy-
5-oxo-2,3-furandicarboxylate .............................................................. 71
2.7.1.3. Synthesis of 3-Hydroxy-5-oxo-tetrahydro-furan-2, 3-
dicarbonyl dichloride....................................................................... 72
2.7.1.4. Synthesis of (2S,3S)-3-hydroxy-2-
(methoxy(methyl)carbamoyl)-5-
oxotetrahydrofuran-3-carboxylic acid .................................... 73
2.7.1.5 Synthesis of (2S,3S)-3-acetoxy-2-(methoxycarbonyl)-5-oxotetrahydrofuran-3-ca
2.7.1.6. Synthesis of Ethyl (2S,3S)-3-acetoxy-3-
(methoxy(methyl)carbamoyl)-5-oxotetra
hydrofuran-2-carboxylate ....................................................... 75
References .................................................................................................................. 76
Chapter 3
Investigations on the synthesis of the non-racemic analogue of
furo[2,3-b]furanol: A non-peptidic high affinity P2 ligand for anti-
HIV drug Darunavir
3.1 Introduction ....................................................................................................... 81
3.1.1. Context of the invention of Darunavir .................................................. 82
3.1.2. Antiretroviral drugs ............................................................................... 84
3.1.2.1. Protease inhibitors. ................................................................. 85
3.1.2.2. Integrase inhibitors ................................................................. 85
3.1.2.3. Nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) .................................................................. 85
3.1.2.4. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) 86
3.1.2.5. Chemokine co-receptor antagonists. ...................................... 86
3.1.2.6. Entry inhibitors ....................................................................... 86
3.2. Various methods towards the synthesis of bis-THF alcohol ............................. 87
3.3. Objective and strategy ....................................................................................... 97
3.4. Results and discussion ....................................................................................... 98
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3.4.1. Synthesis of dimethyl (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylate (264) from (2S,3S)-
terahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid. .................... 100
3.4.2. Synthesis of dimethyl (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylate (264.a) from (2S,3R)-
terahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid ..................... 102
3.4.3. Synthesis of diisopropyl (2S,3S)-terahydro-3-hydroxy-5-
oxo-2,3-furandicarboxylate (264.a) from (2S,3S)-terahydro-
3-hydroxy-5-oxo-2,3-furandicarboxylic acid. ..................................... 104
3.4.4. Synthesis of isopropyl(R)-2-hydroxy-2-((S)-3-hydroxy-1-
isopentyl-2,5-dioxo pyrrolidin-3-yl) acetate. ...................................... 107
3.4.5. Synthesis of methyl (R)-2-hydroxy-2-((S)-3-hydroxy-1-
isopentyl-2,5-dioxo pyrrolidin-3-yl)acetate. ....................................... 109
3.4.6. Synthesis of isopropyl (S)-2-((S)-1-benzyl-3-hydroxy-2,5-
dioxopyrrolidin-3-yl)-2 hydroxyacetate. ............................................. 111
3.4.7. Synthesis of (3R,3aS,6aS)-6-benzyl-3,3a-
dihydroxyhexahydro-5H-furo[2,3-b] pyrrol-5-one. ............................ 114
3.4.8. Synthesis of (3R, 3aS, 6aR, Z)-5-
(benzylimino)hexahydrofuro[2,3-b]furan-3,3a-diol............................ 119
3.5. Conclusion ....................................................................................................... 126
3.6. General experimental details ........................................................................... 126
3.7. Experimental details ........................................................................................ 127
3.7.1. Dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate. ...................................................................................... 127
3.7.2 Dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate. ...................................................................................... 128
3.7.3 (2S,3S)-diisopropyl-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate. ...................................................................................... 129
3.7.4 Isopropyl (R)-2-hydroxy-2-((S)-3-hydroxy-1-isopentyl-2,5-
dioxopyrrolidin-3-yl) acetate............................................................... 130
3.7.5. (2S,3S)-diisopropyl -3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate ....................................................................................... 131
3.7.6 (S)-isopropyl 2-((S)-1-benzyl-3-hydroxy-2,5-
dioxopyrrolidin-3-yl)-2-hydroxyacetate .............................................. 132
3.7.7. (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxytetrahydro-2H-
furo[2,3-b]pyrrol 5(3H)-one ................................................................ 133
3.7.8. (3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-
3,3a(6aH)-diol ..................................................................................... 134
References ................................................................................................................ 135
Chapter 4
Synthesis of Indolizine skeletons employing (2S,3S) and (2S,3R)-
Tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acids
16
4.1. Introduction ..................................................................................................... 138
4.1.1. Naturally occurringIndolizidines......................................................... 139
4.2. Various Synthetic routes towards indolizines moiety. .................................... 150
4.2.1. Scholtz and Tschitschibabin reactions for the synthesis of
indolizines ........................................................................................... 151
4.2.2. Intramolecularcyclizations using acetic anhydride ............................. 153
4.2.3. Cyclo condensation reaction for the synthesis of indolizines ............. 154
4.2.4. Cycloaddition for the synthesis of indolizines .................................... 156
4.2.5. Cyclization /elimination for the synthesis of indolizines .................... 161
4.2.6. Cycloisomerization for the synthesis of indolizines ........................... 162
4.2.7. C-H Activation/Metalation Approaches for the Synthesis of
indolizine derivatives .......................................................................... 163
4.2.8. Indolizines obtained via one-pot reactions .......................................... 163
4.2.9. In Situ Generation of QuinoliniumYlides from Diazo
Compounds.......................................................................................... 166
4.2.10. Green methods for Indolizine synthesis .............................................. 166
4.2.11. Synthesis and study of Au(III)–indolizine
derivatives: turn-on luminescence by photo-induced
controlled release................................................................................. 167
4.3. Structure, physical and chemical properties of Indolizines............................. 167
4.3.1 Structure of Indolizines ....................................................................... 167
4.3.2. Physical properties of indolizines ....................................................... 168
4.4. Objective and strategy ..................................................................................... 168
4.5. Results and discussion ..................................................................................... 170
4.5a. Optimization of the reaction condition............................................................ 170
4.5.1. Synthesis of sodium (1S,2S)-1,2-dihydroxypropane-1,2,3-
tricarboxylate starting from Garcinia acid .......................................... 176
4.5.2. Synthesis of trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-
tricarboxylate starting from Garcinia acid ......................................... 177
4.5.3. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-
((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate ............................ 180
4.5.4. Synthesis of trimethyl indolizine-1,2,3-tricarboxylate ........................ 182
4.5.5. Synthesis of trimethyl 7-methylindolizine-1,2,3-
tricarboxylate 184
4.5.6. Synthesis of trimethyl 6-ethylindolizine-1,2,3-tricarboxylate
and trimethyl 8-ethylindolizine-1,2,3-tricarboxylate ......................... 187
4.5.7. Trimethyl 6,8-dimethyl indolizine-1,2,3-tricarboxylate ..................... 190
4.5.8. Sythesis of trimethyl 7-(tert-butyl) indolizine-1,2,3-
tricarboxylate ....................................................................................... 192
4.5.9. Synthesis of trimethylpyrrolo[1,2-a]quinoline-1,2,3-
tricarboxylate ....................................................................................... 194
17
4.5.10. Synthesis of trimethyl 7-methoxyindolizine-1,2,3-
tricarboxylate ....................................................................................... 197
4.5.11. Synthesis of trimethylpyrrolo[2,1-a]isoquinoline-
1,2,3-tricarboxylate ............................................................................. 199
4.6. Conclusion ....................................................................................................... 202
4.7. General Experimental Details ......................................................................... 202
4.7.1 Experimental Details ........................................................................... 203
4.7.1.1. Synthesis of sodium (1S,2S)-1,2-
dihydroxypropane-1,2,3-tricarboxylate(45) ......................... 203
4.7.1.2 Synthesis of trimethyl (1S,2S)-1,2-dihydroxypropane-
1,2,3- tricarboxylate ...................................................................... 204
4.7.1.3 Synthesis of trimethyl (1S,2S)-2-hydroxy-1-
((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate ............. 205
4.7.1.3a General Procedure for the Synthesis of Indolizine
Derivatives .................................................................................... 206
4.7.1.4. Synthesis of trimethyl indolizine-1,2,3-tricarboxylate .................. 206
4.7.1.5. Synthesis of 1,2,3-trimethoxy-7-methylindolizine............... 207
4.7.1.6. Synthesis of trimethyl 6-ethylindolizine-1,2,3-
tricarboxylate and trimethyl 8-ethylindolizine-
1,2,3-tricarboxylate ............................................................. 208
4.7.1.7. Synthesis of trimethyl 6,8-dimethylindolizine-1,2,3-
tricarboxylate ................................................................................. 209
4.7.1.8. Sythesis of trimethyl 7-(tert-butyl)indolizine-1,2,3-
tricarboxylate ................................................................................. 209
4.7.1.9. Synthesis of trimethylpyrrolo[1,2-a]quinoline-
1,2,3-tricarboxylate ............................................................. 210
4.7.1.10. Synthesis of trimethyl 7-methoxyindolizine-1,2,3-
tricarboxylate ........................................................................ 211
4.7.1.11. Sythesis of trimethylpyrrolo[2,1-a]isoquinoline-
1,2,3-tricarboxylate .............................................................. 212
References ................................................................................................................ 213
18
Chapter 5
Attempted synthesis of enantiomers of(2S,3S)and (2S,3R)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylic acids
5.1. Introduction ..................................................................................................... 220

5.2. Inversion of chiral secondary alcohol ............................................................. 223
5.2.1. Inversion of stereochemistry via Mitsunobureaction .......................... 224
5.2.2. Inversion of stereochemistry of secondary alcohols via
tosylate intermediate ........................................................................... 226
5.2.3. Inversion of stereochemistry of secondary alcohols
viaoxidation-reduction approach ......................................................... 227
5.2.4. Inversion of stereochemistry of secondary alcohols
viaIsourea ether ................................................................................... 229
cesium acetate ..................................................................................... 230
5.2.6. Intramolecular substitutions of secondary and tertiary
alcohols with inversion of stereochemistry by an iron (III)
catalyst 231
phosphorothiolates using a thioiminium salt as coupling
agent 231
5.2.8. Construction of C(sp3)-P bond through non-activated alkyl
halides and alkyl tosylates with inversion of stereochemistry ............ 232
5.3. Objective of the present study ......................................................................... 232
5.4. Results and discussion ..................................................................................... 232
5.4.1. Synthesis of ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-
dioxolane-4,5-diyl)bis methylene) bis(4-
methylbenzenesulfonate) .................................................................... 235
5.4.2. Synthesis of trimethyl(1S,2S)-1-(((E)-N,N'-
dicyclohexylcarbamimidoyl)oxy)-2-hydroxypropane-1,2,3-
tricarboxylate ....................................................................................... 235
5.4.3 Attempted synthesis of trimethyl (1R,2S)-2-hydroxy-1-((4-
nitrobenzoyl)oxy)propane-1,2,3-tricarboxylate, 628
employing Mitsunobu reaction............................................................ 236
5.4.4. Attempted synthesis of (S)-trimethyl 2-hydroxy-1-
oxopropane-1,2,3-tricarboxylate ......................................................... 237
5.4.5 A Mechanistic explanation for the Self defence against
epimerization of C-2 asymmetric centres of Garcinia and
Hibiscus acids. ..................................................................................... 237
5.5.1 Synthesis of trimethyl (1S,2S)-2-hydroxy-1-
(tosyloxy)propane-1,2,3-tricarboxylate ............................................... 239
5.5.2 Synthesis of Trimethyl 1-oxopropane-1,2,3-tricarboxylate
(627) 242
19
5.5.3. Synthesis of dimethyl (5.)-4-(2-methoxy-2-oxoethyl)-2,2-
dimethyl-1,3-dioxolane-4,5-dicarboxylate .......................................... 244
5.5.4. Synthesis of((5R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-
dioxolane-4,5-diyl)dimethan-ol........................................................... 247
5.5.5. Synthesis of ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-
dioxolane-4,5-diyl)bis (methylene) bis(4-
methylbenzenesulfonate) ..................................................................... 251
5.5.6. Synthesis of trimethyl(1S,2S)-1-(((E)-N,N'-
dicyclohexylcarbamimidoyl) oxy)-2-hydroxypropane-1,2,3-
tricarboxylate ........................................................................................... 254
5.6. Conclusion ....................................................................................................... 260
5.7. General Experimental Details ........................................................................ 261
5.7.1. Experimental details ............................................................................ 262
5.7.1.1. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-
(tosyloxy) propane-1,2,3-tricarboxylate ............................... 262
5.7.1.2. Synthesis trimethyl 1-oxopropane-1,2,3-
tricarboxylate ........................................................................ 263
(tosyloxy)propane-1,2,3-tricarboxylate ................................ 264
5.7.1.4. Synthesis of ((5R)-4-(2-hydroxyethyl)-2,2-
dimethyl-1,3-dioxolane-4,5-diyl)dimethanol ....................... 265
5.7.1.5. Synthesis of ((5R)-2,2-dimethyl-4-(2-
(tosyloxy)ethyl)-1,3-dioxolane-4,5-diyl)bis
(methylene) bis(4-methylbenzenesulfonate) (632) .............. 266
(tosyloxy)propane-1,2,3-tricarboxylate ................................ 267
References .......................................................................................................................................... 268
Chapter 6
Summary of the Thesis...................................................................................................... 273
20
ABBREVIATIONS
Ac : Acetyl
AcOH : Acetic acid
AIDS : Acquired Immunodeficiency Syndrome
ATR : Attenuated Total Reflection
B3LYP : Becke, 3-parameter, Lee-Yang-Parr
bis-THF : Bis-tetrahydrofuran
BMS : Boranedimethylsulfide
Bn : Benzyl
BOP : Benzotriazol-1-yloxytris(dimethylamino)
phosphoniumhexafluorophosphate
Boc : di-tert-butyl dicarbonate
CAN : Ceric Ammonium Nitrate
Cbz : Carboxy benzyl
CD4+T cells : Cluster of Differentiation 4 T helper cells
COSY : Correlation Spectroscopy
CRI : Co-Receptor Inhibitor
cART : Combination Antiretroviral Therapy
DCC : N,N'-Dicyclohexylcarbodiimide
DCM : Dichloromethane
DCAD : Di-4-chlorobenzyl azodicarboxylate
DCpAD : Di-cyclopentylazodicarboxylate
DEAD : Diethyl azadicarboxylate
DEPC : Diethyl pyrocarbonate
DEPT : Distortionless Enhancement by Polarisation
Transfer
DIAD : Diisopropylazodicarboxylate
DMAD : Dimethyl acetylenedicarboxylate
DMEAD : Di-2-methoxyethylazodicarboxylate
DMP : 2,2-dimethoxypropane
DMF : Dimethylformamide
21
DMSO : Dimethyl Sulphoxide
DMHA : Dimethyl hydroxylamine
DMTMM : 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-
morpholinium chloride
DNA : Deoxyribonucleic acid
DNAD : Di-4-nitrobenzyl azodicarboxylate
DSSC : Dye sensitized solar cells
EA : Electronic absorption
ee : Enantiomeric excess
ECD : Electronic circular dichroism
EDCl,EDC,EDAc : 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EPC : Enantiomerically pure compounds
FDA : Food and Drug Administration
FTIR : Fourier-Tranform Infrared Spectroscopy
HAART : Highly active antiretroviral therapy
HCA : Hydroxycitric Acid
HIV : Human Immuno Virus
HOBT : Hydroxybenzotriazole
HMBC : Heteronuclear Multiple Bond Coherence
HMQC : Heteronuclear Multiple Quantum Coherence
HRMS : High Resolution Mass Spectrometry
HSQC : Heteronuclear Single Quantum Coherence
HTLV : HumanT-Cell leukemia viruses
INI : Integrase Inhibitors
LAH : Lithium aluminum hydride
MDR1 : Multi-Drug Resistance protein
MsCl/TsCl : Methanesulfonyl chloride/p-Toluenesulfonyl
chloride
NBA : N-bromoacetamide
NBS : N-bromosuccinimide
NCS : N-chlorosuccinimide
NHC : N-heterocyclic carbene
22
NNRTIs : Non-nucleoside Reverse transcriptase Inhibitors
NMR : Nuclear magnetic resonance
ORTEP : Oak Ridge Thermal Ellipsoid Plot
ORD : Optical rotatory dispersion
OARAC : Office of AIDS Research Advisory Council
OLED : Organic light emitting devices
PCC : Pyridiniumchlorochromate
PEG : Polyethylene glycol
PI : Protease Inhibitor
PMB : p-Methoxy benzyl
PPA : Phenylpropanolamine
p-TSA : Para Toluene Sulphonic Acid
Q-TOF : Quadrapole Time-of-Flight
SOR : Specific optical rotation
TBDMS or TBS : t- butyldimethylsilyl ether
TBDPS : t- butyldiphenylsilyl ether
THF : Tetrahydrofuran
TMAD : N,N,N′,N′-Tetramethyldicarboxamide
TPP : Triphenylphosphine
TLC : Thin Layer Chromatography
VCD : Vibrational circular dichroism
VROA : Vibrational Raman optical activity
VEGF : Vascular Endothelial Growth Factor
VOC : Volatile organic compounds
23
Chapter 1
Studies on the isolation of non-racemic hydroxycitric acids, (2S,3S)

and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic
acids, and Chiroptical studies of (S)-(-)-crispine A analogue namely
1,5,6,10b-tetrahydropyrrolo[2,1-a]
isoquinolin-3(2H)-one derived from Garcinia acid
1.2. Introduction
1.1a. Chirality and Organic Molecules
Nature eminently regards the remarkable traits of chirality. Single chirality can be
considered as a signature of life. Nature selection of one chiral molecule over the
1-3
other is definite, recognized and admired, and is the basis of evolution. The
molecules present in biological systems are predominantly chiral. As the biological
effect in the human body is directly depending on the stereochemistry of the
exogenous compound and the receptor, it is immensely vital to know the interaction
of a three-dimensional structure in a chiral atmosphere. Stereochemistry holds
exceptionally a very pertinent position in the anaesthesia and pharmaceutical industry.
Consequently, it is observed that the pure enantiomer potential is an imperative
miracle evident in nature. 1
Enantiomers are defined as the chiral entities that are the mirror image of one another
that rotates the plane-polarized light either in clockwise or counterclockwise
4,5a
orientation. Accordingly, the enantiomers demonstrate the distinct optical activity
with the same physical features. Enantiomeric purity is a fundamental basis for the
definite desired biological function of a molecule. As numerous biological molecules
are enantiomers, there exists a striking difference in the action of two enantiomers on
biological organisms. For example, it is often notable in drugs that a specific
enantiomer of a drug is answerable for the desired physiological effects whereas its
antipode may be either less active or inactive that in some circumstances and even
productive of adverse effects. There are also cases when a particular composition of
enantiomers is an essential criterion for the desired biological function3,4 (for instance,
24
D.frontalis, the natural pheromone was found to be a mixture of two enantiomers in a
ratio of 85:15).5b Truly to this discovery, drugs composed of only one specific
enantiomer can be developed to augment the pharmacological efficacy that may even
eliminate some side effects. An example of such an enantiomer is the L-Dopa, also
known as levodopa (L-3,4-dihydroxyphenylalanine), is an amino acid. Humans, as
well as a portion of the other animals that utilize L-Dopa in their biology, make it via
biosynthesis from the amino acid L-tyrosine. L-Dopa is the precursor to the
neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine
(adrenaline), which are collectively known as catecholamines. L-DOPA itself
mediates neurotrophic factor release by the brain and central nervous system. L-Dopa
is sold as a psychoactive drug with the International nonproprietary name (INN),
levodopa under the trade names Sinemet, Pharmacopa, Atamet, Stalevo, Madopar,
and Prolopa. As a drug, it is used in the clinical treatment of Parkinson's disease and
dopamine-responsive dystonia.L-Dopa has a counterpart with opposite chirality,
D-Dopa and is toxic. The human body produces only the L-isomer.
The administration of enantiopure drugs set out rules and regulations in need of
improved efficacy, further predictable pharmacokinetics and decreased toxicity.7
These advantages forced pharmaceutical companies 8 and health authorities 9 to place
enantiomerically pure substances in a prosperous way so that 7 out of the top 10 most
selling-drugs worldwide in 2010 are commercialized in the form of pure enantiomers.
The foremost three positions are there for Nexium (esomeprazole), Lipitor
(atorvastatin), and Plavix (clopidogrel), with a whole invoicing of 15 billion dollars. 10
Figure 1.1 shows some of the enantiomeric pairs and their biological activities. For
example, the compound (-)-propranolol (3) was introduced in 1960 as a beta-blocker
for the treatment of heart disease, but its antipode, 4 act as a contraceptive, which
clearly evinces enantiomeric purity is essential for clinical use. The alkaloid(-)-
levorphanol 5 is a powerful narcotic analgesic with an activity 5-6 times stronger than
morphine whereas its antipode (+)-Dextrophan 6 is a cough suppressant and is
marketed for this purpose as its methyl ether, which is dextromethorphan (Figure
1.1).10b-e
25
Figure 1.1.Pharmacological efficacy of enantiomer drug molecules
1.1b. Context of the Thesis: Value addition to Indian natural resources.
Terrestrial and marine plants, animals, fungi and bacteria are known to produce a
multitude of secondary metabolites often referred to as natural products.10f From a
medical standpoints majority of these natural products also provide a rich source of
bioactive agents such as anti-tumour, immunosuppressive, anti-insecticidal, anti-
bacterial as well as various clinically relevant activities, which have been widely
exploited for both synthetic and semisynthetic drug discovery and development
efforts. These secondary metabolites are also can be used as starting molecules for the
preparation of structurally and stereochemically related molecules useful to mankind.
There is also interest in finding ideal chiral molecules as leads for the preparation of
enantiopure molecules, which otherwise difficult to synthesis following asymmetric
synthetic protocol. Hence there is added interest to find cheap enantiopure molecules
from nature (chiral pool). There are only select groups of molecules available from
the chiral pool. They are carbohydrate, terpenes aminoacids and hydroxyacids. It is
26
known that the mineral and biological resources of our country have not explored well
for value addition. For instance, tartaric acid is a European acid, well explored and
even several Nobel prizes have been awarded for developing useful molecules from
Tartaric acids because most of the science practitioners are from the west. Though
India is a treasure house of a variety of biological and mineral sources, exploring
these resources for making useful materials have not been undertaken seriously.
According to a report by Department of Science and Technology Govt.of India, the
Indian flora and fauna have so far not taken seriously by Indian Researchers and only
5% of our plant materials have subjected to a systematic study.
This thesis focused on the use of Garcinia and Hibiscus acids, molecules with two
asymmetric centers, obtained from tropical plant source (Kudampuli and Pulichi
Keerai) for the synthesis of diverse structural skeletons of chiral and achiral molecules
of pharmaceutical interest. Thus, these acids have been added to the existing select list
of molecules at the disposal of synthetic chemists.
1.1.2. Enantioselective synthesis: General strategies for Enantiomerically pure

compound synthesis
Organic synthesis is divided into two categories; method-oriented synthesis and
target-oriented synthesis, which is most frequently referred to as total synthesis,
traditionally. The ultimate aim of total synthesis is the establishment of a defined
target molecule through a sequence of consecutive reaction.11 The selection of a
particular target molecule for total synthesis is often motivated by interesting
properties of the final product instantaneously. The biological properties, available
medicinal application and, attractive material properties are some of the examples.11
The most convincing examples that demonstrate the practical utility of total synthesis
indisputably is its applications in the preparation of drugs. Total synthesis is widely
the vital method to supply the necessary amount of drug for clinical testing and
eventually for the distribution to patients. The main reason for this is the low natural
abundance of many natural compounds with an interesting biological profile. 1
The preparation of enantiomerically pure compounds (EPC) is a sustained social

demand due to the clinical advantages that enantiopure drugs handover the racemic
forms. Hence there is a surge for the development of viable methods for obtaining
27
enantiomerically pure compounds with diverse architectures and varying degrees of
complexity. There are three main strategies in the preparation of enantiopure
compounds, which are:
 Chiral resolution in racemates
 Chiral pool approach
 Asymmetric/Enantioconvergent synthesis
1.1.2.1.Chiral resolution in racemates
This method involves preparing the compound in a racemic form and then separating
it into its isomers. Louis Pasture in his pioneering work was able to isolate the isomers
of sodium ammonium tartrate from solution as crystals each time with a different
symmetry.
1.1.2.2.The chiral pool approach
The second method is synthetic transformations in an enantiomerically pure substance

as starting material. In the chiral pool approach, enantiopure molecules from nature
are used as a starting molecule obtained for the synthesis of target molecules.10,11a
Chiral pool refers to a collection of enantiomerically pure molecules available from
nature.
The construction of organic compounds containing one or more chiral centers utilizing
chiral starting molecules is certainly one of the most exciting and remarkable chapters
of the contemporary organic chemistry. Common chiral starting molecules derived from
nature include amino acids, chiral carboxylic acids and monosaccharides. The chiral
pool approach for the synthesis of optically active targets is extremely attractive when
the starting molecule is abundant and can be converted to the desired structure in a
few steps.
Owing to their low cost, high abundance, and general renewability, the chiral pool has
been extensively utilized by synthetic chemists in the synthesis of both natural
products as well as pharmaceutical agents. The major drawback being the lack of
availability of such molecules with the required number of carbons, flexible
functional groups, stereocenters with proper stereochemistry and sense of chirality.
28
Naturally occurring non-racemic hydroxy acids namely ascorbic acid, lactic acid,
malic acid and tartaric acid were frequently encountered in the broad area of
asymmetric synthesis (Table 1.1.1.2). 11b
1.1.2.3.Asymmetric synthesis
The third strategy is the asymmetric synthesis, which uses various techniques to
prepare the desired compound in enantiomeric excess. The use of chiral auxiliaries,
chiral catalysts, the use of enzymes (biocatalysts) will definitely produce the desired
final molecule with correct stereochemistry.
1.1.2.4.Enantioconvergent synthesis
Enantioconvergent synthesis is the synthesis of one enantiomer from a racemic

precursor molecule utilizing both enantiomers. Therefore, the two enantiomers of the
reactant produce the single enantiomer of a product. Interpreting and suppressing
chirality is essential to impersonate the development of biological structures. This
help in the achievement of tailored macroscopic properties.14
According to the FDA, the stereoisomeric composition of a chiral drug should be

recognized so that its effects should be competently signalized from pharmacology,
toxicology and clinical standpoints. Manufacturers are urged to develop quantitative
assays for individual enantiomers in vivo samples early in the developmental process
in order to profile the different stereoisomers of enantiopure drugs.
Table 1.1.1.2. Some of the chiral hydroxyl acids present in nature

Natural source Natural isomer Unnatural isomer References
3
L-(-)-lactic acid D-(+)-lactic acid
Milk
Apple L-(-)- Malic acid D-(+)- Malic acid
29
4
Grape (R,R)-Tartaric acid (S,S) Tartaric acid
Raspberry
(S,R)-Isocitric acid (R,S) Isocitric acid
Almond L-(-)- Mandelic acid D-(+)- Mandelic acid
Banana
L-Ascorbic acid
Hibiscus sabdariffa
Mathippuli
7
Hibiscus acid
Hibiscus furcatus
Uppanacham
8,43
Garcinia acid
Kudampuli
30
1.2. Medicinally pertinent non-racemic molecules
Medicinal chemistry explores the discovery, efficacy and significance of new biologically
active compounds. These compounds, present in nature contain biologically pertinent
heterocyclic moieties. 7 Most biological molecules like proteins and sugars exist only in
one of the main isomeric forms so that either variable enantiomers of a chiral drug
molecule bind differently or will never bind to target receptors. The U.S. Food and Drug
Administration (FDA) has allowed single enantiomers of certain drugs to be marketed
under a different name than the racemic mixture on a case-by-case basis. The United
States Patent Office has granted patents for single enantiomers of certain drugs case-by-
case.
1.2.1. Significance of the chiral compounds
If there are two isomers, the consequences of different activities that exist between them
are:
 half of the product is not absolutely needed, while the costs have been incurred in
its production
 half of the product poses a load on the system to which it is applied for which the
resources have to be devoted to its removal
 half of the product may react with a different cellular receptor and may cause an
unwanted potentially damaging side-effect
The situation is more complex if the molecule has two or more chiral centres in which
there exists more isomers.10 A number of companies are now active in chiral chemistry.
They supply intermediate the pharmaceutical industry, which is active in chiral chemistry.
Classes of natural products like amino acids, hydroxy acids, carbohydrates, alkaloids
were employed as a starting material for the synthesis of enantiomerically pure chiral
agents. Chiral molecules in the enantiomerically pure form are a precondition for
ensuring biological activities as well as certain functional properties.12,13 There is an ever-
increasing demand for enantiomerically pure compounds in the present day as they are
being extensively used in perfume, food and drug industries. Chiral pool approach is the
most convenient and environmentally friendly method for the preparation of
enantiomerically pure entities. There are several of methods available to convert our
starting material in to biologically and industrially important compact molecules.
31
1.2.2. Contemporary compact drug development
Organic synthesis is a compound innovating activity that usually focused on biologically
active compact molecules. Compact drug molecules have been used increasingly as
probes for life processes nowadays. A small molecule that regulates biological processes
will not serve as a drug; it can have a variety of other biological functions. It can serve as
cell signalling molecules such as pesticides in farming and in many other roles. The
reports are available for the invention of small molecule drugs and, encouraged by the
scientific world along with a number of studies. As a small molecule, it is only able to
participate in a limited number of interactions. Accordingly, it must maximize the
energetic contribution from each of them to have an ability to shield other atomic
interactions (Scheme 1.2.2).16
Scheme 1.2.2. Some of the lead molecules, which can be procured

from non-racemic 2-hydroxycitric acids
32
Breslow et al. synthesized an anticancer drug suberoylanilide hydroxamic acid
(SAHA/Vorinostat) which inhibits both class-I and class-II histone deacetylase.17
Today, the latest view of basic research aims to connect the gap between basic scientific
discoveries in organic sciences and new drugs that treat the root cause of human
disease. Within the past few decades, the time and cost of drug development have
soared. Accordingly, the identification of target molecules and to synthesize novel lead
molecules, should reach to act on disease targets. Recently, the researchers Satoshi
Ōmura, and Tu Youyou from China and Japan respectively won the ultimate status
symbol in science as their supervising research team led to the development of malaria
drug “artemisinin” in the late 1960s and 1970s.The identification of lead molecules for
drug discovery and pharmaceutical need constitutes a challenging and thriving area in
modern organic chemistry.18 Newman et al. found out that almost 50% of new drugs
introduced during this particular period have a natural product origin.19
Figure 1.2.2. Structures of the trending drugs in the modern age
1.3. Objective of the present study
The optically active 2-hydroxycitric acids namely, (2S,3S) and (2S,3R)-tetrahydro-3-

hydroxy-5-oxo-2,3-furandicarboxylic acids (Garcinia and Hibiscus acids 1&2) are
widely distributed in tropical plants. These diastereomeric acids are present in plant
species Garcinia cambogia and Hibiscus sabdariffa respectively. Our laboratory has
developed convenient methods for the large-scale isolation of Garcinia and Hibiscus
acids in optically pure form. Further, conversion of these acids to biologically
important molecules having two chiral centers and six carbons were achieved in
minimum steps 3-6,12-14
33
34
It is clear from the above discussion that, these acids are ideally suited for developing
molecules with six carbon framework possessing chiral and achiral centers.
Traditionally, Garcinia acids are known to have anti-obesity properties and
extensively used in food preparations especially in south India.
Synthesis of both natural and unnatural organic compounds in the enantiomerically

pure form is one of the contemporary challenges in the domain of modern organic
chemistry. All the target molecules have found wide implementations in
pharmaceutical industries. The available methods for the synthesis of the proposed
35
molecules involve tedious and time-consuming methods with uncertain
stereochemical outcomes. The methodology in enantio-purity of the target molecules
is guaranteed as the chirality is being transferred from the enantiomerically pure
starting molecules to target molecules currently.
Table 1.3 Some significant non-racemic synthons and compounds which can be
related to 1 and 2.
36
37
1.4. Results and Discussion.
The plant materials are randomly collected from different places depending on the
seasonal availability, every time, the isolation procedure has to be standardized and
the authenticity of the starting molecules should be rechecked using spectroscopic
techniques. Fresh plant materials for Garcinia acid was mostly collected from
Kutanad region of Kerala and the calyxes of Hibiscus sabdariffa was collected from
the coastal region of Allepy, Kerala.
1.4.1 Isolation and characterization of (2S,3S) tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylic acid (1)
The Garcinia acid 1 was isolated from the dried fruit of Garcinia cambogia. The acid
2 was isolated from the leaves of Hibiscus Furcatus and from the calyxes Hibiscus
sabdariffa and Hibiscus cannabinus, all belong to the family Malvaceae. The plant
species were procured from Mahatma Gandhi University Campus also. The isolation
of 1 and 2 have been carried out by the following procedure developed by Ibnusaud
and co-workers.12-14
The dried rind of the fruit of Garcinia. cambogia is popularly known as “Malabar
tamarind” is extensively used all over the west coast of South India for culinary
purposes and commercially for “Colombo curing” of fish 29. The organic acids present
38
in the fruit have been held responsible for the bacteriostatic effect of the pickling
medium by lowering the pH
1. The dried fresh rinds of the fruits of Garcinia cambogia (1 Kg) was cut into small
pieces and soaked in hot water(1L). The water extract was collected after 10-20
hours. The extraction was repeated for 3-4 times. The combined extract was
evaporated to syrup (A).
2. To the syrup (A) sufficient quantity of methanol (3L) was added to remove pectin
completely. The pectin free filtrate was concentrated to syrup (B).
3. After making syrup (B) alkaline by adding a sufficient amount of aqueous alkali
at elevated temperatures, it is cooled and methanol (1L) was added to the solution
till two layers separated. Separated thick mass was washed several times with
various proportions (60-100%) of aqueous methanol (5×100) to get a paste of
alkali salt (C).
4. The alkali salt (C) on neutralization (2N HCl) with mineral acid followed by
evaporation gave the concentrate (D). The concentrate (D) was triturated with a
sufficient quantity of acetone to precipitate the insoluble parts. The filtrate on
concentration yielded crude 1.
5. The crude acid 1was purified by recrystallization from ether and the [ ]25
D
observed for the pure sample is +101.2 (c 1.0, H2O)
By comparing the IR, 1H NMR, 13

