Facile synthesis of a pentasaccharide repeating unit corresponding to the common O-antigen of Salmonella enterica O57 and Escherichia coli O51

Article abstract of DOI:10.1016/j.tetasy.2013.04.001

A concise chemical synthetic strategy has been developed for the synthesis of a pentasaccharide present in the O-antigen of Salmonella enterica O57 and Escherichia coli O51 strains. A sequential glycosylation strategy has been adopted for the synthesis of the target pentasaccharide. All intermediate steps are high yielding and the glycosylation steps are stereoselective. A number of recently developed methodologies have been used in the synthesis.

Full text of DOI:10.1016/j.tetasy.2013.04.001

Tetrahedron: Asymmetry 24 (2013) 606–611
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Facile synthesis of a pentasaccharide repeating unit corresponding
to the common O-antigen of Salmonella enterica O57 and Escherichia coli O51
⇑
Tamashree Ghosh , Abhishek Santra , Anup Kumar Misra
Bose Institute, Division of Molecular Medicine, P-1/12, C.I.T. Scheme VII-M, Kolkata 700054, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 March 2013
Accepted 8 April 2013
A concise chemical synthetic strategy has been developed for the synthesis of a pentasaccharide present
in the O-antigen of Salmonella enterica O57 and Escherichia coli O51 strains. A sequential glycosylation
strategy has been adopted for the synthesis of the target pentasaccharide. All intermediate steps are high
yielding and the glycosylation steps are stereoselective. A number of recently developed methodologies
have been used in the synthesis.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
the host. Due to the emergence of multi-drug resistance in bacterial
strains, the development of newer approach to combat bacterial
Diarrheal infections are a leading cause of deaths of children
and elderly people in developing countries where sanitation is
not adequate.1,2 Most of the diarrheal outbrakes spread through
contaminated food and water.3,4 Microorganisms associated with
the gastrointestinal infections include Salmonella enterica (S. enteri-
ca), enteropathogenic Escherichia coli (E. coli), and Shigella strains.5–7
Salmonella enterica is considered as a leading pathogen for the out-
breaks of food-borne infections in animals and humans in many
countries.8 Major sources of salmonellosis in humans are S. enterica
infected poultry products and cattle.9 Diarrhea causing S. enterica
strains are divided into several serovars with similar virulence
features.10 Virulent E. coli strains are also important pathogens
responsible for diarrheal outbreaks.11 Diarrhea causing E. coli strains
are divided into several pathotypes, which include enteropatho-
genic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasive
E. coli (EIEC), enterohemorrhagic E. coli (EHEC), enteroaggregative
E. coli (EAEC) etc.12 Perepelov et al. characterized the structure of
the pentasaccharide repeating unit of the O-polysaccharide of Sal-
monella enterica O57, which is identical to the repeating unit of the
O-antigen of the enteropathogenic E. coli O51 strain13 (Fig. 1). The
most important component of the cell wall of a Gram-negative bac-
terium for its virulence property is the O-antigen. The O-antigen is a
polysaccharide chain of the cell wall lipopolysaccharides, which
consists of a number of repeating oligosaccharides. The pathogenic
potential of the virulent bacterial strain depends on the structure
of the oligosaccharide repeating units of the O-antigen because of
its presence in the outer layer of the cell wall. The O-antigen plays
an important role in the initial stage of adhesion of the bacteria to
infections is an important area of medicinal chemistry research.
Since cell wall oligosaccharides are directly related to the bacterial
virulence and infections, several studies have appeared in the liter-
ature for the development of antimicrobial agents based on glyco-
conjugates of cell wall oligosaccharides.14–16 Since the repeating
unit of the O-antigen of S. enterica O57 and E. coli O51 is identical
and the pathogenic nature of the two strains is comparable, it would
be worth preparing a glycoconjugate derivative corresponding to
the O-antigen oligosaccharide. However, for the preparation of
glycoconjugate derivatives, it is essential to have enough oligosac-
charides corresponding to the O-antigens. Since a large quantity of
oligosaccharides and their analogues are not accessible from natural
sources, it is pertinent to develop expedient chemical synthetic
strategies for the preparation of oligosaccharides with required
stereochemistry at the glycosyl linkages. Herein, we report a concise
chemical synthetic strategy for the synthesis of the pentasaccharide
repeating unit corresponding to the O-antigen of S. enterica O57 and
E. coli O51 (Fig. 2).
2. Results and discussion
The target pentasaccharide 1 has been synthesized as its 2-(p-
methoxyphenoxy) ethyl glycoside using a sequential glycosylation
approach from suitably protected monosaccharide intermediates
2, 3, 4,17 18, and 6,19 which were prepared from the commercially
5
β-D-GlcpNAc
1
↓
2
→3)-α-L-Rhap-(1→2)-α-L-Rhap-(1→4)-α-D-Glcp-(1→3)-β-D-GalpNAc-(1→
⇑
Corresponding author. Tel.: +91 33 2569 3240; fax: +91 33 2355 3886.
E-mail address: akmisra69@gmail.com (A.K. Misra).
These authors contributed equally to this work.
Figure 1. Structure of the pentasaccharide repeating unit of the O-antigen of
Salmonella enterica O57 and Escherichia coli O51.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.001

T. Ghosh et al. / Tetrahedron: Asymmetry 24 (2013) 606–611
607
OBz
SEt
O
HO
BzO
O
BnO
Ph
SPh
SEt
OBz
BnO
OPMB
OH
HO
O
3
2
O
A
HO
HO
OPMP
HO
O
AcHN
O
O
O
C
HO
O
B
HO
HO
O
O
BnO
O
D
HO
OH
BnO
OH
O
O
OAc
OPMP
N3
5
O
O
HO
HO
O
PMP: p-Methoxyphenyl
4
E
1
Ph
O
NHAc
O
O
SEt
NPhth
AcO
6
Figure 2. Structure of the synthesized pentasaccharide and its synthetic intermediates.
available reducing sugars (Fig. 2). This synthetic strategy has sev-
eral notable features such as, (a) application of iodonium ion med-
iated general glycosylation conditions; (b) a minimum number of
protection–deprotection steps; (c) the use of an ethylene glycol lin-
ker at the anomeric center; (d) application of an ‘armed–disarmed’
glycosylation technique;20 (e) glycosylation and removal of the p-
methoxybenzyl (PMB) group in one-pot;21 and (f) high yield and
stereoselectivity in the glycosylations.
