Directing Effect of Axial and Equatorial Anomeric Substituent in Site Specific Glycosylation of Glucopyranosides

Article abstract of DOI:10.1081/SCC-120028637

Regio- and stereoselective glycosylation of α- and β-octyl glucopyranoside derivatives 2c and 2d, respectively, with glycosyl donor 3 to obtain the corresponding 3-O-linked 5c and 2-O-linked 4d saccharides, respectively, is described, formation of diglyco

Full text of DOI:10.1081/SCC-120028637

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1057–1063, 2004
Directing Effect of Axial and Equatorial
Anomeric Substituent in Site Specific
Glycosylation of Glucopyranosides
*
Hari Babu Mereyala, S. Bhavani, and A. P. Rudradas
Organic Chemistry Division III, Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
Regio- and stereoselective glycosylation of a- and b-octyl glucopyrano-
side derivatives 2c and 2d, respectively, with glycosyl donor 3 to obtain
the corresponding 3-O-linked 5c and 2-O-linked 4d saccharides,
respectively, is described, formation of diglycosylated products 6c and
6d was not observed.
Key Words: Octyl glucopyranoside; 2-Pyridyl-1-thioglucopyranoside;
Iodomethane; Regioselective glycosylation.
*
Correspondence: Hari Babu Mereyala, Organic Chemistry Division III, Indian
Institute of Chemical Technology, Hyderabad 500 007, India; E-mail: mereyalahb@
rediffmail.com.
1057
DOI: 10.1081/SCC-120028637
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Mereyala, Bhavani, and Rudradas
Carbohydrate biopolymers are made up of monomeric units connected to
one another at several sites and in two types of anomeric linkages[1] they
provide almost all variations in their structure and play essential role in many
molecular processes such as fertilization, embryogenesis, and hormone
activity.[2] Oligosaccharide structures change dramatically during develop-
ment of cells and specific sets of oligosaccharides are expressed at distinct
stages of differentiaion. The saccharide processing involves regio- and
stereoselective glycosylation of carbohydrates, extent and site of glycosyla-
tion is attributed to steric crowding in the 3D structure and rate of reactivity of
the hydroxyl groups.[3]
We report our initial studies on the role of anomeric substituent in the site
specific glycosylation of glucopyranosides. Methyl a-(1a) and b-D-gluco-
pyranoside (1b) were severally reacted with a,a-dimethoxy toluene in CH2Cl2
to obtain the corresponding 4,6-O-benzylidene derivatives 2a[4] and 2b,[5]
respectively, as crystalline solids.
Axial glycoside 2a was coupled with 2-pyridyl 2,3,4,6-tetra-O-benzyl-1-
thio-a/b-D-glucopyranoside (3) by iodomethane activation procedure[6] in
CH2Cl2 at 408C for 78 hr to isolate 2-O-glycosylated saccharide 4a (20%
yield), 3-O-glycosylated saccharide 5a (48% yield), and 2,3-di-O-glycosy-
lated saccharide 6a (10% yield). Whereas coupling of equatorial glycoside 2b
with 3 under similar reaction conditions gave 2-O-glycosylated saccharide 4b
(23.5% yield) and 3-O-glycosylated saccharide 5b (46% yield), formation of
diglycosylated derivative was not observed. Stereochemistry of the newly
formed O-glycosidic bond was established as axial.[6] 4a–6a and 4b–5b were
fully characterized from 1H NMR spectra. These experiments have indicated
that in case of axial methyl glycoside acceptors marginal selectivity for
Scheme 1.