CNMR and mass spectra (Figure 1) and [α]D
values with that of the reported values, the structure as well as the optical purity
of Garcinia acid (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid
was confirmed. The IR spectrum of the compound shows the characteristic
absorption bands at  3303 (-OH, broad), 1771 ( -lactone carbonyl) and 1753
and 1714 cm-1 (carboxyl carbonyl groups). The 1H NMR spectrum of 1 shows
signals at 2.72(J = 16 Hz) and 3.23 (J = 20 Hz) ppm (AB quartet; corresponding
to the methylene protons) and at  4.98 ppm(singlet; due to methine proton). Six
different signals in 13C NMR spectrum at  (ppm) 174.04, 171.51, 168.53, 85.11,
80.25 and 40.45. The mass spectrum showed a peak at m/z191 corresponding
to the molecular ion also confirmed the structure of (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylic acid 1
39
IR(ATR)
1
H NMR, 400 MHz, Solvent: Acetone-d6
13
C NMR ,100 MHz, Solvent : Acetone-d6
40
1.4.2. Isolation and characterization of (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylic acid (2)
1. The fresh calyxes or leaves of Hibiscus sabdariffa or leaves of Hibiscus furcatus
were extracted with water and was concentrated to a syrup.
2. To this concentrate, methanol was added to precipitate inorganic materials.
3. The organic layer was concentrated and aqueous alkali(10%NaOH) was added to
yield the sodium salt of 2.
4. The salt was then washed several times with various proportions of aqueous
methanol to get a thick paste of alkali salt.
5. The alkali salt on neutralization with mineral acid (5N HCl) generated the acid,
followed by concentration under vacuum gave the crude acid 2.
41
6. The crude acid residue was triturated with acetone or methanol to obtain 2. The
final purification of 2 was done by repeated extraction and finally by
crystallization from ether.
By comparing the IR, 1H NMR, 13CNMR, Melting point and HRMS (Figure 2) and [α]D
values with that of the reported values, the structure and optical purity of Hibiscus acid
was confirmed The IR (film) spectrum of the compound showed the characteristic
absorption bands at 3303 (-OH, broad), 1771 (γ-lactone carbonyl) and 1750 and 1714
cm-1 (carboxyl carbonyl groups). The 1H NMR spectrum of 2 shows signals at  2.71
(J = 16 Hz) and 3.25 (J = 20 Hz) ppm (AB quartet; corresponding to the methylene
protons) and at  4.98 ppm (singlet; due to methine proton). Six different signals in 13C
NMR spectrum at (ppm) 173.8, 171.38, 168.45, 85.17, 80.31 and 40.37.The mass
spectrum showed a peak at m/z 191 corresponds to the molecular ion also confirmed
the structure of (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid 2.
IR(Liquidfilm)
1
42
13
1.5. General Experimental Details
Commercial solvents are perfectly distilled prior to its use in experiments. Dry
solvents and reagents were prepared following the procedures delineated in
“Purification of Laboratory Chemicals” by D. D. Perrin and W. L. F. Armarego (3rd
edition, Pergamon Press, 1988). Dried fruit rind of Garcinia cambogia was procured
from a local plantation. Leaves or calyxes of Hibiscus sabdariffa and the leaves of
Hibiscus furcatus were gathered from the native area. The reactions demanding
anhydrous condition were executed in the schlenk line. The drying of organic extracts
was with the use of anhydrous sodium sulphate.
43
Thin layer chromatography was performed using glass-backed silica gel plates (Merck
silica gel G for TLC) with 2% aq. KMnO4 as developing agents and column
chromatography was carried out with Merck product silica (silica gel 60-120). Melting
points were determined on ‘’Sunbim’’, which is an electrically heating melting point
apparatus. Infrared spectra were recorded using a Shimadzu IR 470 spectrophotometer
as KBr pellets (solids) or thin films (liquids) or Perkin Elmer Spectrum 400. 1H NMR
spectra were recorded in Brucker AV 400 MHz and chemical shift values are reported
in parts per million (ppm) with tetramethylsilane as the internal standard reference (0.00
13
ppm). C NMR spectra were recorded in Brucker AV 400 MHz and chemical shift
values are reported in parts per million with tetramethylsilane as the internal standard
reference (0.00 ppm). Electron impact mass spectra were recorded in Finnigan MAT
MS 8230 or Jeol D-300. Specific rotations were recorded with the help of Jasco D I P
370, Autopol IV polarimeter. Elemental analyses were implemented with the help of
Carlo-Erba CHNS-O-EA 1108 elemental analyzer.
1.6. Experimental Section
1.6.1 (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1)
Dried rinds of the fruits of Garcinia cambogia (1 Kg) were cut into small pieces and
soaked in hot water (1L). The extract was collected after 20 hours and the process was
repeated 4-5 times. The combined extract was concentrated and methanol (2.5 L) was
added to precipitate pectin. Upon filtration, the filtrate was concentrated to a syrup. It
was made alkaline with a sufficient quantity of 10% aqueous sodium hydroxide,
followed by the addition of methanol (I L) till two layers separated. The sodium salt,
separated as a paste (lower level), was washed with 60% aqueous methanol (5 x 100
mL). The pure sodium salt was dissolved in a sufficient quantity of 2N hydrochloric
acid to regenerate the free acid. It is concentrated and added acetone to precipitate the
impurities. The filtrate upon concentration yielded crude crystals of 1. Pure crystals of 1
were obtained upon the recrystallization from the acetone-ether mixture.
44
Appearance Colourless crystals
Yield 92 %
[]25 +101.2 (c 1.0, H2O). Reported: +100

D
Melting point 178-179 °C. Reported: 178 °C

IR (ATR) 3303, 1771, 1753, 1714, 1382, 1237, 1164 cm-1
 4.98 (s, 1H), 3.23 (d, J = 20 Hz, 1H),2.72,
1
H NMR (CDCl3, 400 MHz)
(d, J = 16 Hz, 1H) ppm
174.1, 171.5, 168.5, 85.11, 80.2, 40.4 ppm.
13
C NMR (CDCl3, 100 MHz)
Molecular Formula C6H6O7
Molecular Mass 190.107
HRMS (TOF MS ES+) m/z calculated 191.0192, found 191
C6H6O7 (M +H)+
1.6.2 (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (2)
a) From the calyxes (Hibiscus sabdariffa (Mathippuli))
Fresh calyxes of Hibiscus sabdariffa (1 Kg) were dried, powdered and extracted with
methanol several (6-8) times. The combined extract is concentrated under reduced
pressure and the concentrate is washed with hexane to remove chlorophyll. The crude
mass is then extracted with ether many times. The ether extract on concentration
yielded 11 g of (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid 2.
b) From leaves (Hibiscus furcatus (Uppanacham))
Fresh green leaves of Hibiscus sabdariffa or Hibiscus furcatus (1 Kg) were soaked in
water (1 L), ground well and extracted two times. The extract is concentrated under
reduced pressure. After washing with hexane to remove chlorophyll, the concentrated
extract was made alkaline with 8N sodium hydroxide solution (80 mL). Methanol was
added to precipitate the sodium salt followed by the addition of 2N hydrochloric acid
to regenerate the acid. Upon concentration followed by the addition of acetone
45
precipitated the impurities. The residue obtained after concentration was further
extracted with ether which on concentration yielded 13 g of (2S,3R)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylic acid 2.
Yield 91 %
[]25 +111.2 (c 1.0, H2O). Reported: +110

D
Melting point 181-182 °C. Reported: 182-183 °C
IR (ATR) 3303, 1771, 1750, 1714 cm-1
 4.98 (s, 1H), 3.26 (d, J = 20 Hz, 1H),2.71,

1
H NMR (CDCl3, 400 MHz)
(d, J = 16 Hz, 1H) ppm
 173.8, 171.3, 168.5, 85.2,80.3, 40,4 ppm

13
C NMR (CDCl3, 100 MHz)
HRMS (TOF MS ES+) m/z for Calculated 191.0192, found 191

C6H6O7 (M +H)+
1.7. Chiroptical studies of (S)-(-)-crispine A analogue namely (1R,10bR)-1-((R)-

1,2-dihydroxyethyl)-1-hydroxy-8,9-dimethoxy-1,5,6,10b-tetrahydro-
pyrrolo[2,1-a]isoquinolin-3(2H)-one (34) related to Garcinia acid.
46
Molecule 34 was prepared following the reported procedure. The diester of Garcinia
acid ((2S,3S)-3-dihydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate) (70) was reacted
with (3,4-dimethoxyphenyl) ethanamine to generate (S)-methyl 2-((S)-1-(3,4-
dimethoxyphenethyl)-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-2-hydroxyacetate(59).
During the conversion of 59 to 34, the optical integrity was maintained. Therefore, it
is logically concluded that the ACs of the chiral carbon atoms 1 and 1’ are (R).
However, a new chiral centre is formed at position 10b, whose AC was suggested
using two-dimensional NMR correlations to be R. An independent verification of this
assignment is needed. For this purpose, single-crystal X-ray diffraction measurements
are undertaken to determine the relative configurations at positions 10b, 1, and 1’.
From the structure 34 (Fig. 1.7) the ACs at 1 and 1’ positions are known since it was
formed from 1, the AC of 35 is (1R, 10bR, 1’R) the synthetic. It has been further
confirmed from chiroptical spectroscopic analysis of the (1R, 10bR, 1’R)
diastereomer. Towards this objective, the structure of 34 with (R)-configuration at
each of the three chiral centres was manually built and used as input for
conformational search using the CONFLEX program. 24
The geometries of 17430 unique conformers generated by CONFLEX were optimized

using the B3LYP functional 25 and the G basis set 26
as implemented in the Gaussian
09 program. The geometries of these six lowest energy conformers were further
optimized using the polarizable continuum model (PCM) for representing methanol
solvent at the CAM37-B3LYP/6-311+ +G(2d,2p)/PCM level and the resulting
structures used for ECD and ORD calculations at the same level. ECD and ORD
calculations are also undertaken for all diastereomers using empirical D3 dispersion
corrections.27 No significant differences could be found between the results obtained
with and without dispersion corrections. For VCD calculations, geometry
optimizations and QC predictions of VCD were undertaken at the B3PW91/6-
311++G(2d,2p)/PCM level. For (1R,10bR,1′R) and (1R,10bS,1′R) diastereomers.
Full geometry optimizations and VCD calculations were also carried out including
empirical D3 dispersion corrections, but the inclusion of dispersion corrections did
not provide improvement over those without dispersion corrections. All ECD and
VCD calculations were also undertaken using the Gaussian 09 program.
47
1.7.1. ORD of the (1R,10bR,1′R) diastereomer
The experimental SORs measured at six different wavelengths are compared to those
predicted at the CAM-B3LYP/6-311++G(2d,2p)/PCM (methanol) level in Figure 1.7.
The signs, as well as magnitudes, of the predicted SORs for the (1R,10bR,1′R)
diastereomer match those observed in the experiment quite well (Fig 1.7).
1.7.2. ERD of the (1R,10bR,1′R) diastereomer

The experimental electronic absorption (EA), ECD, and electronic dissymmetry factor
(EDF) spectra are compared to the corresponding spectra for the (1R,10bR,1′R)
diastereomer in Figure 1.8.
48
The spectral similarity overlap (SSO) plots provide a quantitative assessment of the
agreement between experimental and predicted spectra. The maximum SimEA,
SimECD, and SimEDF values seen for (1R,10bR,1′R) are 0.96, 0.84, and 0.45,
respectively (Fig. 1.9(A)). Ideally, these values should be close to 1 for perfect
agreement, but SimECD, and SimEDF values greater than 0.4, are considered
necessary to reflect a reliable agreement between experiment and predictions.
Therefore, a large SimECD value, and SimEDF value greater than0.4, provides
further support for the conclusions derived from ORD analysis (Fig.1.9)
49
1.7.3. VCD of the (1R,10bR,1′R) diastereomer.
The experimental vibrational absorption (VA), VCD, and vibrational dissymmetry

factor (VDF) spectra of 35 in the 1800-1160 cm-1 region are compared to the
corresponding spectra predicted for the (1R,10bR,1′R) diastereomer, with deuterated
OH groups, in Figure 2. In the left vertical panel of Figure 2, the predicted
wavenumbers are scaled with 0.9815 (which corresponds to the maximum SimVCD
value) and overlaid on the experimental spectra. In the right vertical panel, predicted
spectra with unscaled wavenumbers are stacked over experimental spectra and band
positions labelled.
50
The comparison indicates that most of the experimental bands are satisfactorily
reproduced in the predicted spectra. Additionally, the relative intensities for all
calculated VCD bands match those in the experimental spectrum. The agreement
between experimental and predicted VCD spectra can be seen in Figure 2.1.
51
Hence the ORD, ECD, and VCD analysis individually support the AC assignment as
(1R,10bR,1′R) and do not support the AC assignment as (1R,10bR,1′R).33
In conclusion, the absolute configuration (AC) of the isolated 2-hydroxycitric acids

having two chiral centres namely, (2S,3S) and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-
furan dicarboxylic acids (1&2) and synthesized (1R,10bR)-1′-((R)-1,2-dihydroxyethyl)-1-
hydroxy-8,9-dimethoxy1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one, an
analogue of (-)-crispine A, (34) with three stereogenic centres are established using
the combined information derived from the synthetic scheme and single crystal X-ray
diffraction data. The AC of the synthesized compound could be correctly established
using any one of the three chiroptical spectroscopic methods (ORD, ECD, or VCD)
when the relative configuration is constrained to be that derived from X-ray data or
when the ACs of two of the chiral centres are constrained to be those derived from the
synthetic scheme. In the absence of this outside information, the QC predicted ORD,
ECD, and VCD for incorrect diastereomers are also found to satisfactorily reproduce
the corresponding experimental spectra. Nevertheless, incorrect diastereomers could
be eliminated when combined electronic dissymmetry factor (EDF) and vibrational
dissymmetry factor (VDF) spectral analyses are included, leaving the correct
diastereomer as the sole choice. Thus, the combined EDF and VDF spectral analysis
is seen to be a helpful diastereomer discrimination tool.
52
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W.J.P.; Raap, J.; Rutjes, F.P.J.T and Vlieg. E. Nature Communications, 2014, 5,
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Action and Disposition; Springer. 2003.
8. Caner, H.; Groner, E., Levy, L.; Agranat, I.; Drug Discov. Today, 2004, 9,
105-109.
9. a) Food and Drug Administration, 1992, FDA’s policy statement for the
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Kreitman, M.; Williams, R. M. Angew. Chem. Int. Ed. 2012, 51, 4802.
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Biomolecule- s ,University of Groningen, 2006.(b) Guthrie, R. W.; Kierstead,
R. W. Hydroxycitric acid derivatives. US Patent 4,005,086, 1977.
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Tetrahedron, 2002, 58, 4887-4892.
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6699-6102
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20. Reddy, B. R.; Reddy, K.S.et al. Org. Process Res. Dev, 2014, 18, 163-167.
21. Fry, D. C. Biopolymers (Peptide Science), 2006, 84, 535-552.
22. Erickson, T.J. J.Org. Chem., 1986, 51, 934-935.
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J.; Singaram, B. J. Org. Chem. 2018, 83, 1431-1440.
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25. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
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Polavarapu, P. L. ACS. Omega, 2019, 4, 6154-6164.
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54
Chapter 2
Synthesis and application of Weinreb amides related to

(2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylic acids
2.1. Introduction
The conversion of acid chlorides and esters to ketones and aldehyde using Grignard
reagent or organometallic reagents other than organolithium reagent encounter
difficulty as the over the addition of reagent to the substrate resulted in the formation
of tertiary alcohols (95).1a Nucleophilic attack by the Grignard and organolithium
reagents on simple carbonyl and acetonitrile leads to the formation of a wide range of
organic molecules. Nucleophilic attack by the Grignard reagent fails with a carboxylic
acid. However, the organolithium reagents behave differently with organic acids and
afford ketones by excess addition (Scheme 2.1).
In 1981, Steven M. Weinreb and Steven Nahm overwhelmed this problem by

developing a unique amide of the type 91. The -OMe substitution on the nitrogen
decides the course of the reaction, which leads to the formation of Ketone from
amide, instead of a secondary alcohol. Thus, an acid can be converted to ketone via
Weinreb amide 1 Weinreb amide can be synthesized easily by in situ activation of the
55
carboxyl group and it is an effective acylating agent and shows high stability and
storability and can be used as synthetic equivalents of ketones or aldehydes which
have more reactivity in specific reactions 1e (Scheme 2.2).
The N-methoxy-N-methyl amides (Weinreb amides) are versatile synthetic

intermediates in organic synthesis since they react with Grignard and organometallic
1,2a,2d
reagents to give ketones. The N-Methoxy-N-methyl amide reactions holds the
two sequential nucleophilic acyl substitutions, which is the conversion of an acid
chloride with N,O-dimethyl hydroxylamine that forms Weinreb–Nahm amide and
succeeding treatment of this species with the organometallic reagents like Grignard
reagent or organolithium reagent. The efficiency of Weinreb amide was attributed to
the formation of a stable tetrahedral intermediate (98a & 98b) even in the presence of
excess organometallic reagents.19b These amides yield exclusively ketones even with
a large excess of organometallics. Moreover, the effective chelation of metal ion
between the carbonyl oxygen and N-methoxy oxygen prevents the collapse of the
tetrahedral intermediate 98b until the workup in acidic medium. For these latter
reactions, the two equivalents of the incoming group add to form alcohol rather than a
ketone or aldehyde. This occurs even if the equivalents of nucleophiles are closely
controlled. Weinreb amides have considerable stability, which is purified by
crystallization, distillation, and, column chromatography. Weinreb amide can be
56
employed either as intermediates or reagents for preparing complex amines,
heterocycles, pyrans and, amides (Scheme 2.3).1d
Weinreb amides thrive in peptide chemistry. N-protected amino aldehydes as a crucial

intermediate for many chemoselective transformations evinces its significance in
organic synthesis.4 They are also useful in the synthesis of acetylenes,5 which are
starting materials for the famous click reactions.2.3,6 Weinreb–Nahm amide have
application in heterocyclic chemistry for the synthesis of pyrazoles and pyrrole 1a,b-1e
and commonly used as a synthon in the total synthesis of various natural products
such as DSB-1201g, Xestodecalactone A1h, Dolabriferol1i, Pyochelin1J (Scheme 2.4).
57
N-Methoxy-N-methyl amides were also efficiently used as a synthon for various
industrial processes. An anti-HIV protease inhibitor1k and anti-cancer agent,
Discodermolide (Novartis)1l are synthesized industrially in kilogram scale (Scheme
2.5).
58
2.2. General synthesis of Weinreb amines
Weinreb amines have been prepared from either the acid or its derivatives. N,O-
dimethyl hydroxylamine is commercially available in the form of its hydrochloride
salt although a convenient procedure for its preparation reported. 1c,2d N,O-
dimethylhydroxylamine hydrochloride is generated in situ with the help of one
equivalent of a base in the most synthetic operation.1e,2e,2f
The best etiquette for the synthesis of N-Fmoc-α-amino aldehydes is the reduction of
Weinreb amides derived from N-protected amino acids rather through the oxidation
of corresponding alcohols or by cautious reduction of esters.7 The activation of the
carboxylic group mainly via a mixed anhydride using chloro formates
followed by coupling with N,O-dimethylhydroxylamine is the utmost practised
protocol for converting carboxylic acids into the corresponding Weinreb amides.8
The review is divided into three main sections. The first section describes the
various methods for the preparation of N-methoxy-N-methyl amides from
carboxylic acids and their derivatives. The second section deals with the
preparation of a variety of carbonyl compounds (ketones) by nucleophile addition.
The third section describes the reduction of N-methoxy-N-methyl amides to
aldehydes and alcohols by hydride reagents.
59
2.3 Synthesis of N-methoxy-N-methyl amides
The synthesis of N-methoxy-N-methyl amides involves numerous methods. The

following portion delineates the synthesis of Weinreb–Nahm amide, enunciating the
dominant methodology involved in organic synthesis.
2.3.1. Synthesis of Weinreb amides from the carboxylic acids
The direct conversion of carboxylic acid to its corresponding Weinreb amides

involves numerous synthetic method.2,2e,3a Over the last 20 years, a number of
methods for the conversion of carboxylic acids to N-methoxy-N-methyl amides have
appeared in the following literature. The direct conversion of the carboxylic acid into
the Weinreb amide is the most reported and attractive method as it obviates the need
to first convert acid into one of its derivatives, where this straight transformation
relies on in situ activation of the carboxyl carbon for attack by N, O-dimethyl
hydroxylamine.1e
The procedure comprises some utilization of acid activating, peptide coupling

reagents such as DCC9a, BOP9b-c DEPC9d, HOBT/DCC9e, BOP-PF6 9f HOBT/EDCl 9g,
alkyl chloroformates9h, CDI 9i
, CBr4 /TPP 14
, 2-halo-1-alkylpyridiniumsalts9j, py-
BOP9k, EDCl9l, PPA9m, CDMT9n, TOTT9o, HOTT9o, TODT9o, HODT9o, CPMA10,
DMT-MM11 or polyphosphoric anhydride/N-ethylmorpholine.12,13 The present
attention of the many research group wholly relies on the simple and economically
viable method.1e Einhorn et al. reported a method for the synthesis of Weinreb
amides from carboxylic acids using carbon tetrabromide and triphenylphospine.14 Sibi
et al. recently reported the synthesis of Weinreb amides from carboxylic acids using
15
2-chloro-1-methylpyridinium iodide (CMPI) or BMPI as the coupling agent. These
reactions are expensive in some cases, and the removal of their excess (and/or the
removal of byproducts) from the reaction mixtures may be difficult. Additional
purification of the reaction product is often required. Taking into account that CDMT
may be an irritating agent for eyes and nose. Even with this reagent, the final products
were exclusively the desired Weinreb amides, which can be recovered pure after the
simple aqueous workup of the mixture. However, the condensation of the acids with
DMTMM requires longer times due to the formation of the activated ester (1.5h).
Moreover, the reactions carried out in the presence of DMTMM proceeded, under the
60
conditions employed (8h of stirring at room temperature), with conversions lower
than those performed with CDMT.25
The importance of Weinreb amides is shown by a communication describing a one-

flask synthesis of Weinreb amides of carboxylic and amino acids use a Deoxo-Fluor
fluorinating reagent. Although simple, this method requires the use of an expensive
reagent. Moreover, the crude products need to separate by column chromatography.16
2.3.1.1. Braun and coworkers have synthesised Weinreb intermediate of glycine

derivative starting from N-(benzyloxycarbonyl) glycine (Scheme 2.7).18b
2.3.1.2. Tunoori et al. developed the one-pot synthesis of Weinreb amide from chiral
and achiral carboxylic acids using bis(2-methoxyethyl) amino sulphur trifluoride
(Deoxo-Fluor reagent)16, which is effective for the conversion of alcohol to alkyl
17
fluorides. The carboxylic acids are first converted to acid fluorides by Deoxo-Fluor
reagent in the presence of N,N-diisopropylethylamine. Weinreb amides are formed
after addition of N,O-dimethylhydroxylamine to the intermediate acid fluorides. Since
acyl fluorides possess stability greater than that of the corresponding acid chlorides
towards neutral oxygen nucleophiles such as water and methanol yet are of high
reactivity toward anionic nucleophiles and amines. It is observed that acid fluoride
18
reacts more like active esters than acid halides (Cl, Br, I). Accordingly, this
synthesis is a new suitable and high yielding (82%) method for the preparation of
Weinreb amide.
61
2.3.1.3. Kangani et al. reported a highly efficient conversion of carboxylic acid to
related ketones and aldehydes by a one-pot synthesis in presence of Deoxo-Fluor
reagent (Scheme 2.9).19
2.3.1.4. N-Methoxy-N-methyl amides can also be prepared from the corresponding

carboxylic acid by a variety of coupling procedures. The normal peptide coupling
reagents work quite well in these syntheses. Typical coupling reagents that have
been applied for the preparation of amides are BOP (benzotriazol-1-
yloxytris[dimethylaminominol-phosphonim hexafluorophosphate).10 These procedures
are especially useful for the preparation of amides from α-amino acids without any
racemization of the chiral center (Scheme 2.10). 9b
62
2.3.1.5. Einhom et al. have developed a very mild and efficient method for the
synthesis of N-Methoxy-N-methyl amides from the corresponding carboxylic acids
using carbon tetrabromide and triphenylphosphine (Scheme 2.11). 14
2.3.1.6. Angelastro et al. transformed N-protected peptide or amino acid into its
corresponding Weinreb amide (Scheme 2.12). 20
2.3.1.7. Nugiel et al. synthesized Weinreb amide from commercially available

N-Cbz-D-alanine via the in situ mixed anhydride methodology (Scheme 2.13). 21
63
2.3.18. Reghuram et al. converted direct acid to Weinreb amide by using readily and
cheaply available pivaloyl chloride as an activating agent (Scheme 2.14). 22
2.3.1.9. Weinreb amide derivative can be conveniently prepared from carboxylic acids
and N,O-dimethylhydroxylamine hydrochloride at room temperature using
trichloromethyl chloroformate in the presence of triethylamine. The carboxylic acid
undergoes reaction with trichloromethyl chloroformate in the presence of
triethylamine to give a mixed carbonic anhydride as activated intermediate.
Nucleophilic attack of the N-methoxy-N-methyl amine on the carbonyl carbon in the
activated anhydride affords desired Weinreb amide (Scheme 2.15). 8
64
2.3.1.10. Reetz et al. synthesized the Weinreb amides according to the Weinreb and
Nahm method 23 and reacted with alkyllithium or Grignard reagents to form ketones
(Scheme 2.16).
2.3.1.11. Tiwari and coworkers developed a Weinreb amide derived from propiolic
acid. (Scheme 2.17). 24
2.3.1.12. De luca et al. used 1,3,5-triazine derivatives in organic synthesis and thus
they reported a new simple and high-yielding one-flask synthesis of Weinreb amides
from carboxylic acids and N-protected amino acids that use different 1,3,5-triazine
derivatives as the coupling agents. The method allows the preparation of Weinreb
amides and hydroxamates as O-benzyl and O-silyl hydroxamates that can be easily
transformed into hydroxamic acids (Scheme 2.18). 25
65
2.3.1.13. Recently Niu et al. synthesized Weinreb intermediate from carboxylic
acids using tris[methoxy(methyl)amino]phosphine, a very powerful reagent prepared
from phosphorus trichloride and N,O-dimethyl hydroxylamine (Scheme 2.19). 26
2.3.1.14. Kommidi et al. synthesized Weinreb amide derivative starting from

carboxylic acid in three steps (Scheme 2.20). 27
66
2.3.2. Synthesis of Weinreb amides from Acid Chloride
2.3.2.1. It is relatively straightforward to convert an acid chloride to an N-methoxy-N-

methyl amide. Treatment of an acid chloride in methylene chloride or chloroform and
N,O-dimethylhydroxylamine hydrochloride at 0 °C with 2.2 equivalents of pyridine
affords the corresponding amides in excellent yields. Acid chlorides are inexpensive,
highly reactive intermediates which are easy to prepare and isolate. 29
The product isolation is carried out by aqueous workup. The product amides are stable
and can be purified readily by chromatography, crystallization, and/or distillation.
N,O-dimethylhydroxyl-amine hydrochloride is commercially available (moderately
expensive). Sibi et al. described a convenient procedure for the preparation of the
starting N,O-dimethylhydroxylamine (Scheme 2.21). 2a
2.3.2.2. Carpino et al. have reported the synthesis of Fmoc-α-amino acid chlorides and
demonstrated their utilization in peptide synthesis (Scheme 2.22). 28
2.3.2.3. Also, Sureshbabu et al. described an efficient, cost-effective method for the
preparation of N-Fmoc-α-amino/peptidyl Weinreb amides from the corresponding
acid chlorides and the synthesis of acid chlorides was accelerated by ultrasonication and
were coupled with N,O-dimethylhydroxylamine hydrochloride to obtain the title
29
compounds (Scheme 2.22).
67
2.3.2.4. Tiwari et al. synthesized Weinreb derivative using commercially available
β-bromo-propanoyl chloride with N,O-dimethylhydroxylamine hydrochloride
(Scheme 2.23). 30
2.3.2.5. Jaunky et al. condensed acid chloride with Weinreb amide to afford the
corresponding derivative of the same (Scheme 2.24). 31
2.3.2.6. Jumde et al. synthesized Weinreb amide derivative starting from acid chloride
32
(Scheme 2.25).
68
2.3.3. Synthesis of Weinreb amides from lactones, esters, acetate and amides
Esters and lactones have been converted into their Weinreb amides by the combined
use of 2-5 equivalents of trimethylaluminum or dimethylaluminum chloride or
1e
dibutylaluminum hydride with dimethylhydroxylamine (DMHA) hydrochloride.
The reaction between the aluminium amide derived from N,O-dimethylhydroxyl
amine and lactones also provide a ready route to the N-Methoxy-N-methyl amides.
2.3.3.1. Kocienski and co-workers have used this method for the preparation of
cyclohexenecarboxamide in good yield (Scheme 2.26). 33
2.3.3.2. Evans et al. made use of the transamination procedure developed by

Weinreb in the preparation of many intermediates required in the construction of
34
complex natural products. The cyclic chiral auxiliary is a better leaving group
than N(OMe)Me and can be recovered. The aluminium amide solution is prepared
by careful addition of trimethylaluminum in toluene to a suspension of N,O-
dimethylhydroxylamine hydrochloride in methylene chloride at 0 oC (Scheme
2.27).1c
2.3.3.3. Yun et al.35 synthesized enantiomerically pure 2-acyl aziridines from the
1,2a
corresponding aziridine-2-carboxylate via Weinreb amide (Scheme 2.28).
69
2.3.3.4. Basha and co-workers successfully converted ester to amide in a simple step
since it is a potentially useful synthetic operation. Sometime aminolysis of esters
requires high temperatures and/or long reaction time and strong metal catalysts
(Scheme 2.29). 36
2.3.3.5. Shimizu et al. describe an efficient method for preparation of N-Methoxy-N-

methyl amides from lactones or esters using Me2AlClMeONHMe.HCl. In synthetic
studies of natural products, it was found the general method using Me3A1-
MeONHMe.HCl, however, gave unsatisfactory results in the case of sterically
hindered lactones. After several attempts to improve the aminolysis, they have found
that dimethylaluminum chloride and N, O-dimethylhydroxylamine hydrochloride
(Me2AlCl-MeONHMe.HC1) smoothly reacted with the lactones to afford the
desired N-methoxy-N-methyl amides in excellent yield (Scheme 2.30). 37
70
2.3.3.6. Williams et al. prepared various N-Methoxy-N-methylamides from esters
using isopropyl magnesium chloride (Scheme 2.31). 38
2.3.3.7. Mata et al. synthesized Weinreb amides starting from commercially

available methyl α,α-dimethoxyacetate or ethyl α,α-diethoxyacetate (Scheme
2.32). 39
2.3.4. Synthesis of Weinreb amide from anhydride
The N-methoxy-N-methyl amides can also be obtained from the corresponding

anhydrides and N,O-dimethylhydroxylamine by nucleophilic displacement.
2.3.4.1. The synthesis of the half amide acid, (an intermediate in the synthesis of
37
(+/-)-Paniculide-A) derived from glutaric acid. This method succeeded smoothly
even with sterically hindered lactones or esters (Scheme 2.33).
71
.
2.3.5. Synthesis of Weinreb amide from aldehyde
2.3.5.1. Singh et al. converted the aldehydes directly to Weinreb amide. Aldehydes
under oxidative conditions using N-bromosuccinimide and catalytic AIBN produced
in situ the acyl bromides, which on reaction within the presence of triethylamine
41
afforded the Weinreb amide (Scheme 2.34).
2.3.6. Synthesis of Weinreb amide of α, β -Unsaturated compound.
2.3.6.1. The α,β-Unsaturated N-methoxy-N-methyl amide can be obtained from

