Synthesis and antioxidant activity of a novel class of 4,6-O-protected O-glycosides and their utility in disaccharide synthesis

Article abstract of DOI:10.1016/j.carres.2010.04.020

BF₃·Et₂O-catalysed O-glycosylation of 1,2,3-tri-O-acetyl-4,6-O-butylidene- and ethylidene-β-d-glucopyranose with different aliphatic and aromatic alcohols proceeds for the most part with complete retention of anomeric configuration. Antioxidant activity of O-glycosides shows significant inhibition (IC₅₀ ～77%). 1,3-Dipolar cycloaddition of terminal alkyne derivatives of O-glycosides with glycosyl azide results in disaccharides.

Full text of DOI:10.1016/j.carres.2010.04.020

Carbohydrate Research 345 (2010) 1649–1657
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis and antioxidant activity of a novel class of 4,6-O-protected
O-glycosides and their utility in disaccharide synthesis
Ramanathan Rajaganesh a, Jayaraman Jayakumar a, Chandrasekaran Sivaraj b, Nanjian Raaman b,
Thangamuthu Mohan Das a,
*
a Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
b Department of Botany, CAS, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
BF3ꢀEt2O-catalysed O-glycosylation of 1,2,3-tri-O-acetyl-4,6-O-butylidene- and ethylidene-b-
D-glucopyr-
Received 7 January 2010
Received in revised form 9 February 2010
Accepted 22 April 2010
anose with different aliphatic and aromatic alcohols proceeds for the most part with complete retention
of anomeric configuration. Antioxidant activity of O-glycosides shows significant inhibition (IC50 ꢁ77%).
1,3-Dipolar cycloaddition of terminal alkyne derivatives of O-glycosides with glycosyl azide results in
disaccharides.
Available online 27 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Protected sugars
O-Glycosides
XRD-analysis
Antioxidant activity
Triazole
Disaccharide
1. Introduction
in moderate to good yield.18,19 Mereyala and Gurrala20 reported
the synthesis of allyl and propargyl O-glycosides in the presence of
The ever-increasing importance of the role of carbohydrates in
biological processes relating to immunology, virology and a host
of life-threatening diseases has created an interest in access to spe-
cific sugar-hybrid molecules (Fig. 1).1 In general, glycosylated
products are essential and reliable platforms for the development
of many of our existing front-line drugs2,3 and organic materials.4,5
Recently, the appreciable understanding of the relationship that
exists between the sugars and bioactive entities has shed light on
their biological significance.6,7 In addition, the synthesis of O-gly-
cosides has received considerable attention because of their inhib-
itory activity, and their role as inducers of glycosidases, as well as
their utility as glycosyl donors in the convergent synthesis of oligo-
saccharides.8,9 Common natural antioxidants are generally from
the family of flavonoids and phenolic acids.10,11 They serve not only
as defensive molecules in prevention of different pathological dis-
orders, but are also used in industry for the prevention of oxidative
degradation of polymers and natural pigments.12
BF3ꢀEt2O, which resulted in high yields with good selectivities. Thus
the allyl and propargyl O-glycopyranosides, due to the higher reac-
tivities, are extensively used in the synthesis of oligosaccharides.
These groups can be deprotected by various reagents at any length
of the growing saccharide chain to obtain the reducing sugar,21
and further derivatisation with proteins leads to glycoconju-
gates.22,23 Furthermore, propargyl O-glycosides24,25are of great
interest in ‘click chemistry’ used to provide mimics of various biody-
namic carbohydrate structures26,27 and glycoconjugates.
The recent advance of Cu-catalysed conditions in click chemis-
try affords superior regioselectivity, high tolerance of other
functionalities and quantitative transformation under mild condi-
tions. 1,3-Dipolar cycloaddition reactions have been used in the
synthesis of neoglycoconjugates and also in bioconjugation study
of glycosides.28,29 In the search for new methodologies for the
synthesis of disaccharides, the use of propynyl O-glycosides can
be a versatile and efficient synthon for the construction of disac-
charide derivatives. More recently, the alkyne–azide30 cycloaddi-
tion reaction catalysed by Cu(I) has been given more attention
for the synthesis of saccharide derivatives.31,32 This report de-
scribes the use of 1-(2-propyn-1-yl) 2,3-di-O-acetyl-4,6-O-pro-
Despite the development of many elegant strategies to synthe-
sise O-glycosides,13–17 reactions of per-O-acetylated monosaccha-
rides with aliphatic and aromatic alcohols in the presence of BF3ꢀ
Et2O, TMSOTf and AgClO4 afford the corresponding O-glycosides
tected b-D-glucopyranose for the construction of several
disaccharide derivatives by the reaction with sugar azides through
triazole ring formation.
* Corresponding author. Tel.: +91 44 22202814; fax: +91 44 22352494.
E-mail address: tmdas_72@yahoo.com (T.M. Das).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.04.020

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R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
H3C
O
O
O
O
HO
O
OH
O
OH
H3C
O
CH3
O
O
HO
HO
O
O
O
O
O
H
H3C
HO
HO
CH3
O
OH
CH3 OH CH3
Etoposide
Baiyunoside
Figure 1. O-Glycosylated sugar hybrid compounds.
Phenols, in their capacity as hydrogen donors, react with lipid
radicals33 to form phenoxy radicals and are effective chain-breaking
antioxidants. However, phenol is inactive as an antioxidant, but an
alkyl substituent at either ortho or para position increases the elec-
tron density on the hydroxyl group and thus increases its activity to-
wards the generation of lipid radicals.34 Thus it has been proposed
that these two potentially useful properties could be combined in
a properly functionalised phenol that might act as an efficient
drug.35 In addition to our ongoing research36 in the area of sugar
chemistry, here we report the influence of the sugar skeleton and
aglycon motifs on antioxidant properties using the 1,1-diphenyl-2-
picrylhydrazide (DPPH) radical-scavenging activity assay.
and propargyl alcohol) and aromatic alcohols (phenol, p-methyl-
phenol, p-ethylphenol and p-nitrophenol) resulted in the forma-
tion of the corresponding expected O-glycosides (4a–h) (Table 1)
in 40–72% yield. Use of 2.5 equiv of BF3ꢀEt2O, 1.0 equiv of protected
sugar and 1.5 equiv of alcohol resulted in higher selectivity (95%).
