Synthesis of β-C-Glycopyranosyl Aldehydes and 2,6-Anhydro-heptitols

Article abstract of DOI:10.1021/acs.joc.5b01933

A convenient route has been developed for the diastereoselective synthesis of β-C-glycopyranosyl aldehydes from d-glucose, d-mannose, and d-galactose. The key step in the synthesis of C-glycosyl aldehydes is the aryl driven reductive dehydration on 1-phen

Full text of DOI:10.1021/acs.joc.5b01933

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Note
Synthesis of beta-C-glycopyranosyl aldehydes and 2,6-anhydro-heptitols
Vinod Khatri, Amit Kumar, Balram Singh, Shashwat Malhotra, and Ashok K. Prasad
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01933 • Publication Date (Web): 30 Sep 2015
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Synthesis of β-C-glycopyranosyl aldehydes and 2,6-anhydro-heptitols
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Vinod Khatri, Amit Kumar, Balram Singh, Shashwat Malhotra and Ashok K. Prasad*
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Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
E-mail: ashokenzyme@gmail.com
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Abstract:
A convenient route has been developed for the diastereoselective synthesis of β-C-
glycopyranosyl aldehydes from D-glucose, D-mannose and D-galactose. The key step in the
synthesis of C-glycosyl aldehydes is the aryl driven reductive dehydration on 1-phenyl-2-
(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glycopyranosyl)ethanone to afford alkenes, which on oxidation
afford the desired compounds in good yield. β-C-Glycopyranosyl aldehydes have been converted
to 2,6-anhydro-heptitols in quantitative yields. The 2,6-anhydro-heptitols derived from D-
mannose and D-galactose are enantiomeric and useful linker for the synthesis of
macrocycles/amphiphiles of complimentary chirality.
Keywords: β-C-Glycosides, β-C-glycopyranosyl aldehydes, 2,6-anhydro-heptitols, linker.
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The β-C-glycosides are important stable class of carbohydrate derivatives that possess interesting
biological properties.1-3 They are mainly used as synthetic intermediates to prepare amino acids,4
C-linked disaccharides,5-6 heterocycles of biological importance7 and as models in enzymatic and
metabolic studies because of the fact that the conformations of the native sugars and their C-
linked analogs have little difference.8 The pursuit for the introduction of formyl group during the
synthesis of β-C-glycosides is quite demanding which further leads towards the development of a
variety of biologically active compounds.9,10 Till date, very limited synthetic approaches have
been reported for the preparation of β-C-glycosyl aldehydes.11,12 Genet, et al.11a has reported the
synthesis of β-C-glycopyranosyl aldehydes from sugar lactone either using dithiane or phenyl
acetylene in presence of butyl lithium at low temperature, whereas Lubineau, et al.12b has used
acetyl acetone with the formation of mixture of enol ethers that requires oxidation by
dimethyldioxirane making the whole synthesis cumbersome and inefficient. In most of the other
synthesis of β-C-glycosyl aldehydes either the -anomer has to be isomerized or the β-isomer
has to be separated from the anomeric mixture formed during the synthesis.13 Here in, we report
a convenient and efficient method for the diastereoselective synthesis of β-C-glycopyranosyl
aldehydes and their corresponding 2,6-anhydro-3,4,5-tri-O-benzyl-heptitols & 2,6-anhydro-
heptitols starting from D-glucose, D-mannose and D-galactose sugars. These 2,6-anhydro-
heptitols could find expedient utility as bidendate ligand/linkers due to the presence of two
primary hydroxyl groups and can be used for the synthesis of macrocycles/amphiphilic polymers
by transesterification reaction with different hydrophilic PEG-dimethyl esters.14 It is also
noteworthy that the 2,6-anhydro-heptitols to be derived from D-mannose and D-galactose will be
enantiomeric to each other and can be used for the generation of amphiphiles leading to micelles
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having core with complimentary chirality.15
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Natural, readily available, inexpensive starting materials, i.e. D-glucose, D-mannose and D-
galactose has been used for the synthesis of β-C-glycopyranosyl aldehydes and 2,6-anhydro-
heptitols. Thus the peracetates of β-C-glycosyl benzoylmethane 2a-2c were synthesized from D-
glucose, D-mannose and D-galactose in 85, 82 and 62% yields, respectively in two steps, i.e.
conversion of the native sugar to β-C-glycosyl benzoylmethane 1a-1c on reaction with
dibenzoylmethane-sodium bicarbonate in aqueous-alcoholic solution followed by their
peracetylation with acetic anhydride-DMAP in dimethylformamide (Scheme 1). The reduction of
peracetylated β-C-glycosides 2a-2c with NaBH4 led to the formation of alcohols 3a-3c in 96, 93
and 95% yields, respectively. Although the reduction of compounds 2a and 2c afforded only one
diastereomeric alcohol each, i.e. 3a and 3c, the reduction of 2b afforded diastereomeric mixture
of alcohols 3b (11:9, determined by 1H NMR); this may be due to the stereochemical difference
at C-2ʹ position of the precursor ketone. The optimization of the reaction for tandem mesylation
followed by base catalyzed elimination with different bases or direct dehydration reaction on
alcohol 3a were tried in dichloromethane and also in bulk under microwave reactor condition to
afford the desired alkene (E)-1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethene 4a
(entries 1-6, Table 1). The mesylation-elimination reaction using mesyl chloride with different
bases in dichloromethane resulted in the formation of the desired product 4a in very poor
yields/no reaction (entries 1-3, Table 1) due to the competition between elimination and
substitution reaction affected by the chloride ion generated in the reaction to form 1-chloro-1-
phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethane as major side product.16 Although
the yield of bulk reaction on 3a under microwave condition to form the alkene 4a enhanced from
0-20% to 30-50% (entries 4-6, Table 1); this was also not up to the mark for practical purposes
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because of the lower reaction efficiency and the generation of HCl gas in the microwave reactor.
