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Carbohydrate Research: Annamalai Senthilmurugan, Indrapal Singh Aidhen
Carbohydrate Research: Annamalai Senthilmurugan, Indrapal Singh Aidhen
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
a r t i c l e i n f o a b s t r a c t
Article history: Two synthetic strategies have been developed for the synthesis of spaced sugars with lipophilic 1,4-
Received 9 September 2011 phenylene core. A building block combining the usefulness of Weinreb amide functionality and modified
Received in revised form 3 November 2011 Julia olefination reaction has been explored towards this objective. This building block offers complete
Accepted 4 November 2011
flexibility in attaching any desired sugar derivative across phenylene spacer via C–C bond formation.
Available online 19 November 2011
The other strategy uses carbohydrate based building blocks for the synthesis of symmetrical as well as
unsymmetrical 1,4-phenylene spaced sugars. This is the first report for the synthesis of 1,4-phenylene
Keywords:
spaced sugars via C–C bond formation.
Spaced sugars
Julia olefination
Ó 2011 Elsevier Ltd. All rights reserved.
Sulfones
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.11.005
56 A. Senthilmurugan, I. S. Aidhen / Carbohydrate Research 347 (2012) 55–63
R2
C C C C C C
R1
A 3 B
O
R 1 (Electrophilic) = protected sugar aldehydes
O
O O N
S R 2 (Nucleophilic) = protected sugar sulfone
BT
7
BT - benzo[d]thiazol-1-yl
m-CPBA, 4 Å MS O O
HO NBS, PPh3 Z S
O DMF O CH 2Cl2, r.t., 6 h BT
O O
O O
70%
75%
BnO O BnO O O
BnO
19 21
BTSH (17) 20: Z = Br
NaH, DMF 80%
r.t., 1 h 20a: Z = SBT
Table 1
Reaction of sulfones 14 and 21 with the aldehydes 12 and 13
a) NaH, DMF
12 14 0 οC - r.t., 1-2 h
(or) (or) 22a-d
13 21 b) Pd/C, H 2
ethyl acetate
r.t., 24 h
O
O
O 3 O
1 14 65
O O O O
O H 2
22a
12
O
O O
3
O
2 21 62
2 BnO O
22b
O
O
O
O O 3 O
3 O 14 O O O 67
O O H 2
O
13
22c
O
O O O
O 3
4 21 2 BnO O 65
O
22d
a
Sulfones, aldehydes and all the final products were confirmed by 1H, 13
C NMR and mass spectral analysis.
23. After the initial formation of the carbanion and addition of under gravity and gradient elution, compounds corresponding to
terephthalaldehyde, the reaction mixture was allowed to reach these spots were isolated and identified as the mono-olefinated
room temperature and stirred for 24 h for completion. Besides (E/Z) compound 24 (30%) and the desired bis-olefinated (E/Z) com-
minor amounts of starting material and the anticipated 2-hydroxy pound 25 (60%). The bis-olefin 25 was subjected to palladium cata-
benzothiazole as side product, TLC revealed two new spots with lysed hydrogenation in ethyl acetate at room temperature for 24 h
very close Rf values. After careful silica gel column chromatography to provide the symmetrical 1,4-phenylene spaced sugar 26 as
58 A. Senthilmurugan, I. S. Aidhen / Carbohydrate Research 347 (2012) 55–63
O O
O BT
S
14 O O O
NaH, DMF O
ο O
0 C - r.t., 24 h
23
H O
O O O O O O
O O O O
O H O H
24 , 30% 25, 60%
Pd/C, H 2
O 90 %
r. t., 24 h
O O 3 O
O O O
3
O
26
depicted in Scheme 3. The 1H NMR spectrum of compound 26 dis- conditions, towards the second olefination reaction with the carb-
played a sharp singlet at d 7.09 corresponding to the four protons of anion of sulfone 21. Since, reacting 2.2 equivalents of sulfone 21
the aromatic ring, substantiating the symmetry of the molecule. with terephthalaldehyde 23 was unfruitful with regard to the for-
Also, there were four conspicuous sharp singlets corresponding to mation of compound 28, the equivalence of sulfone in the reaction
the methyl groups of the isopropylidene protection at d 1.33, was reduced. To our delight, 1.0 equivalent of sulfone 21 reacted
1.34, 1.36 and 1.37, respectively. The 13C NMR spectrum of the com- swiftly with terephthalaldehyde 23 in 1 h and afforded mono-olef-
pound 26 displayed conspicuous peaks at d 108.9 and 109.6 corre- inated product, aldehyde 27 in a 60% yield.
sponding to the quaternary carbons of isopropylidene protections. Facile formation, convenient isolation and purification of the
Two signals at d 139.7 and 128.4 corresponded to two quaternary compound 27 was a significant achievement, as it would enable
carbons and four methine carbons of the symmetric phenylene the successful reaction with same/different sulfones facilitating
spacer, respectively. The deduced structure for compound 26 was the synthesis of symmetrical and unsymmetrical 1,4-phenylene
further confirmed by the HRMS study where the mass of spaced sugars. Towards this objective, aldehyde 27 was subjected
585.3385 found matched with the calculated mass 585.3403 for to olefination reaction independently with sulfones 21 and 14, fol-
C32H50O8Na [M+Na]+. lowed by hydrogenation (Scheme 5). The successful obtainment of
Reaction of sulfone 21 (2.2 equiv) with 1.0 equivalent of tereph- symmetrical and unsymmetrical 1,4-phenylene spaced sugars, 29
thalaldehyde 23 under the same condition as described for sulfone and 30, respectively, thereby demonstrates the importance of for-
14, gave a single new product at Rf 0.3 (20% ethyl acetate/hexanes). mation and isolation of mono-olefinated product 27 (Scheme 5).