Thus the high b-selectivity in O-glycosylation reactions under
acidic conditions is attributed to the neighbouring group effect
(C-2 substituent) via the formation of an oxazolinium ion that re-
sults in the preferential formation of the 1,2-trans-glycosylated
product. Evidence for the mechanistic hypothesis is obtained from
the single-crystal XRD analysis of the product, which is derived
from the stabilisation of the oxazolinium intermediate. The ali-
phatic allyl and propargyl alcohols react with 3a and 3b to give
the b product only. The multiplet at d ꢁ5.0–6.0 in the 1H NMR
spectrum and the peaks at d ꢁ72.0 and ꢁ56.0 in the 13C NMR spec-
trum confirm the formation of O-allyl glycosides 4a and 4c. More-
over the structure of 4a is confirmed through a single-crystal XRD
analysis. The characteristic triplet at d ꢁ2.39 (J 2.4 Hz) for the ter-
minal alkyne group in 1H NMR spectrum and peaks at d ꢁ56.1 and
66.4 in the 13C NMR spectrum confirm the formation of 4b and 4d.
The reactivities of aromatic alcohols depend on the substitution on
the aromatic ring, and it is observed that the presence of electron-
releasing groups increase the rate of the reaction. The anomeric
proton appears as a doublet at d 5.13 (d, J 7.5 Hz), 5.07 (d, J
7.5 Hz), 5.08 (d, J 7.2 Hz) and 5.28 (broad peak) with a coupling
constant of J ꢁ7.5 Hz, which confirms the b anomeric form in com-
pounds 4e–h.
2. Results and discussion
2.1. Synthesis of 4,6-O-protected O-glycosides (4a–h)
4,6-O-Ethylidene-
D
-glucopyranose (2a) and 4,6-O-butylidene-
D-
glucopyranose (2b) were synthesised from
D
-glucose (1) by adopt-
ing the literature procedures.37,38 These compounds were also
characterised using different spectral techniques. Acetylation of
the acetals 2a and 2b was (Scheme 1) carried out using acetic
anhydride and sodium acetate and resulted in the formation of
the corresponding b-acetylated products 3a and 3b. The strategy
followed in the synthesis of the O-glycosides basically relied on
the difference in the hard and soft basicities of the anomeric and
aglycon alcohol moieties. In general a hard Lewis acid like BF3ꢀEt2O
catalyses the loss of the acetate group from the anomeric carbon
without affecting the other functionalities. Thus, O-glycosylation
of compounds 3a and 3b with aliphatic alcohols (allyl alcohol
The a:b ratio has been calculated from the reaction mixture by
using 1H NMR spectroscopy. However, after purification by column
chromatography, the product obtained was found to be only the b
O
HO
HO
HO
O
O
O
O
O
O
R
OAc BF3·OEt2
OH
R
OH
OR'
O
R
O
O
Ac2O
Ref. 37, 38
AcO
HO
AcO
NaOAc
Et3N, R'OH
DCM
OH
OAc
OAc
OH
2a
2b
3a R = -CH3
4a-4h
R = -CH3
R = -C3H7
1
( )
R = -C3H7
3b
4a R = -CH3, R' = -C3H5
R = -CH3, R' = -C3H3
4c R = -C3H7, R' = -C3H5
R = -C3H7, R' = -C3H3
4e R = -C3H7, R' = -C6H5
R = -C3H7, R' = -C7H7
4g R = -C3H7, R' = -C8H9
R = -C3H7, R = -4-NO2-C6H4
4b
4d
4f
4h
Scheme 1. Synthesis of O-glycosyl derivatives (4a–h).

R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
1651
Table 1
Synthesis of O-glycosyl derivatives 4a–h
Entry Glycosyl donor (3a, b)
Glycosyl acceptor (R1–OH) Coupled product (4a–h)
Selectivity ratioa (%) Time (h) Isolated yield (%)
CH
3 O
CH
3 O
HO
H
H
H
O
O
O
O
OAc
OAc
O
O
AcO
AcO
1
b-only
5
54
OAc
OAc
3a
3a
4a
CH
CH
3 O
3 O
HO
HO
H
O
O
O
O
AcO
AcO
2
b-only
7
70
OAc
OAc
4b
CH3
CH3
O
O
O
O
H
H
O
O
3
b-only
6
67
O
O
OAc
OAc
O
O
AcO
AcO
OAc
OAc
4c
3b
CH3
CH3
HO
H
H
O
O
O
O
4
b-only
8
72
AcO
AcO
OAc
OAc
3b
4d
CH3
CH3
OH
O
O
H
H
O
O
O
O
5
46:53
10
45
OAc
O
O
O
AcO
AcO
OAc
OAc
3b
4e
CH3
OH
CH3
O
O
H
H
O
O
O
O
CH3
6
OAc
36:64
12
42
AcO
AcO
OAc
OAc
CH3
3b
4f
CH3
OH
CH3
O
O
H
H
O
O
O
O
OAc
7
AcO
b-only
18
49
AcO
CH3
OAc
OAc
CH3
4g
3b
(continued on next page)

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R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
Table 1 (continued)
Entry Glycosyl donor (3a, b)
CH3
Glycosyl acceptor (R1–OH) Coupled product (4a–h)
Selectivity ratioa (%) Time (h) Isolated yield (%)
CH3
OH
O
H
O
H
O
OAc
O
O
AcO
O
O
OAc
AcO
NO2
8
b-only
45
43
OAc
3b
NO2
4h
a
The a
:b ratio was calculated before column chromatographic purification based on 1H NMR studies.