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The direct dehydration reaction on alcohol 3a in the presence of sulfuric acid, orthophosphoric
acid and phosphorus pentaoxide in dichloromethane led to the formation of alkene 4a in 70, 75
and 95% yields, respectively (entries 7-9, Table 1). The observation of moderate yields in the
case of sulfuric acid and orthophosphoric acid as dehydrating agent could be due to charring of
starting material 3a under highly acidic condition. The use of P2O5 as dehydrating agent for the
conversion of compound 3a to 4a was found to be a very effective method due to its non-
nucleophilic nature. Thus P2O5 in dichloromethane was used for the dehydration of 3b and 3c to
obtain 4b and 4c in 91 and 94% yields, respectively (Scheme 1).
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Scheme 1
Table 1. Optimization of synthesis of E-alkene 4a from alcohol 3a
Entry
Solvent
DCM
Temp (oC)
Time
24h
Reagents
MsCl, TEA
MsCl, DBU
% Yielda of 4a
1
2
40
40
20
10
DCM
24h
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DCM
Neat*
Neat*
Neat*
DCM
DCM
DCM
40
80
80
80
25
25
25
24h
5 min
5 min
5 min
3h
MsCl, DIPEA
MsCl, DIPEA
MsCl, DBU
MsCl, TEA
H2SO4
0
50
40
30
70
75
95
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30h
H3PO4
6h
P2O5
*Microwave reactor was used at 80 oC at a power of 100 W, aisolated yield.
The oxidation of acylated sugar alkenes 4a-4c afforded a very unstable product which could not
be isolated in pure form. This prompted us to convert the peracetylated C-glycosides 4a-4c to
their corresponding perbenzylated analogs 5a-5c in one pot two steps reaction, i.e. by
deacetylation using sodium methoxide followed by perbenzylation using benzyl bromide in the
presence of sodium hydride in 90, 80 and 92% overall yields, respectively (Scheme 1). The
oxidation of perbenzylated C-glycopyranosides 5a-5c with OsO4-NaIO4 in the presence of 2,6-
lutidine in dioxane/water successfully afforded the three corresponding β-C-glycopyranosyl
aldehydes 6a-6c in 80, 78 and 81% yields, respectively.17
The β-C-glycopyranosyl aldehydes 6a-6c were further converted to 2,6-anhydro-3,4,5-tri-O-
benzyl-heptitol and then to 2,6-anhydro-heptitol which can be used as a chiral linker involving
its two primary hydroxyl groups for various applications. Thus, β-C-glycopyranosyl aldehydes
6a-6c on reaction with sodium borohydride-methanol afforded the glycosyl carbinols 7a-7c
which in turn on selective removal of primary O-benzyl group using TFA-acetic
anhydride/sodium methoxide-methanol led to the formation of 2,6-anhydro-3,4,5-tri-O-benzyl-
heptitols 8a-8c in 78, 72 and 79% overall yield, respectively (Scheme 2). The 2,6-anhydro-
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heptitols, i.e. 2,6-anhyro-gluco-heptitol (9a), 2,6-anhydro-manno-heptitol (9b) and 2,6-anhydro-
galacto-heptitol (9c) were synthesized by debenzylation of tetra-O-benzylated compounds 7a-7c
using Pd/charcoal under H2 atmosphere in methanol in 90, 87 and 85% yields, respectively.
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Scheme 2
Generally, enantiomers are either synthesized by enantioselective reactions or by chiral
resolution of the racemic product formed in the classical reaction. In the present synthesis of
heptitols, it has been observed that 2,6-anhydro-manno-heptitol (9b) derived from D-mannose
and 2,6-anhydro-galacto-heptitol (9c) derived from D-galactose or their tri-O-benzylated
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derivatives 8b and 8c are enantiomeric to each other. The specific rotation value [α]D for
anhydro-manno-heptitol (8b) and anhydro-galacto-heptitol (8c) were found to be -47.0 (c 1,
methanol) and +47.6 (c 1, methanol), respectively and for 2,6-anhydro-manno-heptitol 9b and
2,6-anhydro-galacto-heptitol 9c were found to be -32.4 (c 1, H2O) and +33.0 (c 1, H2O),
respectively. The structures of all synthesized compounds, i.e. 1a-9a, 1b-9b and 1c-9c were
unambiguously established on the basis of their spectral data (1H, 13C NMR, IR spectra and
HRMS) analysis. The structure of known compounds 1a-1c, 4a, 6a-6c, 7a, 8c and 9a-9c were
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further confirmed on the basis of comparison of their physical and spectral data with those
reported in the literature.18-21
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Conclusion: In summary, a simple and efficient route has been developed for the synthesis of β-
C-glycopyranosyl aldehydes, corresponding 2,6-anhydro-3,4,5-tri-O-benzyl-heptitols and 2,6-
anhydro-heptitols in excellent to good overall yields. The P2O5 has been found to be the excellent
dehydrating reagent for the synthesis of (E)-1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-
glycopyranosyl)ethene from 1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glycopyranosyl)ethanol.