On isolation and characterization, it was found to be only mono- Finally, as an illustration to arrive at fully unprotected 1,4-phe-
olefinated compound 27 with 60% yield (Scheme 4). The reaction nylene spaced sugar, symmetrical di-isopropylidene protected
furnished no trace of the desired bis-olefinated product 28. This re- derivative 26 was subjected to deprotection by treating it with a
sult indicated the poor reactivity of aldehyde 27 under the reaction mixture of trifluoroacetic acid and water (TFA + H2O) in THF as
O O
S
BT O
O
BnO O
21
O
NaH, DMF
O
0 ο C - r.t., 24 h 23
1.0 eq
H
H
O OBn
O O
O O O
O
O
BnO O BnO O
H
27 (60%) 28 (0%)
O O
O O
O O
O O BnO
2 2
O OBn OBn
3 O 2
O O 29 (80%)
30 (82%)
O
OR 4. Experimental section
TFA, H 2 O(1:1)
RO OR 3 OR
THF
26 RO OR OR 4.1. General
ο 3
50 C, 30 min
OR All reactions were carried out in oven dried glasswares. Dry
Ac2 O, Et3 N 31: R =H (98 %)
DMAP, DMF DMF was prepared by stirring in calcium hydride and kept under
CH 2Cl2, r.t., 3 h 32 : R = Ac (95%) 4 Å molecular sieves after downward distillation. Dry THF was pre-
pared by distilling over Na wire. Solvents used for chromatography
Scheme 6. De-protection followed by per-acetylation sequence of 26. were of LR grade and silica gel used was of 100–200 mesh size.
Thin-layer chromatography was performed on aluminium plates
coated with silica gel 60. Visualisation was observed by UV light
solvent. The octa-hydroxy compound 31 was obtained as a white so- irradiation or by dipping into (Hanessian’s stain) a solution of cer-
lid. Its 1H NMR and 13C NMR could be recorded in DMSO-d6. The ium(IV) sulfate (2.5 g) and ammonium molybdate (6.25 g) in 10%
presence of a singlet in 1H NMR at d 7.14 for four protons (–CH) of sulfuric acid (250 mL) followed by charring on a hot plate. For ole-
the phenyl ring, a quaternary signal at d 139.5 and a signal at d fins, permanganate stain was used (3 g potassium permanganate,
128.1 for four –CH in 13C NMR confirms the symmetrical substitu- 20 g potassium carbonate, 5 mL 5% sodium hydroxide and
tion. The presence of four broad singlets at d 4.12, 4.23, 4.35 and 300 mL water). For aldehydes, 2,4-DNP stain prepared by dissolv-
4.79 corresponding to 2 protons each confirms 8 hydroxyl groups ing 6 g of 2,4-dinitrophenylhydrazine in 30 ml of sulfuric acid
in the molecule. The integrity of poorly soluble octa-hydroxy com- and 40 ml of water in 100 ml of 95% ethanol was used. Melting
pound could be further established through per-acetylation leading points were determined in capillaries and were uncorrected. 1H
to the formation of the octa-acetate derivative 32 (Scheme 6). The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
NMR spectrum of compound 32 again displayed a sharp singlet at d with chloroform-d (CDCl3), DMSO-d6 as the solvent and tetrameth-
7.03 corresponding to the four protons of the aromatic ring, which ylsilane (TMS) as reference unless otherwise specified. The num-
proves the symmetry of the molecule. Also, there were a bunch of bering for the spectral assignment (1H chemical shift) for protons
very close conspicuous singlets between d 2.03 and 2.07 corre- follows the numbering of the carbon atoms in the corresponding
sponding to the 24 (–CH3) methyl protons of the acetyl groups pres- name of the compound. Mass spectra were recorded on a MI-
ent. The 13C NMR spectrum of the compound 32 displayed CRO-Q TOF mass spectrometer by using the ESI technique at
conspicuous peaks at d 170.7, 170.5, 170.0 and 169.9 corresponding 10 eV. Optical rotations were measured with an Autopol IV polar-
to the quaternary carbonyl carbons of the acetyl groups; a signal for imeter at room temperature.
two quaternary carbons at d 139.2 and a signal at d 128.4 for the four
methine carbons of the phenylene ring. The deduced structure for
4.2. General procedures
compound 32 was further confirmed by the HRMS study, where
found mass of 761.2997 matched with the calculated mass of
4.2.1. General procedure for the Julia olefination reaction of
761.2993 for C36H50O16Na, [M+Na]+.