1,2-cis glycosylation of the thioglycoside derivative 10 with com-
pound 4 in the presence of a combination of NIS–TMSOTf25 in
dichloromethane–diethyl ether mixture at a low temperature fol-
lowed by the removal of the p-methoxybenzyl group22 in the
same reaction mixture by increasing the temperature furnished
the trisaccharide acceptor 11 in 78% yield. The formation of com-
pound 11 was confirmed from its spectroscopic analysis [signals
at d 5.00 (d, J = 7.5 Hz, H-1A), 4.85 (d, J = 3.5 Hz, H-1B), 4.49 (br
s, H-1C) in the 1H NMR and d 103.9 (C-1C), 99.3 (C-1A), 96.9 (C-
1B) in the 13C NMR spectra]. The stereoselective glycosylation of
The p-methoxybenzylation of ethyl 3,4-di-O-benzyl-1-thio-
a-L
-rhamnopyranoside 722 using p-methoxybenzyl chloride and
sodium hydroxide furnished ethyl 3,4-di-O-benzyl-2-O-(p-
methoxybenzyl)-1-thio- -rhamnopyranoside in 92% yield
(Scheme 1). Phenyl 2,3-di-O-benzoyl-1-thio-b- -glucopyranoside
23 was selectively benzoylated at the primary hydroxyl group using
benzoyl cyanide and pyridine24 to give phenyl 2,3,6-tri-O-benzoy-
compound 11 with L-rhamnosyl thioglycoside 5 in the presence
a-
L
2
D
of a combination of NIS–TMSOTf in dichloromethane furnished
tetrasaccharide derivative 12 in 76% yield, which upon de-O-acet-
ylation using sodium methoxide gave tetrasaccharide acceptor 13
in 95% yield. The formation of compound 12 was confirmed from
its spectroscopic analysis [signals at d 4.99 (br s, H-1D), 4.95 (d,
J = 7.5 Hz, H-1A), 4.83 (d, J = 3.4 Hz, H-1B), 4.46 (br s, H-1C) in
the 1H NMR and d 103.9 (C-1C), 99.0 (C-1D), 98.9 (C-1A), 96.9
(C-1B) in the 13C NMR spectra]. The 1,2-trans glycosylation of
compound 13 with thioglycoside 6 in the presence of a combina-
tion of NIS–TMSOTf in dichloromethane furnished pentasaccha-
ride 14 in 73% yield. The stereochemistry of the glycosyl
linkages in compound 14 was confirmed from its spectroscopic
analysis [signals at d 5.37 (d, J = 8.5 Hz, H-1E), 4.88 (d, J = 8.0 Hz,
H-1A), 4.82 (br s, 2H, H-1B, H-1D), 4.52 (br s, H-1C) in the 1H
NMR and d 103.7 (C-1C), 101.1 (C-1E), 100.4 (2 C, C-1A, C-1D),
98.9 (C-1B) in the 13C NMR spectra]. The stereochemistry at the
glycosyl linkages of compound 14 was further confirmed from
the gated 1H coupled 13C NMR spectrum. The appearance of the
8
lated-1-thio-b-
D
-glucopyranoside 3 in 86% yield (Scheme 1).
SEt
SEt
O
a
b
BnO
O
BnO
BnO
OH
BnO
OPMB
7
2
OH
OBz
O
HO
BzO
O
HO
BzO
SPh
SPh
OBz
OBz
8
3
Scheme 1. Reagents and conditions: (a) p-methoxybenzyl chloride, NaOH, DMF,
room temperature, 3 h, 92%; (b) benzoyl cyanide, pyridine, CH2Cl2, room temper-
ature, 1 h, 86%.
anomeric coupling constant (JC1–H1) values 170 Hz, 165 Hz,
168 Hz, 155 Hz and 148 Hz indicated the presence of three alpha-
and two beta glycosyl linkages27 in compound 14. Compound 14
was subjected to a series of functional group transformations; (a)
removal of the N-phthalimido group using ethylenediamine fol-
lowed by acetylation;28 (b) removal of the benzylidene acetal
and O-benzyl groups and reduction of the azido group using tri-
ethylsilane and 10% palladium on charcoal (Pd–C)29 followed by
N-acetylation; and finally (c) saponification using sodium meth-
oxide to give pentasaccharide 1 as its 2-(p-methoxyphenoxy)
ethyl glycoside, which was purified over a SephadexÒ LH-20 gel
to give pure compound 1 in 62% yield. The formation of com-
pound 1 was confirmed from its spectroscopic analysis [signals
at d 5.05 (br s, H-1D), 4.83 (d, J = 4.0 Hz, H-1B), 4.79 (br s, H-1C),
4.59 (2 d, J = 8.5 Hz each, H-1A, H-1E) in the 1H NMR and d
102.7 (2 C, C-1A, C-1E), 100.9 (C-1D), 99.1 (C-1C), 98.2 (C-1B) in
the 13C NMR spectra] (Scheme 2).