The process is highly selective and straightforward for the synthesis of β-C-glycosyl aldehydes
and 2,6-anhydro-heptitols which have wide scope in the synthesis of various kinds of
biologically important β-C-glycosides and amphiphiles. The enantiomeric anhydro-heptitols
derived from D-mannose and D-galactose may be an expedient linker for the development of a
wide variety of biocompatible polymers/macromolecules with complimentary chirality.
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Experimental Section
General
All solvents were distilled before use. The IR spectra were recorded by making KBr disk for
solid samples and thin film for oils. The optical rotations were measured using light of 589 nm
1
wavelength. H NMR and 13C NMR spectra were recorded using tetramethylsilane (TMS) as
internal standard. The chemical shift values were observed on δ scale and the coupling constant
(J) are in Hz. Signals from OH group(s) in 1H NMR spectra recorded in CDCl3 were verified by
D2O exchange method. HRMS analysis was carried out using Q-TOF mass spectrometer.
Analytical TLCs were performed on precoated fluorescent plates; visualization of the developed
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plates was performed by UV light and charring with 5% alcoholic sulfuric acid. Silica gel (100-
200 mesh) was used for column chromatography.
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General procedure for the synthesis of 1-phenyl-2-(β-D-glycopyranosyl)ethanone (1a-1c)18a
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Compounds 1a-1c were synthesized as per the literature procedure and obtained in 65 to 90%
yields. These compounds are identified on the basis of their spectral data (1H, 13C NMR spectra
and HRMS) analysis. The structure was further confirmed by comparison of its physical and
spectral data with those reported in the literature.18a
General procedure for the synthesis of 1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-
glycopyranosyl)ethanone (2a-2c)
To a solution of 1a-1c (13 g, 46.09 mmol) in DMF (100 mL) was added DMAP (1.40 g, 11.52
mmol) and acetic anhydride (21.75 mL, 230.45 mmol) at 0 oC. The solution was stirred for 1 h at
o
0 C and quenched by addition of ice-cold water (150 mL). The reaction mixture was extracted
with ethyl acetate (2 x 150 mL) and combined organic layer was washed with saturated solution
of NaHCO3 (1 x 150 mL) followed by saturated solution of NaCl (1 x 100 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and then concentrated at reduced pressure to
give the crude product, which was purified over silica gel column using 30% ethyl acetate in
petroleum ether as eluent to afford the pure product (2a-2c).
1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethanone (2a)
It was obtained as a white solid (19.49 g) in 94% yield; m.pt. 104-106 oC; IR (KBr, cm-1): 1751,
1
1741, 1684, 1381, 1263, 1224; [α]26D -25.9 (c 0.4, methanol); H NMR (400 MHz, CDCl3): δ
1.96 (s, 3H), 1.99 (s, 6H), 2.01 (s, 3H), 2.93 (dd, 1H, J = 2.9 & 16.8 Hz), 3.34 (dd, 1H, J = 8.0 &
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16.8 Hz), 3.73-3.75 (m, 1H), 3.99 (d, 1H, J = 12.4 Hz), 4.20-4.26 (m, 2H), 5.02 (t, 1H, J = 9.5
Hz), 5.07 (t, 1H, J = 9.5 Hz), 5.24 (t, 1H, J = 9.5 Hz), 7.43-7.47 (m, 2H), 7.55-7.58 (m, 1H), 7.92
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(d, 2H, J = 8.0 Hz); C NMR (100.6 MHz, CDCl3): δ 20.5, 20.6, 40.4, 61.9, 68.4, 71.6, 73.9,
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74.1, 75.6, 128.2, 128.6, 133.4, 136.6, 169.5, 169.9, 170.2, 170.6, 196.1; HRMS (ESI): m/z =
473.1431 (calculated for C22H26NaO10 [M+Na]+ = 473.1418).
1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-mannopyranosyl)ethanone (2b)
o
It was obtained as a white solid (20.12 g) in 97% yield; m.pt. 83-85 C; IR (KBr, cm-1): 1747,
1726, 1688, 1369, 1249, 1217, 1054; [α]26D -32.3 (c 0.4, methanol); 1H NMR (400 MHz, CDCl3):
δ 1.98 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.18 (s, 3H), 2.99 (dd, 1H, J = 5.3 & 17.4 Hz), 3.38 (dd,
1H, J = 6.9 & 17.3 Hz), 3.70-3.74 (m, 1H), 4.04 (dd, 1H, J = 2.3 & 12.3 Hz), 4.28 (dd, 1H, J =
5.6 & 12.3 Hz), 4.40 (dd, 1H, J = 5.6 & 6.6 Hz), 5.17 (dd, 1H, J = 3.0 & 9.7 Hz), 5.25 (t, 1H, J =
9.7 Hz), 5.46-5.47 (m, 1H), 7.43-7.47 (m, 2H), 7.55-7.59 (m, 1H), 7.89-7.91 (m, 2H); 13C NMR
(100.6 MHz, CDCl3): δ 20.6, 20.8, 39.4, 62.7, 66.1, 70.1, 72.2, 73.2, 76.4, 128.1, 128.7, 133.5,
136.5, 169.8, 170.0, 170.5, 170.7, 195.9; HRMS (ESI): m/z = 473.1421 (calculated for
C22H26NaO10 [M+Na]+ = 473.1418).