anomer. Due to an apparent low stability, the
decompose during the chromatographic purification. For com-
pounds 4e and 4f the observed
:b ratio was analysed using 1H
NMR spectroscopy. The peaks observed for compound 4e at d
ꢁ5.34 and 5.89 correspond to an :b ratio of 46:53, whereas, in
case of compound 4f, the peaks were observed at d ꢁ5.67 and
5.16 with an :b ratio of 36:64.
a
isomer may
mL. A change in colour in the microwell plate was observed ini-
tially (pink to yellow), which indicates positive antioxidant activi-
ties for the tested compounds (see Supplementary data for further
details). It has been observed that the activity increases propor-
tionately with the increase in concentration; thus compound 4d
shows more activity compared to the other derivatives (Fig. 3).
The influence of an aromatic alcohol coupled with glycosyl moiety
is greater when compared to an aliphatic alcohol, which may be
due to the facile release of a hydride radical from the substrate.
The O-glycosyl derivative 4d with a propargyl group as the agly-
con shows comparatively higher activity among the other com-
pounds evaluated. Electron-releasing groups attached at the para
position of the phenol derivative that has a longer alkyl chain show
maximum inhibitory activity (77.3%), whereas the derivatives
without an alkyl chain show only moderate activity (32.3%). From
this it is evident that the antioxidant activity of a 4,6-O-protected
a
a
a
2.2. Synthesis of sugar triazole derivatives (6a, b)
-glucopyranose39 is used for the synthesis of
Per-O-acetylated-
glycosyl azide 5a through
D
a
-acetobromoglucose40 by adopting the
literature procedure.41–45 The 1,3-dipolar cycloaddition reaction
(DCR) between azide and terminal alkynes (Scheme 2) has been
accelerated by the addition of Cu(II) sulfate pentahydrate and so-
dium ascorbate in tert-butanol, which results in the formation of
triazole derivatives 6a and 6b. Thus the reaction between per-O-
D-glucopyranose coupled with an aromatic unit possessing a
acetylated-
D
-glucopyranosyl azide (5a) with 2-propyn-1-yl 2,3-
-glucopyranose
hydrophobic alkyl chain17 increases the antioxidant activity.
In conclusion, we have synthesised a series of novel 4,6-O-pro-
tected alkyl and aryl glycosides using BF3ꢀEt2O as the Lewis acid
catalyst in high yield with good selectivity, providing a convenient
method for constructing protected O-glycosides. The b-configura-
tion of the O-glycosides was determined by NMR spectroscopy
and single-crystal XRD analysis. The 1,3-dipolar cycloaddition
reaction between glycosyl azides and 4,6-O-protected glycosyl ter-
minal alkynes resulted in the formation of 1,4-disubstituted disac-
charides in good yield. The preliminary biological evaluation of
these compounds showed weak to moderate antioxidant activities
with the maximum inhibitory activity of 77.3%.
tri-O-acetyl-4,6-O-ethylidene and -butylidene-b-
D
(4b and 4d) gives the corresponding 1,4-substituted triazoles
Table 2 (6a and 6b) in good yield (78–85%). Appearance of a singlet
at d ꢁ7.8 in the 1H NMR spectrum and peaks at d ꢁ122.0 and 142.0
in the 13C NMR spectrum confirms the formation of the triazole
ring. The doublets that appear at d ꢁ5.87 (d, J 8.1 Hz) and ꢁ5.80
(d, J 9.0 Hz) in the triazole derivatives (6a and 6b) confirm the b
anomeric configuration.
2.3. Biological activities
Sugar derivatives 4a–h were assessed for their capacity to
prevent the formation of 1,1-diphenyl-2-picrylhydrazide (DPPH)
peroxide radicals in a peroxy-generating system as described in
Section 3. The antioxidant activities of all the compounds are
shown in Table S1 in Supplementary data. Except for the 4,6-O-
protected acetylated derivatives 3a and 3b, all the other deriva-
tives exhibit antioxidant activity. However, when the sugar
moieties are coupled with aglycon motifs such as aliphatic and
aromatic alcohols, the resulting O-glycosides show moderate activ-
3. Experimental section
3.1. General methods
D-Glucose, butyraldehyde, paraldehyde, BF3ꢀEt2O and other
alcohols are obtained from SRL, Chennai, Tamil Nadu, India. Acetic
anhydride was purchased from Fischer Chemicals Pvt. Ltd, Chennai,
Tamil Nadu, India. Column chromatography was performed on sil-
ica gel (100–200 mesh). Melting points were measured on a Sigma
micro melting point apparatus and are uncorrected. NMR spectra
ity (Fig. 2) when compared to standard
D
-ascorbic acid which
g/
shows the activity of 92% at a minimum concentration of 20
l
R
H
CuSO4. 5H2O, Sodium ascorbate
R
+
R' N N N
N
N
tert-butanol
R'
N
4b 4d
,
5a
6a-b
Scheme 2. Synthesis of a disaccharide linked through a triazole ring (6a and 6b).