sulfones with aldehydes (A)
To a suspension of NaH (1.1 equiv according to sulfone) in anhy-
3. Conclusion drous DMF, a solution of sulfone (1.2 equiv) in anhydrous DMF
(4 mL/mmol) was added at 0 °C. The solution turned to reddish or-
A building block combining the usefulness of the Weinreb amide ange colour which indicates the formation of carbanion. After
functionality and Julia olefination reaction has enabled novel and 10 min, a solution of aldehyde (1 equiv) in anhydrous DMF
versatile strategy for 1,4-phenylene spaced sugars, with complete (2 mL/mmol) was added to the reaction mixture. The disappear-
flexibility in attaching any desired sugar across the phenylene ance of reddish orange colour was observed. The reaction mixture
spacer via C–C bond. Julia reaction of sugar based sulfones has been was allowed to attain room temperature and maintained for fur-
equally promising in furnishing symmetrical as well as unsymmet- ther 30 min to 1 h. The course of the reaction was observed by
rical 1,4-phenylene spaced sugars on reaction with terephthalalde- TLC analysis (Hanessian’s stain). After the consumption of starting
hyde as a representative of aromatic di-aldehydes. The concept and material, the reaction mixture was quenched with water and ex-
strategy is general and therefore should be applicable to other aro- tracted with ethyl acetate (3 times). The collected organic layer
matic di-aldehydes. Efforts towards exploring these phenylene was washed with ice-cold 10% NaOH solution (5 15 mL) to get
spaced sugars for biological and/or material properties is currently rid of side product 2-hydroxybenzothiazole. The collected organic
underway. The results of these studies will be reported elsewhere. layer was dried over anhydrous Na2SO4, filtered, concentrated
60 A. Senthilmurugan, I. S. Aidhen / Carbohydrate Research 347 (2012) 55–63
and subjected to purification by silica gel column chromatography over anhydrous Na2SO4, filtered, concentrated and subjected to
or subjected to further reaction according to sulfone. purification by silica gel column chromatography or subjected to
further reaction according to sulfone.
4.2.2. General procedure for the reduction of Weinreb amide to
aldehyde (B)
4.3. 4-((Benzo[d]thiazol-2-ylsulfonyl)methyl)-N-methoxy-N-
To a suspension of LiAlH4 (0.6 equiv) in anhydrous THF at 0 °C, a
methylbenzamide (7)5
solution of weinreb amide (1.0 equiv) was added dropwise and the
reaction was maintained at 0 °C for another hour. The course of the
The building block 7 was prepared according to the literature
reaction was monitored by TLC analysis (Hanessian’s stain as well
procedure.5 Yield: 85–88%. Rf: 0.35 (hexanes/ethyl acetate, 6:4),
as 2,4-DNP stain). After the complete consumption of starting
colourless crystals, mp: 142–145 °C. IR (CH2Cl2): 1152, 1332,
material, an approximate amount of Na2SO4 was added to the reac-
1469, 1639, 2929, 2972 cm1. 1H NMR [CDCl3, 400 MHz] d 3.32
tion mixture followed by dropwise addition of water to quench the
(s, 3H, –NCH3), 3.47 (s, 3H, –OCH3), 4.79 (s, 2H, –SO2CH2BT), 7.33
reaction till the reaction colour changes to white suspension from
(d, 2H, J = 8.0 Hz, ArH), 7.56–7.62 (m, 3H, ArH), 7.63–7.69 (m, 1H,
grey suspension. The slurry formed can be relaxed with the addi-
ArH), 7.94 (d, 1H, J = 8.0 Hz, ArH), 8.26 (d, 1H, J = 8.0 Hz, ArH). 13C
tion of DCM. Then the reaction mass was easily filltered through
NMR [CDCl3, 100 MHz] d 32.6, 59.7, 60.1, 121.3, 124.6, 126.8,
celite bed and washed thoroughly with DCM. The collected organic
127.2, 127.8, 127.9, 129.8, 133.9, 136.1, 151.6, 164.1, 168.0. HRMS
layer was dried over anhydrous Na2SO4, filtered, concentrated and
(ESI): m/z Calcd for C17H16N2O4S2 [M+H]+: 377.0630. Found:
subjected to purification by silica gel column chromatography.
377.0618.
4.6. 2-((2-((4S,40 R,5R)-2,2,20 ,20 -Tetramethyl-[4,40 -bi(1,3-di- (m, 1H), 3.81 (d, 1H, J = 2.80 Hz), 4.21–4.28 (m, 1H), 4.45 (d, 1H,
oxolan)]-5-yl)ethyl)thio)benzo[d] thiazole (18) J = 12.0 Hz, OCHaHbPh), 4.59 (d, 1H, J = 4.0 Hz, 6a-CH), 4.67 (d, 1H,
J = 12.0 Hz, –OCHaHbPh), 5.86 (d, 1H, J = 4.0 Hz, 3a-CH), 7.23–7.34
By following general procedure C, bromide 16 was converted to (m, 5H, –OCH2C5H5), 7.57–7.67 (m, 2H, ArH), 8.01 (d, 1H,
sulfide 18. Yield: 73%. Rf: 0.4 (hexanes/ethyl acetate, 9.2:0.8), col- J = 7.60 Hz, ArH), 8.19 (d, 1H, J = 7.6 Hz, ArH). 13C NMR [CDCl3,
ourless gum. ½aD +9.283 (c = 1, CH2Cl2); IR (CH2Cl2): 1076, 1146, 100 MHz] d 21.8, 26.2, 26.7, 51.9, 71.7, 77.8, 81.7, 82.1, 104.7,
1266, 1328, 1377, 1470, 2981 cm1. 1H NMR [CDCl3, 400 MHz] d 111.7, 122.5, 125.5, 127.7, 127.9, 128.0, 128.1, 128.6, 136.8,
1.21 (s, 3H, –CH3), 1.25 (s, 3H, –CH3), 1.29 (s, 3H, –CH3), 1.34 (s, 136.9, 152.7, 165.5. HRMS (ESI): m/z Calcd for C23H26NO6S2
3H, –CH3), 1.96–2.07 (m, 1H, –CH2CH2S), 2.20–2.30 (m, 1H, – [M+H]+: 476.1202. Found: 476.1226.