1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-galactopyranosyl)ethanone (2c)
o
It was obtained as a white crystalline solid (19.91 g) in 96% yield; m.pt. 113-115 C; IR (KBr,
1
cm-1): 1746, 1686, 1369, 1221, 1048; [α]26 +1.43 (c 0.1, methanol); H NMR (400 MHz,
D
CDCl3): δ 1.96 (s, 3H), 1.99 (s, 6H), 2.16 (s, 3H), 2.95 (dd, 1H, J = 3.3 & 16.5 Hz), 3.40 (dd, 1H,
J = 8.1 & 16.5 Hz), 3.92-4.08 (m, 3H), 4.18-4.24 (m, 1H), 5.09 (dd, 1H, J = 3.2 & 10.0 Hz), 5.23
(t, 1H, J = 10.0 Hz), 5.44 (d, 1H, J = 3.3 Hz), 7.47 (t, 2H, J = 7.6 Hz), 7.58 (t, 1H, J = 7.6 Hz),
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7.94 (d, 2H, J = 8.3 Hz); C NMR (100.6 MHz, CDCl3): δ 20.6, 20.7, 40.7, 61.2, 67.6, 69.1,
72.0, 74.2, 74.5, 128.2, 128.6, 133.4, 136.7, 170.1, 170.2, 170.4, 196.5; HRMS (ESI): m/z =
451.1608 (calculated for C22H27O10 [M+H]+ = 451.1599).
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General procedure for the synthesis of 1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-
glycopyranosyl)ethanol (3a-3c)
To a solution of 2a-2c (12.4 g, 27.54 mmol) in methanol (100 mL) was added NaBH4 (1.22 g,
33.05 mmol) and seralite acidic resin (10 g) at 0 oC. The solution was stirred for 1 h at 0 °C. The
seralite resin was removed from the reaction by filteration followed by the removal of methanol
under reduced pressure to give the semi-solid residue which was extracted with ethyl acetate (3 x
125 mL). The combined organic layer was washed with saturated solution of NaCl (1 x 150 mL),
dried over anhydrous Na2SO4, filtered and then concentrated at reduced pressure. The crude
product thus obtained was purified over silica gel column with 40% ethyl acetate in petroleum
ether as eluent to afford pure product (3a-3c).
1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethanol (3a)
o
It was obtained as a white solid (11.95 g) in 96% yield; m.pt. 87-89 C; IR (KBr, cm-1): 3509,
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1751, 1743, 1380, 1216, 1033; [α]26D -10.1 (c 0.6, methanol); H NMR (400 MHz, CDCl3): δ
1.79-1.84 (m, 1H), 1.96-1.98 (m, 7H), 2.02 (s, 3H), 2.11 (s, 3H), 3.15 (brs, 1H), 3.51 (t, 1H, J =
9.2 Hz), 3.63-3.68 (m, 1H), 4.13 (dd, 1H, J = 6.5 & 12.4 Hz), 4.21 (dd, 1H, J = 2.2 & 12.4 Hz),
4.88-4.93 (m, 2H), 5.02 (t, 1H, J = 9.5 Hz), 5.12 (t, 1H, J = 9.2 Hz), 7.27-7.35 (m, 5H); 13C
NMR (100.6 MHz, CDCl3): δ 20.7, 20.8, 40.4, 62.6, 68.7, 71.8, 73.2, 74.0, 75.9, 77.6, 125.9,
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127.9, 128.6, 143.5, 169.5, 169.6, 170.4, 170.8; HRMS (ESI): m/z = 475.1571 (calculated for
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C22H28NaO10 [M+Na]+ = 475.1575).
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1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-mannopyranosyl)ethanol (3b)
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It was obtained as diastereomeric mixture (11:9) as a semi-solid (11.58 g) in 93% yield; IR (thin
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film, cm-1): 3511, 1747, 1369, 1230, 1054; [α]26D -30.1 (c 0.6, methanol); H NMR (400 MHz,
CDCl3): δ 1.64-1.75 (m, 1H) 1.94-2.13 (m, 13H), 2.67 (brs, 0.45H), 2.93 (brs, 0.55H), 3.58-3.66
(m, 1H), 3.71-3.81 (m, 1H), 4.13-4.24 (m, 2H), 4.86 (dd, 0.55H, J = 4.6 & 8.6 Hz), 4.92 (dd,
0.45H, J = 2.3 & 7.9 Hz), 4.96-5.01 (m, 1H), 5.14-5.20 (m, 1H), 5.25 (d, 0.45H, J = 3.3 Hz),
5.31 (d, 0.55, J = 3.3 Hz), 7.24-7.33 (m, 5H); 13C NMR (100.6 MHz, CDCl3): δ 20.6, 20.7, 20.8,
39.2, 39.8, 63.0, 66.2, 66.3, 69.8, 70.5, 70.8, 72.1, 72.3, 72.6, 74.2, 76.3, 76.4, 77.3, 125.4, 127.6,
127.9, 128.6, 143.5, 143.9, 169.8, 170.2, 170.5, 170.6, 170.8; HRMS (ESI): m/z = 475.1573
(calculated for C22H28NaO10 [M+Na]+ = 475.1575).
1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-galactopyranosyl)ethanol (3c)
It was obtained as a semi-solid (11.83 g) in 95% yield; IR (thin film, cm-1): 3462, 1749, 1370,
1
1225, 1051; [α]26D +7.48 (c 0.1, methanol); H NMR (400 MHz, CDCl3): δ 1.84 (ddd, 1H, J =
2.1, 4.2 & 14.6 Hz), 1.97 (s, 3H), 2.01 (s, 3H), 2.04-2.13 (m, 4H), 2.18 (s, 3H), 3.25 (brs, 1H),
3.56 (t, 1H, J = 10.0 Hz), 3.92 (t, 1H, J = 6.5 Hz), 4.14 (d, 2H, J = 6.3 Hz), 4.94 (dd, 1H, J = 4.9
& 9.1 Hz), 4.98 (dd, 1H, J = 3.3 & 9.9 Hz), 5.15 (t, 1H, J = 9.9 Hz), 5.43 (d, 1H, J = 3.2 Hz),
7.28-7.37 (m, 5H); 13C NMR (100.6 MHz, CDCl3): δ 20.5, 20.6, 20.7, 40.3, 62.1, 67.5, 68.9,
71.6, 73.4, 74.5, 78.2, 125.8, 127.7, 128.5, 143.3, 169.6, 170.1, 170.2, 170.5; HRMS (ESI): m/z
= 475.1590 (calculated for C22H28NaO10 [M+Na]+ = 475.1575).