The iodonium ion mediated stereoselective 1,2-trans glycosyl-
ation of thioglycoside 2 with thioglycoside 3 in the presence of a
combination of N-iodosuccinimide (NIS) and trimethylsilyl trifluo-
romethanesulfonate (TMSOTf)25 furnished disaccharide thioglyco-
side derivative 9 in 82% yield. Compound 2 acted as an armed
glycosyl donor because of the presence of a p-methoxybenzyl
group at the C-2 position. On the contrary, the presence of a
benzoyl group at the C-2 position of compound 3 made it a dis-
armed glycosyl acceptor. The formation of compound 9 was con-
firmed from its spectroscopic analysis [signals at d 4.87 (d,
J = 10.0 Hz, H-1B), 4.69 (br s, H-1C) in the 1H NMR and d 99.9
(C-1C), 85.7 (C-1B) in the 13C NMR spectra]. Compound 9 was
transformed into benzylated derivative 10 in 87% yield under
one-pot reaction conditions26 for the de-O-acetylation and O-ben-
zylation using benzyl bromide and solid sodium hydroxide in the
presence of catalytic tetrabutylammonium bromide (TBAB). The

608
T. Ghosh et al. / Tetrahedron: Asymmetry 24 (2013) 606–611
Ph
OR
RO
O
SPh
B
O
5
a
O
4
a
O
2 + 3
O
OR
c
A
O
O
C
BnO
BnO
OPMP
BnO
N
3O
BnO
O
B
BnO
OPMB
O
OBn
9:
10:
R = Bz
R = Bn
C
O
b
BnO
Ph
BnO
11
OH
O
Ph
O
O
O
A
O
O
OPMP
N
BnO
O
BnO
3O
B
O
A
C
O
O
OBn
6
a
BnO
O
OPMP
N
BnO
3O
BnO
O
B
BnO
BnO
BnO
BnO
O
OBn
D
O
C
O
14
O
Ph
O
O
O
O
BnO
E
O
e, f, g, f, d
D
AcO
O
12:
13:
R = Ac
R = H
NPhth
d
BnO
RO
1
Scheme 2. Reagents and conditions: (a) N-iodosuccinimide (NIS), TMSOTf, CH2Cl2, MS 4 Å, ꢁ35 °C, 1 h, 82% for compound 9, 76% for compound 12 and 73% for compound 14;
(b) benzyl bromide, NaOH, TBAB, DMF, room temperature, 5 h, 87%; (c) NIS, TMSOTf, CH2Cl2/Et2O (1:2, v/v), MS 4 Å, ꢁ15 °C, 1 h, then 0 °C, 30 min, 78%; (d) 0.1 M CH3ONa,
CH3OH, 2 h, room temperature, 95%; (e) ethylene diamine, nBuOH, 90 °C, 7 h; (f) acetic anhydride, pyridine, room temperature, 1 h; (g) Et3SiH, 10% Pd-C, CH3OH, AcOH, room
temperature, 6 h, 62% in five steps.
OCH3), 3.82–3.76 (m, 2H, H-2, H-3), 3.63 (t, J = 9.3 Hz each, 1H,
H-4), 2.66–2.52 (m, 2H, SCH2CH3), 1.36 (d, J = 6.0 Hz, 3H, CCH3),
1.27 (t, J = 7.4 Hz each, 3H, SCH2CH3); 13C NMR (CDCl3, 75 MHz):
d 158.9–113.4 (Ar-C), 81.6 (C-1), 80.3 (C-2), 79.9 (C-3), 75.8 (C-4),
74.9 (PhCH2), 71.6 (PhCH2), 71.4 (PhCH2), 68.0 (C-5), 54.7 (OCH3),
24.9 (SCH2CH3), 17.5 (CCH3), 14.6 (SCH2CH3); ESI-MS: 531.2
[M+Na+]; Anal. Calcd for C30H36O5S (508.23): C, 70.84; H, 7.13.
Found: C, 70.67; H, 7.32.
3. Conclusion
In conclusion, a concise synthetic strategy has been developed
for the synthesis of pentasaccharide 1 as its 2-(p-methoxyphen-
oxy) ethyl glycoside, corresponding to the O-antigen of E. coli
O51 and S. enterica O57. The synthesis of target compound 1 was
achieved using the minimum number of steps. The yields of the
intermediate steps of the synthesis were very good and the stereo-
chemical outcome of the glycosylation reactions was excellent.
4.2. Phenyl 2,3,6-tri-O-benzoyl-1-thio-b-D-glucopyranoside 3
4. Experimental
To a solution of compound 8 (4.0 g, mmol, 8.32) in CH2Cl2
(20 mL) were added pyridine (4 mL) and benzoyl cyanide (1.1 g,
8.38 mmol) at 0 °C and the reaction mixture was allowed to stir
at room temperature for 30 min. The reaction mixture was diluted
with water and extracted with CH2Cl2 (100 mL). The organic layer
was washed with satd. NaHCO3 and water, dried (Na2SO4) and con-
centrated. The crude product was purified over SiO2 using hexane/
EtOAc (9:1) as eluant to give pure compound 3 (4.2 g, 86%). White
All reactions were monitored by thin layer chromatography over
silica gel-coated TLC plates. The spots on TLC were visualized by
warming ceric sulfate [2% Ce(SO4)2 in 2 N H2SO4]-sprayed plates
on a hot plate. Silica gel 230–400 mesh was used for column chro-
matography. 1H and 13C NMR, DEPT 135, 2D COSY, HSQC, and gated
1H coupled 13C NMR spectra were recorded on Bruker Avance 300
and 500 MHz spectrometers using CDCl3 and D2O as solvents and
TMS as internal reference unless stated otherwise. Chemical shift
values are expressed in d ppm. MALDI-MS were recorded on a Bru-
ker Daltronics mass spectrometer. Elemental analysis was carried
out on a Carlo Erba analyzer. Optical rotations were measured at
25 °C on a Jasco P-2000 polarimeter. Commercially available grades
of organic solvents of adequate purity are used in all reactions.
solid; mp 172–74 °C [EtOH]; ½a D25
ꢀ
þ 56 (c 1.2, CHCl3); IR (KBr):
3022, 2904, 1621, 1512, 1464, 1229, 757, 697 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz,): d 8.11–7.15 (m, 20H, Ar-H), 5.50 (t, J = 9.5 Hz
each, 1H, H-2), 5.44 (t, J = 9.5 Hz each, 1H, H-3), 5.0 (d, J = 9.6 Hz,
1H, H-1), 4.80–4.68 (m, 2H, H-6ab), 3.90–3.80 (m, 2H, H-4, H-5),
3.55 (br s, 1H, OH); 13C NMR (CDCl3, 75 MHz): d 166.9, 166.2,
164.6 (3 PhCO), 133.0–127.7 (Ar-C), 85.5 (C-1), 78.2 (C-5), 77.6
(C-3), 69.6 (C-4), 69.1 (C-2), 63.1 (C-6); ESI-MS: 607.1 [M+Na+];
Anal. Calcd for C33H28O8S (584.15): C, 67.79; H, 4.83. Found: C,
67.65; H, 5.0.