CH2CH2S), 3.30–3.40 (m, 1H), 3.46–3.54 (m, 1H), 3.53 (t, 1H,
J = 8.0 Hz, 5h-CHaHb), 3.84–3.89 (m, 2H), 3.92–3.99 (m, 3H), 4.10. (4S,40 R,5R)-5-(3-(4-(2-((S)-2,2-Dimethyl-1,3-dioxolan-4-
4.00–4.08 (m, 2H), 7.21 (t, 1H, J = 8.0 Hz, ArH), 7.33 (t, 1H, yl)ethyl)phenyl)propyl)-2,2,20 ,20 -tetramethyl-4,40 -bi(1,3-diox-
J = 8.0 Hz, ArH), 7.67 (d, 1H, J = 8.0 Hz, ArH), 7.78 (d, 1H, olane) (22a)
J = 8.0 Hz, ArH). 13C NMR [CDCl3, 100 MHz] d 25.2, 26.7, 27.0,
27.3, 30.1, 33.5, 67.8, 79.0, 81.1, 109.4, 121.0, 121.5, 124.2, 126.0, By following the general procedure A and general procedure E,
135.2, 153.3, 166.8. HRMS (ESI): m/z Calcd for C19H26NO4S2 compound 12 was converted to 22a. Yield: 65%. Rf: 0.55 (hexanes/
[M+H]+: 396.1303. Found: 396.1316. ethyl acetate, 9:1), colourless liquid. ½aD +1.597 (c = 1, CH2Cl2); IR
(CH2Cl2): 1024, 1086, 1230, 1382, 1440, 2898, 2932 cm1. 1H
4.7. 2-((2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetra- NMR [CDCl3, 400 MHz] d 1.33 (s, 3H, –CH3), 1.34 (s, 3H, –CH3),
hydrofuro[2,3-d][1,3]dioxol-5-yl) ethyl)thio)benzo[d]thiazole 1.35 (s, 3H, –CH3), 1.36 (s, 3H, –CH3), 1.37 (s, 3H, –CH3), 1.42 (s,
(20a) 3H, –CH3), 1.66–2.00 (m, 6H), 2.56–2.80 (m, 4H), 3.49–3.58 (m,
2H), 3.89–3.97 (m, 2H), 3.98–4.04 (m, 2H), 4.06–4.15 (m, 2H),
By following general procedure C, bromide 20 was converted to 7.06–7.12 (m, 4H, ArH). 13C NMR [CDCl3, 100 MHz] d 25.3, 25.7,
sulfide 20a. Yield: 78%. Rf: 0.4 (hexanes/ethyl acetate, 9.2:0.8), col- 26.7, 27.0, 27.4, 27.7, 31.6, 33.2, 35.4, 67.7, 69.3, 75.5, 77.2, 80.3,
ourless gum. ½aD 15.023 (c = 1, CH2Cl2); IR (CH2Cl2): 1051, 1071, 81.0, 108.7, 109.5, 128.2, 128.5, 138.8, 139.9. HRMS (ESI): m/z
1216, 1254, 1376, 2927, 2987 cm1. 1H NMR [CDCl3, 400 MHz] d Calcd for C26H40O6 [M+H]+: 449.2903. Found: 449.2912.
1.24 (s, 3H, –CH3), 1.40 (s, 3H, –CH3), 2.00–2.30 (m, 2H, –SCH2CH2),
3.18–3.28 (m, 1H, –SCH2CHaHb), 3.36–3.45 (m, 1H, –SCH2CHaHb), 4.11. (3aR,5R,6S,6aR)-6-(Benzyloxy)-5-(3-(4-(2-((S)-2,2-di-
3.78 (d, 1H, J = 2.8 Hz, 6-CH), 4.24–4.31 (m, 1H, 5-CH), 4.42 (d, methyl-1, 3-dioxolan-4-yl)ethyl)phenyl)propyl)-2,2-dimethyl
1H, J = 11.6 Hz, –OCHaHbPh), 4.55 (d, 1H, J = 3.6 Hz, 6a-CH), 4.62 tetrahydrofuro[2,3-d][1,3]dioxole (22b)
(d, 1H, J = 12.0 Hz, –OCHaHbPh), 5.85 (d, 1H, J = 3.6 Hz, 3a-CH),
7.15–7.25 (m, 5H, –OCH2Ph; 1H, BT-H), 7.31–7.35 (m, 1H, ArH), By following the general procedure A and general procedure E,
7.66 (d, 1H, J = 8.0 Hz, ArH), 7.77 (d, 1H, J = 8.0 Hz, ArH), 8.19 (d, compound 12 was converted to 22b. Yield: 62%. Rf: 0.4 (hexanes/
1H, J = 7.6 Hz, ArH). 13C NMR [CDCl3, 100 MHz] d 26.2, 26.7, 28.1, ethyl acetate, 9:1), colourless liquid. ½aD 5.043 (c = 2, CH2Cl2);
30.3, 71.8, 78.8, 82.0, 82.3, 104.7, 111.5, 120.9, 121.5, 124.1, IR (CH2Cl2): 1074, 1162, 1215, 1374, 2865, 2930, 2987 cm1. 1H
126.0, 127.7, 128.0, 135.2, 137.3, 153.3, 166.8. HRMS (ESI): m/z NMR [CDCl3, 400 MHz] d 1.31 (s, 3H, –CH3), 1.36 (s, 3H, –CH3),
Calcd for C23H26NO4S2 [M+H]+: 444.1303. Found: 444.1298. 1.43 (s, 3H, –CH3), 1.47 (s, 3H, –CH3), 1.66–2.00 (m, 6H), 2.54–
2.78 (m, 4H), 3.52 (t, 1H, J = 7.6 Hz), 3.75 (d, 1H, J = 2.8 Hz), 3.98–