18a
either the corresponding carboxylic acid or a stabilized Wittig or Wittig-Homer
26
reagent. Reactions with these easily synthesized reagents work well providing the
amides in good to excellent yields. The chemistry of the dimethyl phosphonate
14d
analogue has been reported. The reactions of aldehydes with phosphonate 172
proceed in good yields providing amides 174 with very high enantioselectivity.
(Scheme 2.35). 42
72
2.3.7. Synthesis of Weinreb amides from aryl halides
2.3.7.1. Dang and coworkers synthesized Weinreb amides from aryl bromides using
43
Pd/ZIF-8 catalyzed aminocarbonylation (Scheme 2.36).
2.3.7.2. Martinelli et al. synthesized Weinreb intermediate via Pd-Catalyzed

Aminocarbonylation (Scheme 2.37).44
2.3.8. Synthesis of Weinreb amide from Acetatate derivative
2.3.8.1. Simple vinylogous urea was readily prepared by de Koning et al. by

alkylating 3-(2-thioxo-1-pyrrolidinyl propyl) acetate, a known compound with N-
methoxy-N-methyl-2-bromoacetamide for the enantioselective synthesis of the
amphibian alkaloid (5R,8R,8aS) -(-)-indolizidine (Scheme 2.38). 45
73
2.3.8.2. Nuzillard et al. synthesized Weinreb α-(BTFP sulfonyl) acetamide, an
efficient reagent for the stereoselective synthesis of Weinreb amides by the Julia-
Kocienski olefination of aldehydes by using 2-bromo-N-Methoxy-N-methyl
46
acetamide (Scheme 2.39).
2.3.9. Synthesis from ketone and aldehydes
2.3.9.1. Sakoh et al. tried a direct transformation from ketone to the amide by utilizing a
Horner-Emmons reagent that already possesses a Weinreb amide moiety (Scheme 2.40). 47
74
2.3.9.2. Toy et al. were first converted commercially available 4-(triflouromethyl)
benzaldehyde to the Weinreb amide by Wittig olefination with N-methoxy-N-methyl-
48
2-(triphenylphosphoranylidene)acetamide (Scheme 2.41).
2.3.9.3. Ghosh et al. synthesized N-methoxy-N-methyl-(1,3-benzothiazol-2-

ylsulfonyl)fluoroacetamide, a building block for Julia olefination, was reported
(Scheme 2.27). This regent undergoes condensation reactions with aldehydes and
cyclic ketones to give an α-fluorovinyl Weinreb amide (Scheme 2.42). 49
2.3.10. Synthesis of Weinreb amide by Mitsunobu reaction
2.3.10.1. Hong et al. synthesized Weinreb intermediate by Mitsunobu reaction to

synthesise bicyclic enone (Scheme 2.43).50
75
2.5.Objective and strategy
It is seen that excellent synthetic intermediates developed based on the unique amide
of Weinreb have been extensively used for the preparation of various simple and
complex molecules. It is also expected that the Weinreb amide prepared from the title
acids is an ideal choice for the synthesis of chiral, six carbon bis-furan part of the anti-
HIV Drug Darunavir. (Scheme 2.44 &2.46).
2.5. Results and discussion
The title acids were conveniently converted to regiochemically different Weinreb amides
(78 and 197) as per the Scheme 2.46. Upon reaction of the diacid chloride 203 with N,O-
dimethylhydroxylamine resulted in the formation of 78. Monomethyl ester of Garcinia
76
acid (2S,3S)-3-acetoxy-2-(ethoxycarbonyl)-5-oxotetrahydrofuran-3-carboxylic acid (210),
obtained from the anhydride (85) was converted to the other regioisomer, (2S,3S)-3-
acetoxy-3-(methoxy(methyl)carbamoyl)-5-oxotetrahydrofuran-2-carboxylic acid (197).
2.5.1. Synthesis of Weinreb amide from Acid Chloride of Garcinia acid
The disodium salt of Garcinia acid, disodium (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,

3-dicarboxylate, 202 was converted to the acid chloride (203) and was used for the
preparation of Weinreb amide namely, (2S,3S)-3-hydroxy-2-(methoxy (methyl)
carbamoyl)-5-oxotetrahydrofuran-3-carboxylic acid (78). By stirring the acid chloride
(203) with pyridine (2 equivalents) in dichloromethane, furnished the Weinreb amide
(78) in the crystalline form (Scheme 2.46).
2.5.2. Synthesis of Weinreb amide from anhydride of Garcinia acid
The Weinreb amide also was prepared from the anhydride (85) of Garcinia acid. The
anhydride was converted to the monomethyl ester, (2S,3S)-3-acetoxy-2-
(ethoxycarbonyl)-5-oxotetrahydrofuran-3-carboxylic acid (210), in dichloromethane
medium. Upon treatment of this monoester with Weinreb amine, 117 and oxalyl
chloride in DMF furnished the Weinreb amide, (2S,3S)-3-acetoxy-3-(methoxy
(methyl)carbamoyl)-5-oxotetrahydrofuran-2-carboxylic acid (197). (Scheme 2.46)
77
2.5.3. Synthesis of (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, the
bis furan part of anti HIV drug Darunavir starting from Weinreb amide
Taking advantage of the six carbon skeleton of the Weinreb obtained from the
Garcinia acid, the synthesis of (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-3,3a(6aH)-
diol (30), was carried out. This fused bis-furan molecule is found in the anti-HIV drug
Darunavir (211). In fact, more than 50% of the cost of the drug Darunavir is due to
the molecule 30. Thus, the new method is operationally simple, economically viable
and superior to some of the existing methods. Only Weinreb amid197 can directly
give access to the bis-furan skeleton (Scheme 2.47).
78
2.5.3.1. Synthesis of (3aS,6aS)-2,4,6-trioxotetrahydrofuro[3,4-b]furan-3a(4H)-yl
acetate starting from Garcinia acid
The anhydride was prepared by refluxing Garcinia acid in acetyl chloride for 2.5h
until all the acid dissolves, upon cooling, the solution became solid and it was washed
several times with hexane to remove excess reagent and bi-product to obtain white
crystals of anhydride (3aS,6aS)-2,4,6-trioxotetrahydrofuro[3,4-b]furan-3a(4H)-yl
acetate of Garcinia acid (85) (scheme 2.49).
This solid was characterised using IR, 1H NMR and 13C NMR. The IR spectrum of 78
clearly indicates the characteristic absorption frequencies at 1800.32 and 1738.03 cm-1
corresponds to anhydride and γ-lactone carbonyl groups. The 1H NMR spectrum
shows singlet at δ 5.91 (methine proton), double doublets at δ 3.675 and 3.38
(diastereotopic methylene group in the ring) and a singlet at δ 2.157 (-O-CO-CH3).
The 13C NMR spectrum shows signals at δ 172.5, 171.0,167.5, 166.3, 81.3, 79.5, 36.1
and 19.9 ppm. Exact mass calculated for C8H7O7 (M+H)+ is 215.0192 and value
experimentally found is 215.0182
IR (ATR)
79
1
H NMR, 400 MHz, Solvent : CDCl3
13
C NMR,100 MHz, Solvent : CDCl3
80
2.5.3.2. Synthesis of sodium (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate starting from Garcinia acid
To an aqueous solution of 1 (2.0 g, 10.5 mmol, in 10 mL water), saturated aqueous
sodium bicarbonate was added until the pH of the reaction mixture became neutral.
The residue obtained after evaporation of the reaction mixture under reduced pressure
was triturated and washed with dry acetone (5x20 mL). The product was finally dried
under vacuum to give colourless solid. The product was characterised using IR, 1H
NMR, 13C NMR (Scheme 2.49).
IR (film) spectrum of the compound showed the characteristic absorption bands at 1798
cm-1 (γ-lactone carbonyl), 1601 cm-1 (carboxylate group). The 1H NMR spectrum of
151 showed signals at 3.02-2.65 (AB pattern; due to methylene protons). The 13C NMR
spectrum displayed six signals at 178.1, 175.8, 173.2, 87.7, 80.2 and 41.2.
IR(ATR)
81
1
H NMR, 400 MHz, Solvent : D2O
13
C NMR ,100 MHz, Solvent : D2O
2.5.3.3 Synthesis of (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarbonyl

dichloride starting from disodium salr of Garcinia acid
To a suspension of 151 (1 g, 4.4 mmol) in ether (10 mL), 2 equiv. thionyl chloride (7
mL, 10 mmol) was added. The reaction mixture was stirred for 2h at room
temperature. Filtration followed by evaporation of the reaction mixture yielded acid
chloride (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarbonyl dichloride (203) as
fuming solid (Scheme 2.50).
82
Acid chloride was highly hygroscopic and fuming and it was only able to characterize
using IR.
IR(ATR)
2.5.3.4. Synthesis of (2S,3S)-3-hydroxy-2-(methoxy(methyl)carbamoyl)-5-

oxotetrahydrofuran-3-carboxylic acid
1 mmol of acid chloride (203) (0.7 g, 3.1 mmol) and N,O-dimethyl hydroxylamine
hydrochloride (1.89 g, 3.32 mmol) was dissolved in 10 mL of dichloromethane at
room temperature. The solution was cooled to 0 oC and 6.6 mmol of pyridine was
added. The mixture was stirred at ambient temperature for l h and evaporated in
vacuum. The residue was partitioned between brine and dichloromethane. The organic
layer was dried with sodium sulphate and concentrated to afford the amide which was
purified by silica gel chromatography. Product was obtained as a white crystalline
solid and characterised using IR, 1H NMR, 13
C NMR melting point and XRD
(Scheme 2.51).
83
IR (film) spectrum of the compound showed the characteristic absorption bands at
ν(cm-1) 1775 (γ-lactone carbonyl), 1727 (acid carbonyl), 1658 (amide carbonyl). The
1
H NMR spectrum of 78 shows signals at 5.33(singlet; due to methine proton), 3.78
13
(singlet, due to-OCH3 proton), 3.11 (singlet, due to –NCH3 proton). The C NMR
spectrum signals δ174.9,171.3,169.1 corresponds to carbonyls and other signals at
83.4,79.9,61.9,40.7,33.1. The structure was further confirmed by XRD.
IR(ATR)
84
1
H NMR, 400 MHz, Solvent : Acetone-d6
13
85
HRMS
XRD
86
2.5.3.5. Synthesis of (2S,3S)-3-acetoxy-2-(ethoxycarbonyl)-5-
oxotetrahydrofuran-3-carboxylic acid
1 mmol of acid anhydride (85) was added with excess dry Ethanol at 0 oC. The
solution was cooled to 0 °C and the mixture was stirred at room temperature for l hour
and evaporated in vacuum. Recrystallization of the crude mass in Hexane/
Chloroform obtained 86 as white crystals (Scheme 2.52).
The product was confirmed by 1H NMR, 13C NMR, XRD. The 1H NMR spectrum
showed signals at δ 5.13 (single due to methine proton), δ 4.28-3.57 (AB pattern;
corresponding to the methylene protons), δ 2.21 (singlet- CH3 protons). Ten different
13
signals in the C NMR spectrum at δ 171.7, 169.9, 168.3, 165.6, 83.35, 80.9, 63.1,
37.1, 20.6, 13.8 also confirmed the structure.
IR(ATR)
87
1
13
ORTEP
88
HRMS
2.5.3.6. Synthesis of ethyl (2S,3S)-3-acetoxy-3-(methoxy(methyl)carbamoyl)-5-

oxotetrahydrofuran-2-carboxylate
1 mmol of (2S,3S)-3-acetoxy-2-(ethoxycarbonyl)-5-oxotetrahydrofuran-3-carboxylic acid
(86) was dissolved in DCM. The solution was cooled to 0 oC and oxalyl chloride was
added along with 2-3 drops of DMF to afford monoacid chloride, which was then
quenched with N,O-dimethylhydroxylamine and Pyridine to obtain the 197 (Scheme
2.53).
The product was confirmed with 1HNMR, 13 C NMR, 2D NMR techniques including
COSY, HMBC, HMQC, DEPT-45, DEPT-90, DEPT-135, IR, and Mass spectra. The
1
H NMR spectrum showed signals at δ 5.17 (singlet due to methine proton), δ 4.27-
89
4.22 (multiplet due methylene proton), δ 3.75-2.94 (AB pattern; corresponding to the
methylene protons), δ 3.72 (singlet- OCH3 group), δ 3.16 (singlet- NH3 protons), δ
1.31-1.27 (multiplet due to methyl protons). Twelve different signals in the 13C NMR
spectrum at δ 172.6, 169.1, 165.8, 165.6, 85.9, 81.2, 62.8, 61.1, 37.2, 33.7, 21.0, 13.9
also confirmed the structure. A single crystal XRD analysis was done to confirm the
structure. This is the first report of the single crystal XRD of 197.
IR(ATR)
1
90
13
C NMR,100 MHz, Solvent: CDCl3
DEPT-135 100 MHz, Solvent : CDCl3
COSY, CDCl3
91
HMBC
HSQC
HRMS
92
XRD
2.6. Conclusion
A systematic account of the synthesis and application of Weinreb amides have been
presented. Two different types of Weinreb amides, namely 2S,3S)-3-hydroxy-2-
(methoxy (methyl)carbamoyl)-5-oxotetrahydrofuran-3-carboxylic acid (78) and
(2S,3S)-3-acetoxy-3-(methoxy(methyl) carbamoyl)-5-oxotetrahydrofuran-2-carboxylic
acid (197) have been prepared using naturally occurring (2S,3S)-3-hydroxy-5-
oxotetrahydrofuran-2,3-dicarboxylic acid (1). These molecules are found to be an
ideal choice for the preparation of (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-
3,3a(6aH)-diol (30), a six carbon analougue of bis-furan part of the anti-HIV drug
Darunavir (211). This route towards the synthesis of bis-furan part of Darunavir is
more convenient and inexpensive than the already known methods.
All reagents were commercially available and used without further purification. All
the reaction temperatures shown are bath temperatures. 1H NMR (400 MHz) and 13C
NMR (100 MHz) were measured on a Bruker AV 400 spectrometer. Chemical shifts
are expressed in parts per million (ppm) relative to TMS (δ=0) and coupling constants
are reported as Hertz (Hz). Data are reported as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet
93
of doublet of doublets, dddd = doublet of doublet of doublet of doublets, p = pentet, br
= broad, m = multiplet), coupling constant, and integration. Melting points were
determined on ‘’Sunbim’’ make electrically heated melting point apparatus and were
uncorrected. IR spectra were recorded using a Shimadzu IR 470 spectrophotometer as
KBr pellets (solids) or thin films (liquids) and Thermo Fisher Is 10 FTIR spectrometer
with diamond ATR and is reported as wavenumber (cm–1). Electron impact mass
spectra were recorded on a Finnigan MAT MS 8230 or Jeol D-300, Jeol-JMS600.
HRMS were recorded on Micromass UK, Q-TOF. Optical rotations were measured on
a Rudolph IV Autopol polarimeter operating at the sodium D line with a 100 mm path
length cell, and are reported as follows: (concentration (g/100 mL), solvent).
Column chromatography was carried out with Merck product silica (silica gel 60-120
mesh) and thin-layer chromatography was carried out with Merck product silica
(silica gel G for TLC).
2.7.1. Experimental Details
2.7.1.1 Synthesis of (3aS,6aS)-2,4,6-trioxotetrahydrofuro[3,4-b]furan-3a(4H)-yl

acetate (85)
6 mL of acetyl chloride was added into a round bottom flask containing 1 (7 mmol) at
the ice-cold condition. The reaction mixture was then kept under refluxing conditions
until the acid solubilizes completely. The reaction mixture was then chilled with ice to
obtain solid mass, which then washed several times with dry hexane to obtain white
crystals of 85.
94
Yield 95% (1.09 g)
Melting Point 100-105 °C
IR (ATR) 2955, 2924, 1800, 1738 cm-1.

1
H NMR (CDCl3, 400 MHz) δ 5.91 (s, 1H), 3.65 (d, J =19.2 Hz, 1H),
3.46(d, J =19.2 Hz, 1H), 2.16(s, 3H) ppm.
13
C NMR (CDCl3, 100 MHz) δ 172.5, 170.9, 167.4, 164.3, 81.3, 79.5,
36.1, 19.9 ppm.
2.7.1.2. Synthesis of disodium (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylate (202)
To an aqueous solution of 1 (2.0 g, 10.5 mmol, in 10 mL of water), saturated aqueous

sodium bicarbonate was added till the pH of the reaction mixture became basic (ca 15
mL). The solution was maintained at pH 9 for 4h. The residue obtained after
evaporation of the reaction mixture under reduced pressure was triturated and washed
with dry methanol followed by acetone (5 X 20 mL). The product 202 was finally
dried under vacuum to give a colourless solid.
95
Appearance White powder
Yield 95% (2.45 g)
[]25 +81.8 (c 1.6, H2O)

D
IR (ATR) 3501,1798, 1601 cm-1

1
H NMR (D2O, 400 MHz) δ 3.62 (s, 1H); 3.02 (d, J =16 Hz, 1H), 2.65
(d, J = 16 Hz,1H) ppm.
13
C NMR (D2O, 100 MHz) δ 178.1, 175.8, 173.1, 87.7, 80.2, 41.2 ppm.
Molecular Formula C6H4O7Na2
Found C 30.68, H, 1.70
Calculated C 30.76, H, 1.71
2.7.1.3. Synthesis of 3-Hydroxy-5-oxo-tetrahydro-furan-2, 3-dicarbonyl

dichloride (203)
To a suspension of 202 (1 g, 4.4 mmol) in ether (10 mL), thionyl chloride (7 mL, 10
mmol) was added. The reaction mixture was stirred for 2h at room temperature.
Filtration followed by evaporation of the reaction mixture yielded acid chloride as
fuming solid.
Yield 82%(0.81 g)
IR(ATR) cm-1 1804 (acid chloride),

1755 (γ-lactone)
Molecular formula C6H4Cl2O5
Molecular mass 225.9436
96
2.7.1.4. Synthesis of (2S,3S)-3-hydroxy-2-(methoxy(methyl)carbamoyl)-5-
oxotetrahydrofuran-3-carboxylic acid (78)
1 mmol of acid chloride (203) (0.7 g, 3.1 mmol) and N,O-dimethyl hydroxylamine
hydrochloride (1.89 g, 3.32 mmol) was dissolved in 10 mL of dichloromethane at
room temperature. The solution was cooled to 0 oC and 6.6 mmol of pyridine was
added. The mixture was stirred at ambient temperature for l h and evaporated in
vacuum. The residue was partitioned between brine and dichloromethane. The organic
layer was dried with sodium sulphate and concentrated to afford the amide which was
purified by silica gel chromatography.
Yield 72% (0.67 g)
MP 115 oC
IR (ATR) cm-1 3456, (OH broad), 1775(γ-lactone

carbonyl), 1727 (acid carbonyl),
1658(amide carbonyl).
1
H NMR (Acetone-d6, 400 MHz) 5.33 (s, 1H); 3.78 (s, -OCH3 , 3H), 3.11
(s,- NCH3,3H), 3.18(d,1H),2.58(d,1H)
ppm
13
C NMR (Acetone-d6, 100 MHz) 174.9, 171.3, 169.1, 83.37, 79.9,
61.9,40.7,33.1 ppm.
Molecular Formula C8H11NO7
HRMS (TOF MS ES+) m/z calcd 233.0536, found 233.0309

for C8H11NO7 (M +)
97
2.7.1.5 (2S,3S)-3-acetoxy-2-(methoxycarbonyl)-5-oxotetrahydrofuran-3-
carboxylic acid (86)
To 1 mmol of acid anhydride (85) (1.2 g, 4.6 mmol) was added with excess dry
Ethanol at 0 oC. The solution was cooled to 0 °C and the mixture was stirred at room
temperature for l h and evaporated in vacuum. Recrystallization of the crude mass in
Hexane/ Chloroform obtained 86 as white crystals.
Yield 90% (1.2 g)
MP 121o C-122o C
IR (ATR) cm-1 3486, 1804, 1738

1
H NMR (CDCl3, 400 MHz) δ 5.13(s, 3H), 4.282(q, 2H, J= 4.8 Hz),
3.577(d, 1H), J=18.4 Hz), 3.000(d, 1H,
J= 18.4 Hz), 2.210(s, 3 H), 1.314(s, 3H).
13
C NMR (CDCl3, 100 MHz) δ 171.7, 169.9, 168.3, 165.6, 83.4, 80.9,
63.11, 37.0, 20.7, 13.8 ppm
98
2.7.1.6. Synthesis of Ethyl (2S,3S)-3-acetoxy-3-(methoxy(methyl)carbamoyl)-5-
oxotetra hydrofuran-2-carboxylate (197)
To a solution of hemiester 86 (1 g, 3.5 mmol) in DCM (5 mL), was added oxalyl

chloride (2 mL of 2M solution in DCM, 4 mmol) at room temperature. DMF was
added dropwise to the reaction mixture at 10 °C and gas evolution was observed. The
reaction mixture was stirred at 30 °C for 3 h and was evaporated under reduced
pressure to an orange oil. The oil was co-evaporated with DCM (2 x 5 mL) to remove
residual oxalyl chloride. The resultant oil was dissolved in DCM (5 mL) and cooled to
-5 °C. N,O-dimethylhydroxylamine (470mg, 5 mmol) and pyridine (0.8 mL, 10
mmol) were dissolved in DCM (5 mL), this solution was added dropwise to the acyl
chloride solution at 5 °C over 15 min. The reaction mixture was stirred at room
temperature for 20 h and was diluted with DCM (10 mL) Further, it was washed with
1 N aqueous hydrochloric acid (5x 10 mL), water (50 mL) and brine (50 mL). The
organic solution was dried over anhydrous sodium sulfate, filtered, and evaporated
under reduced pressure to give red solid, purified by column chromatography on silica
gel (SiO2, 7:3 hexane/EtOAc) to afford 197 as a white crystals.

Yield 78% (0.76 g)
MP 93.8 oC
[]25 + 82.143° (c ,0.28, CHCl3)
D
1
H NMR (CDCl3, 400 MHz) δ 5.17(s, 1H), 4.27-4.22(m, 2H), 3.756(d, 1H,
J= 16.2 Hz), 3.727(s, 3H), 3.164(s, 3H),
2.9485(d, 1H, J= 16.2 Hz), 2.173(s, 3H), 1.314-
1.278(m, 3H).
13
C NMR (CDCl3, 100 MHz) 172.6, 169.1, 165.8, 165.6, 85.9, 81.2, 62.8,
61.1, 37.2, 33.7, 21.0, 13.9.
99
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104
Chapter 3
Investigations on the synthesis of the non-racemic analogue

of furo[2,3-b]furanol: A non-peptidic high affinity P2
ligand for anti-HIV drug Darunavir
3.1 Introduction
Human immunodeficiency virus infection and acquired immune deficiency syndrome

(HIV/AIDS) is a spectrum of conditions caused by infection with the human
immunodeficiency virus (HIV)1 and is one of the most destructive epidemics in
documented history and remains a major global health problem due to the emergence
of drug-resistant strains.2 Currently, HAART (highly active antiretroviral therapy)
combining protease inhibitors (PIs) and reverse transcriptase inhibitors is proven to be
an effective treatment against AIDS. To this end, continuous efforts have been
devoted to the development of new and existing classes of HIV PIs due to resistance.
1
Darunavir (211), brecanavir3(212), SPI-2563(213) and GS-83743,4(214) are novel
HIV PIs and have shown high efficacy in the treatment of multidrug-resistant HIV2,3.
Despite the availability of more than 20 approved drugs for the treatment of human
immune deficiency virus(HIV) infection, many new compounds are in development
in both new and existing classes of HIV inhibitors.4 Current protease inhibitors
contain peptide-like fragments that lead to the rapid emergence of drug resistance.
The development of non-peptide molecules active against PI-resistant mutants
brought out the focus on anti-HIV research.
A second-generation PI later developed by Tibotec was first synthesized by Arun K.

5
Ghosh et al. Darunavir is currently approved in over 80 countries and was granted
approval by the FDA on June 23, 2006. Darunavir is one of the most recently
developed protease inhibitors and sold under the name PREZISTA TM 6
Darunavir is a next-generation nonpeptide PI that exhibits potent antiviral activity

with low toxicity in vitro and in vivo. It is extremely potent against both wild-type and
multidrug-resistant (MDR) viruses in vivo as well as in vitro and is administered in
combination with a low dose of ritonavir and other active anti-HIV agents. In 2008,
105
Darunavir received full approval for both treatment-native and treatment-experienced
HIV/AIDS patients. All these compounds are useful for treating human patients
infected with a human retrovirus such as human immune deficiency virus (strains
HIV-1 or HIV-2) or human T-Cell leukaemia viruses (HTLV-1 or HTLV-2) which
results in acquired immune deficiency syndrome(AIDS) and related diseases.7
A common structural feature of the Darunavir (211), brecanavir (212), SPI-256 (213)
and GS-8374(214) are (3R,3aS,6aR)-hexahydrofuro[2,3-b] furan-3-ol(bis-THF
alcohol) moiety and the significance of bis-THF alcohol derivatives for combating
drug resistance is well documented.3,8
3.1.1. Context of the invention of Darunavir
The office of AIDS Research Advisory Council (OARAC) endorsed this treatment
option for treatment-experienced adults and adolescents. Early PI often has side
effects and drug toxicity requires a high therapeutic dose, is pricey to production, and
shows a disturbing susceptibility towards drug-resistant mutations.8a
106
Darunavir exhibits a dual mechanism of action as it is an inhibitor of HIV protease
and a potent inhibitor of the dimerization of HIV protease monomer. 6 Designing
conformationally constrained nonpeptidic molecules of a cyclic or heterocyclic
nature, adopted to maximize the active site interactions. The distinctive observation
that led to the invention of darunavir was that an inhibitor making extensive
hydrogen-bonding interactions with the protein backbone of the wild-type enzyme
will also maintain potency against mutant strains. These observations lead to the
designing of an inhibitor moiety 94017(TMC-114) (211) with a bis-THF as the P2
ligand and p-aminosulfonamide as the P20 ligand. the moiety capable of impressive
inhibitory properties, selected for clinical development at Tibotec-Virco, Belgium and
termed as darunavir.9
The P2 and P20-ligands of Darunavir are involved in extensive hydrogen bonding

with the protein backbone, which is revealed by Inhibitor-bound X-ray structure
analysis. This may be responsible for its potency and wide-spectrum activity against
multi-PI-resistant HIV-1 variants. It was tested against a panel of 20 HIV variants
resistant to current PI’s, but there was no greater than a 5-fold increase in ID50
values, indicating it remained active against the resistant strains. The P20-amine
group displayed more favourable pharmacokinetic properties compared to the P20-
methoxy group in the inhibitor molecule. Clinical trials of ritonavir-boosted darunavir
(DRV/r) were carried out with treatment-experienced patients who were no longer
benefiting from available PIs. Both studies showed that combination therapy using
DRV/r led to a reduction in viral load below 50 copies/mL in 45% of participants
compared with only 12% of participants given another available PI over a period of
six months. Darunavir, used in combination with the fusion inhibitor FUZEON
substantially increases the chance of reaching undetectable viral load, proved in
recent studies.9
107
The bis-THF ligand (177) of Darunavir is present in the fused poly ether templates of
natural products. The cyclic ether templates in the depicted natural products very
likely forms polar hydrogen-bonding interactions with peptides or protein residues. It
occurs as an outcome of millions of years of evolutionary selection and possesses
adequate biological fitness. This phenomenon thrilled and inspired the research group
of A.K. Gosh to synthesize novel bis-THF ligand for HIV-1 protease inhibitors such
as Darunavir that improves antiviral activity and pharmacological properties.9a
A new class of various protein-ligand complexes, nonpeptidic high-affinity P2 ligands for

the HIV protease substrate-binding sites were designed and these ligands are
conformationally constrained with a fused bicyclic feature. The inhibitor incorporating
the P2 ligand- (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-ol is the most potent
compound in the series (177). The moiety evinced stereochemistry, the position of
oxygen, substitution in the ring, and ring size through various structure reactivity studies.
The incorporation of bis-THF ligand not only provided a protease inhibitor with reduced
molecular weight but led to improved aqueous solubility and decreased log P value9b. The
molecular weight of the bis-THF is essentially one-half the combined molecular weight
of the other P2 and P3 active molecule of the inhibitor. It is noticed that ring size, the
position of the oxygens and stereochemistry of the bis-THF ligands are crucial.3,6
3.1.2. Antiretroviral drugs

There are currently 10 FDA-approved protease inhibitors: saquinavir10(216) sold
under the brand names Invirase and Fortovase, Ritonavir11(217), Darunavir1,4(219),
108
Indinavir12 (220), Tipranavir13(222), Fosamprenavir14(223), Nelfinavir15(224),
Atazanavir16 (218), Lopinavir16 (221), and Amprenavir2(225) (Fig 3.1.2.6). With the
exception of tipranavir, all the approved PIs are peptidomimetic transition-state
analogues that contain a nonhydrolyzable transition state isostere. The treatment of
HIV involves antiretroviral medications that fight HIV infection and slows down the
spread of the virus in the body. TMC 114 is a next-generation, synthetic non-peptidic
protease inhibitor(PI).17 People living with HIV generally take a combination of
medications called highly active antiretroviral therapy (HAART) or combination
antiretroviral therapy (cART). There are a number of subgroups of antiretrovirals,
such as: Protease inhibitors, Integrase inhibitors, Nucleoside/ nucleotide reverse
transcriptase inhibitors (NRTIs). Non-nucleoside reverse transcriptase inhibitors
(NNRTIs), and Chemokine co-receptor antagonists and entry inhibitors.
3.1.2.1. Protease inhibitors

Food and Drug Administration (FDA) approved anti-HIV drugs can be divided into
several groups: Protease Inhibitors (PIs), Fusion Inhibitors (FIs), Nucleoside Reverse
Transcriptase Inhibitors (NRTIs), Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Co-Receptor
Inhibitors (CRIs) and Integrase Inhibitors (INIs).Protease is an enzyme that HIV
needs to replicate. These medications bind to the enzyme and inhibit its action,
preventing HIV from making copies of itself. These include: atazanavir / cobicistat
(Evotaz), lopinavir / ritonavir (Kaletra), and darunavir / cobicistat (Prezcobix).
3.1.2.2. Integrase inhibitors

HIV needs integrase, another enzyme, to infect T cells. This drug blocks integrase.
These are often the first line of treatment due to their effectiveness and limited side
effects for many people. Integrase inhibitors include elvitegravir (Vitekta),
dolutegravir (Tivicay), and raltegravir (Isentress).
3.1.2.3. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

These drugs also referred to as "nukes," interfere with HIV as it tries to replicate. This
class of drugs include abacavir (Ziagen), lamivudine/zidovudine (Combivir), and
emtricitabine (Emtriva), tenofovirdisproxil (Viread).
109
3.1.2.4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
NNRTIs work in a similar way to NRTIs, making it more difficult for HIV to
replicate.
3.1.2.5. Chemokine co-receptor antagonists

These drugs block HIV from entering cells. However, doctors in the U.S. do not often
prescribe these because other drugs are more effective.
3.1.2.6. Entry inhibitors

Entry inhibitors prevent HIV from entering T cells. Without access to these cells, HIV
cannot replicate. As with chemokine co-receptor antagonists, they are not common in
the United States. People will often use a combination of these drugs to suppress HIV.
110
3.2. Various methods towards the synthesis of bis-THF alcohol
Various methods are available for the construction of the bis-THF alcohol structure
owing to its importance in drug discovery. One strategy reported by Ghosh et al. used
the exchiral pool approach which was also employed in later syntheses based on
D-diethyl malate, D-glucal and D-glyceraldehyde derivatives. The five-membered
fused nitrogen and oxygen heterocycles are a major constituent of many naturally
occurring and biologically active compounds. The important class of fused heterocycles
are hexahydrofuro[2,3-b]furan (228a), hexahydro-2H-furo[2,3-b]pyrrole (228b),
hexahydro-2H-furo[2,3-b]pyrrole (228c) and octahydropyrrolo[2,3-b]pyrrole (228d).
111
Table 3.2. Fused Nitrogen and Oxygen Heterocycles based on bis-THF alcohol
SI Biological References
Fused bicycles Analogues of fused bicycles
No significance
1 Anti-HIV Drug 2,6,9

candidate
2 Found in 17a
numerous natural
products including
(-)-physovenine
3 Found in 17b
numerous natural
products including
Millingtonin A
diglycosylated
alkaloid
1,2,4-triazolyl 23
octahydropyrrolo
[2,3-b] pyrroles
showing high
affinity and
selectivity at DA
D3 receptor
3.2.1 Sevenich et al. synthesized bis-THF alcohol, a key building block for several
clinical and experimental HIV Protease inhibitors, through a one-pot procedure using
furan and Cbz-protected glycolaldehyde (179) as starting material (Scheme 3.2.1). 3
112
3.2.2 Perhydrofuro[2,3-b]furans have been synthesized in high yield by radical
cyclization of unsaturated bromoacetals. Their transformation into tetrahydro
derivatives is described along with a radical annelation to 2,3-dihydrofuran by
tributyltin iodoacetate. In 1.1 equivalent of Bu3SnH and with initiation by AIBN
(PhH, 80 oC, 8h) cyclization of 234 and 233 occurred smoothly leading to 236 and
235 respectively in almost quantitative yields (scheme3.2.2). 18
3.2.3. Carra and co-workers synthesized crystalline form of GS-8374((3R,3aS,6aR)-

hexahydrofuro[2,3-b]furan-3-yl((1S,2R)-1-(4-((diethoxyphosphoryl)methoxy)phenyl)-3-
hydroxy-4-(4-methoxy-N-(2-methylpropyl)benzenesulphonamide]butan-2-yl)carbamate)7
from amorphous solid. Currently, the compound is known to exist in the amorphous
113
form and the amorphous form is sticky, difficult to disperse and prone to
deliquescence and it is a bis-THF based peptidomimetic HIV protease inhibitor (PI)
for treating HIV infection. Its functionality and method of making and therapeutic
uses are described in U.S.Pat.No.7,649,015B2 issued on Jan.19,2010. This compound
acts to inhibit retroviral proteases and thus inhibits the viral replication7 (Fig.3.2.3.1).
3.2.4. An efficient highly diastereoselective and enantioselective synthesis of the bis-