4.1. Ethyl 3,4-di-O-benzyl-2-O-(p-methoxybenzyl)-1-thio-a-L-
rhamnoside 2
To a solution of compound 7 (2.5 g, 6.43 mmol) in anhydrous
DMF (10 mL) was added powdered solid NaOH (1.2 g, 30 mmol)
and p-methoxybenzyl chloride (1.8 mL, 13.27 mmol) after which
the reaction mixture was allowed to stir at room temperature for
3 h. The reaction mixture was diluted with water and extracted
with CH2Cl2 (100 mL). The organic layer was washed with water,
dried (Na2SO4) and concentrated. The crude product was purified
over SiO2 using hexane/EtOAc (7:1) to give pure compound 2
4.3. Phenyl [3,4-di-O-benzyl-2-O-(p-methoxybenzyl)-
a
-
L
-rha-
mnopyranosyl]-(1?3)-2,3,6-tri-benzoyl-1-thio-b-
D-gluco-
pyranoside 9
To a solution of compound 2 (2.2 g, 4.32 mmol) and compound
3 (2.5 g, 4.27 mmol) in anhydrous CH2Cl2 (20 mL) was added MS-
4 Å (2.0 g) and the reaction mixture was allowed to stir at room
temperature for 30 min under argon. The reaction mixture was
cooled to ꢁ35 °C. To the cooled reaction mixture were added NIS
(3.0 g, 92%). Colorless oil; ½a D25
ꢀ
¼ ꢁ59 (c 1.2, CHCl3); IR (neat):
2944, 1729, 1503, 1446, 1287, 1210, 1088, 797 cmꢁ1
;
1H NMR
(1.0 g, 4.44 mmol) and TMSOTf (20 ll) and then stirred at the same
(CDCl3, 300 MHz,): d 7.35–7.28 (m, 12H, Ar-H), 6.87 (d, J = 9.0 Hz,
2H, Ar-H), 5.24 (br s, 1H, H-1), 4.98 (d, J = 11.0 Hz, 1H, PhCH2),
4.70–4.48 (m, 5H, PhCH2), 4.06–3.98 (m, 1H, H-5), 3.83 (s, 3H,
temperature for 1 h. The reaction mixture was diluted with CH2Cl2
(50 mL) and filtered through a CeliteÒ bed and washed with
CH2Cl2. The combined organic layer was successively washed with

T. Ghosh et al. / Tetrahedron: Asymmetry 24 (2013) 606–611
609
5% Na2S2O3, satd. NaHCO3, and water, dried (Na2SO4) and concen-
trated. The crude product was purified over SiO2 using hexane/
EtOAc (5:1) as eluant to give pure compound 9 (3.6 g, 82%). Yellow
bined organic layer was washed successively with 5% Na2S2O3,
satd. NaHCO3, and water, dried (Na2SO4) and concentrated. The
crude product was purified over SiO2 using hexane/EtOAc (6:1)
as eluant to give pure compound 11 (1.8 g, 78%). Yellow oil;
oil; ½a 2D5
ꢀ
¼ ꢁ21 (c 1.2, CHCl3); IR (neat): 3013, 2932, 1731, 1513,
1453, 1267, 1216, 1088, 1028, 755, 711 cmꢁ1
;
1H NMR (CDCl3,
½
a 2D5
ꢀ
¼ ꢁ16 (c 1.2, CHCl3); IR (neat): 3016, 2917, 1508, 1455,
500 MHz): d 8.11–7.08 (m, 32H, Ar-H), 6.75 (d, 2H, Ar-H), 5.62 (t,
J = 9.5 Hz each, 1H, H-3B), 5.27 (t, J = 9.5 Hz each, 1H, H-2B), 4.87
(d, J = 10.0 Hz, 1H, H-1B), 4.79 (d, J = 11.5 Hz, 1H, PhCH2), 4.69 (br
s, 1H, H-1C), 4.62–4.55 (m, 4H, H-6aB, PhCH2), 4.48 (d, J = 11.5 Hz,
1H, PhCH2), 4.43 (d, J = 11.5 Hz, 1H, PhCH2), 4.11–4.08 (m, 1H, H-
1216, 1048, 756, 699 cmꢁ1 1H NMR (CDCl3, 500 MHz): d 7.35–
;
7.21 (m, 30H, Ar-H), 6.84–6.79 (m, 4H, Ar-H), 5.00 (d, J = 7.5 Hz,
1H, H-1A), 4.97 (s, 1H, PhCH), 4.93 (d, J = 11.0 Hz, 1H, PhCH2),
4.85 (d, J = 3.5 Hz, 1H, H-1B), 4.83 (d, J = 11.0 Hz, 1H, PhCH2),
4.73–4.54 (m, 7H, PhCH2), 4.49 (br s, 1H, H-1C), 4.46 (d,
J = 11.0 Hz, 1H, PhCH2), 4.22–4.17 (m, 1H, H-5C), 4.14–4.10 (m,
2H, OCH2), 3.97–3.88 (m, 3H, H-4A, OCH2), 3.87–3.80 (m, 4H, H-
3A, H-3B, H-6abA), 3.77–3.72 (m, 3H, H-2A, H-3C, H-4B), 3.74 (s,
3H, OCH3), 3.68–3.64 (m, 1H, H-6aB), 3.62–3.56 (m, 2H, H-2B, H-
6bB), 3.92 (t, J = 9.5 Hz each, 1H, H-4B), 3.78–3.75 (m, 1H, H-5B),
3.73 (s, 3H, OCH3), 3.68 (br s, 1H, H-2C), 3.63 (dd, J = 9.0, 2.5 Hz,
1H, H-3C), 3.48–3.43 (m, 1H, H-5C), 3.37 (t, J = 9.0 Hz each, 1H, H-
4C), 0.73 (d, J = 6.0 Hz, 3H, CCH3); 13C NMR (CDCl3, 125 MHz): d
165.8, 165.7, 165.0 (3 PhCO), 159.3–113.7 (Ar-C), 99.9 (C-1C),
85.7 (C-1B), 80.1 (C-4C), 79.1 (C-3C), 77.7 (C-5B), 75.2 (C-2C), 74.7
(C-4B), 74.6 (PhCH2), 74.5 (C-3B), 72.6 (PhCH2), 72.3 (PhCH2), 70.7
(C-2B), 69.2 (C-5C), 62.6 (C-6B), 55.0 (OCH3), 17.4 (CCH3); MALDI-
MS: 1053.3 [M+Na+]; Anal. Calcd for C61H58O13S (1030.35): C,
71.05; H, 5.67. Found: C, 70.88; H, 5.86.