4.8. 2-((2-((4S,40 R,5R)-2,2,20 ,20 -Tetramethyl-[4,40 -bi(1,3-di- 3.44 (m, 1H), 4.06–4.16 (m, 2H), 4.45 (d, 1H, J = 12.0 Hz,
oxolan)]-5-yl)ethyl)sulfonyl)benzo[d]thiazole (14) OCHaHbPh), 4.60 (d, 1H, J = 4.0 Hz, 6a-CH), 4.68 (d, 1H, J = 12.0 Hz,
–OCHaHbPh), 5.90 (d, 1H, J = 4.0 Hz, 3a-CH), 7.06 (d, 2H, J = 8.4 Hz,
By following general procedure D, sulfide 18 was oxidized to sul- ArH), 7.29–7.37 (m, 5H, ArH). 13C NMR [CDCl3, 100 MHz] d 25.8,
fone 14. Yield: 73%. Rf: 0.4 (hexanes/ethyl acetate, 7:3), colourless 26.3, 26.8, 27.1, 27.7, 28.0, 31.7, 35.5, 35.6, 69.4, 71.8, 75.5, 80.4,
crystals, mp: 90 °C. ½aD +10.978 (c = 1, CH2Cl2); IR (CH2Cl2): 1076, 81.9, 81.9, 82.2, 104.7, 108.8, 111.3, 127.8, 128.0, 128.3, 128.6,
1146, 1266, 1328, 1377, 1470, 2981 cm1. 1H NMR [CDCl3, 137.7, 138.9, 139.9. HRMS (ESI): m/z Calcd for C30H40O6 Na
400 MHz] d 1.25 (s, 3H, –CH3), 1.28 (s, 3H, –CH3), 1.29 (s, 3H, – [M+Na]+: 519.2723. Found: 519.2727.
CH3), 1.32 (s, 3H, –CH3), 2.08–2.20 (m, 1H, –CHCH2CH2), 2.31–2.43
(m, 1H, –CHCH2CH2), 3.50 (t, 1H, J = 7.6 Hz, 5h-CHaHb), 3.60–3.83 4.12. (4S,40 R,5R)-2,2,20 ,20 -Tetramethyl-5-(3-(4-(2-((4R,40 R,5S)-
(m, 2H), 3.87–4.01 (m, 3H), 4.08–4.11 (dd, 1H, J = 8.0 Hz, 5.6 Hz), 2,2,20 ,20 -tetramethyl-[4,40 -bi(1,3-dioxolan)]-5-yl)ethyl)phen-
7.59 (t, 1H, J = 7.2 Hz, ArH), 7.64 (d, 1H, J = 7.6 Hz, ArH), 8.01 (d, yl)propyl)-4,40 -bi(1,3-dioxolane) (22c)
1H, J = 7.6 Hz, ArH), 8.21 (d, 1H, J = 8.0 Hz, ArH).13C NMR [CDCl3,
100 MHz] d 25.2, 26.6, 26.7, 27.0, 27.2, 51.9, 67.9, 77.0, 78.3, 81.2, By following the general procedure A and general procedure E,
109.7, 109.8, 122.4, 125.5, 128.1, 136.8, 152.8, 165.6. HRMS (ESI): compound 13 was converted to 22c. Yield: 67%. Rf: 0.5 (hexanes/
m/z Calcd for C19H26NO6S2 [M+H]+: 428.1202. Found: 428.1203. ethyl acetate, 9:1), colourless gum. ½aD +11.597 (c = 3, CH2Cl2); IR
(CH2Cl2): 1066, 1086, 1215, 1253, 1374, 2928, 2980 cm1. 1H
4.9. 2-((2-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetra- NMR [CDCl3, 400 MHz] d 1.33 (s, 3H, –CH3), 1.34 (s, 6H, 2 –
hydrofuro[2,3-d][1,3]dioxol-5-yl) ethyl)sulfonyl)benzo[d]thi- CH3), 1.36 (s, 3H, –CH3), 1.37 (s, 6H, 2 –CH3), 1.39 (s, 3H, –CH3),
azole (21) 1.42 (s, 3H, –CH3), 1.50–1.90 (m, 10H), 2.00–2.10 (m, 2H), 2.60–
2.74 (m, 3H), 2.77–2.87 (m, 1H), 3.50–3.65 (m, 2H), 3.89–3.98
By following general procedure D, sulfide 20a was oxidised to (m, 4H), 3.98–4.50 (m, 2H), 4.08–4.15 (m, 2H), 7.08–7.15 (m, 4H,
sulfone 21. Yield: 75%. Rf: 0.3 (hexanes/ethyl acetate, 4:1), colour- ArH). 13C NMR [CDCl3, 100 MHz] d 25.4, 26.8, 26.9, 27.1, 27.2,
less gum. ½aD 16.855 (c = 0.9, CH2Cl2); IR (CH2Cl2): 1071, 1216, 27.5, 27.54, 27.8, 31.8, 32.0, 33.3, 35.5, 35.6, 67.8 (2 –CH2O),
1254, 1376, 2927, 2987 cm1. 1H NMR [CDCl3, 400 MHz] d 1.29 77.2, 77.4, 80.0, 80.4, 81.1, 81.2, 108.9, 109.0, 109.6, 109.7, 128.4,
(s, 3H, –CH3), 1.42 (s, 3H, –CH3), 2.14–2.25 (m, 1H, –CHCHaHbCH2), 128.5, 139.3, 139.8. HRMS (ESI): m/z Calcd for C31H49O8 [M+H]+:
2.30–2.42 (m, 1H, –CHCHaHbCH2), 3.47–3.57 (m, 1H), 3.64–3.74 549.3348. Found: 549.3356.