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Directing Effect of Axial and Equatorial Anomeric Substituent
1059
3-O-glycosylation was observed over 2-O- and vice versa for equatorial
methyl glycoside derivatives indicating that the stereochemistry at the
anomeric position played a role in directing the glycosylation site. In order to
enhance the regioselectivity (site) in glycosylations we looked at the role of
alkyl groups such as size and linkage (a/b) at the anomeric position. Thus
glycosides possessing long chain alkyl groups at the anomeric position were
considered for glycosylation. Accordingly, n-octyl a-(1c)[7] and -b-D-gluco-
pyranosides (1d)[8] were converted to their corresponding benzylidene deriva-
tives 2c and 2d, respectively, by reaction with a,a-dimethoxy toluene.[4] 2c
and 2d were characterized from 1H NMR spectra by the appearance of
benzylidene acetal protons as two singlets at d 5.50 (0.8 H), d 5.40 (0.2 H),
d 5.45 (0.5 H), and d 5.30 (0.5 H), respectively. 2c and 2d were separately
coupled with glycosyl donor 3 to isolate 3-O-a-5c (58% yield) and 2-O-b-
glycosylated 4d (77% yield) derivatives, respectively, indicating high
regioselectivity. Formation of regioisomers and diglycosylated products was
not observed. 5c and 4d were converted to the corresponding acetyl
derivatives 7c and 8d, respectively, for characterization by 1H NMR spectra.
In the 1H NMR spectra of 7c, acetyl group appeared at d 2.10 (3H, s), H-2 as a
double doublet at d 5.40 (J1,2 ¼ 4.2 Hz, J2,3 ¼ 8.1 Hz) and H-1 appeared at
d 4.30 as a doublet. Irradiation of the proton at d 5.40 resulted in the collapse of
H-1 to a singlet; thus 7c was characterized as the 3-O-glycosylated saccharide.
In the 1H NMR spectrum of 8d the acetyl group appeared at d 2.18 (s, 3H) and
H-3 at d 4.95 (0.5 H, dd) and 5.30 (0.5 H, dd, J3,8 ¼ 2 Hz, J3,4 ¼ 8.5 Hz).
Irradiation of the protons at d 4.95 and d 5.30 did not have any effect on the
multiplicity of H-1 proton that appeared as a doublet at d 4.60 (J1,2 ¼ 8.2 Hz)
indicating 8d to be the 2-O-glycosylated saccharide.
In conclusion, we have shown that axial octyl glycopyranosides exhibited
selective 3-O- and the corresponding equatorial ones the 2-O-glycosylation. In
case of methyl glycosides the selectivity in glycosylation was not significant.
Site selectivity, effect of chain length, and bulk of alkyl substituent at the
anomeric position in glycosylation is under study in the light of these findings.
EXPERIMENTAL SECTION
General Methods
Flame dried glass ware, commercially available solvents and reagents
were used without further purification unless otherwise stated. Melting points
1
were measured using capillary tubes and are uncorrected. H NMR spectra
were measured with a Varian Gemini (200 MHz) spectrometer, with TMS as
an internal standard using CDCl3, as solvent.

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Mereyala, Bhavani, and Rudradas
Methyl 4,6-O-Benzylidene-2-O-(2,3,4,6-tetra-O-bezyl-a-D-
glucopyranosyl)-a-D-glucopyranoside (4a); Methyl 4,6-O-
benzylidene-3-O-(2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-
a-D-glucopyranoside (5a); Methyl 4,6-O-benzylidene-2,3-di-
O-(2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-a-D-
glucopyranoside (6a)
A solution of methyl 4,6-O-benzylidene-a-D-glucopyranoside (3.0 g,
10.3 mmol), 3 (5.8 g, 10.3 mmol), molecular sieves (100 mg) and methyl
iodide (7.5 mL of 6% v/v methyl iodide solution in dichloromethane) in
dichloromethane (100 mL) was refluxed for 78 hr. The reaction mixture was
diluted with dichloromethane (200 mL) and filtered to remove insoluble salts.
The filtrate was concentrated to a volume of 20 mL and chromatographed on a
bed of silica gel [60–120 mesh, hexane : ethylacetate, (6 : 1)] to elute first 2,3-
di-O-glycosylated derivative 6a (0.89 g, 12%) followed by 2-O-glycosylated
derivative 4a (1.71 g, 28%) and 3-O-glycosylated product 5a (3.14 g, 48%) as
syrups.
1
4a: H NMR (200 MHz, CDCl3): d 7.15–7.42 (m, 25H, Ar-H), 5.52
(d, 1H, J ¼ 4.5 Hz, H-1), 5.43 (s, 1H, PhCH), 3.35–4.95 (m, 21H, PhCH2 ꢀ 4,
2-6, 10-60), 3.51 (s, 3H, OCH3); Anal. calcd. for C48H52O11 (804): C, 71.64; H,
6.47, Found: C, 71.32; H, 6.54.
1
5a: H NMR (200 MHz, CDCl3): d 7.20–7.45 (m, 25H, Ar-H), 5.35
(d, 1H, J ¼ 4.5 Hz, H-1), 5.45 (s, 1H, PhCH), 3.30–5.00 (m, 21H, PhCH2 ꢀ 4,
2–6, 10 –60), 3.51 (s, 3H, OCH3); Anal. calcd. for C48H52O11 (804): C, 71.64;
H, 6.47, Found: C, 71.39; H, 6.57.
1
6a: H NMR (200 MHz, CDCl3): d 7.15–7.40 (m, 45H, Ar-H), 5.50
(s, 1H, PhCH), 3.40–5.00 (m, 36H, PhCH2 ꢀ 8, 2–6, 10 –60, 100 –600-H), 3.52
(s, 3H, OCH3); Anal. calcd. for C82H80O16 (1240): C, 74.21; H, 6.48, Found:
C, 73.98; H, 6.57.
Methyl 4,6-O-benzylidene-3-O-(2,3,4,6-tetra-O-bezyl-a-D-
glucopyranosyl)-b-D-glucopyranoside (4b); Methyl 4,6-O-
benzylidene-2-O-(2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-
b-D-glucopyranoside (5b)
Reaction of 2b (1.0 g, 3.5 mmol) in dichloromethane (10 mL), 3 (2.25 g,
3.5 mmol), molecular sieves (100 mg), methyl iodide (15 mL of 6% methyl
iodide in dichloromethane) as described for 4a resulted in the isolation of 3
(0.73 g, 26%) followed by 2-O-glycosylated derivative 5b (410 mg, 23.5%)
and 3-O-glycosylated derivative 4b (0.80 g, 46%). [a]D ¼ 2 31.08 (c 0.94,
CHCl3).