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General procedure for the synthesis of (E)-1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-
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glycopyranosyl)ethene (4a-4c)
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To a solution of compound 3a-3c (5 g, 11.05 mmol) in dichloromethane (300 ml) P2O5 (4.70 g,
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33.17 mmol) was added and the reaction mixture was stirred for 6 h at 25 C. The reaction
mixture was decanted and ice-cold water was added in the decanted solution to completely
quench the reaction. The reaction mixture was extracted with dichloromethane (3 x 100 mL) and
the combined organic layer was washed with saturated solution of NaHCO3 (1 x 100 mL). The
organic layer was dried over anhydrous Na2SO4, filtered and then concentrated at reduced
pressure. The crude product, thus obtained was purified over silica gel column with 20% ethyl
acetate in petroleum ether to afford the pure product 4a-4c.
(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethene (4a)18b
Compound 4a was obtained as a white solid (4.56 g) in 95% yield and identified on the basis of
its spectral data (1H, 13C NMR spectra and HRMS) analysis. HRMS (ESI): m/z = 435.1670
(calculated for C22H27O9 [M+H]+ = 435.1650) (1H- and C NMR spectra has been given in the
13
supporting information). The structure was further confirmed by comparison of its physical and
spectral data with those reported in the literature.18b
(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-mannopyranosyl)ethene (4b)
It was obtained as a semi-solid (4.36 g) in 91% yield; IR (thin film, cm-1): 1747; 1369, 1227,
1054; [α]26D -37.2 (c 0.5, methanol); H NMR (400 MHz, CDCl3): δ 1.95 (s, 3H), 2.01 (s, 3H),
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2.05 (s, 3H), 2.07 (s, 3H), 3.68-3.73 (m, 1H), 4.14 (dd, 2H, J = 2.9 & 12.4 Hz), 4.27 (dd, 1H, J =
5.1 & 12.4 Hz), 4.31 (d, 1H, J = 5.1 Hz), 5.10 (dd, 1H, J = 2.9 & 10.2 Hz), 5.26 (t, 1H, J = 10.2
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Hz), 5.43 (d, 1H, J = 3.6 Hz), 6.01 (dd, 1H, J = 5.8 & 16.1 Hz), 6.63 (d, 1H, J = 16.1 Hz), 7.18-
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7.30 (m, 5H); C NMR (100.6 MHz, CDCl3): δ 20.7, 20.8, 20.9, 63.0, 66.2, 70.3, 72.4, 76.4,
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77.5, 123.3, 126.7, 128.2, 128.7, 133.4, 136.1, 169.8, 170.3, 170.5, 170.9; HRMS (ESI): m/z =
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435.1649 (calculated for C22H27O9 [M+H]+ = 435.1650).
(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-galactopyranosyl)ethene (4c)
It was obtained as a white solid (4.51 g) in 94% yield; m.pt. 121-123 C; IR (film, cm-1): 1749,
o
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1373, 1226, 1054; [α]26D -20.8 (c 0.1, methanol); H NMR (400 MHz, CDCl3): δ 1.95 (s, 3H),
2.01 (s, 3H), 2.06 (s, 3H), 2.19 (s, 3H), 3.97-4.03 (m, 2H), 4.15 (d, 1H, J = 6.5 Hz), 5.12 (dd, 1H,
J = 3.81 & 10.2 Hz), 5.26 (t, 1H, J = 9.9 Hz), 5.48 (d, 1H, J = 3.0 Hz), 6.12 (dd, 1H, J = 7.8 &
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15.9 Hz), 6.64-6.68 (d, 1H, J = 15.8 Hz), 7.27-7.38 (m, 5H); C NMR (100.6 MHz, CDCl3): δ
20.6, 20.7, 61.7, 67.6, 68.6, 71.6, 74.0, 80.2, 124.1, 126.7, 128.2, 128.5, 135.1, 135.8, 169.6,
170.2, 170.3, 170.4; HRMS (ESI): m/z = 435.1634 (calculated for C22H27O9 [M+H]+ =
435.1650).
General procedure for the synthesis of (E)-1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl-β-D-
glycopyranosyl)ethene (5a-5c)
To a solution of 4a-4c (4.7 g, 10.82 mmol) in methanol (50 mL) was added NaOMe (1.75 g,
32.47 mmol) at 25 oC. The solution was stirred for 2 h and it was neutralized with seralite acidic
resin which was further removed by filtration. Methanol was evaporated under reduced pressure,
the residue was taken in DMF (50 mL) followed by the addition of NaH (2.16 g, 90.18 mmol) in
it at 0 °C. The reaction mixture was allowed to stir at 0 oC for 30 min followed by the addition of
benzyl bromide (6.61 mL, 56.36 mmol) after half an hour. On completion, reaction mixture was
poured into ice cold water and extracted with chloroform (2 x 100 mL). The combined organic
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layer was washed with saturated NaCl (1 x 100 mL), dried over anhydrous Na2SO4, filtered and
then concentrated at reduced pressure. The crude product thus obtained was purified over silica
gel column with 5% ethyl acetate in petroleum ether as eluent to afford the pure product 5a-5c.