62 A. Senthilmurugan, I. S. Aidhen / Carbohydrate Research 347 (2012) 55–63
4.13. (3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-(3-(4-(2- in THF (1 mL) and stirred at 50 °C for 30 min. The product octa-
((4S,40 R,5R)-2,2,20 ,20 -tetramethyl-[4,40 -bi(1,3-dioxolan)]-5-yl) hydroxy compound started to precipitate out in few minutes. After
ethyl)phenyl)propyl)tetrahydrofuro[2,3-d][1,3]dioxole (22d) the staring material was consumed, the solvents were evaporated
and co-evaporated with toluene to the product as white solid.
By following the general procedure A and general procedure E, Yield: 98% (70 mg). Insoluble white solid, mp: 182–184 °C. IR
compound 13 was converted to 22d. Yield: 65%. Rf: 0.3 (hexanes/ethyl (neat): 738, 1213, 1465, 3057, 3111 cm1. 1H NMR [DMSO-d6,
acetate, 9:1), colourless liquid. ½aD 0.998 (c = 0.8, CH2Cl2); IR 400 MHz] d 1.40–1.80 (m, 8H), 2.55–2.65 (m, 4H), 3.17 (d, 2H,
(CH2Cl2): 1066, 1147, 1214, 1325, 1375, 2924, 2985 cm1. 1H NMR J = 7.2 Hz), 3.30–3.56 (m, 4H), 3.58–3.67 (m, 2H), 3.68–3.78 (m,
[CDCl3, 400 MHz] d 1.29 (s, 3H, –CH3), 1.33 (s, 3H, –CH3), 1.36 (s, 3H, 2H), 4.12 (br s, 2H, 2 OH), 4.23 (br s, 2H, 2 OH), 4.35 (br s,
–CH3), 1.38 (s, 3H, –CH3), 1.41 (s, 3H, –CH3), 1.45 (s, 3H, –CH3), 1.47 2H, 2 OH), 4.79 (br s, 2H, 2 OH), 7.14 (s, 4H, ArH). 13C NMR
(s, 3H, –CH3),1.60–2.10 (m, 6H), 2.60–2.85 (m, 4H), 3.59 (t, 1H, [DMSO-d6, 100 MHz] d 27.1, 33.1, 34.9, 63.7, 69.1, 71.7, 73.0,
J = 7.6 Hz), 3.91–3.98 (m, 2H), 3.98–4.05 (m, 2H), 4.07–4.14 (m, 2H), 128.1, 139.5.
4.48 (d, 1H, J = 3.2 Hz, 6a-CH), 5.86 (d, 1H, J = 2.8 Hz, 3a-CH), 7.09 (d,
1H, J = 8.0 Hz, ArH), 7.09 (d, 2H, J = 8.0 Hz, ArH), 7.12 (d, 2H, 4.17. (2R,20 R,3S,30 S,4R,40 R)-7,70 -(1,4-Phenylene)-bis(heptane-
J = 7.6 Hz, ArH). 13C NMR [CDCl3, 100 MHz] d 25.4, 26.2, 26.7, 26.8, 1,2,3,4-tetrayl tetraacetate) (32)
27.1, 27.2, 27.5, 27.9, 31.8, 35.5, 35.6, 67.7, 75.5, 77.2, 79.9, 80.3,
81.2, 85.3, 104.3, 109.0, 109.7, 111.5, 128.5, 139.5. HRMS (ESI): m/z To the octa-hydroxy compound 29 (0.070 g, 0.174 mmol) in
Calcd for C28H42O8Na [M+Na]+: 529.2777. Found: 529.2776. CHCl3 (2 mL), two drops of DMF were added to facilitate solubility,
and then acetic anhydride (0.27 mL, 16 equiv, 2.786 mmol) was
4.14. 4-(3-((4S,40 R,5R)-2,2,20 ,20 -Tetramethyl-[4,40 -bi(1,3-diox- added. And a corresponding amount of triethylamine (0.387 mL,
olan)]-5-yl)prop-1-en-1-yl)benzaldehyde (24) 16 equiv, 2.786 mmol) was added and a catalytic amount of
dimethylaminopyridine (10%) was added. The reaction mixture
By following the general procedure F, sulfone 14 was reacted was stirred overnight. After the completion of the reaction, the
with di-aldehyde 23. One of the products obtained was 24, reaction mixture was diluted with CHCl3 and was washed with
mono-olefinated aldehyde 24. Yield: 30%, (E:Z = 0.6:1). Rf: 0.3 (hex- water. The crude product was purified by silica gel column chro-
ane/ethyl acetate, 8:2), viscous liquid. ½aD +9.182 (c = 2, CH2Cl2); IR matography. Yield: 95% (0.116 g). Rf: 0.8 (only hexanes), white so-
(CH2Cl2): 1068, 1160, 1213, 1375, 1602, 1698, 2987 cm1. 1H NMR lid, mp: 90–92 °C. ½aD +14.970 (c = 0.4, CH2Cl2); IR (CH2Cl2): 1071,
[CDCl3, 400 MHz] d 1.24 (s, 3H, –CH3+minor), 1.29 (s, 3H, –CH3+mi- 1219, 1373, 1745, 2926 cm1. 1H NMR [CDCl3, 400 MHz] d 1.45–
nor), 1.33 (s, 3H, –CH3, minor), 1.36 (s, 3H, –CH3), 1.39 (s, 3H, – 1.63 (m, 8H), 2.0–2.01 (m, 24H), 2.53 (t, 4H, J = 6.8 Hz, 2 –CH2Ar),
CH3), 2.49–2.57 (m, 1H, minor), 2.58–2.68 (m, 1H), 2.72–2.88 (m, 4.08–4.12 (dd, 2H, J = 12.4 Hz, 5.2 Hz, –CHaHbCH(O)), 4.20 (d, 2H,