6bB), 3.54 (br s, 1H, H-2C), 3.52–3.50 (m, 1H, H-5B), 3.38–3.35 (m,
2H, H-4C, H-5A),0.99 (d, J = 6.0 Hz, 3H, CCH3); 13C NMR (CDCl3,
125 MHz): d 155.6–114.6 (Ar-C), 103.9 (C-1C), 99.3 (2 C, C-1A,
PhCH), 96.9 (C-1B), 80.5 (C-4C), 80.1 (C-3C), 79.8 (C-3B), 79.7 (C-
4B), 75.5 (C-4A), 75.4 (C-2A), 75.3 (C-3A), 75.0 (3 C, C-5A, C-5B,
PhCH2), 73.6 (2 C, 2 PhCH2), 73.1 (PhCH2), 71.9 (2 C, C-2C, PhCH2),
70.2 (C-5C), 68.6 (2 C, C-6A, C-6B), 67.9 (C-2B), 67.6 (OCH2), 66.4
(OCH2), 55.6 (OCH3), 17.7 (CCH3); MALDI-MS: 1224.5 [M+Na+];
Anal. Calcd for C69H75N3O16 (1201.51): C, 68.93; H, 6.29. Found:
C, 68.76; H, 6.50.
4.4. Phenyl [3,4-di-O-benzyl-2-O-(p-methoxybenzyl)-
a
-L
-rham-
nopyranosyl]-(1?3)-2,3,6-tri-benzyl-1-thio-b-
D-glucopyran-
oside 10
To a solution of compound 9 (3.0 g, 2.91 mmol) in dry DMF
(20 mL) were added powdered NaOH (1.2 g, 30 mmol), benzyl bro-
mide (2.1 mL, 17.65 mmol), and TBAB (250 mg) and the reaction
mixture was allowed to stir for 5 h at room temperature. The reac-
tion mixture was diluted with water and extracted with CH2Cl2
(100 mL). The organic layer was washed with water, dried
(Na2SO4) and concentrated. The crude product was purified over
SiO2 using hexane/EtOAc (7:1) as eluant to give pure compound
4.6. 2-(p-Methoxyphenoxy) ethyl (2-O-acetyl-3,4-di-O-benzyl-
-rhamnopyranosyl)-(1?2)-(3,4-di-O-benzyl- -rhamnopyr-
anosyl)-(1?4)-(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1?3)-
2-azido-4,6-O-benzylidene-2-deoxy-b- -galactopyranoside 12
a-
L
a-L
a-D
D
To a solution of compound 5 (600 mg, 1.39 mmol) and com-
pound 11 (1.5 g, 1.25 mmol) in anhydrous CH2Cl2 (10 mL) was
added MS-4 Å (1.0 g) and the reaction mixture was allowed to stir
at room temperature for 30 min under argon. The reaction mix-
ture was then cooled to ꢁ35 °C. To the cooled reaction mixture
10 (2.5 g, 87%). Yellow oil; ½a D25
¼ ꢁ29 (c 1.2, CHCl3); IR (neat):
ꢀ
3009, 2916, 1611, 1514, 1454, 1249, 1217, 1079, 753, 698 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): d 7.57–7.21 (m, 32H, Ar-H), 6.79 (d,
J = 9.0 Hz, 2H, Ar-H), 5.00 (br s, 1H, H-1C), 4.91–4.87 (m, 3H,
PhCH2), 4.76 (d, J = 10.5 Hz, 1H, PhCH2), 4.70 (d, J = 10.5 Hz, 1H,
PhCH2), 4.62 (d, J = 9.0 Hz, 1H, H-1B), 4.60–4.52 (m, 7H, PhCH2),
3.90–3.86 (m, 1H, H-5C), 3.83–3.77 (m, 2H, H-3C, H-4B), 3.75 (s,
3H, OCH3), 3.71 (br s, 1H, H-2C), 3.63–3.61 (m, 1H, H-6aA), 3.56–
3.49 (m, 4H, H-2B, H-3B, H-4C, H-6bB), 3.38–3.34 (m, 1H, H-5B),
1.04 (d, J = 6.0 Hz, 3H, CCH3); 13C NMR (CDCl3, 125 MHz): d
159.2–113.7 (Ar-C), 98.6 (C-1C), 87.5 (C-1B), 84.9 (C-4C), 81.1 (C-
5B), 80.6 (C-3C), 79.6 (C-4B), 79.5 (C-3B), 75.5 (PhCH2), 75.2 (PhCH2),
75.1 (PhCH2), 74.8 (C-2B), 74.2 (C-2C), 73.59 (PhCH2), 72.2 (PhCH2),
72.0 (PhCH2), 68.8 (2 C, C-5C, C-6B), 55.1 (OCH3), 17.8 (CCH3); MAL-
DI-MS: 1011.3 [M+Na+]; Anal. Calcd for C61H64O10S (988.42): C,
74.06; H, 6.52. Found: C, 73.87; H, 6.73.