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Directing Effect of Axial and Equatorial Anomeric Substituent
1061
4b: m.p. 1558C–1578C; [a]D ¼ 2 118 (c 1.3, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.20–7.40 (m, 25H, Ar-H), 5.35 (d, 1H, J ¼ 6.4 Hz,
H-10), 5.45 (s, 1H, PhCH), 3.40–5.00 (m, 21H, PhCH2 ꢀ 4, 2–6, 10 –60), 3.58
(s, 3H, OCH3); Anal. calcd. for C48H52O11 (804): C, 71.64; H, 6.47, Found: C,
71.39; H, 6.53.
1
5b: syrup; [a]D ¼ 2 318 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3):
d 7.20–7.40 (m, 25H, Ar-H), 5.40 (d, 1H, J ¼ 6.4 Hz, H-1), 5.45 (s, 1H,
PhCH), 3.40–5.00 (m, 21H, PhCH2 ꢀ 4, 2–6, 10 –60), 3.58 (s, 3H, OCH3);
Anal. calcd. for C48H52O11 (804): C, 71.64; H, 6.47, Found: C, 71.39; H, 6.57.
n-Octyl 4,6-O-benzylidene-a-D-glucopyranoside (2c)
To a solution of n-octyl a-D-glucopyranoside (1.5 g, 5.1 mmol) in dry
dichloromethane (5 mL) was added a,a-dimethoxy toluene (912 mg, 6 mmol)
and a catalytic amount of p-TSA (5 mg) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 48 hr, water was added
and extracted into dichloro methane. The organic phase was separated,
washed with water, dried (Na2SO4). The residue obtained was filtered on a bed
of silica gel [60–120 mesh, hexane : ethyl acetate, (1 : 1)] to obtain the title
compound 2c (1.7 g, 89%) as a crystalline solid, m.p. 748C; 1H NMR
(200 MHz, CDCl3): (diastereomeric mixture): d 7.25–7.60 (m, 5H, Ar-H),
5.30–5.50 (2s, 1H, PhCH), 4.35 (d, 1H, J1,2 ¼ 8.3 Hz, H-1), 3.25–4.25
(m, 8H, H-2-6, OCH2), 1.20–1.40 (m, 12H, CH2 ꢀ 6), 0.87 (t, 3H, CH3);
Anal. calcd. for C21H32O6 (380): C, 66.31; H, 8.42, Found: C, 65.24; H, 8.51.
n-Octyl 4,6-O-benzylidene-b-D-glucopyranoside (2d)
To a solution of n-octyl b-D-glucopyranoside (4.5 g, 15.3 mmol) in dry
dichloromethane (20 mL) was added a,a-dimethoxy toluene (1.9 g, 19 mmol)
and a catalytic amount of p-TSA (15 mg) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 48 hr, water was added
and extracted into dichloro methane. The organic phase was separated,
washed with water, dried (Na2SO4) and concentrated. The residue obtained
was filtered on a bed of silica gel [60–120 mesh, hexane : ethyl acetate, (1 : 1)]
to obtain the title compound 2d (5.1 g, 89%) as a crystalline solid, m.p. 1248C;
1H NMR (200 MHz, CDCl3): (diastereomeric mixture): d 7.25–7.60 (m, 5H,
Ar-H), 5.30–5.50 (2s, 1H, PhCH), 4.35 (d, 1H, J1,2 ¼ 8.3 Hz, H-1), 3.25–4.25
(m, 8H, H-2-6, OCH2), 1.20–1.40 (m, 12H, CH2 ꢀ 6), 0.87 (t, 3H, CH3);
Anal. calcd. for C21H32O6 (380): C, 66.31; H, 8.42, Found: C, 66.12; H, 8.53.