1H+minor), 3.56 (t, 1H, J = 7.6 Hz), 3.61 (t, 1H, J = 7.6 Hz, minor), J = 12.4 Hz–CHaHbCH(O)), 5.05–5.13 (m, 2H), 5.14–5.22 (m, 2H),
3.87–4.60 (m, 3H+minor), 5.95–6.04 (dt, 1H, J = 11.6 Hz, 7.2 Hz, 5.26 (d, 2H, J = 8.4 Hz, –CH(O)), 7.03 (s, 4H, ArH). 13C NMR [CDCl3,
olefinH), 6.48–6.53 (m, 1H+minor), 6.58 (d, 1H, J = 11.6 Hz, ole- 100 MHz] d 26.7, 26.8, 26.9, 20.4, 35.2, 62.0, 68.4, 70.3, 70.4,
finH), 7.47 (d, 2H, J = 8.0 Hz, ArH), 7.48 (d, 2H, J = 8.0 Hz, minor, 18.4, 139.2, 169.9, 170.0, 170.5, 170.7. HRMS (ESI): m/z Calcd for
ArH), 7.79 (d, 2H, J = 8.0 Hz, ArH), 7.82 (d, 2H, J = 8.0 Hz, ArH), C36H50O16Na [M+Na]+: 761.2997. Found: 761.2993.
9.94 (s, 1H, CHO, minor), 9.97 (s, 1H, CHO).13C NMR [CDCl3,
100 MHz] d 25.3, 25.36 (minor), 26.6, 26.8 (minor), 27.0, 27.1 (min- 4.18. 4-(3-((3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetra-
or), 27.3, 27.39 (minor), 32.5, 36.9 (minor), 67.9, 77.3 (minor), hydrofuro[2,3-d][1,3]dioxol-5-yl) prop-1-en-1-yl)benzaldehy-
77.37, 79.8 (minor), 79.9, 80.6 (minor), 80.7, 109.3 (minor), de (27)
109.38, 109.71, 109.78 (minor), 126.6, 129.4, 129.7, 130.0, 130.2,
130.3 (minor), 130.8, 131.5, 134.8, 135.2 (minor), 143.6 (minor), By following the general procedure F, sulfone 14 was reacted
143.7, 191.7 (minor), 191.8. HRMS (ESI): m/z Calcd for C20H26O5Na with di-aldehyde 23. The product obtained was 24, mono-olefinated
[M+Na]+: 369.1678. Found: 369.1669. aldehyde 27. Yield: 60%, (E:Z = 1:3). Rf: 0.3 (hexanes/ethyl acetate,
8:2), viscous liquid. ½aD 42.215 (c = 2, CH2Cl2); IR (CH2Cl2): 1018,
4.15. 1,4-Bis(3-((4S,40 R,5R)-2,2,20 ,20 -tetramethyl-[4,40 -bi(1,3- 1076, 1165, 1213, 1378, 1603, 1696, 2989 cm1. 1H NMR [CDCl3,
dioxolan)]-5-yl)propyl)benzene (26) 400 MHz] d 1.36 (s, 3H, –CH3), 1.53(s, 3H, –CH3), 2.60–2.88 (m, 2H,
C@CCH2), 3.87(s, 1H), 3.89 (s, 1H, minor), 4.13–4.21 (m, 1H, minor),
By following the general procedure F, sulfone 14 was reacted 4.27–4.35 (m, 1H), 4.44 (d, 1H, J = 12.0 Hz, –OCHaHbPh), 4.53 (d, 1H,
with di-aldehyde 23. One of the products isolated was bis-olefin J = 12.0 Hz, –OCHaHbPh), 4.68 (m, 2H), 4.79 (m, 1H, minor), 5.80–
25 which was subsequently converted to 26 by hydrogenation using 5.90 (m, 1H), 5.96 (d, 1H, J = 2.8 Hz, 3a-CH), 5.99 (d, 1H, J = 2.8 Hz,
the general procedure E. Yield: 90%. Rf: 0.3 (hexanes/ethyl acetate, 3a-CH, minor), 6.54 (d, 1H, J = 2.8 Hz, OlefinH, minor), 6.57 (d, 1H,
8:2), viscous liquid. ½aD +11.643 (c = 3, CH2Cl2); IR (CH2Cl2): 1066, J = 12.4 Hz, OlefinH), 7.23–7.43 (m, 5H, ArH), 7.48 (d, 1H,
1215, 1253, 1374, 2930, 2986 cm1. 1H NMR [CDCl3, 400 MHz] d J = 7.6 Hz, ArH), 7.83 (d, 1H, J = 7.6 Hz, ArH), 10.0 (s, 1H, –CHO). 13C
1.33 (s, 3H, –CH3), 1.34 (s, 3H, –CH3), 1.36 (s, 3H, –CH3), 1.37 (s, NMR [CDCl3, 100 MHz] d 26.2, 26.7, 27.8, 71.7 (minor), 71.8, 79.7
3H, –CH3), 1.55–1.88 (m, 2H), 2.57–2.66 (m, 4H), 3.54 (t, 1H, (minor), 79.7 (minor), 79.9, 81.7 (minor), 81.8, 82.1 (minor), 82.2,
J = 7.6 Hz, 50 -CH), 3.89–3.96 (m, 4H), 3.97–4.40 (m, 2H), 4.07–4.14 81.8, 82.1 (minor), 82.2, 104.8, 111.5, 126.6 (minor), 127.6, 127.9,
(dd, 2H, J = 8.0 Hz, 6.0 Hz, 4-CH), 7.08 (s, 4H, ArH). 13C NMR [CDCl3, 128.0 (minor), 128.4, 128.6 (minor), 129.3, 129.7, 129.9, 130.1
100 MHz] d 25.4, 26.8, 27.1, 27.5, 27.9, 33.3, 35.5, 67.8, 80.4, 81.1, (minor), 130.7, 131.4 (minor), 134.7, 137.4, 143.5, 191.7 (minor),
108.9, 109.6, 128.4, 139.7. HRMS (ESI): m/z Calcd for C32H50O8Na 191.8. HRMS (ESI): m/z Calcd for C24H26O5Na [M+Na]+: 417.1678.