THF alcohol of several HIV Protease inhibitor, including Brecanavir and Darunavir has
been achieved utilizing an Evans Mukiyamaaldol reactions of (benzyloxy)acetaldehyde and
a silyl ketene acetal19 (Scheme 3.2.4).
3.2.5. Hayashi and coworkers developed an efficient synthetic method of Bis-THF

alcohol using diphenylprolinol catalyzed enantio and diastereoselective cross aldol
reaction of polymeric ethyl glyoxylate with an aldehyde as the key reaction. This
method is highly practical due to the use of environmentally benign organocatalysis
114
and inexpensive reagents, low catalyst loading and great reproducibility by the simple
pretreatment and the achievement of quite high purity with only single crystallization
20
(Scheme 3.2.5).
3.2.6. A simple and one-pot synthesis of enantiopure hexahydrofuro[2,3-b]furan-3-ol

was developed by Kanemitsu et al. The one-pot process involves an organocatalytic
condensation followed by an enzymatic optical resolution. The condensation of 1, 2-
dihydrofuran and glycolaldehyde were achieved using Schreiner’s thiourea catalyst. A
subsequent lipase-catalyzed kinetic resolution gave the target alcohol with >99% ee
21
(Scheme 3.2.6).
3.2.7. Ghosh et al. described a convenient synthesis of (3R,3aS,6aR)-3-

hydroxyhexahydro[2,3-b] furan, a high-affinity non-peptidal ligand for HIV protease
inhibitor UIC-94017. The synthesis utilizes a novel stereoselective photochemical
1,3-dioxolane addition to 5 (S)-benzyloxymethyl-2(5H)-furanone as the key step.
The requisite furanone derivative was prepared in high enantiomeric excess by an
115
immobilized lipase-catalyzed selective acylation of (+/-) -1-(benzyloxy) -3-buten-2-
ol and a ring-closing olefin metathesis with Grubbs catalyst.22 They also converted
optically active bis -THF to protease inhibitor UIC-94017 (Scheme 3.2.7).
3.2.8. The stereoselective novel synthesis of (3R,3aS,6aS)-hexahydrofuro[2,3-b]furan-3-

yl (2R,3S)-4-(4-amino-N-isobutyl phenyl sulfonamido)-3-hydroxy-1-phenylbutan-2-yl-
carbamate has been accomplished in situ from the intermediate 4-amino-N-((2S,3R)-3-
amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulphonamide by Babu and
coworkers. This reaction gives 88% yield, with an optical purity of 99.5% and
diastereomeric purity of 99 % for chiral alcohol 8a (Scheme 3.2.8).
116
3.2.9. Canoy and co-workers synthesized diastereoselective bis-THF alcohol of
Darunavir and other HIV drug candidate utilizing the novel cyclization of
glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalysed by a variety of
catalysts including those formed from tin(II) triflate and common chiral ligands such
as BINAP and Evans’s box ligands. An efficient and unique enzymatic process
enhanced the enantiomeric purity to provide the target in optically pure form
(Scheme 3.2.9). 4
3.2.10. A highly efficient method for synthesizing racemic hexahydro-[2,3-b]furan-3-

ol has been developed by Yu and coworkers utilizing a lanthanide catalyst such as
Yb(fod)3 to promote condensation of 2,3-dihydrofuran and glycolaldehyde dimer
(Scheme 3.2.10). 24
117
3.2.11. Kock et al synthesized substituted aminophenyl sulphonamide compounds
and derivatives, starting from tert-butyl ((S)-1-((S)-oxiran-2-yl)-2-phenylethyl)
carbamate for the development of HIV protease inhibitor (275). It concerns
combinations of the present substituted aminophenyl sulphonamide compounds and
derivatives with another anti-retroviral agent25 (Scheme 3.2.11 ).
3.2.12. Wigerinck and coworkers have synthesized novel bis-THF benzodioxolyl

sulphonamide compounds, an effective protease inhibitor starting from 2,3-
dihydrofuran 26 (Scheme 3.2.12).
118
3.2.13. Lemaire et al. developed a method for the preparation of hexahydrofuro [2,3-b]
furan-3-ol and especially its enantiomer (3R,3aS,6aR) hexahydrofuro[2,3-b]furan-3-ol as
well as certain novel intermediates starting from 2,3-dihydrofuran 27 (scheme 3.2.13).
3.2.14. In 1995, Ghosh et al. synthesized non-peptidyl ligands for the HIV Protease
substrate binding site. They reported the structure-based design of bis-THF ligands
that can effectively replace two amide bonds and a 10π-aromatic system of the present
clinical candidate saquinavir (166). These ligands were synthesized in optically pure
form utilizing 3(S)-or 3(R)-malic acid as starting material, and in their report, they
described an efficient synthetic route to these ligands in racemic form and their
enzymatic resolution providing optically active ligand with high enantiomeric excess
28
(Scheme 3.2.14).
119
3.2.15. In 2005, Ghosh et al. developed a method of synthesizing (3R.3aS,6aR)-3-
hydroxyhexahydrofuro[2,3-b]furan and related compounds in high yield and high
enantiomeric excess 29 (Scheme 3.2.15).
3.2.16. In 2016, Ghosh et al. reported the design, synthesis, X-ray structural studies
and biological evaluation of a novel series of HIV-1 Protease Inhibitors. They
designed a variety of functionalized biphenyl derivatives to make enhanced van der
Waals interactions in the SI Subsite of HIV-1 protease. These biphenyl derivatives
were conveniently synthesized by employing Suzuki-Miyaura cross-coupling
reactions as the key step. They examined the potential of these functionalized
biphenyl derived-PI ligands in combination with 3-(S)-tetrahydrofuranyl urethane
and bis-tetrahydrofuranyl urethane as the P2 ligands 30 (Scheme 3.2.16).
120
3.2.17. Moore et al. described a practical synthesis of (3R,3aS,6aR)-hexahydrofuro
[2,3-b] furan-3-ol, a key intermediate in the synthesis of Darunavir from
monopotassium isocitrate. The isocitric acid salt, obtained from a high yielding
fermentation fed by sunflower oil, was converted in several steps to a tertiary amide.
This amide along with the compound’s ester functionalities was reduced with LAH
and the obtained product was converted to the bicyclic acetyl furofuranol side chain
of Darunavir 31(Scheme 3.2.17).
3.3.Objective and strategy
Through the discussion so far, we have seen that chiral, fused five membered ring
systems, especially bis-THF ring systems, are indispensable structural entities present
in the non-peptide PI-based drugs developed for the treatment of AIDS and in fact this
moiety is responsible for almost 50% of the cost of the drug. In this background, it is
the objective of the present study is to synthesize (3R,3aS,6aS)-tetrahydrofuro[2,3-
b]furan-3,3a(6aH)-diol (30), an analogue of bis-furan part of anti-HIV drug Darunavir
(211). This approach may be the cheapest way to making available the bis-furan
skeleton of the drug Darunavir, as the starting molecule, Garcinia acid is abundantly
available. For the synthesise of 30, the chiral pyrrolidinedione, with substitution on the
3rd position of the ring (311) was prepared from (2S,3S)-tetrahydro-3-hydroxy-5-oxo-
2,3furandicarboxylic acid (1). The reduction of this pyrrolidinedione using NaBH4 in
ethanol (2 equivalent) yielded ((3R,3aS,6aS)-6-benzyl-3,3a-dihydroxyhexahydro-5H-
121
furo[2,3-b]pyrrol-5-one (313) and upon treatment of aqueous HCl/THF resulted in the
formation of (3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol
(80), an analogue of anti-HIV drug Darunavir (Scheme 3.4.1). The bis-THF moiety,
30, may find use as an intermediate for the synthesis of diverse structural entities.
(Scheme 3.1)
Scheme 3.1. Diverse methodologies that reveal bis-furan chemistry

With this background, attempts were made to synthesise the analogue of the bis-THF
part of (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol (30) using Garcinia
acid(1). The conversion of the isopropyl ester (310) to chiral pyrrolidinediones (311)
122
was carried out by refluxing diisopropyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate (264) in a stoichiometric amount of benzyl amines in toluene.
Reduction of isopropyl (S)-2-((S)-1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-2-
hydroxy acetate (311) using NaBH4 (3 equivalents) in ethanol provided (3R, 3aS,
6aS)-6-benzyl-3, 3a-dihydroxytetrahydro-2H-furo [2,3-b] pyrrol-5-one (313) as a
crystalline solid. A ring transformation reaction on this fused ring system is expected
to give (3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, 80.
For this conversion, 313 was refluxed with aqueous HCl-THF, resulted in the
rearrangement of furopyran ring system to the bis-furan ring system. Thus,
(3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol (80) was
isolated as an oil.
A repeated attempt to obtain 30 from 80 was unsuccessful.
123
On the basis of the results described above, a plausible mechanism is proposed in
Scheme 3.4.1.1a.
Alternatively, the furo[2,3-b]furanol part (30) was synthesised using Weinreb amide,
(2S,3S)-3-acetoxy-3-(methoxy(methyl)carbamoyl)-5-oxotetrahydrofuran-2-carboxylic
acid (197) obtained from 1 (Scheme 2.47-page 54).
3.4.1. Synthesis of dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-

dicarboxylate (310a) from (2S,3S)-terahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylic acid (1).
Dimethyl ester of (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid
(310a) has been prepared via refluxing the disodium salt, 202 in dry methanol and
thionyl chloride. The crude reaction mixture was concentrated under vacuum and the
solvent was dried over sodium sulphate. Dimethyl ester was obtained as a yellow oil
in 50% yield. The product was characterized using IR, 1H NMR, 13
C NMR, HRMS
and optical rotation (Scheme 3.4.1.1).
The IR absorption of 310a spectrum displays peaks at 3478 cm-1 (indicating the
presence of –OH groups), at 1801, 1732 cm-1 (due to the lactone and ester carbonyls).
124
The 1H NMR spectrum of 310a shows signals at δ 5.15 (singlet; corresponds to
methine proton), 3.95 and 3.84 (due to methoxy groups) and at 3.10 - 2.87 (AB
13
quartet; corresponding to the methylene protons). The C NMR spectrum showed
eight signals at δ 171.6, 171.4, 165.9, 82.1, 76.7, 54.4, 52.9 and 40.3. The mass
spectrum also shows a peak at m/z 219 corresponds to the molecular ion (Figure 3.5-
3.8).
IR(ATR)
1
125
13
C NMR ,100 MHz, Solvent : CDCl3
Mass spectrum
3.4.2. Synthesis of dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-

dicarboxylate (311a) from (2S,3R)-terahydro-3-hydroxy-5-oxo-2,3-
Dimethyl ester of (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid
(311a) has been prepared via refluxing the Hibiscus acid, 2 in dry methanol. The
crude reaction mixture was concentrated under vacuum and the solvent was dried over
sodium sulphate. Dimethyl ester was obtained as yellow oil in 50% yield. The product
126
was characterized using IR, 1H NMR, 13C NMR, HRMS and optical rotation (Scheme
3.4.1.2).
The IR absorption of 311a spectrum displays peaks at 3471 (indicating the presence
of –OH groups), at 1801, 1729 cm-1 (due to the lactone and ester carbonyls).The 1H
NMR spectrum of 311.a showed signals at δ 5.12 (singlet; corresponds to methine
proton), 3.95 and 3.84 (due to methoxy groups) and at 3.07 - 2.87 (AB quartet;
13
corresponding to the methylene protons). The C NMR spectrum showed eight
signals at δ 171.5, 171.3, 165.9, 82.0, 77.2, 54.4, 52.9 and 40.1. The mass spectrum
also shows a peak at m/z 219 corresponds to the molecular ion (Figure 3.5.a-3.8.a).
IR(ATR)
127
1
13
3.4.3. Synthesis of diisopropyl (2S,3S)-terahydro-3-hydroxy-5-oxo-2,3-

furandicarboxylate (310) from (2S,3S)-terahydro-3-hydroxy-5-oxo-2,3-
Diisopropyl ester of (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acid
(310) has been prepared via refluxing the title acid 1 (1.0 g, 4.4 mmol) in isopropanol
(10 mL) with catalytic amount of H2SO4 for 30hrs. The crude reaction mixture was
concentrated under vacuum and the solvent was dried over sodium sulphate.
Diispropyl ester was obtained as solid white crystal in 92% yield. The product was
128
characterized using IR, 1H NMR, 13
C NMR, HRMS and optical rotation (Scheme
3.4.1.3).
The IR absorption of 310 spectrum displays peaks at 3449 cm-1 (indicating the
presence of –OH groups), at 1799, 1735 cm-1 (due to the lactone and ester carbonyls).
The 1H NMR spectrum of 310 displays signals at δ 5.15-5.04 (multiplet; due to
methine protons of isopropyl group), at δ 4.85 (singlet; corresponds to methine
proton), at δ 3.10-2.81 (AB quartet; corresponding to the methylene protons) and at δ
1.33-1.28 (multiplet; due to methyl protons). The 13C NMR spectrum displays twelve
signals at δ 171.5, 169.9, 165.5, 83.9, 78.4, 72.4, 70.6, 39.8, 21.6, 21.5, 21.5 and 21.3.
The mass spectrum also shows a peak at m/z 274 corresponds to the molecular ion
(Figure 3.9-3.12).
IR(ATR)
129
1
13
Mass spectrum
130
3.4.4. Synthesis of isopropyl(R)-2-hydroxy-2-((S)-3-hydroxy-1-isopentyl-2,5-
dioxo pyrrolidin-3-yl) acetate (312)
Diisopropyl (2S,3S)-3-hydroxy-5-oxotetrahydro-2,3-furandicarboxylate (310) was
refluxed with one equivalent of 3-methylbutyl amine using a Dean-Stark apparatus in
toluene for 8h. The reaction mixture was concentrated under reduced pressure and
chromatographic purification over silica gel (EtOAc: Hexane, 8:2) afforded
pyrrolidinedione (312) as a yellow oil in 80% yield (Scheme 3.4.1.4).
IR (film) spectrum of the compound 312 showed the characteristic absorption bands
at ν 1784(ester carbonyl), 1700 (amide carbonyl)cm-1. The 1H NMR spectrum of 312
showed signals at δ 5.06 (singlet; due to to the methine proton in OCH(CH3)2 group),
δ4.28 (singlet, due to the methine proton), δ3.37 (singlet, due to -CH2N group) δ2.95-
2.59 (AB pattern; due to methylene protons), δ1.55(Singlet, due to proton in
CH(CH3)2 group), δ1.53 (singlet ,due to proton in CH2CH(CH3)2 group), δ1.4 (singlet,
due to proton in methyl group) and at δ1.38 (singlet, due to proton in methyl group of
13
isopentyl amine). The C NMR spectrum displayed signals at δ177.1, 174.3, 170.4,
75.8, 72.5, 71.2, 39.5, 37.4, 35.9, 25.7, 22.2, 22.1, 21.5 and 21.5 (Figure 3.13-3.16).
131
IR(ATR)
1
H NMR, 400 MHz, Solvent: CDCl3
13
C NMR , 100 MHz, Solvent: CDCl3
132
HRMS
3.4.5. Synthesis of methyl (R)-2-hydroxy-2-((S)-3-hydroxy-1-isopentyl-2,5-dioxo

pyrrolidin-3-yl)acetate (312a)
Dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate (310a) was
refluxed with one equivalent of 3-methylbutyl amine using a Dean-Stark apparatus in
toluene for 8h. The reaction mixture was concentrated under reduced pressure and
chromatographic purification over silica gel (EtOAc: Hexane, 8:2) afforded
pyrrolidinedione (312a) as a yellow oil in 78% yield (Scheme 3.4.1.5).
IR (film) spectrum of the compound 312a showed the characteristic absorption bands
at v 1784 (ester carbonyl), 1700 (amide carbonyl) cm-1. The 1H NMR spectrum of
312a showed signals at δ4.37(singlet; due to to the methine proton), δ3.83 (singlet,
due to –OCH3), 3.45 (triplet,2H due to -CH2N group ) δ3.05-2.67 (AB pattern; due to
methylene protons), δ1.50(multiplet, 2H, due to proton in CH2-C group), δ1.49
133
(singlet, due to proton in CH(CH3)2 group) and δ0.87 (singlet, due to proton in
13
C(CH3)2. The C NMR spectrum displayed signals at δ177.2, 174.3, 171.6 due to
carbonyl carbon and other carbon displayed at 77.4, 72.5, 53.4, 39.5, 37.5, 36.1, 25.8,
22.3. LCMS (TOF MS ES+) calculated for C12H19NO6 (M) 273.1212, found 273.0948
(Figure 3.17-3.20).
IR(ATR)
1
134
13
LCMS
3.4.6. Synthesis of isopropyl (S)-2-((S)-1-benzyl-3-hydroxy-2,5-

dioxopyrrolidin-3-yl)-2 hydroxyacetate (311)
Reaction of (2S,3S)-diisopropyl 3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate
(310) with 4-methoxybenzylamine in refluxing toluene furnished the 3-substituted
135
chiral pyrrolidinedione, namely isopropyl (S)-2-((S)-1-benzyl-3-hydroxy-2,5-
dioxopyrrolidin-3-yl)-2-hydroxy acetate (311). The structures 311 was confirmed on
the basis of IR, 1H,13C NMR, optical rotation and mass spectra (Scheme 3.4.1.6).
The IR spectrum of 311 displays absorption frequencies at 3414 cm-1 (due to OH

cm-1
group), at 1735, and at 1654 (due to the ester and imide carbonyl groups
respectively). The 1H NMR spectrum shows signals at δ 7.51 and 7.2 (due to the
aromatic protons), at δ 5.3 (septet; due to methine proton), δ 4.7 (singlet due to
benzyl-CH2 proton), at δ 4.33 (singlet; due to methine proton), δ 3.2 and 2.75 (AB
quartet; methylene protons of imide ring) and at δ 1.35 (doublet of doublet; due to six
methyl protons). The 13CNMR spectrum displayed 15 different signals. HRMS (TOF
MS ES+) calculated for C16H19NO6 (M+Na)+ 344.1110, found 344.1100 (Figure
3.21-3.24).
IR(ATR)
136
1
13
HRMS
137
3.4.7. Synthesis of (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxyhexahydro-5H-
furo[2,3-b] pyrrol-5-one (313) from 311
To a solution of 311 in ethanol (5 mL), 3 equivalents of NaBH4 was added at 0°C.
followed by stirring the reaction mixture for 3 hours at room temperature. 2N HCl (20
mL) was added to the reaction mixture and the solvent was removed under reduced
pressure. The ether layer was evaporated under reduced pressure after the workup
using sodium bicarbonate. The simultaneous reduction of one of the imide carbonyl
and the ester carbonyl of 311 was carried out followed by the cyclization of N-acyl
iminium ion intermediate formed from 313.a via 5-exo-trig pathway to furnish
enantiopure concave (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxyhexahydro-5H-furo[2,3-
b]pyrrol-5-one38 (313) in 80% isolated yield. The compound 313 was characterized
using of IR,1H,13C NMR, HMQC, DEPT, optical rotation and mass spectra (Scheme
3.4.1.7).
The IR spectrum of 313 displays absorption frequencies at 3373 (due to OH group), at

1671 (imide carbonyl group) cm-1. The 1H NMR spectrum of 313 shows signals at δ
7.35and 7.25 (multiplet; due to aromatic protons), at δ 4.96(singlet; due to aminal
proton), at δ 4.88 (broad singlet; D2O exchangeable), δ 4.88 and 4.77 (doublets; due
to benzyl protons), δ 4.28 (triplet; due to oxymethine proton)multiplet at δ 4.09-4.0
and multiplet at δ 3.39 due to methylene protons, δ 3.19 and 2.33 (AB quartet; due to
13
methylene protons of lactam ring). The C NMR spectrum showed 12 different
signals. The DEPT experiment revealed the presence of two methines (δC 98.24,
78.27) and three methylenes (δ C 71.4, 43.7, 38.8) (Figure 313). HRMS (TOF MS
ES+) calculated for C13H15NNaO4 (M+Na)+ 272.0899, found 272.0907 (Fig.3.25-
3.28).
138
IR(ATR)
1
139
13
DEPT 135
DEPT 90
140
HRMS
141
The 2D HMQC, HSQC and DEPT experiments allowed an unequivocal assignment of
proton connectivity to the respective proton-bearing carbons of the furo[2,3-
b]pyrrolone 313. The heteronuclear single quantum coherence spectroscopy of 313
reveals the correlations of H-9,10,11,12 (δ 7.31-7.25 (m, 5H)) and C9,10,11,12 (δ
137.9, 129.3, 129.0, 128.1). Also, the HSQC spectroscopy reveals H-4(δ 4.96 (s, 1H)
coupled with C-4 (δ 98.1), H-8 at δ 4.77-4.74 (doublets; due to benzyl protons) with
C-8 at δ 43.1, H-2 at δ 4.28with C-2 at δ 82.7, H-3 at δ 3.39 with C-3 at δ 71.3 and
that of H-7 at δ 3.19 and 2.33 (AB quartet; due to methylene protons of lactam ring))
with C-7 at δ 38.9 revealed the structure 313. The correlation diagram is represented
in Figure 3.4.8
The 2D HMQC data also support structure 313. The 1H-13C short-range correlations
observed in the HMQC spectra allowed the assignment of all protons and carbon
signals (Figure 3.4.9).
142
3.4.8. Synthesis of (3R, 3aS, 6aR, Z)-5-(benzylimino)hexahydrofuro[2,3-b]furan-
3,3a-diol (80) starting from 313
The compound 313 (350 mg 1.405 mmol) was dissolved in THF (8ml) at room
temperature followed by stirring (10 min). 2 mL of 4N HCl (1:4) (2 mL HCl +8 mL
THF) was added and refluxed for 3h. The reaction mixture was then concentrated and
added 10 mL distilled H2O. The reaction mixture was extracted with acetone and
dried with Na2SO4 and concentrated in vacuum. The crude mass was purified by
column chromatography (60-120 mesh silica gel, 5:5 DCM-Hexane mixture) to afford
80 as an oil in 45% yield. The compound 80 was characterized using of IR, 1H, 13
C
NMR, HMQC, DEPT, optical rotation and mass spectra (Scheme 3.4.1.8)
143
The IR spectrum of 80 displays absorption frequencies at 3404 (due to OH group), at
1674 (C=N group) cm-1. The 1H NMR spectrum of 80 shows signals at δ 7.23,7.21and
7.19 (multiplets; due to aromatic protons), at δ 4.72 (singlet; due to acetal proton), at δ
4.54 (singlet; 2H, D2O exchangeable), δ 4.70 and 3.98 (doublets; due to benzyl
protons), δ 4.05 and 3.29(doublet; due to methine proton), δ 3.51(doublet; due to
methylene protons of hydroxyfuran ring), δ 3.10 and 2.25 (AB quartet; due to
methylene protons of lactam ring). The 13C NMR spectrum shows 12 different
signals. The DEPT experiment revealed the presence of two methines (δC 98.2, 78.3),
and three methylenes (δC 71.4, 43.7, 38.8). HRMS (TOF MS ES+) calculated for
C13H15NNaO4 (M+Na)+ 272.0899, found 272.0894 (Figure 3.32-3.35).
IR(ATR)
144
1
1
H NMR, 400 MHz, Solvent : D2O (Expanded)
13
C NMR, 100 MHz, Solvent : Acetone-d6
145
DEPT 90
DEPT 135
HRMS
146
The 2D HSQC and DEPT experiments allowed a clear-cut assignment of proton
connectivity to the respective proton-bearing carbons of the analogue of bis-THF, 80
(Figure 3.34, 3.37). The HSQC spectrum of 80 reveals the correlations of
H-9,10,11,12 at δ 7.23-7.19 (m, 5H) with C-9,10,11,12 at δ129.7, 129.3, 128.9,
128.08), H-4 at δ 4.7 (s, 1H) with C-4 at δ 98.2, H-8 (δ 4.70 and 3.9, doublets; due to
benzyl protons) with C-8 (δ 43.73), H-2 at δ 3.29 and 4.05 (doublet; due to methane
proton with C-2 at δ 78.31. Correlation of H-3 at δ 3.51(doublet; due to methylene
protons of hydroxyfuran ring) with C-3 (δ 71.38) and that of H-7 at δ 3.10 and 2.25
(AB quartet; due to methylene protons of lactam ring with C-7 at δ 38.9 revealed the
structure 80. The correlation diagram is represented in Figure 3.4.8
147
The 2D COSY, data also supports the structure 80. The 1H-1H and 1H-13C short-range
correlations observed in the COSY spectra allowed the assignment of all protons and
carbon signals.
148
149
3.5. Conclusion
Synthesis of various chiral bis-furan part of nonpeptidic high-affinity P2 ligand for anti-
HIV drug Darunavir and relative molecules have been discussed in detail. Attempts were
made for the synthesis of the non-racemic analogue of the bis-THF part (30) of anti-HIV
drug Darunavir, has been carried out starting with 3-substituted chiral pyrrolidine namely
isopropyl(S)-2-((S)-1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-2-hydroxyacetate 2,5-
dione (310), obtained from Garcinia acid(1). This approach seems to be the most
economical way of synthesising the bis furan part of Darunavir.
The acid catalysed sodium borohydride reduction of 3-substituted pyrrolidine-2,5-dione

(311) yielded (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxytetrahydro-2H-furo[2,3-b]pyrrol-
5(3H)-one (313). Upon the treatment of 313 with aqueous HCl-THF, resulted in the
rearrangement of furopyran ring system to bis-furan ring system. Thus, (3R,3aS,6aR,Z)-5-
(benzylimino)tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol (80) was isolated as an oil.
Independently the bis-furan part namely (3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-
3,3a(6aH)-diol, (30) has been cumulated using the Weinreb intermediate, (2S,3S)-3-
acetoxy-3-(methoxy(methyl)carbamoyl)-5-oxotetrahydrofuran-2-carboxylic acid (197)
obtained from Garcinia acid (1).
3.6. General experimental details

All commercial solvents are distilled prior to use. Dry solvents and reagents are
prepared following the procedures described in “Purification of Laboratory
Chemicals” by D. D. Perrin and W. L. F. Armarego (3rd edition, Pergamon Press,
1988). Dried fruit rind of Garciniacambogiais procured from a local plantation.
Leaves or calyxes of Hibiscus sabdariffa and the leaves of Hibiscus furcatusare
collected from the local area. All reactions which require anhydrous condition are
carried out under a nitrogen atmosphere. All the reaction temperatures shown are bath
temperatures. Anhydrous sodium sulphate is used to dry organic extracts.
Melting points are determined on ‘’Stuart-melting point-SMP30’’ make electrically

heated melting point apparatus. IR spectra are recorded using Thermoscientific
FTIR spectrophotometer with diamond ATR and are reported as wavenumber (cm–1).
1 13
H NMR (400 MHz) and C NMR (100 MHz) are measured on a Bruker AV 400
spectrometer. Chemical shifts are expressed in parts per million (ppm) relative to
TMS (δ = 0) and coupling constants are reported as Hertz (Hz). Data are reported as
150
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
dd = doublet of doublet, ddd = doublet of doublet of doublets, dddd = doublet of
doublet of doublet of doublets, p = pentet, br = broad, m = multiplet), coupling
constant, and integration. Electron impact mass spectra are recorded on a Finnigan
MAT MS 8230 or Jeol D-300. Optical rotations are measured on a Rudolph IV
Autopol polarimeter operating at the sodium D line with a 100 mm path length cell,
and are reported as follows: (concentration (g/100 mL), solvent). Column
chromatography is carried out with Merck product silica (silica gel 60-120 mesh)
and thin-layer chromatography is carried out with Merck product silica (silica gel G
for TLC).
3.7. Experimental details

3.7.1. Dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate
(310a)
To a precooled (-5-0 °C) suspension of disodium salt, 202 (1.0 g, 4.4 mmol) in dry
methyl alcohol (10 mL), thionyl chloride (0.7 mL, 10 mmol) was added. The mixture
was then stirred for 48 h at room temperature. After filtration of the reaction mixture,
the pH of the filtrate was adjusted to 7.0 by adding saturated aqueous sodium
bicarbonate and was extracted with chloroform (3 X 10 mL). The combined extract
upon drying and evaporation furnished the compound, 202 as a yellow oil.
Appearance Pale yellow oil

Yield 49%(0.57 g)
[]25 +65.3 (c 0.32, CHCl3)

D
IR (Liquid film) 3478, 1801,1732 and 1682. cm-1

1
H MR (CDCl3, 400 MHz) δ 5.15 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.10 (d,
J = 17.6 Hz, 1H), 2.87 (d, J = 18 Hz, 1H) ppm.
13
C NMR (CDCl3, 100 MHz) δ 171.6, 171.4, 165.9, 82.1, 76.7, 54.4, 52.9,
40.3ppm.
151
Mass spectrum C8H10O7( m/z calculated 218.0427 Found 219
(M+))
3.7.2. Dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate

(311.a)
To a precooled (-5-0 °C) suspension of Hibiscus acid 2 (1.0 g, 4.4 mmol) in dry
methyl alcohol (10 mL), catalytic amount PTSA was added. The mixture was then
stirred for 30 h at room temperature. After filtration of the reaction mixture, the pH of
the filtrate was adjusted to 7.0, by adding saturated aqueous sodium bicarbonate and
was extracted with chloroform (3 X 10 mL). The combined extract upon drying and
evaporation furnished the compound, 311.a as yellow oil.

Yield 50% (0.58 g)
[]25 +63.0 (c 0.32, CHCl3)

D
IR (Liquid film) 3471, 1801,1729. cm-1

1
H MR (CDCl3, 400 MHz) δ 5.11 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.07
(d, J = 17.6 Hz, 1H), 2.87 (d, J = 18 Hz,
1H)ppm
13
C NMR (CDCl3, 100 MHz) δ 171.5, 171.3, 165.9, 82.0, 77.2, 54.4, 52.9,
40.2.
Mass spectrum C8H10O7( m/z calculated 218.0427 Found 219
(M+)
152
3.7.3. (2S,3S)-diisopropyl-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate
(310)
To a stirred solution of 1 (1 g, 5.26 mmol) in isopropanol was added 2 mL of conc.