were added NIS (350 mg, 1.55 mmol) and TMSOTf (5 ll) and then
stirred at same temperature for 1 h. The reaction mixture was di-
luted with CH2Cl2 (50 mL) and filtered through a CeliteÒ bed and
washed with CH2Cl2. The combined organic layer was succes-
sively washed with 5% Na2S2O3, satd. NaHCO3, and water, dried
(Na2SO4) and concentrated. The crude product was purified over
SiO2 using hexane/EtOAc (6:1) as eluant to give pure compound
12 (1.5 g, 76%). Yellow oil; ½a D25
ꢀ
¼ ꢁ4 (c 1.2, CHCl3); IR (neat):
3017, 2930, 1740, 1508, 1455, 1216, 1054, 756, 699 cmꢁ1
;
1H
NMR (CDCl3, 500 MHz): d 7.34–7.15 (m, 40H, Ar-H), 6.81–6.77
(m, 4H, Ar-H), 5.52 (br s, 1H, H-2D), 4.99 (br s, 2H, H-1D, PhCH),
4.95 (d, J = 7.5 Hz, 1H, H-1A), 4.94–4.84 (m, 2H, PhCH2), 4.83 (d,
J = 3.4 Hz, 1H, H-1B), 4.73–4.48 (m, 12H, PhCH2), 4.46 (br s, 1H,
H-1C), 4.18–4.08 (m, 3H, H-5C, OCH2), 3.95–3.86 (m, 5H, H-3A,
H-4A, H-5D, OCH2), 3.84–3.74 (m, 7H, H-2A, H-3B, H-3C, H-3D, H-
4B, H-6abA), 3.73 (s, 3H, OCH3), 3.66–3.63 (m, 1H, H-6aB), 3.58–
3.52 (m, 3H, H-2B, H-2C, H-6bB), 3.51–3.47 (m, 1H, H-5B), 3.37–
3.33 (m, 3H, H-4C, H-4D, H-5A), 2.11 (s, 3H, COCH3), 1.20, 1.00
(2 d, J = 6.0 Hz each, 6H, 2 CCH3); 13C NMR (CDCl3, 125 MHz): d
169.8 (COCH3), 155.3–114.6 (Ar-C), 103.9 (C-1C), 99.3 (PhCH),
99.0 (C-1D), 98.9 (C-1A), 96.9 (C-1B), 80.7 (C-4B), 80.0 (2 C, C-4D,
C-5A), 79.8 (C-4C), 77.7 (2 C, C-3C, C-3D), 75.4 (PhCH2), 75.3 (2
C, C-3B, PhCH2), 75.1 (2 C, C-2A, PhCH2), 75.0 (C-5B), 74.7 (C-4A),
74.6 (C-3A), 73.4 (PhCH2), 73.0 (PhCH2), 71.9 (PhCH2), 71.8
(PhCH2), 68.9 (2 C, C-2C, C-5D), 68.7 (C-2D), 68.5 (C-5C), 68.3 (2
C, H-2B, H-6B), 67.7 (C-6A), 67.6 (OCH2), 66.3 (OCH2), 55.5
(OCH3), 21.1 (COCH3), 18.0, 17.8 (2 CCH3); MALDI-MS: 1592.6
[M+Na+]; Anal. Calcd for C91H99N3O21 (1569.67): C, 69.58; H,
6.35. Found: C, 69.40; H, 6.50.
4.5. 2-(p-Methoxyphenoxy) ethyl (3,4-di-O-benzyl-
(1?4)-(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1?3)-2-azido-
4,6-O-benzylidene-2-deoxy-b- -galactopyranoside 11
a-L-rhamno)-
a-D
D
To a solution of compound 4 (850 mg, 1.92 mmol) and com-
pound 10 (2.0 g, 2.02 mmol) in anhydrous CH2Cl2/Et2O (15 mL;
1:2 v/v) was added MS-4 Å (2.0 g) and the reaction mixture was al-
lowed to stir at room temperature for 30 min under argon. The
reaction mixture was cooled to ꢁ15 °C. To the cooled reaction mix-
ture were added NIS (500 mg, 2.22 mmol) and TMSOTf (15 ll) and
it was then stirred at the same temperature for 1 h. The tempera-
ture of the reaction mixture was raised and it was stirred at 0 °C for
30 min. The reaction mixture was diluted with CH2Cl2 (50 mL) and
filtered through a CeliteÒ bed and washed with CH2Cl2. The com-

610
T. Ghosh et al. / Tetrahedron: Asymmetry 24 (2013) 606–611
4.7. 2-(p-Methoxyphenoxy) ethyl (3,4-di-O-benzyl-
pyranosyl)-(1?2)-(3,4-di-O-benzyl- -rhamnopyranosyl)-
(1?4)-(2,3,6-tri-O-benzyl- -glucopyranosyl)-(1?3)-2-azido-
4,6-O-benzylidene-2-deoxy-b- -galactopyranoside 13
a
-
L
-rhamno-
2.98 (m, 2H, H-4C, H-4D), 1.93 (s, 3H, COCH3), 1.06 (d, J = 6.0 Hz,
3H, CCH3), 0.88 (d, J = 6.0 Hz, 3H, CCH3); 13C NMR (CDCl3,
125 MHz): d 169.9 (COCH3), 155.3–121.4 (Ar-C), 103.7 (C-1C),
101.6 (2 C, 2 PhCH), 101.1 (C-1E), 100.4 (2 C, C-1A, C-1D), 98.9 (C-
1B), 85.5 (C-4A), 82.5 (C-4B), 82.4 (2 C, C-3A, C-3C), 80.6 (C-5A),
80.5 (C-4C), 79.2 (2 C, C-3D, C-4D), 79.1 (C-3B), 78.8 (C-4E), 77.7
(C-5B), 77.1 (C-5E), 75.9 (C-3E), 75.3 (C-5D), 75.1 (2 C, 2 PhCH2),
75.0 (C-2C), 74.9 (PhCH2), 74.6 (PhCH2), 73.4 (PhCH2), 72.7 (PhCH2),
71.6 (PhCH2), 69.8 (OCH2), 69.3 (C-2D), 68.6 (2 C, C-6A, C-6E), 68.4
(OCH2), 68.3 (C-2B), 67.6 (C-6B), 65.7 (C-5C), 57.0 (2 C, C-2A,
OCH3), 55.3 (C-2E), 20.7 (COCH3), 17.8, 17.7 (2 CCH3); MALDI-MS:
1971.7 [M+Na+]; Anal. Calcd for C112H116N4O27 (1948.78): C,
68.98; H, 6.00. Found: C, 68.80; H, 6.22.
a
-L
a-D
D
A solution of compound 12 (1.2 g, 0.76 mmol) in 0.1 M CH3ONa
in CH3OH (15 mL) was allowed to stir at room temperature for 2 h.