[M+Na]+: 585.3403. Found: 585.3385. Found: 417.1667.
A mixture of trifluroaceticacid and water (1:1, 1 + 1 mL) was To a suspension of NaH (1.1 equiv according to sulfone) in anhy-
added to a solution of the tetraacetonide 26 (0.100 g, 0.178 mmol) drous DMF, a solution of sulfone 21 (1.0 equiv) in anhydrous DMF
A. Senthilmurugan, I. S. Aidhen / Carbohydrate Research 347 (2012) 55–63 63
(4 mL/mmol) was added at 0 °C. The solution turned to reddish or- OCHaHbPh, furo ring), 5.90 (d, 2H, J = 4.0 Hz, 3a-CH, furo ring),
ange colour which indicates the formation of carbanion. After 7.05 (d, 2H, J = 8.0 Hz, –CH2C6H4CH2–), 7.08 (d, 2H, J = 8.0 Hz, –
10 min, a solution of aldehyde 24 (1.0 equiv) in anhydrous DMF CH2C6H4CH2–), 7.27–7.37 (m, 5H, –OCH2C6H5, furo ring). 13C
(2 mL/mmol) was added to the reaction mixture. The disappearance NMR [CDCl3, 100 MHz] d 25.4, 26.3, 26.8, 27.1, 27.5, 27.7, 27.8,
of reddish orange colour was observed. The reaction mixture was al- 20.0, 33.3, 35.5, 35.6, 67.8, 71.8, 77.3, 80.4, 80.5, 81.2, 82.0, 82.3,
lowed to attain room temperature and maintained for further 1 h. 104.7, 108.9, 109.6, 111.3, 127.8, 128.0, 128.4, 128.45, 128.5,
The course of the reaction was observed by TLC analysis (Hanes- 137.7, 139.6, 139.7. HRMS (ESI): m/z Calcd for C36H50O8Na
sian’s stain and 2,4-DNP solution). After the consumption of starting [M+Na]+: 633.3403. Found: 633.3404.
material, the reaction mixture was quenched with water and ex-
tracted with ethyl acetate (3 times). The collected organic layer Acknowledgement
was washed with ice-cold 10% NaOH solution (5 15 mL) to get
rid of side product 2-hydroxybenzothiazole. The collected organic The authors thank the DST New Delhi for funding towards the
layer was dried over anhydrous Na2SO4, filtered, concentrated and 400 MHz NMR spectrometer to the Department of Chemistry, IIT-
subjected to hydrogenation by following the general procedure E Madras under the IRPHA scheme and ESI-MS facility under the
to furnish 29. Yield: 80%. Rf: 0.3 (hexanes/ethyl acetate, 8:2). viscous FIST programme. Funding from CSIR, Project No.: 01(1971)/05/
liquid. ½aD +37.147 (c = 3.6, CH2Cl2). IR (CH2Cl2): 1017, 1076, 1165, EMR-II is gratefully acknowledged. Senthilmurugan A. is thankful
1215, 1374, 2929, 2989 cm1. 1H NMR [CDCl3, 400 MHz] d 1.32 (s, to IIT-Madras for HTRA fellowship and initial support from the
6H, 2 CH3), 1.48 (s, 6H, 2 CH3), 1.50–1.60 (m, 2H), 1.67–1.86 CSIR project.
(m, 6H), 2.57–2.64 (m, 4H, –CH2C6H4), 3.76 (d, 2H, J = 2.8 Hz, 5-
CH), 4.11–4.16 (m, 2H, 6-CH), 4.46 (d, 2H, J = 12.0 Hz, –OCHaHbPh), Supplementary data
4.61 (d, 2H, J = 4.0 Hz, 6a-CH), 4.68 (d, 2H, J = 12.0 Hz, –OCHaHbPh),
5.91 (d, 2H, J = 3.6 Hz, 3a-CH), 7.04 (s, 4H, –CH2C6H4CH2–), 7.27– Supplementary data associated with this article can be found, in
7.37 (m, 10H, –OCH2C6H5). 13C NMR [CDCl3, 100 MHz] d 26.3, 26.7, the online version, at doi:10.1016/j.carres.2011.11.005.
27.7, 28.0, 35.6, 71.8, 80.4, 82.0, 82.3, 104.7, 111.3, 127.8, 128.0,
128.4, 128.5, 137.7, 139.6. HRMS (ESI): m/z Calcd for C40H50O8Na References
[M+Na]+: 681.3403. Found: 681.3398.
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