Straightforward sequential and one-pot synthesis of a pentasaccharide repeating unit corresponding to the cell wall O-antigen of Shigella boydii type 18

Article abstract of DOI:10.1016/j.tet.2019.130697

Synthesis of a pentasaccharide repeating unit corresponding to the cell of wall O-antigen Shigella boydii type 18 has been achieved by sequential as well as iterative glycosylations in one-pot. Use of p-methoxybenzyl group (PMB) as an in situ removable pr

Full text of DOI:10.1016/j.tet.2019.130697

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Straightforward sequential and one-pot synthesis of a pentasaccharide repeating unit
corresponding to the cell wall O-antigen of Shigella boydii type 18
Pradip Shit, Arin Gucchait, Anup Kumar Misra
PII:
S0040-4020(19)31074-9
https://doi.org/10.1016/j.tet.2019.130697
TET 130697
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 September 2019
Revised Date: 14 October 2019
Accepted Date: 15 October 2019
Please cite this article as: Shit P, Gucchait A, Misra AK, Straightforward sequential and one-pot
synthesis of a pentasaccharide repeating unit corresponding to the cell wall O-antigen of Shigella boydii
type 18, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130697.
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Graphical Abstract
Leave this area blank for abstract info.
Straightforward sequential and one-pot
synthesis of a pentasaccharide repeating unit
corresponding to the cell wall O-antigen of
Shigella boydii type 18
Pradip Shit, Arin Gucchait and Anup Kumar Misra
*
O
HO
OH
O
B
HO
HO
OH
O
Monosaccharide
thioglycosides
with PMB and
picoloyl groups
NIS
HClO4-SiO2
O
A
O
C
O
AcHN
Sequential
and One-pot
glycosylations
HO
OPMP
HO
O
D
O
O
E
O
HO
HO
OH
HO
OH

1
Tetrahedron
TETRAHEDRON
Pergamon
Straightforward sequential and one-pot synthesis of a
pentasaccharide repeating unit corresponding to the cell wall O-
antigen of Shigella boydii type 18
Pradip Shit, Arin Gucchait and Anup Kumar Misra*
Bose Institute, Molecular Medicine Division, P-1/12, C.I.T. Scheme VII M, Kolkata 700054
Abstract— Synthesis of a pentasaccharide repeating unit corresponding to the cell of wall O-antigen Shigella boydii type 18 has been
achieved by sequential as well as iterative glycosylations in one-pot. Use of p-methoxybenzyl group (PMB) as an in situ removable
protecting group allowed obtaining the desired pentasaccharide derivative in a generalized glycosylation condition and in one-pot
condition. Synthesis of a beta-L-rhamnosidic linkage present in the molecule has been successfully achieved using L-rhamnosyl
thioglycoside donor having a picoloyl group at remote C-3 position influencing beta selectivity in the glycosylation. A combination of N-
iodosuccinimide (NIS) and perchloric acid supported over silica (HClO4-SiO2) has been used as thiophilic glycosylation promoter in all
glycosylation reactions. TEMPO mediated selective oxidation of the primary hydroxyl group has been carried out at the late stage of the
synthetic strategy.
Keywords: Pentasaccharide; one-pot; iterative glycosylation; TEMPO oxidation; Shigella boydii type 18.
*Corresponding author. Tel.: (+91)(-33) 25693240; Fax: (+91)(-33) 2355-3886; E-mail: akmisra69@gmail.com