R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
1653
Table 2
Synthesis of a disaccharide linked through a triazole (6a and b)
Entry
R
R0
Triazole product
Time (h)
Yield (%)
CH
O
H
AcO
AcO
AcO
3 O
O
O
AcO
OAc
OAc
O
OAc
AcO
O
N3
H
AcO
O
O
N
N
N
O
O
O
N
N
1
O
O
28
78
CH3
AcO
OAc
OAc
H
OAc
5a
5a
6a
4b
CH3
H
AcO
AcO
AcO
AcO
AcO
AcO
O
OAc
N3
O
O
N
O
O
H
OAc
OAc
O
H
H3C
2
23
85
O
AcO
6b
OAc
4d
are given in hertz. UV–vis absorbance was measured at 517 nm
using a Beckman DU-40 UV–vis spectrophotometer at the Univer-
sity of Madras (Chennai, Tamil Nadu, India). Elemental analyses
were performed using a Perkin–Elmer 2400 elemental analyser at
IIT Bombay (Powai, Maharastra, India). Single-crystal XRD studies
were performed using a Bruker axs (kappa apex 2) analyser at IIT
Madras (Chennai, Tamil Nadu, India).
4a
80
70
60
50
40
30
20
10
0
4b
4c
4d
4e
4f
4g
4h
3.2. Preparation of 4,6-O-ethylidene-
D-glucopyranose (2a) and
4,6-O-butylidene- -glucopyranose (2b)
D
Published procedures for 2a37 and 2b38 were used.
3.2.1. 4,6-O-Ethylidene- -glucopyranose (2a)
D
White solid; mp 178–180 °C; (lit.37 179–181 °C); 1H NMR
(300 MHz, CDCl3): dY 6.53 (d, J 3.3 Hz, 1H), 5.08–5.18 (m, 2H),
4.70–4.74 (m, 1H), 4.50–4.54 (m, 1H), 3.97–4.08 (m, 1H), 3.37–
3.53 (m, 2H), 3.28–3.42 (m, 1H), 3.15–3.22 (m, 2H), 1.32 (t, J
4.8.Hz, 3H). 13C NMR (75 MHz, CDCl3) dC 97.2, 96.7, 83.8, 79.2,
76.3, 72.9, 69.0, 20.0.
200
400
600
800
1000
Concentration (µg/mL)
3.2.2. 4,6-O-Butylidene-D-glucopyranose (2b)
White solid; mp 161–163 °C; (lit.38 164–165 °C); 1H NMR
(300 MHz, CDCl3 dY 5.14 (d, J 3.6 Hz, 1H), 4.54–4.58 (m, 1H),
4.03–4.11 (m, 2H), 3.76–3.88 (m, 2H), 3.50–3.60 (m, 2H), 3.43–
3.47 (m, 1H), 3.17–3.30 (m, 2H), 1.58–1.62 (m, 2H), 1.40–1.47
(m, 2H), 0.93 (t, J 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) dC 100.8,
96.7, 84.1, 79.2, 76.3, 72.9, 69.3, 36.6, 14.4, 13.2.
Figure 2. Percentage inhibition of compounds 4a–h.
3.3. Synthesis of 1,2,3-tri-O-acetyl-4,6-O-ethylidene-b-D-
glucopyranose (3a) and 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-
glucopyranose (3b)
To a stirred suspension of anhyd NaOAc (2 g, 243 mmol) in Ac2O
(12.5 mL, 132 mmol) heated on a boiling water bath for about 10–
15 min, 4,6-O-ethylidene-D-glucopyranose (2a) (2.5 g, 12.13 mmol)
was added slowly. The reaction mixture was heated for 1 h, and the
contents were then poured into ice water and stirred. The resulting
precipitate 3a was filtered off, washed with water and dried. A
similar procedure was adopted for the synthesis of compound 3b.
Figure 3. Change in colour intensity of 4d in different concentrations (
control (b) 200 (c) 400 (d) 600 (e) 800 and (f) 1000.
lg/mL) (a)
3.3.1. 1,2,3-Tri-O-acetyl-4,6-O-ethylidene-b-D-glucopyranose
were recorded on Bruker DRX 300-MHz instrument in CDCl3 or
DMSO-d6 at the University of Madras (Chennai, Tamil Nadu, India).
TMS was used as the internal standard (d = 0.00) and all the J values
(3a)
White solid (3.42 g, 85%); mp 100–102 °C; 1H NMR (300 MHz,
CDCl3): dY 5.74 (d, J 8.1 Hz, 1H), 5.06 (t, J 8.4 Hz, 1H), 5.22–5.28

1654
R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
(m, 1H), 4.65–4.70 (m, 1H), 4.20–4.22 (m, 1H), 3.46–3.53 (m, 3H),
2.09 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 1.33 (d, J 5.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dC 169.0, 169.4, 168.8, 102.7, 99.8, 92.2, 78.2,
71.8, 71.3, 67.8, 20.6 (3C), 19.8.
3.38–3.48 (m, 2H), 2.04 (s, 3H), 2.05 (d, 3H), 1.56–1.61 (m, 2H),
1.34–1.41 (m, 2H), 0.88 (t, J 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
dC 170.2, 169.6, 133.3, 117.5, 102.6, 100.2, 78.0, 72.1, 71.9, 70.2,
68.1, 66.5, 36.0, 20.7 (2C), 17.4, 13.8. Anal. Calcd for C17H26O8: C,
56.97; H, 7.31. Found: C, 57.31; H, 7.15.
3.3.2. 1,2,3-Tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose
(3b)
3.4.4. 2-Propyn-1-yl 2,3-di-O-acetyl-4,6-O-butylidene-b-D-
glucopyranoside (4d)
From 4,6-O-butylidene-D-glucopyranose (2b) (2.5 g, 10.60
mmol) using anhyd NaOAc (2 g, 243 mmol) in Ac2O (12.5 mL,
132 mmol).
From 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
(3.60 g, 10 mmol), propargyl alcohol (0.84 mL, 15 mmol) and BF3ꢀ
White solid (3.56 g, 90%); mp 110–112 °C;. 1H NMR (300 MHz,
CDCl3): dH 5.67 (d, J 3.6 Hz, 1H), 4.96–5.03 (m, 1H), 4.60 (m, 1H),
4.14–4.44 (m, 2H), 4.05–4.19 (m, 1H), 3.38–3.84 (m, 2H), 2.02 (s,
3H),1.99 (s, 3H), 1.56 (m, 2H), 1.34 (m, 2H), 0.85 (t, J 8 Hz, 3H).