The reaction mixture was neutralized with Dowex 50 W-X8 (H+)
resin, filtered and concentrated. The crude product was passed
through a small pad of SiO2 using hexane/EtOAc (1:1) as eluant
to give pure compound 13 (1.1 g, 95%). Yellow oil; ½a D25
¼ ꢁ10 (c
ꢀ
1.2, CHCl3); IR (neat): 3018, 2918, 1508, 1216, 1052, 758 cmꢁ1
;
1H NMR (CDCl3, 500 MHz): d 7.32–7.16 (m, 40H, Ar-H), 6.81–6.78
(m, 4H, Ar-H), 5.04 (d, J = 7.5 Hz, 1H, H-1A), 5.00 (s, 1H, PhCH),
4.96 (d, J = 11.0 Hz, 1H, PhCH2), 4.94 (br s, 1H, H-1D), 4.86 (d,
J = 3.5 Hz, 1H, H-1B), 4.85–4.81 (m, 2H, PhCH2), 4.72–4.50 (m,
11H, PhCH2), 4.48 (br s, 1H, H-1C), 4.20–4.07 (m, 4H, H-2D, H-5C,
OCH2), 3.95–3.86 (m, 4H, H-3A, H-5D, OCH2), 3.85–3.74 (m, 8H,
H-2A, H-3B, H-3C, H-3D, H-4A, H-4B, H-6abA), 3.73 (s, 3H, OCH3),
3.68–3.63 (m, 1H, H-6aB), 3.58–3.54 (m, 3H, H-2C, H-5B, H-6bB),
3.52–3.47 (m, 1H, H-2B), 3.44 (t, J = 9.0 Hz each,1H, H-4C), 3.38–
3.30 (m, 2H, H-4D, H-5A), 1.21 (d, J = 6.0 Hz, 3H, CCH3), 0.99 (d,
J = 6.0 Hz, 3H, CCH3); 13C NMR (CDCl3, 125 MHz): d 155.2–114.6
(Ar-C), 103.9 (C-1C), 100.7 (PhCH), 100.6 (C-1D), 98.9 (C-1A), 96.8
(C-1B), 80.7 (C-4B), 80.4 (C-4D), 80.1 (2 C, C-4C, C-5A), 79.6 (C-3C),
79.5 (C-3D), 75.4 (PhCH2), 75.3 (PhCH2), 75.2 (C-3A), 75.1 (C-3B),
75.0 (C-5B), 74.6 (2 C, C-4A, PhCH2), 73.4 (PhCH2), 73.0 (PhCH2),
72.2 (PhCH2), 72.1 (PhCH2), 68.7 (2 C, C-2C, C-5D), 68.6 (C-6B),
68.5 (C-2D), 67.9 (2 C, C-2B, C-5C), 67.7 (C-6A), 67.6 (CH2), 66.3
(CH2), 55.6 (2 C, C-2A, OCH3), 18.0 (CCH3), 17.9 (CCH3); MALDI-
MS: 1550.6 [M+Na+]; Anal. Calcd for C89H97N3O20 (1527.66): C,
69.92; H, 6.40. Found: C, 69.76; H, 6.58.
4.9. 2-(p-Methoxyphenoxy) ethyl (2-acetamido-2-deoxy-b-D-
glucopyranosyl)-(1?2)-(
mnopyranosyl)-(1?4)-(
acetamido-2-deoxy-b-
a
-
L
-rhamnopyranosyl)-(1?2)-(
a-L-rha-
a
-
D-glucopyranosyl)-(1?3)-2-
D
-galactopyranoside 1
To a solution of compound 14 (800 mg, 0.41 mmol) in nBuOH
(5 mL) was added ethylene diamine (0.5 mL, 7.49 mmol) and the
reaction mixture was allowed to stir at 90 °C for 7 h. The solvents
were then removed under reduced pressure. A solution of the crude
product in acetic anhydride/pyridine (2 mL, 1:1 v/v) was kept at
room temperature for 1 h and concentrated under reduced pres-
sure. To the solution of the acetylated crude product in CH3OH/
AcOH (5 mL, 20:1, v/v) were added 10% Pd–C (100 mg) and Et3SiH
(2 mL, 12.5 mmol) and the reaction mixture was stirred at room
temperature for 6 h. The reaction mixture was filtered through a
CeliteÒ bed, washed with warm CH3OH and then concentrated un-
der reduced pressure. A solution of the crude product in acetic
anhydride/pyridine (2 mL, 1:1 v/v) was kept at room temperature
for 1 h and concentrated under reduced pressure. A solution of
the acetylated crude product in 0.1 M CH3ONa in CH3OH (5 mL)
was allowed to stir at room temperature for 2 h. The reaction mix-
ture was neutralized with Dowex 50 W-X8 (H+) resin, filtered and
concentrated. The crude product was passed through a SephadexÒ
LH-20 column using CH3OH/H2O (2:1) as eluant to give pure com-
4.8. 2-(p-Methoxyphenoxy) ethyl (3-O-acetyl-4,6-O-benzyl-
idene-2-deoxy-2-N-phthalimido-b-
(3,4-di-O-benzyl- -rhamnopyranosyl)-(1?2)-(3,4-di-O-
benzyl- -rhamnopyranosyl)-(1?4)-(2,3,6-tri-O-benzyl-
glucopyranosyl)-(1?3)-2-azido-4,6-O-benzylidene-2-deoxy-b-
D-glucopyranosyl)-(1?2)-