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(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl-β-D-glucopyranosyl)ethene (5a)
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It was obtained as a white solid (6.1 g) in 90% yield; m.pt. 107-109 C; IR (KBr, cm-1): 1636,
1402, 1060; [α]26D +64.5 (c 0.1, chloroform); 1H NMR (400 MHz, CDCl3): δ 3.42 (t, 1H, J = 9.1
Hz), 3.50-3.54 (m, 1H), 3.66-3.77 (m, 4H), 3.94 (dd, 1H, J = 7.3 & 9.1 Hz), 4.56 (d, 2H, J = 9.7
Hz), 4.62 (d, 1H, J = 8.1 Hz), 4.65 (d, 1H, J = 9.7 Hz), 4.74 (d, 1H, J = 10.3 Hz), 4.84 (d, 1H, J =
10.9 Hz), 4.90 (d, 1H, J = 10.9 Hz), 4.95 (d, 1H, J = 10.9 Hz), 6.23 (dd, 1H, J = 7.0 & 16.0 Hz),
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6.74 (d, 1H, J = 16.0 Hz), 7.14-7.37 (m, 25H); C NMR (100.6 MHz, CDCl3): δ 69.0, 73.6,
75.1, 75.3, 75.7, 78.2, 78.8, 80.4, 82.5, 86.9, 126.6, 127.7, 127.8, 128.0, 128.4, 128.5, 128.6,
133.4, 136.7, 137.8, 138.1, 138.2, 138.7; HRMS (ESI): m/z = 649.2917 (calculated for
C42H42NaO5 [M+Na]+ = 649.2924).
(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl-β-D-mannopyranosyl)ethene (5b)
It was obtained as a gel (5.4 g) in 80% yield; IR (thin film, cm-1): 2917, 1719, 1452, 1095; [α]26
D
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-23.0 (c 0.2, chloroform); H NMR (400 MHz, CDCl3): δ 3.51-3.55 (m, 1H), 3.67 (dd, 1H, J =
2.8 & 9.4 Hz), 3.72-3.80 (m, 2H), 3.85 (d, 1H, J = 2.1 Hz), 3.96 (t, 1H, J = 9.6 Hz), 4.00 (d, 1H,
J = 6.2 Hz), 4.57 (dd, 2H, J = 7.5 & 11.4 Hz), 4.63-4.74 (m, 4H), 4.90 (dd, 2H, J = 6.6 & 11.4
Hz), 6.20 (dd, 1H, J = 6.1 & 16.1 Hz), 6.60 (d, 1H, J = 16.1 Hz), 7.15-7.36 (m, 25H); 13C NMR
(100.6 MHz, CDCl3): δ 69.8, 72.5, 73.6, 74.5, 75.3, 75.4, 76.7, 79.4, 79.8, 85.0, 126.7, 127.1,
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127.6, 127.7, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 131.7, 136.9, 138.5, 138.6; HRMS
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(ESI): m/z = 649.2923 (calculated for C42H42NaO5 [M+Na]+ = 649.2924).
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(E)-1-Phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl-β-D-galactopyranosyl)ethene (5c)
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It was obtained as a gel (6.23 g) in 92% yield; IR (thin film, cm-1): 1635, 1457, 1097, 1027;
[α]26D -31.1 (c 0.6, chloroform); 1H NMR (400 MHz, CDCl3): δ 3.53-3.66 (m, 4H), 3.82 (t, 1H, J
= 9.1 Hz), 3.90 (dd, 1H, 6.8 & 9.1Hz), 4.01 (d, 1H, J = 3.0 Hz), 4.42 (d, 1H, J = 11.9 Hz), 4.47
(d, 1H, J = 11.9 Hz) 4.62 (d, 1H, J = 10.6 Hz), 4.66 (d, 1H, J = 11.7 Hz), 4.72-4.76 (m, 2H), 4.81
(d, 1H, J = 10.6 Hz), 4.97 (d, 1H, J = 11.6 Hz), 6.25 (dd, 1H, J = 6.8 & 16.0 Hz), 6.71 (d, 1H, J
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= 16.0 Hz), 7.22-7.39 (m, 25H); C NMR (100.6 MHz, CDCl3): δ 69.0, 72.7, 73.6, 74.0, 74.7,
75.5, 77.0, 79.0, 80.8, 84.4, 126.7, 127.6, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 128.6,
133.4, 136.9, 137.9, 138.2, 138.5, 138.8; HRMS (ESI): m/z = 627.3087 (calculated for C42H43O5
[M+H]+ = 627.3105).
General procedure for the synthesis of 1-formyl-2,3,4,6-tetra-O-benzyl-β-D-
glycopyranoside (6a-6c)17
To a suspension of 5a-5c (5 g, 7.98 mmol) in dioxane-water (3:1, 100 mL) was added 2,6-
lutidine (0.41 mL, 15.97 mmol), OsO4 (38.1 mg, 0.15 mmol) and NaIO4 (6.78 g, 31.92 mmol).