13C NMR (75 MHz, CDCl3): dC 169.9 169.4, 168.8, 102.7, 92.2,
71.8, 71.2, 67.8, 67.1, 35.9, 20.6, 20.5, 17.3, 13.7.
OEt2 (3.52 mL, 25 mmol).
White solid (2.56 g, 72%); mp 102–104 °C; 1H NMR (300 MHz,
CDCl3): dH 5.15 (t, J 9.3 Hz, 1H), 4.88 (t, J 8.1 Hz, 1H), 4.72 (d, J
7.8 Hz, 1H), 4.43 (t, J 5.1 Hz, 1H), 4.27 (d, J 2.4 Hz, 2H), 4.11–
4.16 (m, 1H), 3.31–3.51 (m, 3H), 2.39 (t, J 2.4 Hz, 1H), 1.99 (d,
6H), 1.51–1.54 (m, 2H), 1.30–1.37 (m, 2H), 0.82 (t, J 7.5 Hz,
3H). 13C NMR (75 MHz, CDCl3): dC 170.1, 169.7, 102.6, 98.9,
78.2, 77.9, 76.6, 75.4, 71.8, 71.9, 68.0, 66.6, 56.1, 36.0, 20.7,
17.4, 13.8. Anal. Calcd for C17H24O8: C, 57.30; H, 6.79. Found:
C, 57.18; H, 6.93.
3.4. General method of synthesis of O-glycosides (4a–h)
To a mixture of 4,6-O-protected-1,2,3-tri-O-acetyl-b-D-gluco-
pyranose (3a–b, 10 mmol) and the alcohol (15 mmol) under
nitrogen atmosphere was added Et3N (5 mmol) in DCM (20 mL)
followed by BF3ꢀOEt2 (25 mmol) in DCM (5 mL) over 30 min. The
reaction mixture was then kept stirring until the TLC showed com-
pletion of the reaction. A Satd aq NaHCO3 (20 mL) was added, and
the reaction mixture was then extracted with EtOAc (30 mL ꢂ 2).
The organic layer was dried over anhyd MgSO4 followed by column
chromatographic purification on silica gel to give the correspond-
ing O-glycosides (4a–h).
3.4.5. Phenyl 2,3-di-O-acetyl-4,6-O-butylidene b-D-gluco-
pyranoside (4e)
From 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
(3.60 g, 10 mmol), phenol (1.41 mL, 15 mmol) and BF3ꢀOEt2 (3.52 mL,
25 mmol).
White solid (1.84 g, 45%); mp 156–158 °C; 1H NMR (300 MHz,
CDCl3): dH 7.27–7.33 (m, 2H), 7.05–7.10 (m, 1H), 6.96–6.99 (m,
2H), 5.20–5.32 (m, 2H), 5.13 (d, J 7.5 Hz, 1H), 4.53 (t, J 5.1 Hz,
1H), 4.22–4.26 (m, 1H), 3.49–3.63 (m, 3H), 2.06 (s, 6H), 1.60 (m,
2H), 1.35–1.45 (m, 2H), 0.89 (t, J 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dC 170.2, 169.6, 156.9, 129.6 (2C), 123.4, 117.0 (2C),
102.7, 99.6, 77.8, 72.0, 71.8, 68.0, 66.7, 36.0, 20.7 (2C), 17.4, 13.8.
Anal. Calcd for C20H26O8: C, 60.90; H, 6.64. Found: C, 61.32; H, 6.84.
3.4.1. 2-Propen-1-yl 2,3-di-O-acetyl-4,6-O-ethylidene-b-D-
glucopyranoside (4a)
From 1,2,3-tri-O-acetyl-4,6-O-ethylidene-b-D-glucopyranose (3a)
(3.32 g, 10 mmol), allyl alcohol (0.97 mL, 15 mmol) and BF3ꢀOEt2
(3.52 mL, 25 mmol).
White solid (1.78 g, 54%); mp 118–120 °C. 1H NMR (300 MHz,
CDCl3): dH 5.18–5.30 (m, 1H), 4.94–5.00 (m, 3H), 4.67–4.70 (m,
1H), 4.57 (d, J 7.8 Hz, 1H), 4.28–4.35 (m, 1H), 4.07–4.21 (m, 3H),
3.53–3.61 (m, 3H), 2.17 (s, 3H), 2.06 (s, 3H) 1.32 (d, J 4.8 Hz, 3H).
13C NMR (75 MHz, CDCl3,): dC 170.2, 169.5, 133.3, 117.9, 100.2,
99.7, 77.9, 72.3, 71.9, 70.1, 66.30, 62.5, 20.8 (2C), 20.7, 20.2. Anal.
Calcd for C15H22O8: C, 54.54; H, 6.71. Found: C, 54.72; H, 6.94.
3.4.6. 4-Methylphenyl 2,3-di-O-acetyl-4,6-O-butylidene b-D-
glucopyranoside (4f)
From 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
(3.60 g, 10 mmol), p-methylphenol (1.62 mL, 15 mmol) and BF3ꢀOEt2
(3.52 mL, 25 mmol).