Tetrahedron
2
1. Introduction
it is essential to have a significant quantity of
oligosaccharides to carry out a wide variety of
Diarrhoeal epidemics with life threatening incidences
are worldwide health concern, which are the result of
the consumption of contaminated food and water.1
Particularly, enteric infections are common in the
developing countries where adequate sanitation is
absent.2 In most of the cases, the gastrointestinal
disorders are caused by the infection of are Shigella,
Salmonella and E. coli bacteria.3,4,5 One of the long
known well studied bacterial infections leading to
devastating Diarrhoea is Shigellosis,6 which is caused
by the infection of different species of Shigella bacilli,
such as Shigella boydii (S. boydii), Shigella dysenteriae
(S. dysenteriae), Shigella flexneri (S. flexneri) and
Shigella sonnei (S. sonnei), which are also classified as
Shigella subgroups A, B, C, and D, respectively.7 The
majority of Shigella infections are caused by S. boydii,
S. dysenteriae, S. flexneri. The virulence properties of
Shigella strains appeared from the structure of their cell
wall O-antigens, which are polysaccharide fragments
containing some acidic constituents such as uronic
acid, pseudaminic acid, lactic acid, pyruvic acid etc.7
The structure of the cell wall O-antigen of Shigella
boydii type 18 was reported by Feng et al.8 It is a
pentasaccharide repeating unit, acidic in nature
biological studies. Hence,
a
concise, multistep
synthetic strategy for the synthesis of a pentasaccharide
repeating unit corresponding to the cell wall
polysaccharide of Shigella boydii type 18 is presented
herein. The synthetic strategy has been designed to
carry out stereoselective glycosylations of suitably
functionalized monosaccharide units with in situ
removable temporary protecting groups to achieve the
pentasaccharide moiety in step-economic approach
avoiding lengthy protection-deprotection steps. In
addition to the sequential glycosylation strategy, a one-
pot approach for the synthesis of the pentasaccharide
derivative has also been developed applying iterative
glycosylations of monosaccharide intermediates
protected with PMB groups.
O
HO
OH
O
B
HO
HO
OH
O
O
A
O
C
O
AcHN
HO
OPMP
HO
O
D
O
consisting of one α-
D
-galactouronic acid, one β-
L-
O
E
O
rhamnose, two α- -rhamnose and one α-
L
D
-galactose.
HO
HO
OH
1
Bacterial cell wall polysaccharide derived glycoprotein
conjugate vaccines are used in the clinics for several
years to control bacterial infections, such as
pneumonia,9,10 Haemophilia influenza type b (Hib)
infection,11 meningitides,12 cholera,13 hemorrhagic
diarrhoeal infections,14 urinary tract infections to name
a few.9-15 However, use of polysaccharides from the
natural sources using bacterial fermentations suffer
from several drawbacks, which include handling of live
bacterial strains; lack of homogeneity, batch to batch
variation; difficulties associated with the removal of
biological impurities etc. Therefore, it is quite pertinent
to identify alternative approaches to obtain significant
quantity of oligosaccharide fragments corresponding to
the natural polysaccharides with precise structures and
adequate purity. Developments of chemical synthetic
strategies for the synthesis of oligosaccharides are the
best choice to address this issue.
HO
OH
Ph
AcO
HO
OAc
O
O
O
O
OPMB
N3
SiPr
BnO
OPMP
3
4
SEt
SEt
O
O
BnO
PMBO
BnO
O
OPMB
O
SEt
5
6
O
BnO
PicO
OBn
7
Emergence of multidrug resistant bacterial strains is a
serious concern for controlling of infectious diseases.
In spite of development of various therapeutic
measures against diarrhoeal infections caused by
different strains of Shigella, there is a demand of
alternative approaches for the controlling Shigellosis.
Since, cell wall polysaccharides are found to be
Figure 1: Structure of the synthesized pentasaccharide
and its synthetic intermediates.
2. Results and discussion
In order to synthesize the target pentasaccharide 1, it
was decided to apply a generalized reaction condition
for the stereoselective glycosylation of monosaccharide
units. For this purpose, a set of monosaccharide
thioglycoside derivatives 3, 4,21 5,22 623 containing p-
methoxybenzyl (PMB) group in suitable positions and
724 having a picoloyl group at C-3 position were
prepared following earlier reported reaction conditions
immunogenic
in
nature,
development
of
glycoconjugate derivatives using oligosaccharides
corresponding to the cell wall of Shigella could be
useful as potential glycoconjugate vaccine lead against
Shigellosis. A significant number of reports appeared
in the past for the development of anti-shigellosis
agents using glycoconjugate derivatives.16-20 However,