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Mereyala, Bhavani, and Rudradas
n-Octyl 4,6-O-benzylidene-3-O-(2,3,4,6-tetra-O-bezyl-a-D-
glucopyranosyl)-a-D-glucopyranoside (5c); n-Octyl 4,6-O-
benzylidene-2-O-(2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-
b-D-glucopyranoside (4d)
Prepared from 2c (1.0 g, 2.6 mmol) CH2Cl2 (12 mL), 3 (1.65 g, 2.6 mmol)
methyl iodide (1 mL of 6% methyl iodide in dichloromethane) as described for
compound 4b to obtain the title compound 5c (0.5 g, 48%) as a syrup:
[a]D ¼ 608 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.05–7.40 (m, 25H,
Ar-H), 5.52–5.50 (2s, 1H, PhCH), 5.35 (d, 1H, J1,2 ¼ 2.1 Hz, H-1), 3.30–5.00
(m, 22H, H-2-6, 10 –60, OCH2, PhCH2O ꢀ 3, PhCH-), 1.15–1.45 (m, 12H,
CH2 ꢀ 6), 0.87 (t, 3H, CH3); Anal. calcd. for C55H68O11 (904): C, 72.97; H,
7.52, Found: C, 72.78; H, 7.59.
4d: [a]D ¼ 14.68 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.00–7.40
(m, 25H, Ar-H), 5.25–5.50 (2s, 1H, PhCH), 3.30–5.00 (m, 22H, H-2-6, 10 –60,
OCH2, PhCH2O ꢀ 3, PhCH-), 1.15–1.45 (m, 12H, CH2 ꢀ 6), 0.87 (t, 3H,
CH3); Anal. calcd. for C55H68O11 (904): C, 72.97; H, 7.52, Found: C, 72.88;
H, 7.49.
n-Octyl 2-O-acetyl-4,6-O-benzylidene-3-O-(2,3,4,6-tetra-O-
bezyl-a-D-glucopyrano- syl)-a-D-glucopyranoside (7c)
2d (0.1 g, 0.09 mmol) was acetylated in pyridine (0.5 mL, 7.5 mmol)
acetic anhydride (0.25 mL, 2.75 mmol) at 08C to obtain the title compound 7c
1
(96 mg, 95%) as a syrup; [a]D ¼ 368 (c 1, CHCl3); H NMR (200 MHz,
CDCl3): d 7.15–7.40 (m, 25H, Ar-H), 5.52 (d, 1H, J1 2 ¼ 5.6 Hz, H-10), 5.42-
5.30 (2s, 1H, PhCH), 4.85 (d, 1H, J1,2 ¼ 4.7 Hz, H-2), 3.30–5.00 (m, 22H,
H-1, 3-6, 20 –60, PhCH2O ꢀ 4, –OCH2–), 2.05 (s, 3H, COCH3), 1.20–1.50
(m, 12H, CH2 ꢀ 6), 0.90 (t, 3H, CH3); Anal. calcd. for C57H70O12 (946): C,
72.31; H, 7.41, Found: C, 71.21; H, 7.49.
0
0
n-Octyl-3-O-acetyl-4,6-O-benzylidene-2-O-(2,3,4,6-tetra-O-
benzyl-a-D-glucopyrano-syl)-b-D-glucopyranoside (8d)
To a solution of 4d (200 mg, 0.22 mmol) in pyridine (0.5 mL, 7.5 mmol) at
08C, was added acetic anhydride (0.25 mL, 2.3 mmol). The reaction mass was
stirred at room temperature for 1 hr. The reaction mixture was worked up and
filtered on a bed of silica gel [60–120 mesh, hexane: ethyl acetate (5 : 1)] to
obtain the title compound 8d (192 mg, 92%) as a syrup; [a]D ¼ 198 (c 1,
1
CHCl3); H NMR (200 MHz, CDCl3): d 6.95–7.45 (m, 25H, Ar-H), 5.50–

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Directing Effect of Axial and Equatorial Anomeric Substituent
1063
0
0
5.60 (2s, 1H, J1 2 ¼ 3.2 Hz), 5.28–5.45 (2s, 1H, 1H), 3.30–5.60 (d, 1H,
J1,2 ¼ 4.7 Hz, H-2), 3.30–5.60 (m, 22H, H-1, 3-6, 20 –60, PhCH2O ꢀ 4,
–OCH2–), 5.10 (dd, J2,3 ¼ 80 Hz, J3,4 ¼ 8.8 Hz, H-3 merged), 2.00 (s, 3H,
COCH3), 1.20–1.35 (m, 12H, CH2 ꢀ 6), 0.70 (t, 3H, CH3); Anal. calcd. for
C57H70O12 (946): C, 72.31; H, 7.41, Found: C, 71.31; H, 7.38.
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Received in India September 11, 2003

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