White solid (1.78 g, 42%); mp 146–148 °C; 1H NMR (300 MHz,
CDCl3): dH 7.07–7.10 (m, 2H), 6.82–6.88 (m, 2H), 5.17–5.31 (m,
2H), 5.07 (d, J 7.5 Hz, 1H), 4.52 (t, J 5.1 Hz, 1H), 4.20–4.25 (m,
1H), 3.43–3.62 (m, 3H), 2.30 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H)
1.58–1.62 (m, 2H), 1.32–1.42 (m, 2H), 0.89 (t, J 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3): dC 170.3, 169.6, 154.8, 132.9, 130.1, 127.5,
117.0, 115.6, 102.7, 100.0, 77.8, 72.1, 71.9, 68.1, 66.7, 36.0, 20.8,
20.7, 20.6, 17.4, 13.9. Anal. Calcd for C21H28O8: C, 61.75; H, 6.91.
Found: C, 61.41; H, 7.22.
3.4.2. 2-Propyn-1-yl 2,3-di-O-acetyl-4,6-O-ethylidene-b-D-
glucopyranoside (4b)
From 1,2,3-tri-O-acetyl-4,6-O-ethylidene-b-D-glucopyranose (3a)
(3.32 g, 10 mmol), propargyl alcohol (0.84 mL, 15 mmol) and BF3ꢀ
OEt2 (3.52 mL, 25 mmol).
White solid (2.30 g, 70%); mp 136–138 °C; 1H NMR (300 MHz,
CDCl3): dH 5.24 (t, J 9.3 Hz, 1H), 4.92–4.98 (t, J 9.0 Hz, 1H), 4.78
(d, J 7.8 Hz, 1H), 4.65–4.70 (q, J 4.8 Hz, 1H), 4.34–4.35 (s, 2H),
4.17–4.22 (m, 1H), 3.53–3.60 (m, 1H), 3.39–3.50 (m, 2H), 2.47 (t,
J 2.4 Hz, 1H), 2.04 (s, 3H), 2.06 (s, 3H), 1.32 (d, J 4.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): dC 170.2, 169.7, 99.7, 98.8, 78.1, 77.8,
75.4, 72.0, 71.8, 68.0, 66.4, 56.1, 20.8 (2C), 20.2. Anal. Calcd for
3.4.7. 4-Ethylphenyl 2,3-di-O-acetyl-4,6-O-butylidene-b-D-
glucopyranoside (4g)
From 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
(3.60 g, 10 mmol), p-ethylphenol (1.83 mL, 15 mmol) and BF3ꢀOEt2
C15H20O8: C, 54.87; H, 6.14. Found: C, 54.41; H, 5.96.
(3.52 mL, 25 mmol).
White solid (2.15 g, 49%); mp 122–124 °C; 1H NMR (300 MHz,
CDCl3): dH 7.10–7.13 (m, 2H), 6.88–6.91 (m, 2H), 5.18–5.31 (m,
2H), 5.08 (d, J 7.2 Hz, 1H), 4.52 (t, J 5.1 Hz, 1H), 4.20–4.25 (m,
1H), 3.50–3.62 (m, 3H), 2.56–2.61 (q, J 7.5 Hz, 2H), 2.04 (s, 3H),
2.07 (s, 3H), 1.59–1.62 (m, 2H), 1.35–1.45 (m, 2H), 1.19 (t, J
7.5 Hz, 3H), 0.89 (t, J 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): dC
170.2, 169.6, 154.9, 139.3, 128.8 (2C), 117.0 (2C), 102.7, 100.0,
77.8, 72.1, 71.9, 68.1, 66.7, 36.0, 28.1, 20.7 (2C), 17.4, 15.7, 13.8.
Anal. Calcd for C22H30O8: C, 62.55; H, 7.16. Found: C, 62.73; H, 7.45.
3.4.3. 2-Propen-1-yl 2,3-di-O-acetyl-4,6-O-butylidene-b-D-
glucopyranoside (4c)
From
1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose
(3b) (3.60 g, 10 mmol), allyl alcohol (0.97 mL, 15 mmol) and
BF3ꢀOEt2 (3.52 mL, 25 mmol).
White solid (2.39 g, 67%); mp 120–124 °C; 1H NMR (300 MHz,
CDCl3): dH 5.77–5.90 (m, 1H), 5.17–5.33 (m, 3H), 4.93–5.00 (m,
1H), 4.57 (d, J 7.8 Hz, 1H), 4.49 (t, J 5.1 Hz, 1H), 4.29–4.35 (m,
1H), 4.17–4.22 (m, 1H), 4.05–4.11 (m, 1H), 3.50–3.59 (m, 1H),

R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
1655
3.4.8. 4-Nitrophenyl 2,3-di-O-acetyl-4,6-O-butylidene b-
D
-
3H). 13C NMR: (75 MHz, CDCl3): dC 170.5, 169.8, 169.7, 169.4,
glucopyranoside (4h)
86.5, 72.1, 70.6, 70.2, 67.2, 60.9, 20.6 (2C), 20.6, 20.5
From 1,2,3-tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
(3.60 g, 10 mmol), p-nitrophenol (2.85 g, 15 mmol) and BF3ꢀOEt2
3.5.3. 2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl azide (5a)
(3.52 mL, 25 mmol).
White solid; (0.350 g, 83%); mp 124–126 °C (lit.42 126–127 °C);
1H NMR (300 MHz, CDCl3): dH 5.18–5.00 (m, 2H), 4.86–4.92 (m,
1H), 4.56 (d, J 9.0 Hz, 1H), 4.18–4.24 (m, 2H), 3.70–3.76 (m, 1H),
2.04 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H) 13C NMR:
(75 MHz, CDCl3): dC 170.6, 170.1, 169.3, 169.2, 87.9, 74.0, 72.6,
70.7, 67.9, 61.7, 20.6, 20.5 (2C), 20.4.