o
The reaction mixture was stirred at 25 C for 8 h and after completion it was extracted with
dichloromethane (2 x 75 mL) and combined organic layer was first washed with saturated
solution of NaHCO3 (1 x 75 mL) and then with saturated NaCl solution (1 x 75 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and then concentrated at reduced pressure to
afford the crude products 6a, 6b and 6c in 80, 78 and 81% yields, respectively. The crude
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product as such was used for spectral studies, because an effort of purification of compounds
over silica gel column led to the partial decomposition of the aldehyde function present in the
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molecule. Compounds 6a, 6b and 6c were identified on the basis of their spectral data (1H, C
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NMR spectra and HRMS) analysis. HRMS (ESI) of 6a: m/z = 575.2414 (calculated for
C35H36NaO6 [M+Na]+ = 575.2404); HRMS (ESI) of 6b: m/z = 553.2556 (calculated for C35H37O6
[M+H]+ = 553.2585) and HRMS (ESI) of 6c: m/z = 575.2413 (calculated for C35H36NaO6
[M+Na]+ = 575.2404). The 1H- and 13C NMR spectra of the three compounds have been given in
the supporting information. The structure was further confirmed by comparison of its physical
and spectral data with those reported in the literature.17,20
General
procedure
for
the
synthesis
of
(2,3,4,6-tetra-O-benzyl-β-D-
glycopyranosyl)methanol (7a-7c)
To a solution of 6a-6c (4 g, 7.21 mmol) in methanol (40 mL) was added NaBH4 (0.275 g, 7.21
o
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mmol) at 0 C and the mixture was stirred for 1 h at 0 C. After completion of the reaction
methanol was removed under reduced pressure and the residue was extracted with ethyl acetate
(2 x 50 mL). The combined organic layer was washed with saturated NaCl solution (1 x 50 mL),
dried over anhydrous Na2SO4, filtered and then concentrated at reduced pressure. The crude
product thus obtained was purified over silica gel column with 20% ethyl acetate in petroleum
ether as eluent to afford pure product 7a-7c.
(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)methanol (7a)19a
Compound 7a was obtained as a white solid (3.68 g) in 92% yield and identified on the basis of
its spectral data (1H, 13C NMR spectra and HRMS) analysis. HRMS (ESI): m/z = 577.2567
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(calculated for C35H38NaO6 [M+Na]+ = 577.2561) (1H- and 13C NMR spectra have been given in
the supporting information). The structure of the pure compound was further confirmed by
comparison of its physical and spectral data with those reported in the literature.19a
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(2,3,4,6-Tetra-O-benzyl-β-D-mannopyranosyl)methanol (7b)
It was obtained as a gel (3.6 g) in 90% yield; IR (thin film, cm-1): 3437, 3030, 2859, 1365, 1092;
[α]26D -23.0 (c 0.6, methanol); 1H NMR (400 MHz, CDCl3): δ 2.36 (brs, 1H), 3.41-3.49 (m, 3H),
3.60-3.81 (m, 4H), 3.86-3.92 (m, 2H), 4.54 (dd, 2H, J = 6.1 & 10.3 Hz), 4.60 (d, 1H, J = 12.2
Hz), 4.67 (d, 1H, J = 11.6 Hz), 4.73 (d, 1H, J = 11.6 Hz), 4.78 (d, 1H, J = 11.6 Hz), 4.89 (d, 1H,
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J = 10.3 Hz), 4.97 (d, 1H, J = 11.6 Hz), 7.15-7.39 (m, 20H); C NMR (100.6 MHz, CDCl3): δ
62.5, 69.6, 72.5, 73.4, 74.1, 75.2, 75.4, 78.7, 79.4, 84.9, 127.6, 127.7, 127.8, 127.9, 128.0, 128.3,
128.4, 138.0, 138.2, 138.3; HRMS (ESI): m/z = 577.2555 (calculated for C35H38NaO6 [M+Na]+ =
577.2561).
(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)methanol (7c)
It was obtained as a gel (3.8 g) in 95% yield; IR (thin film, cm-1): 3448, 1454, 1104; [α]26D +33.8
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(c 0.1, methanol); H NMR (400 MHz, CDCl3): δ 1.84 (brs, 1H), 3.36 (ddd, 1H, J = 2.2, 4.5 &
7.6 Hz), 3.49-3.60 (m, 3H), 3.64 (dd, 1H, J = 2.6 & 9.5 Hz), 3.71 (dd, 1H, J = 5.2 & 11.8 Hz),
3.86 (dd, 1H, J = 2.6 & 11.8 Hz), 3.94 (t, 1H, J = 9.5 Hz) 3.99 (d, 1H, J = 2.6 Hz), 4.43 (d, 1H, J
= 11.8 Hz), 4.48 (d, 1H, J = 11.8 Hz), 4.61 (d, 1H, J = 11.6 Hz), 4.66 (d, 1H, J = 10.8 Hz), 4.71
(d, 1H, J = 11.8 Hz), 4.78 (d, 1H, J = 11.7 Hz), 4.95 (dd, 2H, J = 8.4 & 11.1 Hz), 7.27-7.39 (m,
20H); 13C NMR (100.6 MHz, CDCl3): δ 62.4, 68.8, 72.2, 73.4, 73.6, 74.4, 75.1, 75.2, 79.4, 84.5,
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(ESI): m/z = 577.2560 (calculated for C35H38NaO6 [M+Na]+ = 577.2561).
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8c)
To a solution of 7a-7c (3.8 g, 6.85 mmol) in acetic anhydride (36 mL) was added trifluoroacetic
o
acid (9 mL) and the solution was stirred for 2 h at 25 C. The reaction mixture was evaporated
under reduced pressure, coevaporated twice with toluene and dried under high vacuum. The
residue obtained was taken in methanol (50 mL) and sodium methoxide (1.84 g, 34.25 mmol)
was added into it. The reaction mixture was stirred for 1 h at 25 oC, methanol was removed under
reduced pressure and the residue was extracted with ethyl acetate (2 x 50 mL). The combined
organic layer was washed with saturated aqueous NaCl solution (1 x 50 mL), dried over
anhydrous Na2SO4, filtered and then concentrated at reduced pressure. The crude product thus
obtained was purified over silica gel column with 50% ethyl acetate in petroleum ether as eluent
to afford the pure product 8a-8c.