H2SO4 dropwise at 0oC and the reaction flask was equipped with a reflux condenser.
The solution was refluxed at 90oC. After 12 hours, the reaction mixture was
concentrated under reduced pressure. The crude mixture was dissolved in DCM (40
mL) and was extracted with aq. NaHCO3 solution (2 x 25 mL). The combined organic
layers were dried over anhydrous sodium sulphate and concentrated under reduced
pressure to obtain a white solid which was recrystallized using Hexane/CHCl 3 to
obtain 310 as white crystals.
Yield 1.15 g (80%)
Melting Point 100-105 °C
[]25 +32.0 (c 1.0, CHCl3)

D
IR (Liquid film) 3449, 2984,1799, 1735. cm-1

1
H NMR (CDCl3, 400 MHz) δ 5.15-5.04 (m, 2H), 4.85 (s, 1H), 3.10 (d,
J=17.6 Hz, 1H), 2.81 (d, J = 17.6 Hz, 1H), 1.33
- 1.28 (m, 12H) ppm.
13
C NMR (CDCl3, 100 MHz) δ171.5, 169.9, 165.5, 83.9, 78.4, 72.4, 70.6, 39.8,
21.6, 21.5, 21.5, 21.3 ppm.
calculated 274.1053, found 274

Mass spectrum for
C12H18O7Molecular Mass
153
3.7.4. Isopropyl (R)-2-hydroxy-2-((S)-3-hydroxy-1-isopentyl-2,5-
dioxopyrrolidin-3-yl)acetate (312)
To a stirred solution of 310 (1 g, 3.64 mmol) in toluene was added with 3-

methylbutylamine (0.84 mL,7.31 mmol) drop. The solution was refluxed for 5 h. The
crude mixture was dissolved in DCM (40 mL) and was extracted with aq. NaHCO3
solution (2 x 25 mL). The combined organic layers were dried over anhydrous sodium
sulphate and concentrated under reduced pressure to obtain 312 as an oily liquid,
which was recrystallized using Hexane/CHCl3 to obtain 312 as a single enantiomer.
Yield 65%, (0.76 g)
[]25 -11.43 (c 0.3, CHCl3)

D
IR (ATR) 3438, 1784.15, 1700.08 cm-1

1
H NMR (CDCl3, 400 MHz) δ 5.06(s, 1H), 4.28(s, 1H), 4.3(s, 1H), 3.38(m,
2H), 2.95(d, J = 18.4 Hz, 1H), 2.59(d, J =
18.4 Hz, 1H),1.44 (m,1H), 1.34(m,2H), 1.20(s,
6H),0.80(d, J = 6.4 Hz, 6H
13
C NMR (CDCl3, 100 MHz) δ 177.0, 174.3, 170.4, 75.9, 72.5, 71.2, 39.5,
37.4, 36.0, 25.7, 22.2, 22.1, 21.5, 21.4.
HRMS (ESI/Q-TOF) m/z: calculated C14H23NNaO6[M + Na]+ 324.1423,

found 324.1420.
154
3.7.5. (2S,3S)-diisopropyl -3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate
(312a)
To a stirred solution of 310 (1 g, 3.64 mmol) in toluene was added with 3-

methylbutylamine (0.84ml,7.31 mmol) drop. The solution was refluxed for 5 h. The
crude mixture was dissolved in DCM (40 mL) and was extracted with aq. NaHCO3
solution (2 x 25 mL). The combined organic layers were dried over anhydrous sodium
sulphate and concentrated under reduced pressure to obtain 312a as an oily liquid,
which was recrystallized using Hexane/EtOAc to obtain 312a as a single enantiomer.
Yield 60%, (0.64 g)
IR (Liquid film) 1784(ester carbonyl), 1700(amide carbonyl)

cm-1
1
H MR (CDCl3, 400 MHz) δ 4.37 (s, 1H), 3.83 (s, 3H), 3.43(s,2H),
3.045(d, J=18.4 Hz, 1H),2.675 (d, J = 18.4 Hz,
1H), 1.53 (s,2H), 1.49 (s,1H), 0.88(s, 6H).ppm
13
C NMR (CDCl3, 100 MHz) δ 177.2, 174.3, 171.6, 72.5, 75.9, 72.5, 53.4,
39.5, 37.5, 36.0, 25. 8, 25.8, 25.7, 22.3, 22.3
22.2 ppm
Molecular Formula C12H19 NO6
Mass spectrum calculated 273.1053, found 273.0948

for C12H18O7
155
3.7.6. (S)-isopropyl 2-((S)-1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-2-
hydroxyacetate (311)
To a solution of 310 (1 g, 3.65 mmol) in toluene Benzyl amine (3.65 mmol) was added
and refluxed with dean and stark apparatus for 8 hours to complete cyclization. The crude
mixture was dissolved in DCM (40 mL) and was extracted with aq. NaHCO3 solution
(2 x 25 mL). The combined organic layers were dried over anhydrous sodium
sulphate and concentrated under reduced pressure to obtain 311 as colourless crystals,
which was recrystallized using Hexane/EtOAc to obtain 311 as a single enantiomer.
Yield 79% (0.92 g)
[]25
D
+17.35 (c 0.11, CHCl3)
Melting point 70-72 °C
IR (ATR) 3414, 3332, 2984.,1735.45, 1714,1654. cm-1

1
H NMR (CDCl3, 400 MHz) δ 7.33-7.28 (m, 5H), 5.32-5.26 (m, 1H), 4.67
(s, 2H), 4.25(s,1H), 4.22 (br s, 1H), 3.183 (d,
J = 18.0 Hz, 1H), 2.77 (d, J = 18.0 Hz, 1H)
1.66-1.35 (m,6H). ppm
13
C NMR (CDCl3, 100 MHz) δ 176.8, 173.6, 170.8, 135.2, 128.7, 128.4,
128.0, 77.33, 72.3, 72.04, 42.5, 39.9, 21.6.ppm
HRMS (TOF MS ES+) m/z calcd 344.1110, found 344.1100

for C16H19NO6 Na (M +Na)+
156
3.7.7. (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxytetrahydro-2H-furo[2,3-b]pyrrol
5(3H)-one (313)
To a solution of 311 (1 g, 3.11 mmol) in methanol or ethanol (5 mL), 2 equivalents of

NaBH4 was added at 0 °C. Then the ice bath was removed and the reaction was
stirred for 3 hours at room temperature. 2N HCl (20 mL) was added and the solvent
was removed under reduced pressure.The ether layer was evaporated under reduced
pressure after the work up using sodium bicarbonate. The compound 313 was
obtained as colourless crystals.
Yield 80% (0.68 g)
[]25
D
-46.2 (c 0.10, CH3OH)
IR (ATR) 3373, 1671 cm-1

1
H NMR (Acetone-d6, 400 MHz) δ 7.35-7.25 (m, 5H), 4.96 (s, 1H), 4.88 (br
s, 1H), 4.88 (br s, 1H), 4.77 (d, J = 15.2
Hz, 1H), 4.28 (t, J = 7.4 Hz, 1H), 4.09 (d,
J =14.8 Hz, 1H), 4.00 (dd, J = 9.2, 6.8
Hz, 1H) 3.39 (t, J = 8.8 Hz, 1H), 3.19 (d,
J = 17.8 Hz, 1H), 2.33 (d, J = 18.0 Hz,
1H) ppm.
13
C NMR (Acetone- d6, 100 MHz) δ 172.6, 137.9, 129.3, 129.0, 128.1, 98.24,
82.8, 78.3, 71.4, 43.7, 38.9 ppm
HRMS (TOF MS ES+) m/z calcd for 272.0899,found 272.0907

C13H15NO4Na(M+Na)+
157
3.7.8. (3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol
(80)
The compound 313 (1 g , 3.64 ml) was dissolved in THF (8ml) at room temperature
followed by stirring (10 min). 2 mL of 4N HCl (1:4) (2 mL HCl +8 mL THF) was
added. The reaction was refluxed for 3hrs. The reaction mixture was then
concentrated and added 10 mL distilled H2O. The reaction mixture was extracted with
acetone and dried with Na2SO4 and concentrated in vacuum. The crude mass was
purified by column chromatography (60-120 mesh silica gel, 5:5 DCM-Hexane
mixture) to afford 80 as an oil in 45% yield. The compound 80 was characterized
using of IR, 1H, 13
C NMR, HMQC, DEPT, optical rotation and mass spectra
(Scheme 3.4.1.8)
Yield 45% (0.44 g)
IR (ATR) 3404, 1674 cm-1

1
H NMR (MeOD, 400 MHz) δ 7.23-7.19 (m, 5H), 4.72 (s, 1H), 4.54 (br s,
2H), 4.77 - 4.68(d, J = 15.2 Hz, 1H) and
3.99-3.97(d, J = 9.2 Hz, 1H) 3.29 and 4.05
(d, J = 7.4 Hz, 1H), 3.51(d, J=30.8 Hz, 2H),
3.10 (d, J = 17.8Hz, 1H) and 2.25 (d, J =
18.0, Hz, 1H) ppm
13
C NMR (MeOD, 100 MHz) δ 172.5, 129.7, 129.3, 128.9, 128.1, 98.2,
82.7,78.3, 71.4, 43.7, 38.8 ppm
HRMS (TOF MS ES+) m/z calcd 272.0899,found 272.0907

for C13H15NO4Na(M+Na)+
158
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Chapter 4
Synthesis of Indolizine skeletons employing (2S,3S) and

(2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furan
dicarboxylic acids
4.1. Introduction
Indolizines denote a privileged class of heterocycles with a fused structure of pyrrole

and pyridine and abridged nitrogen atom.1a,1c They drawn substantial attention among
biologist and synthetic organic chemist as it exhibits a diverse array of biological
activities such as anti-inflammatory, anticancer, antimicrobial, and antitubercular
agents.1c Indolizine is an important ring system in view of its similarity to indole. Like
indole, it has a delocalized 10𝜋-electron system that confers aromaticity, in contrast to
its analogues, pyrrolizine and quinolizine. Consequently, it has theoretical and practical
interest.1 Their structures can be described either as derivatives of the aromatic bicyclic
indolizine or as indolizidine (Figure 4.1).
In 1890, an Italian chemist Angeli reported the preparation of the imine anhydride of
pyrroylpyruvic acid1d and suggested the name pyrindole for the completely unsaturated
parent base1e. Twenty two years later, Scholtz reported the first synthesis of Indolizine
by the thermal reaction of 2-methylpyridine with acetic anhydride to afford picolide
acid. 1f,1b,1g Hydrolysis of picolide acid afforded a colorless crystalline solid, indolizine
which had weakly basic properties. In view of this observation, it was speculated that
this compound could not be a true derivative of pyridine. Furthermore, this new
compound gave reactions characteristic of pyrroles and indoles and had the same
empirical formula (C8H7N).
162
Some of the Indolizine synthetic derivatives are known to act as a potential inhibitor of
Vascular Endothelial Growth Factor1h-1i (VEGF) and in neuropilin-1 (NRP1) synergy, 1i
as agents with anti-cancer,2a-2d antitubercular,2e-2f antidiabetics,2g anti-HIV,2i,2j antiviral,2h
anti-inflammatory properties.2k-2n. They also serve as phosphodiesterase V inhibitors,2o
histamine H3 receptor antagonists,2p or as selective chemical probes for the
bromodomains BAZ2A and BAZ2B.2q However, the major part of the investigations
on indolizine derivatives is focused on anticancer drug discovery3. Indolizine
derivatives have also been investigated for their suitability as dyes for dye sensitized
solar cells (DSSC)1i,4a,4d or organic light emitting devices (OLEDs),1i,4b,c owing to their
appreciable photophysical properties5a-5c also some indolizine derivatives have also
shown applications in the agricultural sector as herbicides5d,5e and fungicides.5f
A total 3041 research articles are available in Scifinder for the concept "Indolizine",
1557 references found containing the concept "Indolizine synthesis", and 50 references
found containing the two concepts "Indolizine" and "natural product".
4.1.1. Naturally occurring Indolizidines.
A pair of racemic indolizidine enantiomers, (±)-homocrepidine A (278), and a

piperidine derivative, homocrepidine B (279), were isolated from plant Dendrobium
6a
crepidatum and their absolute configurations were assigned from the single-crystal
X-ray diffraction data by Hu et al. The plants of the Dendrobium genus (Orchidaceae),
comprising more than 1,000 species, are widespread throughout Asia, Europe, and
Australia. Many Dendrobium species have been used as medicinal herbs in China for a
long time with a view to nourishing the stomach, promoting the production of body
163
fluid, and clearing fever. Phytochemical studies revealed that the plants of this genus
contained diversified components, such as alkaloids, coumarins, bibenzyls, fluorenones,
phenanthrenes, and sesquiterpenoids. However, only six indolizidine alkaloids were
isolated from Dendrobium plants.6b-6f
Indolizine (octahydroindolizine) alkaloids are widely distributed in bacteria, fungi,

higher plants, invertebrates, and vertebrates of both terrestrial and marine sources as
well. The three potent glycosidase inhibitors like lentiginosine, (-)-swainsonine, and
(+)-castanospermine the best-known plant-derived polyhydroxylated indolizidines7a-7c.
The indolizine frameworks are present in the core structures of natural products
including lamellarins and camptothecin.8a Lamellarins compounds were first isolated
from the prosobranch mollusc Lamellaria sp.8d The discovery of camptothecin and its
analogues were the major step forward through which Indolizine moiety came into
limelight.8a,8b Wall et al. discovered the camptothecin and studied its impact on the
treatment of cancer and other diseases, the biological potential of the indolizine
nucleus is still largely unexplored.8c A leading example is the discovery of irinotecan
and topotecan, the anticancer derivatives of camptothecin. Considering the biological
efficacy of indolizine derivatives, a number of drugs are in different phases of clinical
trial.8c
Most of the naturally occurring indolizidines have been isolated from species of the
genus Dendrobates (poison frog), Dendrobium (orchids), Leguminosae family
(plants), Monomorium (ants), and Tylophora. Among them, the lipophilic-
pumiliotoxins and hydrophilic polyhydroxy indolizidines are the two most important
classes of compounds. Pumiliotoxins (280) A and B were the second and third
164
dendrobatid alkaloids to be isolated and were initially obtained in 1967 from the skin
of the Panamanian poison frog-Dendrobates pumilio. The pumiliotoxin A and
allopumiliotoxin classes of dendrobatid alkaloids are a group of alkylidene
indolizidine alkaloids that display particularly significant pharmacological
activities.1g,9 Tylophorine,(282) a phenanthroindolizidine alkaloid isolated from
Tylophora indica exerts antiangiogenic and antitumor activity.9
Swainsonine (281) belonging to the family of indolizine alkaloid with a strong

neurologically toxic effect on herbivorously livestock. A great amount of evidence
recently, confirmed that Indolizine alkaloid displayed a vide range of bioactivities
especially anti-cancer biological effects.8a,11 Since its discovery as a skeleton of high
potential in medicinal chemistry, in particular for anticancer drug discovery, the
indolizine ring, considered as a biosteric analogue of the popular indole, has largely
expanded its scope of applications. Besides being classified today as a privileged
165
2a-f
medicinal sca old displaying various important biological activities (Scheme
4.1.1b). Indolilizines and substituted indolizines are considered as an important
scaffold for the preparation of novel pharmaceuticals and electronic material as
illustrated in Table 4.1.1.
Table 4.1.1 Inventory of useful bioactive indolilizines based molecules
Refer
Starting material Product Application
ence
Anti-bacterial, 12
anti-fungal
activity
cancer activity
Anti-herpes
activity:
Human
cytomegalovir 1i
us
(HCMV)
activity
VEGF 1i,
inhibitor 13
1i,
PDESA 14,
inhibitor
17,
19
166
Antibacterial
activity:
Against 19
Mycobacteriu
m tuberculosis
Organic
Sensitizers
for Solar-Cell
1i,
Dye for DSSC 5c
Anti-tumor
activity:
microtubule
inhibitor 15,
Anti-cancer 21
(STA-5312)
Active 3
antagonist of
5-
hydroxytrypta
mine
(5-HT)
Antihistamine 3
167
Antibacterial 16,
activity,
8a
anti-
tuberculosis
Histamine H3 3,
receptor
16,
antagonist
17
5-HTIA 3,
Receptor
Ligand
16,
17
Leukotriene 17
Synthesis
Inhibitor
Anti- 18,
inflammatory:
inhibitors of 8a
secreted
phospholipase
s
A2 (sPLA2s)
168
Anti-cancer
activity:
16
antiproliferativ
e activity
against
Hep-G2
cancer
cell line
L-Type
Calcium
17,
channel
blocker 21,
60
Antimycobacte 19
rial
Non-steroidal
estrogen
22
Agonist
NNC 45-0095
Antibacterial
8a
169
Antioxidant
8a
Enzyme
inhibitor:
Non-steroidal
inhibitors of
23
steroid 5α-
reductase;
potential drug
for the
treatment
of benign
prostatic
hyperplasia
(BPH)
FK 687 34
GSK-3β
inhibitor
170
Antioxidant
19
Antiinflammat 19,
ory
Anticonvulsan
21,
t 60
Anti-cancer
23
Anticonvulsan 19,
t
21,
60
Bioimaging 34
fluorescent
probe
171
1i,
Sensitizer 4a,
component for
DSSC
4d,
34,
60
Antihypertensi 21,
ve
L-Type
60
calcium
channel
blocker
Turn on/off 1i,

fluorescent
sensor
4a,
4d
34,
60
Phosphatase 8a
inhibitor
PLA2 8a
inhibitor
172
Turn on
luminescence,
indolizine
derivatives 26
release tunable
wavelength.
Indolizine 27
based
Chromophores
1i
VEG Inhibitor
13
Both 19,
Lamaellarian
D&L – 28,
Cytotoxic to a
wide range of 29,
cancer cell
lines
31
Apoptosis 27,
inducers
31
173
Indolizine 30
biosensor:
Seoul-Fluor
Anti bacterial 31
agent
Indolizine- 33
squaraines
NIR
Fluorescent
material
Dye-sensitized
32
solar cells
DSSC
174
4.2. Various Synthetic routes towards indolizines moiety.
This diversity of functional properties of these classes of alkaloids has encouraged the
search for new leads for the efficient synthesis of indolizine class of molecules.
Aromatic indolizines are commonly prepared from pyridines and pyrroles by several
synthetic strategies including the classic Tschitschibabin reaction, cycloaddition
reactions, intramolecular cyclizations, and cycloisomerisations3.3,35-37. Also, the
electron rich nature of the heterocyclic ring electrophilic substitution is relatively facile
leading to preferential substitution at C-1 and C-338. Selective C-3 substitution can be
achieved through palladium catalyzed C–H activation, although this probably also
proceeds via a SEAr mechanism. Direct lithiation of the ring is also possible
4.2.1. Scholtz and Tschitschibabin reactions for the synthesis of indolizines
4.2.1a. In 1912, Scholtz1f,1b,1g reported the first synthesis of indolizine by treating 2-

methylpyridine with acetic anhydride at 200 °C–220 °C to give what he called picoline
acid(1,3-diacetyl indolizine (398), hydrolysis of which afforded a colourless crystalline
solid, subsequently identified as indolizine compound, 315. The validity of Scholtz’s
formulation was confirmed by Diels and Alder1b. The new compound 315, a colourless
crystalline solid, m.p. 74 °C. and b.p. 205 oC, volatile in steam and had weakly basic
properties. This synthesis, originally devised by Tschitschibabin is still the most widely
used because it can easily be modified to yield substituted indolizines1b(scheme 4.2).
4.2.1b. A similar reaction, using an α-bromoester instead of an α-bromoketone,

furnished 441, the first reported 2-hydroxy- indolizine1b (Scheme 4.3).
175
4.2.1c. Hurst et al. synthesized indolizin-1-amine starting from 2-(nitromethyl)-1-(2-
oxoethyl)pyridin-1-ium (442) and examined in some detail.39and reaction gave 1-
nitroindolizine, (443) which was reduced to the corresponding amino compound(444)
(Scheme 4.4).
4.2.1d. Also, 1-nitroindolizine (446) was obtained by ring closure of the quaternary salt
with nitromethane. Presumably, a Tschitschibabin reaction follows nitromethylation with
oxidation at some stage. This method has been applied mainly to the cyclization of
quaternary salts of quinolines and isoquinolines to form benzindolizines.1b,1g (Scheme 4.5).
4.2.1e. Krohnke et al. synthesized ethyl indolizine-3-carboxylate, 451 using secondary

amine such as piperidine starting from quinolizin-5-ium bromide 447.40 (Scheme 4.6).
176
4.2.1f. If a α-bromoketone was used instead of the α-bromo ester of Scheme 4.6, the
quaternary salts could be cyclized on an alumina column1 to afford 453 (Scheme 4.7).
4.2.1g. Kreutzberger et al. synthesized derivative of indolizine by treating p-

nitrobenzyl-alpha- picolinium chloride (454a) with s-triazine in pyridine gave an 80%
yield of the cyclized indolizine (456) presumably via the resonance-stabilized
intermediate41 (455) (Scheme 4.8).
177
4.2.2. Intramolecular cyclizations using acetic anhydride
4.2.2.1. Melton et al. synthesized indolizine derivatives 459 or 460 starting from a
quaternary salt which is acylated and dehydrobrominated in one step to give 458.
Heating 458 under reflux with acetic anhydride gives the indolizine 459 or 460, which
involves ring closure at the 2-3 positions to form indolizine derivatives42 (Scheme 4.9).
4.2.2.2. Melton et al. synthesized indolizine derivative by the conversion of

1-phenacyl-2-picolinium bromide (462) into a mixture of 3-benzoyl-2-phenylindolizine
(465) and 1-benzoyl-2-phenylindolizine (466) using benzoic anhydride and
triethylamine. Herein formed a highly activated methylene group. The reaction could
proceed through either of two intermediates, 463 or 464. 1 (Scheme 4.10)
4.2.3. Cyclo condensation reaction for the synthesis of Indolizines
178
4.2.3.1. Opatz’s group recently developed an efficient method for the synthesis of 2-
aminoindolizines 474 by the 5-exo-trig cyclization of 2-alkyl-1-(1-cyanoalkyl)
pyridinium salts. These surrogates were obtained by N-alkylation of 2-alkylpyridines
with easily accessible cyanohydrin triflates, 473. 44 (Scheme 4.12).
4.2.3.2 An efficient strategy for the synthesis of indolizine-1-carboxylates (477)

through the iodine-catalyzed Ortoleva–King reaction of 2-pyridylacetate with various
benzophenones followed by the aldol condensation of pyridinium intermediate (476)
has been described by Mohan et al.45 (Scheme 4.13).
179
4.2.3.3. Park et al. synthesized 6,7 substituted indolizine (480) from methyl (Z)-2-
(bromomethyl)-3-(4-nitrophenyl) acrylate via two successive base mediated reactions.
(Scheme 4.14).46
4.2.3.4. Zhu et al. synthesized substituted indolizines from readily available 2-

(pyridine-2-yl)acetyl derivatives (482) using (trimethylsilyl) diazomethane are
described (Scheme 4.15). 17
4.2.3.5. Li et al. synthesised a novel microtubule inhibitor STA5312 (3-[(4-

cyanophenyl)methyl]-N-(3-methyl-5-isothiazolyl)-oxo-1-indolizine acetamide) (348)
starting from 4-(2-bromoacetyl)benzonitrile 21 (Scheme 4.16).
180
4.2.4. Cycloaddition for the synthesis of indolizines
4.2.4.1. Piltan et al. synthesized indolizine derivatives (491) with dialkyl

acetylenedicarboxylates in the presence of dialkyl chloromalonates in CH3CN at room
temperature (Scheme 4.17). 19
4.2.4.2. Sandeep et al. undertake synthesis and characterization of ethyl 7 –acetyl-3-(4-

substituted benzoyl)-2-substituted indolizine -1-carboxylate (495) for in vitro anti-
cancer properties (Scheme 4.18).1g
181
4.2.4.3. Recently, Wang et al. described one-pot, three-component cascade reaction
between pyridines, α-acylmethyl bromides, and maleic anhydride leading to direct
access of 1-bromo indolizines in high yields. This procedure is completed via a
sequence of 1,3-dipolar cycloaddition of the pyridinium ylide with maleic anhydride,
oxidative decarboxylation of the primary cycloadduct, and dehydrogenative
bromination of the resulting 1-unsubstituted indolizine intermediate (498). Copper
chloride was used as a catalyst and oxygen as the oxidant. This reaction represents the
only example of transition metal-catalyzed direct dehydrogenative bromination of
indolizine at C-1 position (499) (Scheme 4.19).47
4.2.4.4. Li et al. demonstrated the base-promoted 1,3-dipolar cycloadditions of 4-

acetoxy allenoates (500) with various dipoles. Allenoates react with various pyridinium
salts via a cycloaddition pathway followed by oxidative aromatization to give
indolizines (502). Itis proved that the reaction proceeds via a thermal 1,3-dipolar
cycloaddition and the subsequent elimination of HOAc (Scheme 4.20). 48
182
4.2.4.5. Electron-deficient ynamides have been successfully elaborated in a 1,3-dipolar
cycloaddition with stabilized pyridinium ylides for the first time. These reactions afford
efficient and general access toward a variety of substituted 2-amino indolizines (505).
(Scheme 4.21). 49
4.2.4.6. Raj et al. synthesized indolizine derivatives using Gold-catalyzed bicyclic

annulations of 4-methoxy1,2-dienyl-5-ynes with isoxazoles to form indolizine
derivatives via an Au-p-allene intermediate. Gold-catalyzed bicyclic annulations of
4-methoxy-1,2-dienyl-5-ynes with isoxazoles afford indolizine derivatives (508) with a
structural rearrangement. The mechanism of these new annulations does not involve
alpha-imino gold carbenes generated from gold pi-alkyne intermediates (Scheme
4.22).8a
183
4.2.4.7 A metal-free three-component annulation reaction for the synthesis of
Indolizine thiones via tandem C−C/C− N/C−S bond formation was developed by Chen
et al. Various 2-alkyl pyridines with aromatic ynals and elemental sulfur proceeded
smoothly under catalyst-free conditions, and the desired products (512) were obtained
in moderate to excellent yields (Scheme 4.23). 50
4.2.4.8. Dohmen et al. synthesized Indolizine derivatives by irradiation of

N-alkylpyridinium derivatives and dimethyl acetylene dicarboxylate, thus providing a
competitive and complementary base and catalyst-free synthesis. The first example of a
crystallochromic indolizine is prepared (515), whose colour in the solid-state depends
on the out of plane torsion of the benzoyl substituent (Scheme 4.24). 51
4.2.4.9. A gold-catalyzed method for the construction of indolizines with eight-

membered ring has been developed by Liu et al. he reaction proceeded through a two-
fold hydroarylation with indole or pyrrole derivatives containing an 1,6-diyne using
tri(1adamantyl)phosphine gold complex as the catalyst, affording 1,8disubstituted
indolizines (517) in moderate to good yields in DCE at 80 oC. The potential usefulness
of these indolizines as blue or green OLEDs (Scheme 4.25) .52
184
4.2.4.10. An iron-catalyzed reaction of pyridine and α-substituted allenoate has been
carried out by Jin et al. The present strategy incorporates the aerobic oxidation into
annulation involving substituted allenoate, to synthesize a novel functionalized
indolizine53 (520) (Scheme 4.26).
4.2.5. Cyclization /elimination for the synthesis of Indolizines
4.2.5.1. In 2015, a mild cupric acetate/I2-mediated oxidative cross-coupling/cyclization

of 2-(pyridin-2-yl)acetates and simple olefins was demonstrated, which provides a
straight forward and efficient access to densely substituted indolizines. A series of 1,3-
di- and 1,2,3-trisubstituted indolizines are easily obtained in modest to excellent yields
(524) (Scheme 4.27). 54
185
4.2.5.2. Xiang et al. showcased a direct method for the synthesis of substituted
indolizines by means of I2-mediated oxidative tandem cyclization via C−N/C−C bond
formation. Number of substituted aromatic and aliphatic enolizable aldehydes
underwent efficient reaction with 2-pyridyl acetates and the desired 1,3-disubstituted
indolizines were produced in moderate to good yields (527) (Scheme 4.28). 55
4.2.5.3. Sahoo et al. demonstrated a novel blue LED-mediated synthetic method that
gives access to functionally diverse indolizines from various brominated pyridines and
enol carbamates under mild conditions. The tetracyclic and pentacyclic structures
obtained by using this approach represent a new class of heterocyclic scaffold. (530)
(Scheme 4.29). 56
4.2.6. Cycloisomerization for the synthesis of Indolizines
186
4.2.6.1. Oh et al. reported a base-mediated Cu-catalyzed tandem cyclization/alkylation
of propargylic pyridines that provided access to densely functionalized Indolizines. The
reaction first proceeded through a 5-endo-trig aminocupration, followed by a coupling
between the copper intermediate and alkynyl bromide, to afford the products in good
yields (532) (Scheme 4.30). 57
4.2.6.2. Very recently an efficient Pd-catalyzed cross-coupling/ cycloisomerization of

3-(2-pyridyl)propargyl carbonates with arylboronic acids has been established, which
provides a straightforward route for the synthesis of 1,3-disubstituted Indolizines with a
wide variety of substituents (534) (Scheme 4.31). 58
4.2.6.3. Zhang et al. described the elegant synthesis of indolizines utilizing silver
catalyzed cyclization of 2-pyridyl alkynyl carbinols with isocyanides. This method
outlines an effective route to highly functionalized indolizines in modest to excellent
yields (536) (Scheme 4.32). 59
187
4.2.7. C-H Activation/Metalation Approaches for the Synthesis of indolizine
derivatives
The C–H borylation of indolizines was first reported by Bertallo et al. Herein the
initially formed boronate ester proved difficult to purify and confirmation of
regiochemistry was obtained by in situ Suzuki–Miyaura cross-coupling reactions that
afforded products (538 & 539) in 33 and 12 % yields, respectively. Through these
methodologies, it was possible to obtain a library of substituted indolizines
functionalized on both the pyridinic and pyrrole rings (538 & 539)) (Scheme 4.33). 60
4.2.8. Indolizines obtained via one-pot reactions
One-pot reactions imply obtaining the product in a single step, by adding all the
necessary reagents in the same reaction medium, without having to isolate and purify
any precursors of the desired product. This type of procedure offers advantages such as
swiftness, the preparation of complex compounds from readily available material,
simplification of workup and atom economy.
4.2.8.1. Mishra et al. present a method to obtain 1-aminoindolizines from aldehydes,

secondary amines, and terminal alkynes, in a one-pot reaction. After testing several
solvents and metal catalysts, the best results are obtained with CuCl in PEG and
188
synthesized 15 substituted indolizines with yields exceeding 70%, after 3–4 h reaction
time (542)(Scheme 4.34). 61
4.2.8.2 The synthesis of 2-acetyl-3-(phenylamino)indolizine-1-carboxamides could also

be achieved in a single step by combining pyridine-2-carbaldehyde, acetoacetanilide
and isocyanides in toluene at reflux, with yields around 90% for the four compounds
obtained (545) (Scheme 4.35). 62
4.2.8.3. Syntheses of the 7,8,9,10-tetrahydropyrrolo[2,1-a]isoquinolines
Ghinea et al. synthesized pyrroloisoquinoline derivatives by 1,3-dipolar cycloadditions

reactions and herein N-ylides generated employing 1,2-epoxybutane as both solvent
and deprotonation agent, or by using triethylamine in DCM, with ethyl propiolate or
DMAD as dipolarophiles, or again coupling the ylide with acrylonitrile and using
TPCD for the aromatization step, all methods with similar medium to good yields
(Scheme 4.36). 63
189
4.2.8.4. Krishnan et al. have synthesized an NHC (N-heterocyclic carbene) mediated
pyrrolo[2,1-a]isoquinoline and indolizine derivatives with potential biological activity. The
preliminary photophysical studies of such compounds reveal that they have potential
application in the sensing of volatile organic compounds (VOCs) (Scheme 4.37). 31
190
4.2.9 In Situ Generation of Quinolinium Ylides from Diazo Compounds:
Copper-Catalyzed Synthesis of Indolizine
The Cu-catalyzed three-component reaction between quinolines, diazo compounds, and
alkenes has been established by Chen et al. for direct construction of indolizine
derivatives (558) via quinolinium ylides. This methodology is distinguished by the use
of a commercially inexpensive catalyst and readily available starting materials, wide
substrate scope, and operational simplicity (Scheme 4.38). 64
4.2.10. Green methods for Indolizine synthesis
During the synthesis of N-heterocycles there are many problems of health and safety in
addition to the environmental problems caused by their use and disposition as waste.
Green methods are a route towards increasing the efficiency of Indoles and Indolizines
synthesis and strive to use less toxic solvents, to reduce the stages of the synthetic
routes and minimize waste as far as practically possible for sustainable development. A
potential method to make synthetic chemistry more environment-friendly would be to
reuse catalysts, such as ion-exchanging resins. Amberlite-IRA 402 (OH) could be
employed as the scope of selective heterocycles from organic and pharmaceutical
perspective 1,2a ylide-forming base in the reaction between phenacyl pyridinium,
quinolinium and isoquinolinium salts and alkynes 65(Scheme 4.39).
191
4.2.11. Synthesis and study of Au(III)–indolizine derivatives: turn-on
luminescence by photo-induced controlled release
The photo- and structural properties of a series of Au(III) indolizine complexes were
determined. Controlled release of halogenated indolizine derivatives from the
corresponding Au(III) complexes was achieved by photoinduced C–X bond formation,
which provided turn-on luminescence with an increase in emission intensity of up to 67
times (Scheme 4.40). 66
4.3. Structure, physical and chemical properties of Indolizines