Tetrahedron
3
(Figure 1). The monosaccharide derivatives were
judiciously functionalized to achieve the best outcome
of the stereoselective glycosylations. The PMB groups
were installed in the monosaccharide intermediates as
an in situ removable temporary protecting group.25 The
derivative 8 in 76% yield in which 2-hydroxy group in
the -galactose moiety was available for next step
D
glycosylation. A minor quantity (~5%) of 1,2-trans
glycosylation product was also formed, which was
separated by column chromatography. The presence of
signals at δ 5.49 (d, J = 3.5 Hz, H-1A), 5.42 (s, PhCH),
5.26 (d, J = 3.5 Hz, H-1B) in the 1H NMR spectrum and
at δ 100.9 (PhCH), 98.1 (C-1A), 97.5 (C-1B) in the 13C
NMR spectrum confirmed the formation of compound
3-O-picoloylated -rhamnosyl thioglycoside (7) was
L
employed for the synthesis of β-rhamnosidic linkage
exploiting the influence of the remotely positioned
picoloyl group in β-glycosylation as described earlier
by Demchenko et al. and Kulkarni et al.26 All
stereoselective glycosylation reactions were carried out
using a combination27 of N-iodosuccinimide (NIS) and
perchloric acid supported over silica (HClO4-SiO2)28,29
as thiophilic activator. HClO4-SiO2 was used as a solid
protonic acid avoiding the use of corrosive and
moisture sensitive TMSOTf or TfOH. Besides, this
solid acid is cheap and can be prepared in the
laboratory easily. Since HClO4-SiO2 is a solid acid, it
can be removed from the reaction mixture by simple
filtration. Presence of in situ removable p-
methoxybenzyl group25 in the glycosyl donors allowed
completing the reaction sequence in significantly
minimum number of steps. Selection of in situ removal
PMB protecting groups also allowed carrying out the
synthesis of the protected pentasaccharide derivative
11 in a one-pot manner using iterative glycosylations
of monosaccharide intermediates. The selective
8. Stereoselective 1,2-trans glycosylation of
L-
rhamnosyl thioglycoside 5 with disaccharide acceptor 8
in the presence of a combination27 of NIS and HClO4-
SiO2 and in situ removal25 of the PMB group furnished
trisaccharide derivative 9 in 72% yield in which 2-
hydroxy group in the -rhamnose moiety can be used
L
for next step glycosylation. The presence of signals at δ
5.45 (d, J = 3.5 Hz, H-1A), 5.43 (s, PhCH), 5.24 (d, J =
1
1.5 Hz, H-1C), 5.21 (d, J = 3.0 Hz, H-1B) in the H
NMR spectrum and at δ 100.8 (C-1C), 100.7 (PhCH),
98.1 (C-1A), 97.7 (C-1B) in the 13C NMR spectrum
confirmed the formation of compound 9.
Stereoselective 1,2-trans glycosylation of -rhamnosyl
L
thioglycoside 6 with trisaccharide acceptor 9 promoted
by a combination27 of NIS and HClO4-SiO2 and in situ
removal25 of the PMB group furnished tetrasaccharide
derivative 10 in 74% yield in which 4-hydroxy group
oxidation of primary hydroxyl group in the -galactose
D
moiety keeping the secondary hydroxyl groups
unaffected was achieved using TEMPO mediated
BAIB oxidation30 in a late stage of the synthetic
sequence.
in the -rhamnose moiety was available for next step
L
glycosylation. The presence of signals at δ 5.44 (d, J =
3.0 Hz, H-1A), 5.35 (s, PhCH), 5.24 (d, J = 2.0 Hz, H-
1C), 5.21 (d, J = 3.5 Hz, H-1B), 5.11 (s, 1 H, PhCH) in
1
p-Methoxyphenyl 2-azido-4,6-O-benzylidene-2-deoxy-
the H NMR spectrum and at δ 100.7 (C-1C), 100.6
α-
-galactopyranoside (2)31 was subjected to a three
D
(PhCH), 98.3 (C-1A), 98.0 (C-1D), 97.0 (C-1B) in the
step reaction sequence involving (a) allylation using
13C NMR spectrum confirmed the formation of
allyl bromide and sodium hydroxide;32 (b) treatment of
compound 10. At this stage, incorporation of the L-
the allylated product with acetic anhydride in the
33
rhamnosyl moiety to the tetrasaccharide acceptor 10 in
a β-glycosidic linkage was quite challenging since only
a few reports were available to date for the β-
presence of HClO4-SiO2 and (c) removal of allyl
ether using palladium chloride34 to give p-
methoxyphenyl 4,6-di-O-acetyl-2-azido-2-deoxy-α- -
D
galactopyranoside (3) in 85% over all yield (Scheme
glycosylation of
Demchenko et. al.26a and recently Kulkarni and co-
workers26b have successfully carried out β-
rhamnosylation using the -rhamnosyl thioglycoside
L-rhamnosyl moiety. Initially
1).
Ph
L-
O
L
AcO
HO
OAc
O
O
donor equipped with a picolinoyl group at the C-3
position exploiting the picolinoyl group mediated
a, b, c
O
HO
N3
hydrogen bond aglycon delivery for β-
rhamnosylation. With this information, stereoselective
1,2-cis glycosylation of 3-O-picolinoylated
rhamnosyl thioglycoside with tetrasaccharide
acceptor 10 was attempted using NIS and HClO4-SiO2
as glycosylation promoter.27 Most gratifyingly β-
L-
N3
OPMP
OPMP
3
2
L-
Scheme 1: (a) Allyl bromide, NaOH, TBAB, DMF,
room temperature, 2 h, 95%; (b) acetic anhydride,
HClO4-SiO2, room temperature, 10 min; (c) PdCl2,
CH3OH, room temperature, 30 min, 86% in three steps.
7
L-
rhamnose incorporated pentasaccharide derivative 11
was obtained in 72% yield. A minor amount (~5%) of
other isomeric product has also been formed as
observed in TLC, which was separated by column
chromatography. The presence of signals at δ 5.44 (d, J
= 3.5 Hz, H-1A), 5.32 (s, PhCH), 5.22 (d, J = 1.5 Hz,
Stereoselective 1,2-cis glycosylation of compound 3
with -galactosyl thioglycoside donor 4 in the presence
D
of a combination27 of NIS and HClO4-SiO2 and in situ
removal25 of the PMB group by tuning the reaction
condition resulted in the formation of disaccharide