2,6-Anhydro-3,4,5-tri-O-benzyl-gluco-heptitol (8a)
It was obtained as a white solid (2.7 g) in 85% yield; m.pt. 142-144 C; IR (KBr, cm-1): 3432,
o
1453, 1348, 1102, 1065; [α]26D +0.01 (c 0.5, methanol); 1H NMR (400 MHz, CDCl3): δ 2.58 (brs,
2H), 3.36-3.40 (m, 2H), 3.56 (t, 2H, J = 9.3 Hz), 3.67-3.70 (m, 2H), 3.75 (t, 1H, J = 9.3 Hz), 3.85
(d, 2H, J = 11.7 Hz), 4.67 (d, 2H, J = 10.9 Hz), 4.87 (d, 2H, J = 10.9 Hz), 4.93 (s, 2H), 7.27-7.34
(m, 15H); 13C NMR (100.6 MHz, CDCl3): δ 61.7, 75.0, 75.6, 77.7, 79.1, 86.8, 127.7, 127.9,
128.0, 128.4, 128.5, 137.9, 138.4; HRMS (ESI): m/z = 487.2101 (calculated for C28H32NaO6
[M+Na]+ = 487.2091).
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2,6-Anhydro-3,4,5-tri-O-benzyl-manno-heptitol (8b)
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It was obtained as a gel (2.54 g) in 80% yield; IR (thin film, cm-1): 3437, 2922, 1104; [α]26D -47.0
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(c 1.0, methanol); H NMR (400 MHz, CDCl3): δ 2.12 (brs, 2H), 3.33-3.37 (m, 1H), 3.40-3.46
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(m, 2H), 3.63 (dd, 1H, J = 2.6 & 9.5 Hz), 3.71 (dd, 1H, J = 5.4 & 11.9 Hz), 3.77 (dd, 1H, J = 4.2
& 9.4 Hz), 3.85 (dd, 2H, J = 2.2 & 5.8 Hz), 3.92 (t, 1H, J = 9.5 Hz), 4.65 (t, 2H, J = 11.6 Hz),
4.75 (d, 1H, J = 11.9 Hz), 4.79 (d, 1H, J = 11.9 Hz), 4.93 (d, 1H, J = 10.8 Hz), 4.97 (d, 1H, J =
11.8 Hz), 7.28-7.40 (m, 15H); 13C NMR (100.6 MHz, CDCl3): δ 62.2, 62.6, 72.5, 74.0, 74.2,
75.1, 75.2, 78.4, 79.8, 84.5, 127.4, 127.6, 127.9, 128.0, 128.3, 128.4, 137.9, 138.0, 138.1; HRMS
(ESI): m/z = 487.2094 (calculated for C28H32NaO6 [M+Na]+ = 487.2091).
2,6-Anhydro-3,4,5-tri-O-benzyl-galacto-heptitol (8c)19b
Compound 8c was obtained as a gel (2.63 g) in 83% yield and identified on the basis of its
spectral data (1H, 13C NMR spectra and HRMS) analysis. HRMS (ESI): m/z = 465.2271
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(calculated for C28H33O6 [M+H]+ = 465.2272) (1H- and C NMR spectra has been given in the
supporting information). The structure was further confirmed by comparison of its physical and
spectral data with those reported in the literature.19b
General procedure for the synthesis of 2,6-anhydro-glyco-heptitol (9a-9c)
To a solution 7a-7c (600 mg, 1.08 mmol) in methanol (5 mL) was added 10% Pd/C (100 mg)
o
and the suspension was stirred for 12 h at 25 C under H2 atmosphere. The Pd/C was removed
from reaction by filtration followed by the removal of methanol under reduced pressure to give
the crude product. The crude product thus obtained was purified over silica gel column with 20%
methanol in chloroform as eluent to afford the pure product 9a, 9b and 9c in 90, 87 and 85%
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yields, respectively. Compounds 9a, 9b and 9c were identified on the basis of their spectral data
(1H, 13C NMR spectra and HRMS) analysis. HRMS (ESI) of 9a: m/z = 195.0858 (calculated for
C7H15O6 [M+H]+ = 195.0863); HRMS (ESI) of 9b: m/z = 195.0861 (calculated for C7H15O6
[M+H]+ = 195.0863); HRMS (ESI) of 9c: m/z = 195.0860 (calculated for C7H15O6 [M+H]+ =
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195.0863). H- and 13C NMR spectra has been given in supporting information. The structure
was further confirmed by comparison of their physical and spectral data with those reported in
the literature.21
1
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Supporting Information: H and C NMR spectra of compounds 2a-9a, 2b-9b, 2c-9c and 1-
chloro-1-phenyl-2-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-acetyl-β-D-glucopyranosyl)ethane have been given in
supporting information. This material is available free of charge via internet at
http://pubs.acs.org.
Acknowledgments: We are grateful to University of Delhi for providing financial support under
DU-DST Purse grant and under a scheme to strengthen research and development. We are also
thankful to CIF-USIC, University of Delhi, for providing the NMR spectral and HRMS
recording facility. V.K. and B.S. thank CSIR, New Delhi for the award of Junior/Senior
Research Fellowships. A.K. thanks IGSTC Gurgaon for providing research fellowship.
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