4.3.1. Structure of Indolizines
Following an early argument that any resonance stabilization in indolizines is simply

due to the presence of the pyrrole ring, the parent indolizine was first considered to be
best represented by structure (A). However, the resonance energy (R.E) calculated for
192
indolizine was found to be 0.29 kcal/mol, which is larger than the total R.E of
pyrrole (0.23 kcal/mol). Furthermore, NMR studies have conclusively established
delocalization throughout both rings. Therefore, indolizine is now considered to be best
represented by a resonance hybrid to which the canonical structures (A), (B), and (C)
contribute. 1g(Scheme 4.41).
4.3.2. Physical properties of Indolizines
The parent Indolizine and its alkyl derivatives are either low melting solids or high-
boiling liquids, sensitive to air and light, and volatile in steam. However, when a
phenyl group is attached at the 2 or 5 positions, the Indolizines are found to be stable
solids and nonvolatile in steam. Most indolizines are highly fluorescent and show
feeble basic properties.44 Chemical properties of Indolizines reference has already
been made to the structure of Indolizines and in particular to its delocalized orbitals.
Indolizines readily undergo electrophilic substitution and show resistance to
nucleophilic attack. In their chemical reactivity, Indolizines resemble pyrroles,
indoles, and isoindoles. The following section deals with reactions of indolizines with
electrophiles, oxidation, reduction, and other miscellaneous reactions.
4.4. Objective and strategy
The above discussion reveals that indolizines are a versatile class of molecules,
always has a demand and any new methods for their synthesis will be an added
advantage to the existing literature. These are indispensable structural entities found
extensively in many biological systems and pharmaceuticals (Scheme 4.1.1b & Table
4.1.1) Majority of the available methods for their synthesis are environmentally
contagious, expensive and cumbersome.
We have accidentally observed that the triesters of Garcinia or Hibiscus acids namely
(2S,3S) and (2S,3R) -3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acid) are ideal
193
choices for the preparation of liberally substituted indolizine skeletons. Accordingly,
our laboratory has developed schemes for the construction of indolizine skeletons
utilizing naturally occurring Garcinia and Hibiscus acids (1&2). Having access to the
pyrrole part of indolizine in hand, we utilized commercially available substituted
pyridines for the construction of indoziline skeleton. The scheme for the synthesis of
polysubstituted indolizines starting from Garcinia acid is summarized in Scheme
4.42. Thus, this approach is more economically viable, environmentally acceptable
and convenient.
It was the purpose of the study to carry out inversion of the C-2 asymmetric carbons
of (2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids
(Garcinia and Hibiscus acids,1&2) via a SN2 oxygen nucleophilic substitution
reaction, to get the (2R,3S) and the (2R,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylic acids,(1.a &2.a)(Scheme 4.42a)
To execute this strategy, triesters of Garcinia and Hibiscus acids namely trimethyl
(1S, 2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate (46) trimethyl (1S, 2R)-1,2-
dihydroxypropane-1,2,3-tricarboxylate and (46a) were prepared. The ester 46 was
then converted to the tritosyl and mesyl derivatives namely trimethyl (1S, 2S) and (1S,
2R)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate (47 & 47a) and trimethyl (1S,
2S) and (1S, 2R)--2-hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate (57
& 57a). Attempts were made to invert the configuration of C-2 carbon of 47 and 57
using acetate anion in pyridine. . Instead of the inverted product, trimethyl (1R, 2S)-1-
acetoxy-2-hydroxypropane-1,2,3-tricarboxylate (626), dimethyl ester of Garcinia acid
(310a) was isolated. When the reaction was carried out at an elevated temperature,
surprisingly the trimethyl indolizine-1,2,3-tricarboxylate,(569) was isolated as a
crystalline solid.
194
The similar experiments were attempted with the tosyl and mesyl derivatives of
Hibiscus acid namely trimethyl (1S, 2R)-2-hydroxy-1-(tosyloxy)propane-1,2,3-
tricarboxylate (47a) and trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)
propane-1,2,3-tricarboxylate (57a) , which furnished the dimethyl ester of Hibiscus
acid (311a) and trimethyl indolizine-1,2,3-tricarboxylate (569) respectively.
With six carbon basic skeletal bearing amendable substitutions and ease of
conversion, the triesters (46 & 46a) of 1 and 2 are expected to be an ideal choice for
the construction of achiral structural skeletal of indolizine alkaloids (569-578)
(Scheme 4.42b). These alkaloids are the privileged class of N-fused heterocyclic
polycyclic molecules. The majority of synthetic protocols leading to the formation of
indolizines involve C2-functionalized pyridines. There are only a few reports of the
direct annulation reactions of pyridine rings that involve N-alkylation/nucleophilic
cyclisation. The trimethyl ester 46 was converted to the mono-mesylate derivative 57
using mesyl chloride and excess of pyridine under reflux conditions, further the
pyridine displaces the mesylate group followed by a sequential cyclisation-
aromatization reaction to afford 569 in 60% isolated yield. The moderate yield was
due to the sensitiveness of indolizine under the chromatographic conditions (Table
4.5).
4.5.a. Optimization of the reaction condition
195
Consequently it is concluded that, a new method for the synthesis of substituted
indolizines has been developed by the cyclisation of mono-sulfonate esters with
pyridine itself and substituted pyridines under solvent-free conditions in moderate to
good yields. The substrates pyridine and mono mesylate derivative of Garcinia acid
(57) were chosen as model compounds for optimization of this cyclization reaction.
On the basis of this premise, (1S,2S)-trimethyl 2-hydroxy-1-(mesyloxy)propane-1,2,3-

tricarboxylate (57) and pyridine (4 equiv.) were subjected to the transformation in
acetonitrile at 80 oC for 24 h in the air, but did not detect the formation of indolizine
product 569 (Table 4.4, entry 1). Changing solvent to DMF, toluene or methanol still
did not make any improvement (Table 4.4, entry 2 - 4). To our pleasure, the expected
product 569 was isolated in 25% yield (Table 4.4, entry 5), when the reaction was
carried out under solvent free conditions at 80 oC in the air. This result seemed
pleasing; as indolizines are highly sensitive to chromatographic media. In this
background, we report the development of this reaction into a general protocol for the
synthesis of substituted indolizines from pyridines and monosulfonate ester
derivatives of Garcinia acid (57).
Table 4.4: Optimization of reaction conditions
Entry Catalyst Solvent T (oC) t (h) Yield (%)
1 No catalyst Acetonitrile 80 24 0
2 No catalyst DMF rt - 120 24 0
3 No catalyst Toluene rt - 120 24 0
4 No catalyst Methanol 80 24 0
5 No catalyst Neat 80 24 25
6 20% - 1 equiv Neat 80 24 10 - 20
Et3N, K2CO3,
DMAP
20% I2
8 Neat 80 36 Trace
20% FeCl2
9 Toluene 80 – 100 48 0
20%
10 DMF 80 – 100 48 0
Cu(OAc)2
196
With this experimental background, we have extended the scope of the reaction to
synthesise a series of indolizine derivatives using commercially available substituted
pyridines. The reaction was conducted using a 4:1 mixture of pyridine and monotosyl
derivative namely trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-
tricarboxylate (57) under different conditions. Several bases were evaluated as a
catalyst in the reaction, including Et3N, K2CO3, DMAP and pyridine; these were all
added initially in catalytic amount (20 mol %) and gradually increased to the
stoichiometric amount. The efficiency of pyridine was the highest in stoichiometric
amount. Subsequently, oxidants including H2O2, I2 air were added into the reaction
system, and we found that only with air as oxidant the expected product was formed.
Considering the economic efficiency and environmental benignancy of using air, we
chose air as the terminal oxidant. Finally, the reaction was performed at different
temperatures to determine the optimum reaction temperature. The reaction was
conducted with 4 equiv. of pyridine at 120, 100, 80 oC and at room temperature. The
best yield was obtained at 80 oC, and it was observed that the efficiency decreased with
increasing the reaction temperature, whereas no product was obtained at room
temperature.
With the optimum reaction conditions in hand, we evaluated the scope of the
transformation using a series of substituted pyridines and (1S, 2S)-trimethyl 2-hydroxy-1-
(mesyloxy)propane-1,2,3-tricarboxylate (57) and the results are illustrated in Table 4.5.
197
To generalize the new synthetic method, pyridines with varying electronic status were
used. This includes mono-substitution at C-2, C-3 and C-4 of pyridine, as well as di-
substituted and benzo- fused pyridines; which furnished indolizines (569-576) and
pyrrolo[2,1-a]isoquinoline (577) and pyrrolo[2,1-a]quinoline (578). Though the
reaction between 57 with isoquinoline is expected to give two regioisomers (577 &
577a) only the isomer 577 was formed exclusively (Scheme 4.42c). The structure of
577 was confirmed on the basis of 1H, 13C and HRMS. The 1H NMR signals at 9.35
ppm (d, J = 7.2 Hz) attributable to proton H-8 couples with H-9 signal at 7.25 ppm (d,
198
J = 7.2 Hz) indicated the ring fusion at C1 of isoquinoline. The structure of 577 was
further established with single-crystal XRD.
The present synthesis of indolizines is green as the reaction is metal-free, solvent-free

as well as the cyclisation step involves only air-oxidation step. The general
mechanism for the formation of indolizines is shown in Figure 4.4a.
Hence the results indicated that pyridines with different electronic status reacted with
mono mesylate derivative of Garcinia acid namely (1S,2S)-trimethyl 2-hydroxy-1-
(mesyloxy)propane-1,2,3-tricarboxylate (57) to generate the desired products in
moderate to good yields. Thus yet another convenient method for the construction of
199
indolizidine alkaloids was developed. We have verified these reactions with Hibiscus
acid and which furnished the same molecules under identical conditions as that of
Garcinia acid.
Further studies showed that the electronic nature of the pyridine significantly affected
the efficiency of the reaction in terms of the yield of the products. When R group of
the pyridine was changed from Me to OMe, the yield of the product increased.
Notably, when the R group was altered to CO2Me or CHO, no desired product was
formed.
In order to extend the scope of this reaction, further experiments were conducted for
the reaction of benzo-fused pyridines and (1S,2S)-trimethyl 2-hydroxy-1-
(mesyloxy)propane-1,2,3-tricarboxylate (57) under optimized conditions, and the
results are shown in Table 4.5. Interestingly, simple benzo-fused pyridines were
found to work well, leading to more complex products in moderate yields (577 &
578).
The reaction tolerated substitution of various kinds at C-4 of pyridine. Besides alkyl
groups such as methyl and tertiary butyl, which afforded indolizines 570 and 571 in
59% and 58% yield, respectively, another functional group like OMe was also
compatible with the protocol (572). On the contrary, the reaction was rather
ineffective in the case of electron-withdrawing substituted pyridines. In fact, 4-
dimethyl aminopyridine and other amino pyridines like 4-amino and 2-dimethyl
amino pyridines led to complex mixtures of products which could not be isolated.
This reaction was also accessible to di-substituted pyridines. Thus, treatment of 3,5-
dimethyl pyridine with mono mesylate derivative of Garcinia acid under the standard
reaction conditions afforded in excellent yield the indolizine derivative, 574.
The issue of the regioselectivity of the annulation of 3-substituted pyridines and mono
mesylate derivative of Garcinia acid was also represented. It was interesting to note
that, the ratio of isomers resulting from the cyclization toward C-6 and C-2 is
different. The indolizine isomer resulting from C-6 cyclization was greater than that
formed from cyclization at C-2 position of pyridine. For 3-ethyl pyridine, the ratio of
isomers was in the ratio 60:40 for C-6 and C-2 respectively (575 & 576) and they
200
were isolated as non-separable isomers. It was pleasing to note that pyridine bearing
substitution at all positions was perfectly tolerated under the optimized conditions.
4.5.1. Synthesis of sodium (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate

starting from Garcinia acid
To an aqueous solution of 1 (1.0 g, 5.25 mmol, in 5 mL water), 2N of sodium
hydroxide solution was added at 80 oC, till reaction mixture is alkaline (~ pH = 9.0).
The residue obtained after evaporation under reduced pressure was triturated with dry
methanol (5 x 25 mL). The solid 2 obtained was finally dried under vacuum (Scheme
4.43).
The 1H NMR (400MHz, D2O) spectrum shows the characteristic peak at δ, 3.63
(singlet; due to methine proton), 3.02 (J = 17.2 Hz) and 2.65 (J = 18.8 Hz) ppm (AB
13
quartet; corresponding to the methylene protons). Six different signals in C NMR
spectrum at (ppm) 179.9, 179.1, 177.7, 78.3, 76.4 and 42.5 also confirmed the
structure of 45.
201
1
H NMR, 400 MHz, Solvent: D2O
13
C NMR,100 MHz, Solvent: D2O
4.5.2. Synthesis of trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate

(46) starting from Garcinia acid.
To a suspension of 525 (1.0 g, 3.65 mmol) in dry methanol (10 mL), thionyl chloride
(1.5 mL, 20 mmol) was added at 0 oC. After refluxing for two hours, the reaction
mixture was cooled and neutralized with an aqueous saturated sodium bicarbonate
solution. The residue obtained upon concentration under reduced pressure was
202
extracted with chloroform (3 x20 mL). The combined extract was dried and
concentrated to afford 526 in 50% yields as yellow oil 67 (Scheme 4.44).
The IR spectrum shows the characteristic absorption bands at 3483 (-OH group), 2960
(aliphatic CH group), 1800 and 1732 (ester group) cm-1. 1H NMR spectrum of 46 was
characterised by signals at δ 4.25 (singlet, due to methine proton), 3.79, 3.61 (due to –
OCH3 group), 2.99 (doublet, J = 16.8 Hz, due to methylene proton) and 2.94 (doublet, J =
16.8 Hz, due to methylene proton). The 13C NMR spectrum showed nine peaks at δ 172.6,
171.0, 170.4, 84.4, 74.8, 53.4, 53.0, 52.1 and 39.6.
IR(ATR)
1
203
13
HRMS
204
4.5.3. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-
1,2,3-tricarboxylate (57)
The obtained trimethyl ester (46) contains free secondary hydroxyl group which is in
the α-position of neighbouring carboxylic acid. The mesylation was done by stirring a
mixture of 46 in CH2Cl2 (2 mL) with mesyl chloride (1.5 equiv) and pyridine (4 equiv)
for 8 hours. The structure of trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)
propane-1,2,3-tricarboxylate (57) was determined using various spectroscopic tools
including 1HNMR, 13C-NMR, FT-IR and X-ray diffraction studies (Scheme 4.46).
The IR spectrum shows the characteristic absorption bands at 3485 (-OH group), 2959
(aliphatic CH group), 1736 (ester group), 1357 and 1177 (-S=O group) cm-1. 1H NMR
spectrum of 57 was characterised by signals at δ 5.20 (singlet, due to methine group),
3.90, 3.89 (due to –OCH3 group), 3.21 – 3.17 (doublet, J = 13.67 Hz, due to methylene
proton), 3.17 (singlet, due to sulfonate CH3 group) and 3.08 – 3.04 (doublet, J = 16.40
13
Hz, due to methylene proton). The C NMR spectrum showed ten peaks at δ 171.0,
169.8, 165.9, 79.6, 76.5, 53.9, 53.3, 52.2, 39.2 and 39.2. The structure of 57 was further
confirmed by single crystal XRD.
IR(ATR)
205
1
13
HRMS
206
4.5.4. Synthesis of trimethyl indolizine-1,2,3-tricarboxylate(569)
Trimethyl indolizine-1,2,3-tricarboxylate (569) was synthesized following a one-pot

reaction between 57 and pyridine (4 equiv) under solvent-free conditions, employing
air as an oxidant. The structure of the product was confirmed using FTIR, 1H NMR,
and 13C NMR spectra (Scheme 4.47).
The IR spectrum shows the characteristic absorption bands at 1739.4 and 1690 (ester
group) cm-1. 1H NMR spectrum of 569 was characterised by signals at δ 9.54 (doublet,
J = 7.08 Hz, due to aromatic C-H), 8.35 (doublet, J = 9.00 Hz, due to aromatic C-H),
7.41 (triplet, J = 7.32 Hz, due to aromatic C-H), 7.07 (triplet, J = 6.64 Hz, due to
13
aromatic C-H), 4.02 and 3.92 (due to nine –OCH3 group). The C NMR spectrum
showed fourteen peaks at δ 166.3, 163.3, 160.5, 137.9, 130.6, 127.9, 126.8, 119.9,
115.4, 111.9, 103.0, 52.9, 51.9 and 51.6. The structure of 569 was further confirmed by
HRMS and single crystal XRD.
207
IR(ATR)
1
13
208
HRMS
4.5.5. Synthesis of trimethyl 7-methylindolizine-1,2,3-tricarboxylate (570)
Trimethyl 7-methylindolizine-1,2,3-tricarboxylate (570) was synthesized following a

one-pot reaction between 57 and 4-methylpyridine 570a (4 equiv) under solvent-free
conditions, employing air as an oxidant. The structure of the product was confirmed
using IR, 1H NMR, and 13C NMR spectra (Scheme 4.48).
209
IR spectrum shows the characteristic absorption bands at ʋ 2925, 1741 and 1696 (ester
group) cm-1. 1H NMR spectrum of 570 was characterised by signals at δ 9.31 (doublet,
J = 7.20 Hz, due to aromatic C-H), 8.04 (singlet, due to aromatic C-H), 6.815 (doublet
of doublet, J = 7.24 Hz and J = 1.60 Hz, due to aromatic C-H), 3.92, 3.82 (due to nine –
OCH3 group) and 2.39 (a singlet due to aliphatic CH3 group). The 13C NMR spectrum
showed fifteen peaks at δ 166.4, 163.5, 160.5, 138.4, 138.3, 130.7, 127.3, 118.5, 118.0,
111.3, 101.8, 52.9, 51.9, 51.6 and 21.4. The structure of 570 was further confirmed by
HRMS.
IR(ATR)
210
1
13
HRMS
211
4.5.6. Synthesis of trimethyl 6-ethylindolizine-1,2,3-tricarboxylate (575) and
trimethyl 8-ethylindolizine-1,2,3-tricarboxylate(576)
Trimethyl 6-ethylindolizine-1,2,3-tricarboxylate (575) and trimethyl 8-ethylindolizine-
1,2,3-tricarboxylate (576) was synthesized following a one-pot reaction between 57 and
3-ethylpyridine 576a (4 equiv) under solvent-free conditions, employing air as an
oxidant. The structure of the product was confirmed using IR, 1H NMR, and 13C NMR
spectra (Scheme 4.49).
IR spectrum shows the characteristic absorption bands at ʋ 1740 and 1694 (ester group)
cm-1. 1H NMR spectrum of major product 575 was characterised by signals at δ 9.28
(singlet, due to aromatic C-H), 8.17 (doublet, J = 9.08 Hz, due to aromatic C-H), 7.21
(doublet, J = 12.32 Hz, due to aromatic C-H) 3.92, 3.82 (due to nine –OCH3 group),
2.64 (quartet, J = 7.36 Hz, due to aliphatic CH2 group) and 1.23 (triplet, J = 7.44 Hz,
due to aliphatic CH3 group). 1H NMR spectrum of minor product 576 was characterised
by signals at δ 9.43 (doublet, J = 6.8 Hz, due to aromatic C-H), 7.10 (doublet, J = 6.8
Hz, due to aromatic C-H), 6.91 (doublet, J = 7.2 Hz, due to aromatic C-H) 3.89, 3.83,
3.79 (due to nine –OCH3 group), 3.11 (quartet, J = 7.6 Hz, due to aliphatic CH2 group)
13
and 1.16 (triplet, J = 7.6 Hz, due to aliphatic CH3 group). The C NMR spectrum
showed thirty two peaks together for 575 and 576 at δ 166.6, 166.5, 163.6, 163.4,
160.6, 160.4, 136.8, 136.3, 136.1, 131.7, 131.3, 130.3, 128.9, 125.9, 125.8, 125.2,
119.4, 115.3, 111.5, 111.3, 105.3, 102.7, 52.9, 52.7, 52.0, 52.0, 51.9, 51.6, 26.9, 26.2,
14.9 and 14.4. The structures of 575and 576 were further confirmed by HRMS.
212
IR(ATR)
1
13
213
DEPT 90: 100 MHz, CDCl3
DEPT 135: 100 MHz, CDCl3
HRMS
214
4.5.7. Trimethyl 6,8-dimethyl indolizine-1,2,3-tricarboxylate (574)
Trimethyl 6,8-dimethyl indolizine-1,2,3-tricarboxylate 537 was synthesized following

a one-pot synthesis between 57 and 3,5-dimethylpyridine 574a (4 equiv) under
solvent-free conditions, employing air as an oxidant. The structure of the product was
confirmed using IR, 1H NMR, and 13C NMR spectra (Scheme 4.50).
IR spectrum shows the characteristic absorption bands at ʋ 1724 and 1698 (ester
group) cm-1. 1H NMR spectrum of 574 was characterised by signals at δ 9.22 (singlet,
due to aromatic C-H), 6.91 (singlet, due to aromatic C-H), 3.89, 3.82, 3.77 (due to
13
nine –OCH3 group) and 2.59 and 2.26 (due to aliphatic CH3 groups). The C NMR
spectrum showed fifteen peaks at δ 166.6, 163.4, 160.5, 135.5, 130.9, 129.3, 125.0,
123.6, 110.9, 105.0, 52.6, 51.9, 51.8, 21.5 and 18.3. The structure of 574 was further
confirmed by HRMS.
IR(ATR)
215
1
13
HRMS
216
4.5.8. Synthesis of trimethyl 7-(t-butyl) indolizine-1,2,3-tricarboxylate (571)
Trimethyl 7-(t-butyl)indolizine-1,2,3-tricarboxylate (571) was synthesized following a

one-pot reaction between 57 and 4-t-butyl pyridine 571a (4 equiv) under solvent-free
conditions, employing air as an oxidant. The structure of the product was confirmed
using IR, 1H NMR, and 13C NMR spectra (Scheme 4.51).
cm-1. 1H NMR spectrum of 571 was characterised by signals at δ 9.33 (doublet, J =
7.44 Hz, due to aromatic C-H), 8.20 (doublet, J = 1.20 Hz, due to aromatic C-H), 7.04
(doublet of double J = 7.48 Hz and J = 2.00 Hz, due to aromatic C-H), 3.92, 3.82 (due
to nine –OCH3 group) and 1.31 (a singlet due to nine protons of t-butyl group). The 13C
NMR spectrum showed sixteen peaks at δ 166.5, 163.6, 160.5, 151.3, 138.4, 130.6,
127.4, 114.8, 114.6, 111.1, 102.2, 52.9, 51.9, 51.6, 35.1 and 30.4. The structure of 571
was further confirmed by HRMS.
IR(ATR)
217
1
13
HRMS
218
4.5.9. Synthesis of trimethyl pyrrolo[1,2-a]quinoline-1,2,3-tricarboxylate(578)
Trimethyl pyrrolo[1,2-a]quinoline-1,2,3-tricarboxylate (578) was synthesized
following a one-pot reaction between 57 and quinoline 578a (4 equiv) under solvent-
free conditions, employing air as an oxidant. The structure of the product was
confirmed using IR, 1H NMR, and 13C NMR spectra (Scheme 4.52).
cm-1. 1H NMR spectrum of 578 was characterised by signals at δ 9.265 (doublet, J=9.2
Hz due to aromatic C-H), 7.575 (doublet, J = 8.4 Hz, due to aromatic C-H), 6.65
(doublet, J= 7.2 Hz, due to aromatic C-H), 3.91 (3H, singlet, J = 9.6 Hz due to aromatic
C-H), 3.86, 3.81 and 3.80(due to nine –OCH3 group). The 13C NMR spectrum showed
14 peaks at δ 166.4, 163.7, 160.5, 159.1, 140.6, 130.7, 129.1, 110.8, 109.8, 101.01,
97.47, 55.75, 52.8, and 51.8. The structure, 578 was further confirmed by HRMS and
single crystal XRD.
IR(ATR)
219
1
1
H NMR, 400 MHz, Expanded Solvent :CDCl3
220
13
HRMS
ORTEP
221
4.5.10. Synthesis of trimethyl 7-methoxyindolizine-1,2,3-tricarboxylate (572)
Trimethyl 7-methoxyindolizine-1,2,3-tricarboxylate (572) was synthesized following

a one-pot reaction between 57 and 4-methoxypyridine 572a (4 equiv) under solvent-
free conditions, employing air as an oxidant. The structure of the product was
confirmed using IR, 1H NMR, and 13C NMR spectra (Scheme 4.53)
IR spectrum shows the characteristic absorption bands at 1738 and 1688 (ester group)
cm-1. 1H NMR spectrum of 572 was characterised by signals at δ 9.265 (doublet, J =
7.72 Hz, due to aromatic C-H), 7.58 (doublet, J = 2.44 Hz, due to aromatic C-H), 6.65
(doublet of doublet, J = 7.72 Hz and 2.68 Hz) 3.91, 3.86, 3.81 and 3.80 (due to twelve
–OCH3 group). The 13C NMR spectrum showed fifteen peaks at δ 166.4, 163.7, 160.5,
159.1, 140.6, 130.7, 129.1, 110.7, 109.8, 101.0, 97.4, 55.7, 52.8, 51.8 and 51.5. The
structure, 572 was further confirmed by HRMS
IR(ATR)
222
1
13
HRMS
223
4.5.11. Synthesis of trimethyl pyrrolo[2,1-a] isoquinoline-1,2,3-tricarboxylate (577)
Trimethyl pyrrolo[2,1-a]isoquinoline-1,2,3-tricarboxylate (577) was synthesized

following a one-pot reaction between 57 and isoquinoline 577a (4 equiv) under
solvent-free conditions, employing air as an oxidant. The structure of the product was
confirmed using IR, 1H NMR, and 13C NMR spectra (Scheme 4.53)
IR spectrum shows the characteristic absorption bands at 1738 and 1673 (ester group) cm-1.
1
H NMR spectrum of 577 was characterised by signals at δ 9.47 – 9.44 (multiplet, due to
aromatic C-H), 9.35 (doublet, J = 7.48 Hz, due to aromatic C-H), 7.76 – 7.73 (multiplet,
due to aromatic C-H), 7.65 (doublet, J = 6.00 Hz), 7.64 (doublet, J = 6.00 Hz), 7.25
(doublet, J = 7.52 Hz), 4.00 and 3.95 (nine protons due to –OCH3 group). The 13C NMR
spectrum showed seventeen peaks at δ 166.5, 164.3, 160.4, 134.7, 130.3, 129.8, 129.3,
128.0, 127.2, 127.0, 124.4, 123.8, 116.0, 113.3, 107.8, 52.7, 52.2. The structure was further
confirmed by HRMS and a single crystal XRD.
224
IR(ATR)
1
13
225
13
C NMR,100 MHz, DEPT 135 Solvent: CDCl3
HRMS
ORTEP
226
4.6. Conclusion
A new metal-free, solvent-free route towards the construction of the privileged class of
indolizines, pyrrolo[2,1-a]quinoline and pyrrolo[2,1-a]isoquinoline using ((1S,2S)-
trimethyl 1,2-dihydroxypropane-1,2,3-tricarboxylate have been developed from
naturally occurring Garcinia and Hibiscus acids. The trimethyl ester of Garcinia and
Hibiscus acids namely trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate and
trimethyl (1R,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate were successfully
converted to its mesityl or tosyl derivatives, (1S,2S)-trimethyl 2-hydroxy-1-(mesyloxy)
propane-1,2,3-tricarboxylate and trimethyl (1R,2S)-2-hydroxy-1-((methylsulfonyl)
oxy)propane-1,2,3-tricarboxylate respectively for the successful conversion of
indolizine skeletons. Upon the treatment of these electrophilic derivatives of Garcinia
and Hibiscus acids, with pyridines of various electronic status, resulting in the
formation of an inventory of trimethyl indolizine-1,2,3-tricarboxylate derivatives in
moderate to good yields. The procedure was successful with mono substitution at the
fourth position like methyl, t-butyl and methoxy pyridines in 59%, 58%, and 70%
respectively. The regioselectivity of the annulation of 3-ethyl pyridine resulted in a
mixture of regioisomers in the ratio 60 (isomer resulting from C-6 cyclization) to 40
(isomer resulting from C2 cyclization). The reaction was successful with benzo-fused
analogues with quinolone and isoquinoline resulting in pyrrolo[2,1-a]isoquinoline
(64% yield) and pyrrolo[1,2-a]quinolone (63% yield) derivatives respectively. It was
observed that the electronic nature of substituents affected the efficiency of reaction in
terms of isolated yield. The reaction was successful with electron-donating
substituents where as a failure with electron withdrawing substituents. This new
synthetic protocol is environmentally benign as the reaction is solvent-free, metal-free
as well as the important oxidation- aromatization step is spontaneous using air as
oxidant. The reported strategy needs improvement for electron-withdrawing
substituents and also for improving the yield of the final product.
All reagents were commercially available and used without further purification. All
the reaction temperatures shown are bath temperatures. 1H NMR (400 MHz) and 13C
NMR (100 MHz) were measured on a Bruker AV 400 spectrometer. Chemical shifts
227
are expressed in parts per million (ppm) relative to TMS (δ = 0) and coupling
constants are reported as Hertz (Hz). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet,
ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of
doublets, p = pentet, br = broad, m = multiplet), coupling constant, and integration.
Melting points were determined on ‘’Sunbim’’ make electrically heated melting point
apparatus and were uncorrected. IR spectra were recorded using a Shimadzu IR 470
spectrophotometer as KBr pellets (solids) or thin films (liquids) and Thermo Fisher iS
10 FTIR spectrometer with diamond ATR and is reported as wavenumber (cm–1).
Electron impact mass spectra were recorded on a Finnigan MAT MS 8230 or Jeol D-
300, Jeol-JMS600. HRMS were recorded on Micromass UK, Q-TOF. Optical
rotations were measured on a Rudolph IV Autopol polarimeter operating at the
sodium D line with a 100 mm path length cell, and are reported as follows:
[α]25
𝐷 (Concentration (g/100 mL), solvent). Column chromatography was carried out
with Merck product silica (silica gel 60-120 mesh) and thin layer chromatography was
carried out with Merck product silica (silica gel G for TLC).
4.7.1. Experimental Details
4.7.1.1. Sodium (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate(45)
To 1 (1 g, 5.549 mmol), aq.NaOH (0.8 g, 20.002 mmol) is added and completely

dissolved. The reaction mixture is then kept at 80 °C for 4 hours. The reaction mixture
is then concentrated under reduced pressure and washed with methanol to obtain a
white powder of pure 45.
Yield 91% (1.4 g)
228
1
H NMR (CDCl3, 400 MHz) δ 3.63 (s, 1 H) 3.02 (d, J = 1.6 Hz) and 2.65
(d, J = 16.8 Hz)ppm
13
C NMR (CDCl3, 100 δ 179.9, 179.1, 177.72, 78.34, 76.43, 42.5ppm.
MHz)
Molecular Formula C6H5Na3O8
4.7.1.2. Synthesis of trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-

tricarboxylate(46)
To a suspension of 45 (1.0 g, 3.65 mmol) in dry methanol (10 mL), thionyl chloride
(1.5 mL, 20 mmol,3 equiv) was added at 0 oC. After refluxing for two hours, the
reaction mixture was cooled and neutralized with a saturated aqueous solution of
sodium bicarbonate until the HCl formed was quenched. The residue obtained upon
concentration under reduced pressure was extracted with chloroform (3 x20 mL). The
combined extract was dried and concentrated to afford 46 as a yellow oil.
Yield 70% (0.52 g)
[α]25
𝐷 23(0.49c, CHCl3)
IR (FT IR) 3483, 1800, 1741, 1732. cm-1

1
H NMR: (400 MHz, CDCl3) δ = 4.25 (s, 1 H), 3.79 (d, J = 1.6 Hz, 9H), 2.99 (d,
J = 16.8 Hz,1H), 2.94(d, J = 16.8 Hz, 1H) ppm
13
C NMR: (100 MHz, CDCl3) δ 172.6, 171.0, 170.4, 84.4, 74.8, 53.5, 53.0, 52.1
and 39.6. ppm
HRMS 250
229
4.7.1.3. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-
1,2,3-tricarboxylate(57)
To a stirred solution of 46 (1.0 g, 4 mmol, 1 equiv) in dry DCM (2 mL) was added
pyridine (0.65 mL, 8 mmol, 2 equiv) under N2 atmosphere and was cooled down to 0
°C. To the cooled reaction mixture was added MsCl (0.6 mL, 6 mmol, 1.5 equiv) while
stirring. After 24 hours at room temperature, the reaction mixture was diluted with
DCM (50 mL) and was washed with water (3 x 100 mL). The organic layer was dried
over anhydrous Na2SO4, evaporated under reduced pressure and purified by column
chromatography on silica gel 60–120 mesh (CHCl3) to afford 57 as colourless crystals.
Yield 60% (0.78 g)
Melting point 74 ºC
[α]25
𝐷 +32.7 (0.49 c, CHCl3)
IR (FT IR) 3485, 2959, 1736, 1438, 1537, 1204, 1177, 1135, cm-1
1
H NMR: (400 MHz, CDCl3) δ 5.20 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.71 (s, 3H),
3.20 – 3.16 (d, J = 13.67 Hz, 1H), 3.17 (s, 3H), 3.08 –
3.04 (d, J = 16.40 Hz, 1H) ppm
13
C NMR: (100 MHz, CDCl3) δ 170.9, 169.8, 165.8, 79.5, 76.5, 53.8, 53.2, 52.2,
39.2, 39.2. ppm
Molecular Formula C10H16O10S
HRMS m/z for [C10H16NaO10S]+ calculated :351.0362: measured: 351.0353

([M+Na]+)
230
4.7.1.3a. General Procedure for the Synthesis of Indolizine Derivatives
To a stirred solution of 46 or 57 (1.0 g, 4 mmol, 1 equiv) in dry DCM (2 mL) was

added pyridine derivative (8 mmol, 2 equiv) under N2 atmosphere and was cooled
down to 0 °C. To the cooled reaction mixture was added TsCl (1.14 g, 6 mmol, 1.5
equiv) or MsCl (0.6 mL, 6 mmol, 1.5 equiv) while stirring. After being stirred for 24
hours at room temperature, pyridine derivative (2 equiv) was added to the reaction
mixture. The reaction flask was equipped with a dry air balloon, and stirring was
continued for 24 h at 80 oC. The reaction mixture was diluted with DCM (50 mL) and
washed with water (50 mL x 6). The organic layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure. The resultant crude residue was purified by
column chromatography on silica gel 60-120 mesh (0 – 2 % EtOAc/CHCl3) to obtain
569-578
4.7.1.4. Synthesis of Trimethyl indolizine-1,2,3-tricarboxylate (569)
Prepared following general procedure on a 4 mmol scale from 57 (1 g, 4.0 mmol, 1.0 equiv)
and pyridine (1.28 mL, 16.0 mmol, 4.0 equiv) to afford 569 as colorless crystals.
Yield 60% (0.63 g)
Melting point 146-147 oC
IR (FT IR) 2954, 1739,1690, 1506, 1456, 1443, 1385 cm-1

1
H NMR: (400 MHz, δ 9.54 (d, J = 7.08 Hz, 1H), 8.35 (d, J =9.00 Hz,
CDCl3) 1H), 7.40 (t, J = 7.32 Hz, 1H), 7.07 (t, J = 6.64 Hz,
1H), 4.02 (s, 3H), 3.93 (s, 6H) ppm.
13
C NMR: (100 MHz, δ 166.3, 163.3, 160.4, 137.9, 130.6, 127.9, 126.8,
CDCl3) 119.9, 115.4, 111.9, 103.0, 52.9, 52.0, 51.7. ppm
231
HRMS m/z for calculated :292.0821: measured: 292.0846

[C10H16NaO10S]+ ([M+H]+)
4.7.1.5. Synthesis of 1,2,3-trimethoxy-7-methylindolizine (570)
and 4-methylpyridine (1.56 mL, 16.0 mmol, 4.0 equiv) to afford 570 as colourless crystals.
Yield 59% (0.71 g)
IR (FT IR) 2925, 1741, 1696, 1505, 1457. cm-1

1
H NMR: (400 MHz, CDCl3) δ 9.32 (d, J = 7.20 Hz, 1H), 8.04 (s, 1H), 6.82 (dd,
J = 7.24, 1.60 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 6H),
2.39 (s, 3H) ppm
13
C NMR: (100 MHz, CDCl3) δ 166.4, 163.5, 160.4, 138.4, 138.3, 130.6,
127.3, 118.5, 118.0, 111.3, 101.8, 52.8, 51.8
, 51.5, 21.5. ppm
HRMS m/z for [C10H16NaO10S]+ calculated :328.0797: measured: 328.079.