a
-L
a-
L
a-D-
D-galactopyranoside 14
pound 1 (260 mg, 62%). Glass; ½a D25
ꢀ
¼ ꢁ1 (c 1.2, H2O); IR (KBr):
3433, 2935, 1629, 1356, 1155, 1077, 699 cmꢁ1
;
1H NMR (D2O,
To a solution of compound 6 (380 mg, 0.78 mmol) and com-
500 MHz): d 6.96–6.85 (m, 4H, Ar-H), 5.05 (br s, 1H, H-1D), 4.83
(d, J = 4.0 Hz, 1H, H-1B), 4.79 (br s, 1H, H-1C), 4.59 (2d, J = 8.5 Hz
each, 2H, H-1A, H-1E), 4.25–4.07 (m, 1H, OCH2), 4.02 (br s, 1H, H-
2D), 3.95–3.87 (m, 3H, H-4A, OCH2), 3.79 (br s, 1H, H-2C), 3.78–
3.71 (m, 6H, H-3A, H-3C, H-3B, H-3E, H-6abA), 3.70 (s, 3H, OCH3),
3.67–3.53 (m, 6H, H-2A, H-2E, H-5A, H-5C, H-6abB), 3.50–3.33 (m,
8H, H-2B, H-3D, H-4B, H-4E, H-5D, H-5E, H-6abE), 3.25–3.20 (m, 3H,
H-4C, H-4D, H-5B), 1.94 (s, 6H, 2 COCH3), 1.16, 1.14 (2d, J = 6.0 Hz
each, 6H, 2 CCH3); 13C NMR (D2O, 125 MHz): d 174.8 (2 C, 2 COCH3),
153.5–115.0 (Ar-C), 102.7 (2 C, C-1A, C-1E), 100.9 (C-1D), 99.1 (C-1C),
98.2 (C-1B), 78.7 (C-2D), 78.3 (C-2C), 76.5 (C-4B), 75.7 (2 C, C-3D,
C-5E), 73.6 (2 C, C-3A, C-5A), 72.2 (C-2B), 72.0 (C-3B), 71.5 (2 C, C-
4E, C-5D), 70.6 (C-5B), 70.0 (C-3C), 69.7 (2 C, C-4C, C-4D), 69.6 (C-
3E), 69.1 (C-5C), 69.0 (C-4A), 67.7 (OCH2), 66.6 (OCH2), 60.6 (2 C,
C-6A, C-6E), 59.7 (C-6B), 55.9 (OCH3), 55.8 (2C, C-2A, C-2E), 22.2
(COCH3), 16.6, 16.4 (2 CCH3); MALDI-MS: 1051.3 [M+Na+]; Anal.
Calcd for C43H68N2O26 (1028.40): C, 50.19; H, 6.66. Found: C, 50.0;
H, 6.87.
pound 13 (1.0 g, 0.65 mmol) in anhydrous CH2Cl2 (5 mL) was
added MS-4 Å (500 mg) and the reaction mixture was allowed to
stir at room temperature for 30 min under argon. The reaction mix-
ture was cooled to ꢁ35 °C. To the cooled reaction mixture were
added NIS (200 mg, 0.88 mmol) and TMSOTf (3 ll) and then stirred
at the same temperature for 1 h. The reaction mixture was diluted
with CH2Cl2 (50 mL) and filtered through a CeliteÒ bed and washed
with CH2Cl2. The combined organic layer was successively washed
with 5% Na2S2O3, satd. NaHCO3, and water, dried (Na2SO4) and con-
centrated. The crude product was purified over SiO2 using hexane/
EtOAc (5:1) as eluant to give pure compound 14 (925 mg, 73%).
Yellow oil; ½a 2D5
ꢀ
¼ ꢁ11 (c 1.2, CHCl3); IR (neat): 2922, 1718,
1438, 1388, 1261, 1216, 1092, 759, 698 cmꢁ1
;
1H NMR (CDCl3,
500 MHz): d 7.58–7.02 (m, 53H, Ar-H), 6.02 (t, J = 8.0 Hz each,
1H, H-3E), 5.42 (br s, 2H, 2 PhCH), 5.37 (d, J = 8.5 Hz, 1H, H-1E),
4.88 (d, J = 8.0 Hz, 1H, H-1A), 4.86 (d, J = 11.0 Hz, 1H, PhCH2), 4.82
(br s, 2H, H-1B, H-1D), 4.70 (d, J = 10.5 Hz, 1H, PhCH2), 4.62–4.58
(m, 2H, PhCH2), 4.56–4.53 (m, 4H, PhCH2), 4.52 (br s, 1H, H-1C),
4.44 (d, J = 11.0 Hz, 1H, PhCH2), 4.36 (dd, J = 8.5 Hz each, 1H, H-
2E), 4.26 (d, J = 11.0 Hz, 1H, PhCH2), 4.18–3.95 (m, 7H, H-2D, H-5C,
H-5E, OCH2, PhCH2), 3.93–3.82 (m, 3H, H-5D, H-6aB, PhCH2), 3.81–
3.74 (m, 3H, H-6bB, OCH2), 3.78 (s, 3H, OCH3), 3.73–3.61 (m, 7H,
H-2A, H-3A, H-3B, H-3C, H-3D, H-4B, H-4E), 3.59–3.42 (m, 8H, H-2B,
H-2C, H-4A, H-5A, H-6abA, H-6abE), 3.36–3.31 (m, 1H, H-5B), 3.08–
Acknowledgments
T.G. and A.S. thank CSIR, New Delhi for providing Junior and Se-
nior Research Fellowships. This work was supported by DST, New
Delhi (No. SR/S1/OC-83/2010).

T. Ghosh et al. / Tetrahedron: Asymmetry 24 (2013) 606–611
15. Pozsgay, V. Angew. Chem., Int. Ed. 1998, 37, 138–142.
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