Pale-yellow solid (1.95 g, 43%); mp 178–180 °C;. 1H NMR
(300 MHz, CDCl3): dH 8.20–8.23 (d, J 9.3 Hz, 2H), 7.04–7.07 (d, J
9.0 Hz, 2H), 5.25–5.28 (br, 3H), 4.53 (t, J 5.1 Hz, 1H), 4.24–4.26
(m, 1H), 3.57–3.58 (br, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 1.60 (m,
2H), 1.36–1.43 (m, 2H), 0.90 (t, J 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): dC 170.1, 169.4, 161.1, 143.2, 125.9 (2C), 116.6 (2C),
102.8, 98.6, 77.8, 71.8, 71.6, 67.9, 67.0, 35.9, 20.7, 20.6, 17.3,
13.8. Anal. Calcd for C20H25NO10: C, 54.67; H, 5.73; N, 3.19. Found:
C, 54.50; H, 5.98, N, 2.91.
3.5.4. 4-(Methyl 2,3,di-O-acetyl-4,6-O-ethylidene-b-D-
glucopyranosyl)-1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
1,2,3-triazole (6a)
White solid; (0.65 g, 78%); mp 140–142 °C; 1H NMR (300 MHz,
CDCl3): dH 7.78 (s, 1H); 5.87 (d, J 8.1 Hz, 1H), 5.37–5.47 (m, 2H),
5.16–5.27 (m, 2H), 4.89–4.96 (m, 2H), 4.67–4.79 (m, 2H), 4.58 (d,
J 7.8 Hz, 1H) 4.12–4.34 (m, 4H), 4.01 (br s, 1H), 3.55–3.62 (m,
2H), 3.44–3.55 (m, 3H), 2.1 (s, 6H,), 2.0 (s, 3H), 1.97 (s, 3H), 1.91
(s, 3H), 1.33 (t, 3H). 13C NMR (75 MHz, CDCl3): dC 170.4, 170.2,
169.9, 169.6, 169.3, 169.0 144.3, 121.7, 99.7, 99.3, 85.8, 78.0,
75.2, 72.4, 72.1, 71.7, 70.3, 68.0, 67.7, 66.3, 61.8, 61.5, 20.8 (2C),
20.6 (2C), 20.5, 20.2, 20.1. Anal. Calcd for C29H39N3O17: C, 49.64;
H, 5.60; N, 5.99. Found: C, 50.03; H, 5.94; N, 5.71.
3.5. Synthesis of sugar triazole disaccharides (6a, b)
The 2,3,4,6-tetra-O-acetyl-b-
(0.39 g, 1.2 mmol) and 2-propyn-1-yl 2,3-di-O-acetyl-4,6-O-ethyli-
dene-b- -glucopyranoside (4b) (0.344 g, 1.0 mmol) were sus-
D
-glucopyranosyl azide41–45 (5a)
D
pended in 1:1 t-BuOH–H2O (20 mL). Then CuSO4ꢀ5H2O (0.02 g,
2 mmol) and sodium ascorbate (0.04 g, 4 mmol) in 5 mL of distilled
water were added. The deep-yellow suspension was stirred at
40 °C for 16–30 h (monitored by TLC). After the reaction was com-
plete DCM (2 ꢂ 10 mL) was added to extract the product. The com-
bined organic layers were washed with brine and dried over anhyd
MgSO4 to afford crude solid residue 6a, which was further purified
by column chromatography. A similar procedure was adapted for
the synthesis of compound 6b.
3.5.5. 4-(Methyl 2,3,di-O-acetyl-4,6-O-butylidene-b-D-
glucopyranosyl)-1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
1,2,3-triazole (6b)
From 2,3,4,6-tetra-O-acetyl-b-
(0.39 g, 1.2 mmol), 2-propyn-1-yl 2,3-di-O-acetyl-4,6-O-butyli-
dene-b- -glucopyranoside (4d) (0.372 g, 1.0 mmol).
D-glucopyranosyl azide (5a)
3.5.1. 1,2,3,4,6-Penta-O-acetyl-
a
-D
-glucopyranose
D
White solid; mp 110–112 °C, (lit.39 mp 112–114 °C) 1H NMR
(300 MHz, CDCl3): dH 6.33 (d, J 3.6 Hz, 1H), 5.44–5.50 (m, 1H),
5.07–5.12 (m, 2H), 4.24–4.28 (m, 1H), 4.07–4.14 (m, 2H), 2.18 (s,
3H) 2.09 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H). 13C NMR:
(75 MHz, CDCl3): dC 170.6, 170.2, 169.6, 169.4, 168.7, 91.7, 89.1,
72.8, 69.8, 67.8, 61.5, 20.8, 20.7, 20.6, 20.5, 20.4
White solid (0.74 g, 85%); mp 148–150 °C; 1H NMR (300 MHz,
CDCl3): dH 7.71 (s, 1H), 5.80 (d, J 9.0 Hz, 2H), 5.30–5.40 (m, 2H),
5.08–5.20 (m, 2H), 4.82–4.90 (m, 2H), 4.50–4.52 (d, J 7.8 Hz, 1H),
4.43 (t, J 5.1 Hz, 1H), 4.15–4.27 (dd, 2H), 4.04–4.08 (m, 1H),
3.92–4.0 (m, 1H), 3.47–3.53 (m, 1H), 3.35–3.38 (m, 2H), 2.02 (s,
3H), 2.0 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.90 (s, 3H), 1.84 (s,
3H) 1.49–1.54 (m, 2H), 1.26–1.1.34 (m, 2H), 0.82 (t, J 7.5 Hz, 3H).
13C NMR (75 MHz, CDCl3): dC 170.4, 170.1, 169.8, 169.6, 169.3,
169.0, 144.3, 121.7, 102.6, 99.4, 85.8, 78.02, 75.2, 72.4, 71.9, 71.7,
70.3, 68.1, 67.7, 66.5, 61.9, 61.5, 36.0, 20.7,(2C), 20.6 (2C), 20.5,
20.1, 17.40, 13.79. Anal. Calcd for C31H43N3O17: C, 51.03; H, 5.94;
N, 5.76. Found: C, 51.45, H, 6.10, N, 6.15.