([M+Na]+)
232
4.7.1.6. Synthesis of trimethyl 6-ethylindolizine-1,2,3-tricarboxylate and
trimethyl 8-ethylindolizine-1,2,3-tricarboxylate (575 & 576)
Prepared following general procedure on a 4 mmol scale from 57 (1 g, 4.0 mmol, 1.0
equiv) and 3-ethylpyridine (1.80 mL, 16.0 mmol, 4.0 equiv) to afford 575 and 576 in
the ratio 60:40.

Yield 58% (0.74 g)
IR (FT IR) 2960, 1740, 1694, 1523, 148, 1445, 1383.cm-1.
1
H NMR: (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.17 (d, J = 9.08 Hz, 1H), 7.21 (d,
J = 12.32 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 6H), 2.64
(q, J = 7.36 Hz, 2H), 1.23 (t, J = 7.44 Hz, 3H)
(575) ppm
δ 9.43 (d, J = 6.8 Hz), 7.10 (d, J = 6.8 Hz), 6.91
(d, J = 7.2 Hz), 3.89 (s, 3H), 3.83 (s, 3H), 3.79 (s,
3H), 3.11 (q, J = 7.6 Hz), 1.16 (t, J = 7.6 Hz) (576)
ppm
13
C NMR: (100 MHz, CDCl3) δ 166.6, 166.5, 163.6, 163.4, 160.6,1
160.4, 136.8, 136.3, 136.1, 131.7, 131.3,
130.3, 128.9, 125.9, 125.8, 125.2, 119.4,
115.3, 111.5, 111.3, 105.3, 102.7, 52.9,
52.7, 52.0, 52.0, 51.9, 51.6, 26.9, 26.2, 14.9, 14.4. ppm
Molecular Formula C32H34N2O12
HRMS (ESI) m/z: for Calculated : 342.0954, Found: 342.0939.
C16H17NO6Na[M+Na]+
233
4.7.1.7. Synthesis of trimethyl 6,8-dimethylindolizine-1,2,3-tricarboxylate (574)
and 3,5-dimethylpyridine (1.83 mL, 16.0 mmol, 4.0 equiv) to afford 574 as colourless crystals.
Yield 65% (0.82 g)
IR (FT IR) 2952, 1724, 1698, 1518, 1492, 1439, 1376cm-1

1
H NMR: (400 MHz, CDCl3) 9.21 (s, 1H), 6.90 (s, 1H), 3.88 (s, 3H), 3.81, (s,
3H), 3.76 (s, 3H), 2.58 (s, 3H), 2.26 (s, 3H) ppm.
13
C NMR: (100 MHz, CDCl3) δ 166.7, 163.4, 160.5, 135.5, 130.9, 129.3,
125.0, 123.6, 110.9, 105.0, 52.6, 51.8, 51.7,
21.4, 18.3. ppm
HRMS m/z for [C16H17NaNO6]+ calculated :342.0954: measured: 342.0946.

[M+Na]+
4.7.1.8. Sythesis of trimethyl 7-(tert-butyl)indolizine-1,2,3-tricarboxylate (570)
and 4-tertiarybutylpyridine (2.34 mL, 16.0 mmol, 4.0 equiv) to afford 570 as yellow oil.
234
Yield 58% (0.80 g)
IR (FT IR) 2951, 1751, 1690, 1644, 1519, 1493, 1446, cm-1
1
H NMR: (400 MHz, CDCl3) δ 9.33 (d, J = 7.44 Hz, 1H), 8.20 (d, J = 1.20 Hz,
1H), 7.04 (dd, J = 7.48, 2.00 Hz, 1H), 3.92 (s, 3H),
3.82 (s, 6H), 1.31 (s, 9H) ppm
13
C NMR: (100 MHz, CDCl3) δ 166.4, 163.5, 160.5, 151.2, 138.4, 130.6,
127.3, 114.7, 114.5, 111.1, 102.2, 52.8, 51.8,
51.5, 30.3, 35.1. ppm
HRMS m/z for [C18H21NaNO6]+ calculated :370.1267: measured: 370.1261

[M+Na]+
4.7.1.9. Synthesis of trimethyl pyrrolo[1,2-a]quinoline-1,2,3-tricarboxylate (578)
equiv) and pyridine (1.28 mL, 16.0 mmol, 4.0 equiv) to afford 578 as colorless crystals.
Yield 63% (0.85 g)
IR (FT IR) 2949, 2849, 1739, 1703,1619, 1544.cm-1

1
H NMR: (400 MHz, δ 8.24 (d, J = 9.20 Hz, 1H), 8.09 (d, J =8.4 Hz, 1H),
CDCl3) 7.79 (d, J = 7.6 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.52
(t, J = 7.6 Hz), 4.02 (s, 3H), 3.98 (s, 3H), 3.93 (s,
3H) ppm.
235
13
C NMR: (100 MHz, δ 166.2, 163.4, 161.2, 137.9, 132.8,131.0, 128.9, 128.7,
CDCl3) 128.6, 125.9, 125.4, 119.5,117.7, 117.6, 105.2, 52.9, 52.5,
51.8 ppm.
HRMS(ESI) m/z for calculated :342.0978: measured: 342.0971.

[C18H15HNO6]+ [M+H]+
4.7.1.10. Synthesis of trimethyl 7-methoxyindolizine-1,2,3-tricarboxylate (572)
equiv) and 4-methoxypyridine (1.62 mL, 16.0 mmol, 4.0 equiv) to afford 572 as
colourless crystals.

Yield 60% (0.77 g)
IR (FT IR) 3014,2951,2915, 2849, 1738,1688, 1541.cm-1
1
H NMR: (400 MHz, CDCl3) δ 9.27 (d, J = 7.72 Hz, 1H), 7.58 (d, J = 2.44 Hz,
1H), 6.65 (dd, J = 7.72, 2.68 Hz, 1H), 3.91(s,
3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H) ppm.
13
C NMR: (100 MHz, CDCl3) δ 166.3, 163.6, 160.4, 159.0, 140.6, 130.7, 129.1,
110.7, 109.8, 101.0, 97.4, 55.7, 52.8, 51.8, 51.4
ppm
HRMS(ESI) m/z for calculated :344.0746: measured: 344.0745.
[C18H15NaNO6]+ [M+Na]+
236
4.7.1.11. Sythesis of trimethyl pyrrolo[2,1-a]isoquinoline-1,2,3-tricarboxylate -
(577)
and isoquinoline (1.88 mL, 16.0 mmol, 4.0 equiv) to afford 577 as colourless crystals.
Yield 51% (0.83 g)
IR (FT IR) 2925,2853,1738, 1673, 1627, 1598.cm-1
δ 9.47 – 9.44 (m, 48 Hz, 1H), 7.76 – 7.73 (m,

1 1H), 7.65 (d, J = 6.00 Hz, 1H), 7.64 (d, J = 6.00
H NMR: (400 MHz, CDCl3)
Hz, 1H), 7.25 (d, J = 7.52 Hz, 1H), 4.00 (s, 3H),
3.95 (d, J = 2.32 Hz, 6H) ppm.
δ 166.5, 164.2, 160.4, 134.6, 130.2, 129.8,

13
C NMR: (100 MHz, CDCl3) 129.3, 128.0, 127.2, 126.9, 124.4, 123.8,
116.0, 113.3, 107.8, 52.7, 52.2 ppm.
HRMS(ESI) m/z for

calculated :364.0797: measured: 364.0788.
[C18H15NaNO6]+ [M+Na]+
237
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Chapter 5
Attempted synthesis of enantiomers of

(2S,3S) and (2S,3R)-3-hydroxy-
5-oxotetrahydrofuran-2,3-dicarboxylic acids
5.1. Introduction
Enantiomers are non-super imposable mirror images of each other that possess
identical physical and chemical properties, in an achiral environment, only differ in
the direction of optical rotation1a-1eand contributes to the remarkable trait of chirality
in organic entities. Nature shows a remarkable degree of specificity in the recognition
of chiral molecules, resulting in the mirror image arrangements of the two forms
eliciting quite different biological responses. 1a
There is a close relationship between biological activities and absolute configurations

of synthetic compounds, or natural products, used as drugs, agrochemicals and/or
fragrance. The self-organization of bio-molecules leading to the properties beyond
those of individual molecules relies on the enantiomeric purity of chiral compounds.
The two enantiomers of a synthetic chiral drug interact differently with its receptor
site and often lead to different biological effects.2a-2g In several cases undesirable side
effects or even toxic effects may occur with the antipode. There are also cases when a
particular composition of enantiomers is an essential criterion for the desired
biological function.1v,2f-2g For example, the different smell of oranges and lemons
comes from two molecules that are identical except their three-dimensional spatial
arrangement1f-r
Many classes of natural products like amino acids, hydroxyl acids, carbohydrates,
alkaloids were employed as starting molecules for the synthesis of enantiomerically
pure molecules and this approach is known as chiral pool approach. There are several
approaches towards obtaining enantiomerically pure molecules and out of that the
chiral pool approach is the most convenient, economically viable and environmentally
friendly method for the preparation of enantiomerically pure molecules. (page no.6)
Hydroxy acids, consists of a carboxylic acid and hydroxyl group in the same
245
molecule.the more popular hydroxyl acids are useful building blocks in organic
synthesis (Fig 5.1). 1s, 3-13
However, the major limitation associated with this approach is the non-availability of
both enantiomers in nature at the disposal of synthetic organic chemists.2J This
limitations also exist in the case of optical isomers of 2-hydroxycitric acids. Optically
active 2-hydroxy citric acids namely, (2S,3S) and (2S,3R)-tetrahydro-3-hydroxy-5-
oxo-2,3-furandicarboxylic acids (Garcinia and Hibiscus acids) are abundantly
distributed in tropical plants (page 13). Due to the presence of γ-hydroxyl group
within the molecule, the acid can only be isolated in lactonized forms (Scheme 5.1).
Since the molecule contains two chiral centres, four optical isomers are expected. Out
of these, the diastereomers, namely, Garcinia and Hibiscus acids are known to present
in several plant species including Garcinia cambogia and Hibiscus sabdariffa
7-8
respectively. and to best of our knowledge, the natural distribution of the other two
isomers such as (2R,3R) and (2R,3S) tetrahydro-3-hydroxy-5-oxo-2,3-furan
dicarboxylic acids (enantiomer of Hibiscus and Garcinia acids) remains unknown
(Scheme 5).
246
Our laboratory has identified (2S,3S) and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-
furandicarboxylic acids (1&2) (Garcinia and Hibiscus acids) as an ideal choice for the
construction of molecules with six carbon skeleton having two chiral centres in
minimum steps. 9-14 This has been revealed through the earlier chapters of this Thesis
(Chapter 1).
The limitation of the non-availability of (2R,3R) and (2R,3S)-tetrahydro-3-hydroxy-5-

oxo-2,3-furandicarboxylic acids (1.a and 2.a isomers) (scheme 5.2&5.3) can be
overcome by the epimerization of the C-2 carbons of the available natural acids
namely Garcinia and Hibiscus acids(1 and 2).
247
Thus it may be logically concluded that an inversion of the C-2 asymmetric centre of
Garcinia acid is expected to give the enantiomers of Hibiscus acid and the inversion
of the C-2 asymmetric centre of Hibuscus acid is expected to give rise to the
enantiomer of Garciniaacid .
As a consequence, it was the objective of the present study to synthesise the optical
isomers (2R,3R) and (2R,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids
(1.a and 2.a) using naturally occurring (2S,3S) and (2S,3R)-tetrahydro-3-hydroxy-5-
oxo-2,3-furandicarboxylic acids (1 and 2).
A literature survey reveals that there are several methods available for cumulating the
inversion of asymmetric centres. The ensuing discussion reveals some of the
important methods of carrying out inversion reactions.
5.2. Inversion of chiral secondary alcohol

1g-k
Inversion of chiral alcohol is a fundamental task in organic synthesis. Two
principal methods are often used for this purpose (Scheme 5.1). The first one is a
direct method (Method A), in which chiral alcohols are inverted via the
Mitsunobu reaction and the second one is an indirect method (Method B), in
which chiral alcohols are first converted to their sulfonates which are then subject
to SN2 replacement by oxygen nucleophiles with the sulfonyloxy moieties as
leaving groups.
248
5.2.1. Inversion of stereochemistry via Mitsunobu reaction
The Mitsunobu reaction established by Oyo Mitsunobu and co-workers in 1967

gained wide acceptance in organic synthesis due to its outstanding effectiveness and
16a
versatility. Strategy for the inversion of the configuration of secondary alcohols
using Mitsunobu procedure for inverting esterification are of considerable preparative
interest. Such methods can be employed to establish the correct stereochemistry of
secondary alcohols in those cases where the direct synthesis only leads to the
undesired false stereoisomer. In connection with the resolution of racemates,
inversion procedures are also of interest as a way of utilizing the undesired
enantiomer, thereby making chiral synthesis more economical. 15
Due to the wide scope, stereospecificity, and mild reaction conditions, Mitsunobu
reaction has enjoyed a privileged role in the organic synthesis and medicinal
17
chemistry. It has been quite successfully employed in the total synthesis and
18a
modification of numerous natural compounds. This reaction permits condensation
of an acidic component with primary or secondary alcohol in the presence of
triphenylphosphine 590 and diethyl azodicarboxylate DEAD (591) and its derivatives
(592-597) (Fig 5.2).18b
249
The Mitsunobu reaction allows the conversion of primary and secondary alcohols to
esters, phenyl ethers, thioethers and various other compounds. One of the major
problems associated with Mitsunobu reaction was the laborious purification of the
product from dihydro-DEAD and triphenylphosphine. Hence the inversion of chiral
alcohols via the Mitsunobu reaction maybe not suitable for large-scale
11r,21
preparations and potential industrial syntheses. The nucleophile employed
should be acidic since one of the reagents (DEAD, diethylazodicarboxylate) must be
protonated during the course of the reaction to prevent from side reactions.
Mitsunobu et al 19 initially reported the esterification of carboxylic acids with primary

19
and secondary alcohols using diethyl azodicarboxylate and triphenylphosphine.
Further work by Mitsunobuand coworkers demonstrated the ability of this reaction to
bring about the complete inversion of the stereochemistry of secondary alcohols
during esterification and returned the inverted product after hydrolysis (Scheme
5.2).20a
250
Several important variations were discovered by Mitsunobu and his co-workers in the
early stages of its development as a synthetic tool. Fletcher et al. reviewed recent
advances and applications of Mitsunobu chemistry and published in 2015.20b
5.2.2. Inversion of the stereochemistry of secondary alcohols via tosylate

intermediate
Inversion of the stereochemistry of secondary alcohols via nucleophilic substitution
reaction (SN2) can also be done by converting alcohols into a leaving group using
tosylation. A tosyl/mesyl/triflate groups (Ts /Ms/Tf(CH3C6H4SO2 /CH3SO2/ CF3SO2)
can function as a protecting group in organic synthesis. In SN2 reactions, alkyl
alcohols can also be converted to alkyl tosylates/mesylates, often through the addition
of tosyl chloride/mesyl chloride 22-23(Fig. 5.3).
Preparation of sulfonates can be done on the use of the corresponding sulfonic acids,
sulfonyl chloride or anhydride in the presence of pyridine24 triethylamine25-26 1,4-
diazabicyclo[2.2.2]octane (DABCO)27 or aqueous base. Some catalysts like
Cobalt(II)chloridehexahydrate (CoCl26H2O) 28dibutyltin oxide, 29 and ZrCl430 helps to
obtain rapid sulphonylation product were also reported.
In 2010, Shi et al. developed a simple and versatile procedure for the inversion of
chiral secondary alcohol based on the SN2 reactions of sulfonates with tunable
complex of R3N-R1COOH. This new process allows the conversion of various chiral
251
sulfonates to inverted carboxylates in the low polar solvent toluene in good to
excellent yields (Scheme 5.3).31
Reports are available for the selective tosylation/mesylation of a primary hydroxy

group in the presence of a secondary hydroxy group 27,29 or vice Versa.28
The resultant hydroxysulfonate is the precursors to the synthesis of several numbers

32
of natural products and drugs . At the same time, if a molecule contains both
secondary and tertiary hydroxy groups, a selective O-protection of a secondary
hydroxy group in the presence of a tertiary hydroxy group was also reported.33
5.2.3. Inversion of stereochemistry of secondary alcohols via oxidation-

reduction approach
The oxidation of alcohols to carbonyl compounds is a fundamental synthetic
transformation and a wide variety of reagents have been developed for this important
reaction. Favourable attributes of an alcohol oxidation procedure include excellent
yield, the absence of side products, the use of available, inexpensive, non-toxic
reagents, mild conditions, high chemoselectivity, and compatibility with other
functional groups. Many commonly used reagents oxidize secondary alcohols at rates
slightly faster than primary alcohol, but these have not been practical for selective
oxidations because of the small magnitude of the rate differences.
The oxidation-reduction strategy involves the oxidation of a secondary hydroxyl

group followed by the reduction of the ketone to yield all the possible isomers. The
difficulty associated with this strategy was the successful oxidation of secondary
alcohols in the presence of the sensitive neighbouring functional group. Several
reagents have been developed for the stereoselective reduction of ketones to chiral
alcohols. The products will be diastereomers if the molecule already contains a
stereocenter.
252
Pyridinium chlorochromate (PCC) oxidizes a wide variety of alcohols to carbonyl
compounds with high efficiency34. The reaction involves simply the addition of
alcohols to a well-stirred suspension of PCC in methylene chloride. Although PCC
oxidations are routinely performed in organic transformations, the requirement of at
least a stoichiometric amount of PCC to complete the oxidation is a disadvantage
because of the high toxicity of chromium reagents.35
Oxidation of secondary alcohols has been a key area of interest in organic synthesis.
The chromic acid in aqueous sulfuric acid is one of the oldest methods used to convert
alcohols to carbonyl compounds. The first description of oxidation of alcohols with
potassium dichromate in aqueous sulfuric acid was made by G. Stadeler.36 Although
chromic acid oxidation has long been a standard method, many modified procedures
have been developed to simplify the isolation process, to achieve chemoselectivity
and to improve the yield of the product37(Scheme 5.4).
A variety of N-halogenated reagents have been used by Arterburn et al. for the
selective oxidation of secondary alcohol, including N-bromoacetamide (NBA), N-
bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) as in Scheme 5.5. 38
253
Rapoport et al. revealed that silver carbonate when prepared from aqueous silver
nitrate and sodium bicarbonate can oxidize some alcohols in refluxing benzene under
neutral conditions and the resulting active silver carbonate involved time-consuming
filtering and washing steps.39 Fetizon et al. showed that silver carbonate is generated
from aqueous silver nitrate and sodium carbonate in the presence of Celite, a form of
silver carbonate on Celiteis generated that is very easily filtered and washed, and
possesses an enhanced reactivity.40 Fetizon’s reagent has a great tendency to oxidize
lactols to lactones, relative to the oxidation of primary and secondary alcohols
(Scheme 5.6).41
5.2.4. Inversion of the stereochemistry of secondary alcohols via Isourea ether
The esterification of secondary alcohols via isourea ethers which has been known in
principle for many years offers a new, simple procedure for the inversion of the
configuration of chiral secondary alcohols.15
Kaulen and coworkers converted the secondary alcohol 612 (as the pure enantiomer or
diastereomer) in situ into the isourea ether 613 by addition to dicyclohexylcarbodiimide.
When 613, without isolation, is allowed to react further with carboxylic acids in a
one-pot procedure, the esters 614 are obtained in a smooth reaction; the
dicyclohexylurea that is formed simultaneously can be removed by filtration and
subsequent esterification proceeds with practically complete inversion of the
configuration so that the ester 614 has the inverted configuration of the alcohol 612
(inverting esterification) (Scheme 5.7).
254
5.2.5. Inversion of the stereochemistry of secondary alcohols via acetate
Shimizu et al. have synthesized the inverted alcohol 617 in excellent yield by treating
chloromethanesulfonate with cesium acetate. They have carried out inversion of a
variety of secondary alcohol using the chloromethylsulfonyloxy group as a favourable
leaving group with cesium acetate in presence of 18-crown-6 in comparison with the
reaction of the corresponding mesylate and triflates617b1t (Scheme 5.8).
255
5.2.6. Intramolecular substitutions of secondary and tertiary alcohols with
inversion of stereochemistry by an iron (III) catalyst
Watile et al. demonstrate that a simple, inexpensive, and naturally benign iron(III)
catalyst 618a encourages the direct intramolecular substitution of enantiomerically
enriched secondary and tertiary alcohols with -O, -N, and –S centred nucleophiles 618
to generate valuable five-membered, six-membered and aryl fused 6-membered
heterocyclic compounds with chirality transfer 619. They used this methodology in
the total synthesis of (+)-lentiginosine from D-glucose (Scheme 5.9).1u
5.2.7. Inversion of the stereochemistry of secondary alcohols via

phosphorothiolates using a thioiminium salt as a coupling agent
Grounds et al. reported a method for the direct and rapid conversion of primary and
secondary alcohols to the corresponding phosphorothiolate 599 using a thioiminium
salt as a coupling agent. The reaction of secondary alcohols proceeds stereospecifically
in yields ranging from 64% to 97%, with inversion of configuration (Scheme 5.10).2h
256
5.2.8. Construction of C(sp3)-P bond through non-activated alkyl halides and
alkyl tosylates with inversion of stereochemistry
Yang et al. synthesized stereocontrolled C(sp3)-P bond through non-activated alkyl
halides and alkyl tosylates. The C(sp3)-P bond is formed via the reaction between P-H
compounds and non-activated electrophiles. The X-ray crystal analysis of synthesized
compound (623 and 625) indicated an inversion of configuration, which confirmed
the hypothetical SN2 mechanism of the reaction(Scheme 5.11).2i
5.3. Objective of the present study
The purpose of this study is to carry out inversion of the C-2 asymmetric carbons of
(2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (Garcinia
and Hibiscus acids, 1&2) via a SN2 oxygen nucleophilic substitution reaction, to
furnish (2R,3S) and (2R,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids,
1.a &2.a). Various strategies, including Mitsunobu reaction, oxidation reduction
reaction or conversion of the chiral alcohol to a good leaving group followed by SN2
substitution reaction were attempted to invert the configuration of C-2 chiral centers
of molecules 1 & 2.
To execute the above strategies, triersters of Garcinia and Hibiscus acids namely
trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate (46) and trimethyl
(1S,2R)-1,2-dihydroxypropane-1,2,3-tricarboxylate (46a) were prepared. The
Garcinia trimethyl ester was then converted to their tosyl and mesyl derivatives
namely trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate (47)
257
and trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate
(57). Attempts were made to invert the configuration of C-2 carbon of 47 and 57
using acetate anion in pyridine. Instead of the inverted product, trimethyl (1R,2S)-1-
acetoxy-2-hydroxypropane-1,2,3-tricarboxylate (626), dimethyl ester of Garcinia acid
was isolated (310a). When the reaction was carried out at an elevated temperature,
surprisingly the trimethyl indolizine-1,2,3-tricarboxylate, (569 ) was isolated as a
crystalline solid.
The similar experiments were attempted with the tosyl and mesyl derivatives of
Hibiscus acid namely trimethyl (1S,2R)-2-hydroxy-1-(tosyloxy)propane-1,2,3-
tricarboxylate (47a) and trimethyl (1S,2R)-2-hydroxy-1-((methylsulfonyl)oxy)
propane-1,2,3-tricarboxylate (57a), which furnished the Hibiscus dimethyl ester
namely dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylate (311a)
and indolizine, trimethyl indolizine-1,2,3-tricarboxylate (569) (Scheme 5.12).
The formation of dimethyl esters of Garcinia and Hibiscus acids (310a and 311a) are
quite interesting as the molecules resist undergoing epimerization on C-2 asymmetric
centre. This “self-defence mechanism” can be explained on the basis of the suggested
mechanism (Scheme.5.13.) Hence it is obvious that out of the four isomers of non-
racemic 2- hydroxycitric acid, to best of our knowledge, only two of them are
encountered in nature (1 and 2).
258
Interestingly, when (1S,2S)-trimethyl 2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate
(47) as refluxed with toluene in the presence of triethylamine, without acetate anion,
trimethyl 1-oxopropane-1,2,3-tricarboxylate (627) was isolated. A careful
examination of the structure of this product revealed that a 1,2 shift has taken place
leading to the formation of the rearranged product (627) (Scheme 5.14).
Mitsnobu reaction and oxidation-reduction strategy have also been carried out on
trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate (47) to afford trimethyl
(1R,2S)-2-hydroxy-1-((4-nitrobenzoyl)oxy)propane-1,2,3-tricarboxylate (628) and
trimethyl (R)-2-hydroxy-1-oxopropane-1,2,3-tricarboxylate (629) respectively and
was a failure.
259
5.4.1. Synthesis of ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-dioxolane-4,5-
diyl)bis methylene) bis(4-methylbenzenesulfonate) (584)
The tritosyl derivative of Garcinia acid namely ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-
1,3-dioxolane-4,5-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (632) was
successfully synthesized starting from trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-
tricarboxylate (46) using Kagan’s procedure for DIOP. However, further conversion
of 632 to chiral triphenyl phosphene derivative (633), an analogue of DIOP and is
expected to be an asymmetric catalyst for the enantioselective synthesis, was failed
(Scheme.5.15).45
5.4.2. Synthesis of trimethyl(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamimidoyl)oxy) -

2-hydroxypropane-1,2,3-tricarboxylate (634)
When the trimethylester of Garcinia acid (1S,2S)-trimethyl 1,2-dihydroxypropane-
1,2,3-tricarboxylate (46) was treated with the isourea ether 635 in DCC resulted the
260
formation of trimethyl(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamim -idoyl)oxy)-2-
hydroxypropane-1,2,3-tricarboxylate (634). However further substitution with
carboxylic acid was failed. (Scheme 5.16).
5.4.3 Attempted synthesis of trimethyl (1R,2S)-2-hydroxy-1-((4-

nitrobenzoyl)oxy)propane-1,2,3-tricarboxylate, 628 employing
Mitsunobu reaction.
To a solution of trimethyl ester of Garcinia acid namely, (1S,2S)-trimethyl 1,2-
dihydroxypropane-1,2,3-tricarboxylate (46) in THF, 4-nitrobenzoic acid and
triphenylphosphine (TPP) were added. To this, diethyl azadicarboxylate (DEAD) was
added dropwise at 0 oC. The reaction mixture was stirred at room temperature for 24
hours to afford (1R,2S)-trimethyl 2-hydroxy-1-((4-nitrobenzoyl)oxy) propane-1,2,3-
tricarboxylate (628) (Scheme 5.17). The reaction mixture was passed through a silica
plug of 2cm diameter and 5 cm in length with DCM until a colourless liquid was
obtained. The reaction mixture was concentrated first and then made to 50 mL, then
washed with 50 mL of 15% H2O2. The DCM layer was washed with aqueous
NaHCO3 and back-extracted with DCM. Combined DCM layer was washed with
water. Even though the TLC of the reaction showed the formation of the new product,
the isolation of the product in pure form was a failure (scheme 5.17).
261
The above-mentioned strategies provide an inexpensive and enantiopure method via a
stereospecific nucleophilic substitution reaction
5.4.4. Attempted synthesis of (S)-trimethyl 2-hydroxy-1-oxopropane-1,2,3-

tricarboxylate (629)
Trimethyl ester of Garcinia acid (1S,2S)-trimethyl 1,2-dihydroxypropane-1,2,3-
tricarboxylate 46 was treated with Potassium dichromate and sulfuric acid in diethyl
ether and the reaction mixture was stirred at room temperature expected to obtain (S)-
trimethyl 2-hydroxy-1-oxopropane-1,2,3-tricarboxylate 629 (Scheme 5.18). However,
in the presence of the strong acidic condition, the reaction yielded the diester of
Garcinia acid namely dimethyl (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylate (310a).
5.4.5 A Mechanistic explanation for the Self defence against epimerization of

C-2 asymmetric centres of Garcinia and Hibiscus acids.
Upon treatment of monotosyl derivative of Garcinia acid namely, trimethyl (1S,2S)-2-
hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate (47) with triethylamine–acetic acid
complex in 2:1 mixture in toluene, expecting to undergo SN2 inversion reaction,
resulting trimethyl (1R,2S)-1-acetoxy-2-hydroxypropane-1,2,3-tricarboxylate (626), the
indolizine-1,2,3-tricarboxylate (569) was obtained. The epimerisation on C-2 carbon
was not proceded due to anchimeric assistance, ultimately leading to the retention of
configuration affording exclusively the diester of Garcinia acid (310a) (scheme 5.19
and scheme 5.13.
262
The reaction was conducted as given below.
To a solution of trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate

(47) (1.04 g) in toluene (5 mL) was added acetic acid-triethylamine mixture (2:1)
(2.40 g). The solution was then stirred at room temperature for half an hour. The
mixture was heated to 80 °C, and stirring was then continued at this temperature
for 4 h. After being cooled down to room temperature, the reaction mixture was
diluted with toluene (30 mL). The solution was transferred into separatory funnel
and was washed successively with aqueous HCl solution (2 M, 20 mL), aqueous
K2CO3 solution (10% w/v, 25 mL), and brine (8 mL). After the organic solution
was dried over anhydrous Na2SO4, the solvent was removed by distillation in
vacuo to give the crude product which was purified by column chromatography.
263
Eventually, two consecutive SN2 reactions on the tosylates namely, (trimethyl
(1S,2S) and (1S,2R)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylates (47 and
47a)) obtained from Garcinia acid or Hibiscus acid resulted in the compounds having
same stereochemistry of the starting molecules (Scheme 5.20).
This may be probably occurring as we have observed that triesters of Garcinia acid
and Hibiscus acid, trimethyl (1S,2S) and (1S,2R)-1,2-dihydroxypropane-1,2,3-
tricarboxylates (46 & 46a) upon prolonged storage are getting converted to respective
diesters namely, (2S,3S) and (2S,3R) -3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylates (310a & 311a) (Scheme 5.20)
5.5.1. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-

tricarboxylate
The obtained trimethyl ester (46) contains free secondary hydroxyl group which is in
the α-position of neighbouring carboxylic acid. The tosylation was done by stirring a
mixture of 46 in CH2Cl2 (2 mL) with tosyl chloride (1.5 equiv) and pyridine (4 equiv)
for 8 hours. The structure of (1S,2S)-trimethyl 2-hydroxy-1-(tosyloxy)propane-1,2,3-
tricarboxylate(47) was determined using various spectroscopic techniques including
1
HNMR,13C-NMR, FT-IR and X-ray diffraction studies (Scheme 5.21).
264
IR spectrum shows the characteristic absorption bands at 3486 (-OH group), 2960
(aliphatic CH group), 1738 (ester group), 1361 and 1176 (-S=O group) cm-1. 1H NMR
spectrum of 47 was characterised by signals at δ 7.78 (doublet, J = 8.4 Hz, due to
aromatic proton), 7.36 (doublet, J = 8.0 Hz, due to aromatic proton), 5.03 (singlet, due
to methine group), 3.71, 3.66 (due to –OCH3 group), 3.03 (singlet, due to methylene
proton) and 2.45 (singlet, three protons due to CH3 group attached to aromatic ring).
The 13C NMR spectrum showed fourteen peaks at δ 170.9, 169.7, 165.8, 145.5, 132.8,
129.8, 128.2, 79.4, 76.2, 53.6, 53.0, 52.2, 39.2 and 21.7. The structure of 47 was further
confirmed by HRMS and single-crystal XRD.
IR(ATR)
1
265
13
HRMS
266
5.5.2. Synthesis of Trimethyl 1-oxopropane-1,2,3-tricarboxylate (627)
Trimethyl 1-oxopropane-1,2,3-tricarboxylate (627) was synthesized following reaction
between (1S,2S)-trimethyl 2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate (47)
refluxed in the presence of triethylamine and toluene at 90 °C. The structure of the
product was confirmed using IR, 1H NMR, and 13C NMR and FT-IR spectra (Scheme
5.22).
267
IR spectrum shows the characteristic absorption bands at 1731(ester group), 1361,1437
and 1258 cm-1. 1H NMR spectrum of 627 was characterised by signals at δ 4.74-4.68
(multiplet, due to methine group), 3.93,3.75 and 3.70 (due to –OCH3 group), 3.14-3.02
(multiplet, due to methylene proton) and 3.00-2.92 (multiplet, due to methylene
proton). The 13C NMR spectrum showed fourteen peaks at δ 187.8, 171.2, 168.2, 160.6,
53.5, 53.1, 52.4, 48.9, 31.9. The structure of 627 was further confirmed by HRMS.
IR(ATR)
1
268
13
13
13
269
5.5.3. Synthesis of dimethyl (5.)-4-(2-methoxy-2-oxoethyl)-2,2-dimethyl-1,3-
dioxolane-4,5-dicarboxylate (630)
Synthesis of trimethylpyrrolo[2,1-a]isoquinoline-1,2,3-tricarboxylate (630) was
successfully done using dry acetone by stirring in the presence of lewis acid BF3OEt2
complex. The structure of the product was confirmed using IR, 1H NMR, and 13C NMR
and HRMS spectra (Scheme 5.23).
The IR spectrum shows the characteristic absorption bands at 2955, 1739 (ester group)
1437 1358.4 cm-1. 1H NMR spectrum of 630 was characterised by signals at 4.91
(singlet, due to methine proton), 3.86, 3.80, 3.67 (due to –OCH3 group), 2.98 (doublet,
J = 16.8 Hz, due to methylene proton) and 2.84 (doublet, J = 16.8 Hz, due to methylene
proton). 1.59 (singlet, due to methyl proton), 1.48 (singlet, due to methyl proton).The
13
C NMR spectrum showed nine peaks at δ 170.8, 169.6,168.1, 113.1, 82.7, 79.1, 76.7,
53.2, 52.6, 52.0, 39.2, 27.7 and 25.8. The structure was further confirmed by HRMS.
270
IR(ATR)
1
13
271
13
HRMS
5.5.4. Synthesis of((5R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,5-

diyl)dimethan-ol (631).
Tandem reduction of diol protected trimethylester 630 to ((5R)-4-(2-hydroxyethyl)-
2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethan-ol (631) was successfully carried out
using NaBH4, MeOH at 0 oC. The structure of the product was confirmed using IR,
1
H NMR, and 13C NMR and HRMS spectra (Scheme 5.24).
272
The IR spectrum shows the characteristic absorption bands at 3345(-OH group), 2935
and 1371 cm-1. 1H NMR spectrum of 631 was characterised by signals at δ 4.14
(singlet, due to methine proton), 3.72 (doublet, J = 16.8 Hz, due to methylene proton)
3.56 (doublet, J = 16.6 Hz, due to methylene proton), 1.74 (doublet, J = 17 Hz, due to
methylene proton), 1.42 (singlet, due to methyl proton), 1.35 (singlet, due to methyl
13
proton). The C NMR spectrum showed eight peaks at δ 109.4, 84.1,82.8,
65.7,61.5,34.7,28.7,26.9. The structure was further confirmed by HRMS.
IR(ATR)
273
1
13
C NMR,100 MHz, Solvent: Acetone-d6
13
C NMR,100 MHz, DEPT 45 Solvent: Acetone-d6
274
13
C NMR,100 MHz, DEPT 90 Solvent: Acetone-d6
13
C NMR,100 MHz, DEPT135 Solvent: Acetone-d6
275
HRMS
5.5.5. Synthesis of ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-dioxolane-4,5-

diyl)bis (methylene) bis(4-methylbenzenesulfonate)(632)
The tritosyl derivative ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-dioxolane-4,5-
diyl)bis (methylene)bis(4-methylbenzenesulfonate)(632) was synthesized by treating
((5R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol(631) with
paratoluenesulphonyl chloride and pyridine under 0 oC for continuous stirring of 12 hrs.
The structure of the product was confirmed using IR, 1H NMR, and 13
C NMR spectra
(Scheme 5.25).
The IR spectrum shows the characteristic absorption bands at 2987, 1803,1702, 1597
cm-1.1H NMR spectrum of 632 was characterised by signals at 7.82-7.51 (multiplet,
due to aromatic proton), 7.51-7.47 (multiplet, due to aromatic proton) 4.22 (multiplet
due to methylene proton), 4.07-4.01 (multiplet due to methylene proton), 2.47 (singlet,
due to 9 methine group attached to aromatic ring), 2.04-1.72 (multiplet due to
methylene group), and 1.18 (singlet, due to CH3group).The 13C NMR spectrum showed
276
eight peaks at δ 146.3,146.3,146.0,134.1,133.8, 133.6, 131.1, 130.9,130.9, 128.8,
128.8, 128.7, 110.6, 80.7,78.1, 70.8, 68.5,66.7, 31.2,28.0, 26.3,21.6,21.5.
IR(ATR)
1
277
13
C NMR,100 MHz, Solvent: Acetone-d6
DEPT 90 NMR,100 MHz, DEPT 90 Solvent: Acetone-d6
278
100 MHz, DEPT 135 Solvent: Acetone-d6
5.5.6. Synthesis of trimethyl(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamimidoyl)

oxy)-2-hydroxypropane-1,2,3-tricarboxylate( 634)
When the trimethylester of Garcinia acid (1S, 2S)-trimethyl 1,2-dihydroxypropane-
1,2,3-tricarboxylate (46) was treated with DCC in 1,4 dioxane resulted the formation
of trimethyl(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamim-idoyl)oxy)-2-hydroxypropane-
1,2,3-tricarboxylate (634). However, further substitution with carboxylic acid was
failed. The structure of the product was confirmed using IR, 1H NMR, and 13C NMR
spectra (Scheme 5.26).
The IR spectrum shows the characteristic absorption bands at 3537,2189, 1732,1730

(ester group) and 1201(CN stretch) cm-1. 1H NMR spectrum of 634 was characterised
279
by signals at δ 4.86 (singlet, due to methine proton), 3.90, 3.72,3.55 (singlet due to –
OCH3 group) 3.05 (doublet, J = 17.6 Hz, due to methylene proton), 2.96 (doublet, J =
17 Hz, due to methylene proton), 1.84-1.28 (multiplet, due to 20 cyclohexyl proton).
The 13C NMR spectrum showed eight peaks at δ 170.9, 169.6, 169.4, 154.5, 79.6, 75.3,
54.15,54.0, 53.4, 52.4, 52.3, 38.1, 28.8, 25.7,25.7, 24.9.
IR(ATR )
1
280
13
281
DEPT 90 Solvent: CDCl3
DEPT 135 Solvent: CDCl3
282
HSQC Expanded
283
HSQC Expanded
HMQC
284
COSY
5.6. Conclusion
There are four possible optical isomers for non-racemic 2-hydroxycitric acid. Among
these, two of the isomers [(2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylic acids) (1 and 2)] are extensively distributed in nature. The existence of the
other two isomers is yet to be known. To make available all the optical isomers of 2-
Hydroxycitric acid, attempts were made to invert the configurations of C-2 carbon atoms
of 1 and 2. Various known methods were attempted, which includes Mitsunobu reaction,
inversion using mono tosyl/mesityl derivatives namely trimethyl (1S,2S)-2-hydroxy-1-
(tosyloxy)propane-1,2,3-tricarboxylate (47) and trimethyl (1S,2S)-2-hydroxy-1-
((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate (57) the isourea ether, trimethyl
(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamim-idoyl)oxy)-2-hydroxypropane-1,2,3-tri
carboxylate (634) and oxidation-reduction strategy. The acids 1 and 2 were successfully
converted to (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate (47) and
trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate (57).
Using these electrophiles, inversion reactions were attempted with acetate anion, in
pyridine solvent. Instead of the inverted product, dimethyl esters (310a & 311a) of
285
Garcinia and Hibiscus acids were isolated. When the reaction was carried out at an
elevated temperature, surprisingly the trimethyl indolizine-1,2,3-tricarboxylate, (569)
was isolated as a crystalline solid. Thus a new method for the construction of indolizidine
skeleton was developed. The epimerisation on C-2 carbon was not happened due to
anchimeric assistance, eventually leads to the retention of configuration to afford only the
diester of Garcinia acid on hydrolysis. When (1S,2S)-trimethyl 2-hydroxy-1-
(tosyloxy)propane-1,2,3-tricarboxylate (47) was refluxed in toluene in the presence of
triethylamine, without acetate anion, trimethyl 1-oxopropane-1,2,3-tricarboxylate (627)
an α-keto ester, a 1,2 rearranged product was isolated. The triesters of Garcinia and
Hibiscus acids were successfully converted to the tritosyl derivatives (632) for
synthesizing a new class of chiral trisphosphine catalyst (633).
All reagents were commercially available and used without further purification. All the
reaction temperatures shown are bath temperatures. 1H NMR (400 MHz) and 13C NMR
(100 MHz) were measured on a Bruker AV 400 spectrometer. Chemical shifts are
expressed in parts per million (ppm) relative to TMS (δ = 0) and coupling constants are
reported as Hertz (Hz). Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet
of doublet of doublets, dddd = doublet of doublet of doublet of doublets, p = pentet, br
= broad, m = multiplet), coupling constant, and integration. Melting points were
determined on ‘’Sunbim’’ make electrically heated melting point apparatus and were
uncorrected. IR spectra were recorded using a Shimadzu IR 470 spectrophotometer as
KBr pellets (solids) or thin films (liquids) and Thermo Fisher iS 10 FTIR spectrometer
with diamond ATR and is reported as wavenumber (cm–1). Electron impact mass
spectra were recorded on a Finnigan MAT MS 8230 or Jeol D-300, Jeol-JMS600.
HRMS were recorded on MicromassUK, Q-TOF. Optical rotations were measured on a
Rudolph IV Autopol polarimeter operating at the sodium D line with a 100 mm path
length cell, and are reported as follows: (concentration (g/100 mL), solvent).
Column chromatography was carried out with Merck product silica (silica gel 60-120
mesh) and thin-layer chromatography was carried out with Merck product silica (silica
gel G for TLC).
286
5.7. 1. Experimental details
5.7.1.1 Synthesis of trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy) propane-1,2,3-

tricarboxylate(47)
To a precooled stirred solution of 46 (1.0 g, 4 mmol) in dry DCM (2 mL) was added
pyridine (0.65 mL, 8 mmol, 2 equiv) under N2 atmosphere and was cooled down to 0
°C. To the cooled reaction mixture was added TsCl (1.14 g, 6 mmol, 1.5 equiv) while
stirring. After 12 hours at room temperature, the reaction mixture was diluted with
DCM (50 mL) and was washed with water (3 x 100 mL). The organic layer was dried
over anhydrous Na2SO4, evaporated under reduced pressure and purified by column
chromatography on silica gel 60–120 mesh (CHCl3) to afford 47 as colourless crystals.
Yield 82% (1.32 g)
Melting point 68 oC
[α]25
𝐷 +32.7 (0.49 c, CHCl3)
IR (FT IR) 3486, 2960, 1738, 1596.02, 1442. cm-1

1
H NMR: (400 MHz, δ 7.78 (d, J = 8.4 Hz, 2H), 7.36
CDCl3) 36 (d, J = 8.0 Hz, 2H), 5.03 (s, 1H), 3.71 (s, 6H), 3.66
(s,3H), 3.03 (s, 2H), 2.45 (s, 3H). ppm
13
C NMR: (100 MHz, δ 170.9, 169.7, 165.8, 145.5, 132.8, 129.8, 128.2, 79.4,
CDCl3) 76.2, 53.6, 53.0, 52.2, 39.2 and 21.7. ppm
Molecular Formula C16H20O10S
HRMS m/z for calculated :427.0699: measured:427.0659

+
[C16H20NaO10S]
([M+Na]+)
287
5.7.1.2. Synthesis trimethyl 1-oxopropane-1,2,3-tricarboxylate(627)
To a solution of (1S,2S)-trimethyl 2-hydroxy-1-(mesyloxy)propane-1,2,3-tricarboxylate

(57) (320 mg, 0.79 mmol) in toluene (5 mL) triethyl amine(0.79 mmol) was added.
To a precooled stirred solution of 46 (320 mg, 0.79 mmol) in toluene (5 mL) triethyl
amine (0.79 mmol) was added under N2 atmosphere. The mixture was heated at
refluxing condition. After 3hrs, the reaction mixture was cooled down to room
temperature diluted with 10 mL toluene. The solution was transferred into a
separatory funnel and was washed successively with aqueous HCl solution (2 M, 25
mL), and brine (10 mL). The solvent was removed by distillation in vacuo to give the
crude product (627) which was then purified by column chromatography to afford
coloured oil.
Appearance Coloured oil
Yield 42% (0.076 g)
IR (FT IR) 1731,1437,1258. cm-1

1
H NMR: (400 MHz, δ 4.74 - 4.68 (m, 1H), 3.93 (s, 3H), 3.75 (s, 3H), 3.70
CDCl3) (s, 3H), 3.14 - 3.02 (m, 1H), 3.00 - 2.92 (m, 1H) ppm
13
C NMR: (100 MHz, δ 187.8,171.2,168.5,160.5,53.5,53. 1,52.4,48.9,31.9
CDCl3) ppm
288
5.7.1.3. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-
To a precooled stirred solution of 46 (1 g, 4 mmol) in a round bottom flask is equipped

with a magnetic stirring bar and a pressure-equalized addition funnel in dry acetone
(50 mL) was added with excess dry acetone(50 mL) at 0 °C. To the clear solution is
added with boron trifluoride diethyl etherate (6.4 mL) dropwise. The resulting yellow
solution is stirred for an additional 7 h duringwhich time the colour of the solution
become red-brown. The reaction mixture was then neutralized using aqueous sodium
bicarbonate solution and extracted with ethyl acetate(3 x 50 mL). The ethyl acetate
layer was then washed twice with water (2 x 100 mL) and dried over anhydrous
Na2SO4, evaporated under reduced pressure and purified by column chromatography on
silica gel 60–120 mesh (CHCl3) to afford 630 as yellow oil.
Yield 65% (0.75 g)
[α]25
𝐷 +45.561 (0.123 c, acetone)
IR (FT IR) 2955, 1739, 1437, 1358 cm-1

1
H NMR: (400 MHz, δ (ppm):4.91 (s, 1H), 3.86 (s,3H),3.80(s,3H),3.67
CDCl3)
(s,3H), 2.98 (d, J = 16.8Hz, 1H), 2.84 (d, J =
16.8Hz,1H), 1.59 (s,3H), 1.48 (s,3H) ppm
13
C NMR: (100 MHz, δ(ppm):170.8, 169.6,168.1,113.1,82.7,79.1,76. 7,
CDCl3)
53.2,52. 6,52.0,39.2,27.6 and 25.7. ppm
HRMSm/zfor[C12H18NaO8]+ calculated :313.899: measured:313.0845

([M+Na]+)
289
5.7.1.4. Synthesis of ((5R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4,5-
diyl)dimethanol (631)
A long neck round bottom flask of 100 mL is charged with 545 (0.5 g, 1.7 mmol) under
an inert atmosphere. To this 3 mL dry MeOH is added.The mixture is held at 0 oC in a
low-temperature bath and to this NaBH4 (0.228 g, 6 mmols) is added and the mixture is
stirred at 0 oC for 3h.
Yield 50 % (0.17 g)
[α]25
𝐷 +39.158 (0.138 c, acetone)
IR (FT IR) 3345, 2935, 1371cm-1

1
H NMR: (400 MHz, δ (ppm): 4.14 (s, 1H), 3.72 (d, J = 16.8 Hz, 4H) 3.56
CDCl3) (d, J = 16.6 Hz, 2H), 1.74 (d, J = 17 Hz, 2H), 1.42
(singlet, 3H), 1.35 (singlet,3H) ppm
13
C NMR: (100 MHz, δ 109.6, 84.1,82.7,65.7,61.46,3.7,28.7and 26.9.ppm
CDCl3)
HRMS m/z for calculated :229.1052: measured:229.1051

[C9H18NaO5]+ ([M+Na]+)
290
5.7.1.5. Synthesis of ((5R)-2,2-dimethyl-4-(2-(tosyloxy)ethyl)-1,3-dioxolane-4,5-
diyl)bis (methylene) bis(4-methylbenzenesulfonate) (632)
To a precooled stirred solution of 631 (1.0 g, 4.8 mmol, 1 equiv) in dry DCM (2 mL)
was added pyridine (0.65 mL, 8 mmol, 2 equiv) under N2 atmosphere and was cooled
down to 0 °C. To the cooled reaction mixture was added TsCl (1.14 g, 6 mmol, 1.5
equiv) while stirring. After 12 hours at room temperature, the reaction mixture was
diluted with DCM (50 mL) and was washed with water (3 x 100 mL). The organic
layer was dried over anhydrous Na2SO4, evaporated under reduced pressure and
purified by column chromatography on silica gel 60–120 mesh (CHCl3) to afford 548
as a white powder.
Yield 82% (2.6 g)
Melting point 68 oC
[α]25
𝐷 +32.7 (0.49 c, CHCl3)
IR (FT IR) 2987, 1803,1702, 1597 cm-1

1
H NMR: (400 MHz, δ 7.82-7.51 (m,6H), 7.51-7.47 (m,6H) 4.22 (m,2H),
CDCl3) 4.07-4.01 (m,2H), 2.47 (s,9H), 2.04-1.72 (m,4H), 1.18
(S,6H).ppm
13
C NMR: (100 MHz, δ 146.3, 146.2, 146.1, 134.0, 133.8, 133.6, 131.1,
CDCl3) 130.9, 130.92, 128.8, 128.7, 128.7, 110.6, 80.7, 78.1,
70.8, 68.5, 66.7, 31.2, 28.0, 26.3, 21.6, 21.5.ppm
Molecular Formula C30H36O11S3
291
5.7.1.6. Synthesis of trimethyl (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-
To a precooled stirred solution of 526 (90a 0 mg, 3.6 mmol, 2 equiv) in dry 1,4 dioxane
(10 mL) was added catalytic amount CuCl(0.036 g) under N2 atmosphere and was
cooled down to 0 °C. To the cooled reaction mixture was added DCC (785 mg, 4
mmol, 1.4 equiv) while stirring at room temperature. After 10 hours, the reaction
mixture was diluted with DCM (50 mL) and was washed with water (3 x 100 mL). The
organic layer was dried over anhydrous Na2SO4, evaporated under reduced pressure
and purified by column chromatography on silica gel 60–120 mesh (CHCl3) to afford
571 as a white powder.
Yield 58% (0.95 g)
Melting point 146oC
IR (FT IR) 3537,2189,1732,1730, 1201 cm-1

1
H NMR: (400 MHz, δ 4.86 (s,1H), 3.90 (s,3H), 3.72 (s,3H),3.55 (s,3H
CDCl3) 3.05 (d, J = 17.6 Hz, 2H), 2.96 (d, J = 17 Hz, 2H),
1.84-1.28 (m,20H) ppm
13
C NMR: (100 MHz, δ (ppm):170.9, 169.6, 169.3, 154.4, 79.6,
CDCl3)
75.3, 54.1,54.0, 53.4, 52.4, 52.3, 38.1, 28.8,
25.7, 25.6, 24.9.ppm
Molecular Formula C22H36O8N2
292
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Chapter 6
Summary of the Thesis
This thesis concerns with the identification of (2S,3S) and (2S,3R)-3-hydroxy-5-

oxotetrahydrofuran-2,3-dicarboxylic acids, isolated in large amounts from plant
sources, as an ideal choice for the construction of a range of chiral and achiral
molecules of potential biological applications.This approach is based on a
combination of different reaction strategies which delivered a diverse matrix of
polycyclic fused ring systems. The furo[2,3-b]furanol is the (bis-THF) part of HIV
drug Darunavir. A new metal-free, solvent-free route towards the construction of the
privileged class of indolizine frameworks has been developed. The bicyclic furo[2,3-
b]pyrrolo skeleton is present in many natural products. Thus the uniqueness of
relatively cheap, naturally occurring chiral 2-hydroxycitric acids as chirons/synthons
have been demonstrated by the construction of some important molecular skeletons
that are otherwise difficult to synthesize.
Chapter 1 deals with the convenient method for the large scale isolation and
characterization of diastereomeric hydroxy acids namely Garcinia and Hibiscus acids
obtained from tropical plant sources. Also , the Chiroptical studies of (S)-(-)-crispine
A analogue namely (1R,10bR)-1-((R)-1,2-dihydroxyethyl)-1-hydroxy-8,9-dimethoxy-
1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one derived from Garcinia acid
have been carried out. The experimental chiroptical tools are used to evaluate the
absolute configuration (AC). In the absence of such outside information, separate
independent analysis of ORD, ECD, and VCD does not entail a unique solution to the
AC, and multiple diastereomers present themselves as viable candidates for the AC of
(-)-crispine A analogue. Combined EDF and VDF spectral analysis, however, rules
out the incorrect diastereomers. Thus, the combined EDF and VDF spectral analysis is
seen as a useful diastereomer discrimination tool.
A systematic account of the synthesis and application of Weinreb amides have been
described in Chapter 2. A convenient method for the synthesis of Weinreb amides have
been developed using naturally occurring (2S,3S)-3-hydroxy-5-oxotetrahydrofuran-2,3-
298
dicarboxylic acid. Consequently a novel class of Weinreb amides namely 2S,3S)-3-
hydroxy-2-(methoxy (methyl)carbamoyl)-5-oxotetrahydrofuran-3-carboxylic acid and
(2S,3S)-3-acetoxy-3-(methoxy(methyl) carbamoyl)-5-oxotetrahydrofuran-2-carboxylic
acid have been prepared. Using the Weinreb amide, (2S,3S)-3-acetoxy-3-(methoxy
(methyl) carbamoyl)-5-oxotetrahydrofuran-2-carboxylic acid synthesis of (3R,3aS,6aS)-
tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, a six carbon bis-furan part of the anti-
HIV drug Darunavir have been carried out in one step.
Synthesis of various chiral bis-furan part of nonpeptidic high-affinity P2 ligand for

anti-HIV drug Darunavir and relative molecules have been discussed in chapter 3. A
facile one-pot synthesis of the non-racemic analogue of bis-THF part of anti-HIV drug
Darunavir has been carried out starting with 3-substituted chiral pyrrolidine namely
isopropyl(S)-2-((S)-1-benzyl-3-hydroxy-2,5-dioxopyrrolidin-3-yl)-2-hydroxyacetate
2,5-dione, obtained from Garcinia acid. This approach seems to be the most
economical way of synthesising the bis-furan part of Darunavir, an anti-HIV protein
inhibitor drug. The acid catalysed sodium borohydride reduction of 3-substituted
pyrrolidine-2,5-dione yielded (3R,3aS,6aS)-6-benzyl-3,3a-dihydroxytetrahydro-2H-
furo[2,3-b]pyrrol-5(3H)-one. The treatment of the synthesized furopyran with
aqueous HCl-THF, resulted in the rearrangement of furopyran ring system to bis-
furan ring system. Thus, (3R,3aS,6aR,Z)-5-(benzylimino)tetrahydrofuro[2,3-b]furan-
3,3a(6aH)-diol was isolated as an oil. Independently, the bis-furan part namely
(3R,3aS,6aS)-tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, has been cumulated using
the Weinreb intermediate, (2S,3S)-3-acetoxy-3-(methoxy(methyl)carbamoyl)-5-
oxotetrahydrofuran- 2-carboxylic acid obtained from Garcinia acid.
Chapter 4 describes a new metal-free, solvent-free route towards the construction of the
privileged class of indolizines, pyrrolo[2,1-a]quinoline and pyrrolo[2,1-a]isoquinoline
using ((1S,2S)-trimethyl 1,2-dihydroxypropane-1,2,3-tricarboxylate have been obtained
from naturally occurring Garcinia and Hibiscus acids. The trimethyl ester of Garcinia
and Hibiscus acids namely trimethyl (1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate
and trimethyl (1R,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylate were succesfullly
converted to its mesityl derivatives, (1S,2S)-trimethyl 2-hydroxy-1-(mesyloxy)propane-
1,2,3-tricarboxylate and trimethyl (1R,2S)-2-hydroxy-1-((methylsulfonyl)oxy) propane-
1,2,3-tricarboxylate respectively for the successful conversion of indolizine skeletons.
299
Upon the treatment of these mesityl derivatives with pyridine and substituted pyridine
resulted in the formation of trimethyl indolizine-1,2,3-tricarboxylate and substituted
indolizines in moderate to good yields. The procedure was successful with mono
substitution at the fourth position like methyl, t-butyl and methoxy pyridines in 59%,
58%, and 60% respectively. The regioselectivity of the annulation of 3-ethyl pyridine
resulted in a mixture of regioisomers in the ratio 60 (isomer resulting from C6
cyclization) to 40 (isomer resulting from C2 cyclization). The reaction was successful
with benzo-fused analogues with quinolone and isoquinoline resulting in pyrrolo[2,1-
a]isoquinoline (64% yield) and pyrrolo[1,2-a]quinolone (63% yield) derivatives
respectively. It was observed that the electronic nature of substituents affected the
efficiency of reaction in terms of isolated yield. The reaction was successful with
electron-donating substituents whereas a failure with electron-withdrawing
substituents. The strategy was environmentally benign in solvent-free and metal-free
approach as well as using air as oxidant. The reported strategy needs improvement for
electron-withdrawing substituents and also for increasing the efficiency of the
reaction.
Chapter 5 deals with the attempted synthesis of enantiomers of (2S,3S)and (2S,3R)-3-

hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (Garcinia and Hibiscus acids)
There are four possible optical isomers for non-racemic 2-hydroxycitric acid. Among
these, two of the isomers (2S,3S) and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-
dicarboxylic acids) are extensively distributed in nature. The existence of the other
two isomers is yet to be known. To make available all optical isomers of 2-
hydroxycitric acid, attempts were made to invert the configurations of C-2 carbon
atoms of 1 and 2. Various known methods were attempted, which includes Mitsunobu
reaction, inversion using mono tosyl/mesityl derivatives namely trimethyl (1S,2S)-2-
hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate and trimethyl (1S,2S)-2-hydroxy-
1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate, the isourea ether namely
trimethyl(1S,2S)-1-(((E)-N,N'-dicyclohexylcarbamimidoyl)oxy)-2-hydroxypropane-
1,2,3-tricarboxylate and oxidation-reduction strategy. The acids 1 and 2 were
successfully converted to (1S,2S)-2-hydroxy-1-(tosyloxy)propane-1,2,3-tricarboxylate
and trimethyl (1S,2S)-2-hydroxy-1-((methylsulfonyl)oxy)propane-1,2,3-tricarboxylate.
Using these electrophiles, inversion reactions were attempted with acetate anion, in
300
pyridine solvent. Instead of the inverted product, dimethyl esters of Garcinia and
Hibiscus acids were isolated. When the reaction was carried out at an elevated
temperature, surprisingly the trimethyl indolizine-1,2,3-tricarboxylate, was isolated
as a crystalline solid. Thus a new method for the construction of indolizidine skeleton
was developed. The epimerisation on C-2 carbon was not happened due to anchimeric
assistance, eventually leads to the retention of configuration to afford only the diester
of Garcinia acid on hydrolysis. When (1S,2S)-trimethyl 2-hydroxy-1-(tosyloxy)
propane-1,2,3-tricarboxylate was refluxed in toluene in the presence of triethylamine,
without acetate anion, trimethyl 1-oxopropane-1,2,3-tricarboxylate, an α-keto ester, a
1,2 rearranged product was isolated. The triesters of Garcinia and Hibiscus acids were
successfully converted to the tritosyl derivatives for synthesizing a new class of chiral
trisphosphine catalyst.
As a whole, the thesis demonstrates the use of Garcinia and Hibiscus acids, obtained
from the chiral pool, as Chiron/Synthon for the collective construction of several
molecular skeletons of biological interest.
301

Syntheses of Medicinally Important Enantiopure Compounds Using

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Syntheses of Medicinally Important

Enantiopure Compounds Using (2S,3S) and

Institute for Integrated Programmes and Research inBasic Sciences

I hereby declare that the thesis entitled “Syntheses of Medicinally Important

This is to certify that the thesis entitled “Syntheses of Medicinally Important

Kottayam Prof. (Dr). I. Ibnusaud

Molecules namely, furo[2,3-b]furanol, the (bis-THF) part of anti-HIV drug Darunavir.

1. Johnson, Jordan.; Nair, S. Divya.; Pillai, M. Sarath.; Johnson, Didimos.;

2. Habel, Deenamma Nair, S. Divya.; Prakasan, C. Prasanth.; Pillai, M. Sarath.;

List of Symposium / Conference Proceedings

2. Skeletal Diversity from Naturally Occuring Non Racemic 2-Hydroxycitric

3. Syntheses of chiral intermediates using (2S,3S) and (2S,3R) - tetrahydro-3-

4. Synthesis of Biologically and Functionally Useful Enantiopure Molecules

5. Enantiopure Synthesis of Indolizinoindole, Pyrroloisoquinoline and Imidazole

2.1. Introduction ....................................................................................................... 31

5.1. Introduction ..................................................................................................... 220

Studies on the isolation of non-racemic hydroxycitric acids, (2S,3S)

1.1a. Chirality and Organic Molecules

1.1b. Context of the Thesis: Value addition to Indian natural resources.

1.1.2. Enantioselective synthesis: General strategies for Enantiomerically pure

The preparation of enantiomerically pure compounds (EPC) is a sustained social

 Chiral resolution in racemates

 Chiral pool approach

1.1.2.1.Chiral resolution in racemates

1.1.2.2.The chiral pool approach

The second method is synthetic transformations in an enantiomerically pure substance

Enantioconvergent synthesis is the synthesis of one enantiomer from a racemic

According to the FDA, the stereoisomeric composition of a chiral drug should be

Table 1.1.1.2. Some of the chiral hydroxyl acids present in nature

Apple L-(-)- Malic acid D-(+)- Malic acid

Grape (R,R)-Tartaric acid (S,S) Tartaric acid

Almond L-(-)- Mandelic acid D-(+)- Mandelic acid

Scheme 1.2.2. Some of the lead molecules, which can be procured

Figure 1.2.2. Structures of the trending drugs in the modern age

1.3. Objective of the present study

The optically active 2-hydroxycitric acids namely, (2S,3S) and (2S,3R)-tetrahydro-3-

Synthesis of both natural and unnatural organic compounds in the enantiomerically

1.4.1 Isolation and characterization of (2S,3S) tetrahydro-3-hydroxy-5-oxo-2,3-

observed for the pure sample is +101.2 (c 1.0, H2O)

By comparing the IR, 1H NMR, 13

2. To this concentrate, methanol was added to precipitate inorganic materials.

1.5. General Experimental Details

1.6. Experimental Section

1.6.1 (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (1)

[]25 +101.2 (c 1.0, H2O). Reported: +100

Melting point 178-179 °C. Reported: 178 °C

1.6.2 (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (2)

a) From the calyxes (Hibiscus sabdariffa (Mathippuli))

b) From leaves (Hibiscus furcatus (Uppanacham))

Appearance Colourless crystals

[]25 +111.2 (c 1.0, H2O). Reported: +110

Melting point 181-182 °C. Reported: 182-183 °C

IR (ATR) 3303, 1771, 1750, 1714 cm-1

 4.98 (s, 1H), 3.26 (d, J = 20 Hz, 1H),2.71,

 173.8, 171.3, 168.5, 85.2,80.3, 40,4 ppm

Molecular Formula C6H6O7

Molecular Mass 190.107

HRMS (TOF MS ES+) m/z for Calculated 191.0192, found 191

1.7. Chiroptical studies of (S)-(-)-crispine A analogue namely (1R,10bR)-1-((R)-

The geometries of 17430 unique conformers generated by CONFLEX were optimized

1.7.2. ERD of the (1R,10bR,1′R) diastereomer

The experimental vibrational absorption (VA), VCD, and vibrational dissymmetry

In conclusion, the absolute conﬁguration (AC) of the isolated 2-hydroxycitric acids