3.5.2. 2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl bromide
White solid; mp 86–88 °C, (lit.40 mp 84–86 °C) 1H NMR
(300 MHz, CDCl3): dH 6.54 (d, J 3.9 Hz, 1H), 5.45–5.52 (m, 1H),
5.063–5.128 (m, 1H), 4.75–4.79 (dd, 1H), 4.20–4.24 (m, 2H),
4.03–4.08 (m, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.97 (s,
Figure 4. (a) ORTEP plot of 3b showing atom numbering scheme, (b) its stereoview showing 50% probability thermal ellipsoids using ORTEP.

1656
R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
Table 3
C–Hꢀ ꢀ ꢀO hydrogen bonds (Table 3). The inter- and intramole-
Hydrogen bonds for compound 3b (A and deg.)a
cular hydrogen-bond distances are within the limits of standard
deviation. The packing of the molecule in the unit cell is shown in
D–Hꢀ ꢀ ꢀA
d(D–H)
#1
d(Hꢀ ꢀ ꢀA)
2.55
d(Dꢀ ꢀ ꢀA)
3.44
3.27
3.54
3.35
\(DHA)
150.9
130.9
169.6
148.0
0.980
0.970
0.980
0.960
Figure 5. Crystal data for 3b: C16H24O9, MW = 360.35, orthorhombic,
0
a = 8.1488 (6), b = 11.3622 (8), c = 20.5491 (12) ÅA, V = 1902.6 (2) Å3,
#2
2.55
#3
2.57
T = 293 (2) K, space group P212121,
reflections measured, 2618 unique (Rint = 0.0326), R(I > 2.00
0.0504), Rw (I > 2.00 (I)) = 0.1264.
2-Propen-1-yl 2,3-di-O-acetyl-4,6-O-ethylidene-b-
l (Mo Ka
) = 0.103 mmꢃ1, 9005
#4
2.50
r(I)) =
C(3)–H(3)ꢀ ꢀ ꢀO(3)#1, C(7)–H(7A)ꢀ ꢀ ꢀO(5)#2.
r
C(2)–H(2)ꢀ ꢀ ꢀO(7)#3, C(12)–H(12C)ꢀ ꢀ ꢀO(9)#4.
D-glucopy-
a
Symmetry transformations used to generate equivalent atoms: #1 x ꢃ 1/2,
ꢃy + 1/2, ꢃz, #2 x + 1, y, z, #3 x + 1/2, ꢃy ꢃ 1/2, ꢃz, #4 ꢃx + 1/2, ꢃy, z + 1.
ranoside (4a) crystallises in an orthorhombic lattice with space
group P212121 in EtOH. An ORTEP view of molecule 4a is shown
in Figure 6a. A stereoview of this molecule, Figure 6b, supports
the presence of the saccharide in the 4C1 conformation along with
its b anomeric form. The presence of the b anomeric form of the
saccharide moiety is further confirmed from the torsional angles
[O(4)–C(4)–O(3)–C(3) = ꢃ179.82°(17)] and [O(3)–C(4)–C(5)–O(5) =
ꢃ175.35°(16)]. The inter- and intramolecular hydrogen-bond dis-
tances are within the limits of standard deviation. The packing of
the molecule in the unit cell is shown in Figure 7. Crystal data
for 4a: C15H21O8, MW = 329.32, orthorhombic, a = 8.7198 (8),
0
b = 11.3622 (8), c = 18.8915(16) ÅA, V = 1720.2(3) Å3, T = 293 (2) K,
space group P212121,
measured, 4241 unique (Rint = 0.0222), R(I > 2.00
Rw (I > 2.00 (I)) = 0.1069.
l (Mo Ka
) = 0.104 mmꢃ1, 11048 reflections
r(I)) = 0.0455),
r
Figure 5. Packing of the molecule, 3b in the unit cell.
3.6. Single-crystal X-ray crystallographic analysis of 3b and 4a
1,2,3-Tri-O-acetyl-4,6-O-butylidene-b-D-glucopyranose (3b)
crystallises in an orthorhombic lattice with space group P212121 in
EtOH. An ORTEP view of the molecule 3b is shown in Figure 4a. A
stereoview of this molecule (Fig. 4b) supports the presence of the
saccharide in the 4C1 conformation along with its b anomeric form.
The presence of the b anomeric form of the saccharide moiety
in compound 3b is also confirmed from the torsional angles,
[O(8)–C(5)–O(2)–C(6) = ꢃ176.4°(2)] and [O(8)–C(5)–C(4)–C(13) =
ꢃ168.9°(3)]. The molecule is stabilised through intermolecular
Figure 7. Packing of the molecule 4a in the unit cell.
Figure 6. (a) ORTEP plot of 4a showing atom numbering scheme, (b) its stereoview showing 50% probability thermal ellipsoids using ORTEP.

R. Rajaganesh et al. / Carbohydrate Research 345 (2010) 1649–1657
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Acknowledgements
T.M. acknowledges financial support from the CSIR, New Delhi.
We thank SAIF, IIT Madras, Chennai, for crystallographic data col-
lection and Dr. Babu Varghese, IIT Madras, Chennai, for interpreting
the crystallographic data. We also thank DST, New Delhi, for a
300 MHz NMR spectrometer under FIST scheme to the Department
of Organic Chemistry, University of Madras, Chennai.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.04.020. Full crys-
tallographic details, have been deposited with Cambridge Crystal-
lographic Data Centre for structure 3a (CCDC 665413) and (CCDC
757968) for 4a. These data may be obtained, on request from The
Director, CCDC, 12 Union Road, Cambridge CBZ 1EZ, UK. (Email: de-
posit@cdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
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