Tetrahedron
4
H-1C), 5.18 (d, J = 3.5 Hz, H-1B), 5.05 (br s, H-1D),
4.71 (br s, 1 H, H-1E) in the 1H NMR spectrum and at δ
100.9 (C-1E), 100.8 (PhCH), 100.6 (C-1C), 98.1 (2 C,
C-1A, C-1B), 97.1 (C-1D) in the 13C NMR spectrum
confirmed the formation of compound 11 (Scheme 2).
spectrum unambiguously confirmed the formation of
compound 1 (Scheme 2).
3. Conclusions
In summary, a straight forward synthetic strategy has
been developed for the synthesis of the pentasaccharide
repeating unit corresponding to the cell wall O-antigen
of Shigella boydii type 18 in excellent yield. A
generalized reaction condition has been used in all
stereoselective glycosylation steps using a combination
of NIS and HClO4-SiO2 as glycosylation activator.
Presence of the in situ removable PMB groups in the
thioglycoside intermediates allowed achieving the
pentasaccharide derivative 11 in minimum number of
steps. A one-pot reaction sequence applying iterative
glycosylation steps has also been developed for the
synthesis of pentasaccharide derivative 11 in
satisfactory yield. Finally late stage selective oxidation
of primary hydroxyl group into a carboxylic acid
followed by de-protection of functional groups
furnished desired pentasaccharide 1.
In order to simplify the synthetic strategy, it was
decided to explore the possibility of carrying out
multiple numbers of glycosylation steps in a one-pot
iterative manner considering the fact that PMB
protecting group can be removed in situ after each
glycosylation steps by simple tuning the reaction
conditions. For this purpose, the monosaccharide
acceptor 3 was allowed to react with the -galactosyl
D
thioglycoside donor 4 containing a C-2 PMB group in
the presence of a combination of NIS and HClO4-SiO2
at −30 °C for 45 min and then at 0 °C for 30 min. After
consumption of the starting materials and formation of
a new major spot in the TLC plate, the reaction mixture
was cooled to −30 °C and glycosyl donor 5 was added
to the reaction mixture followed by NIS. The same
sequence was repeated another two times using
glycosyl donors 6 and 7 and finally the pentasaccharide
derivative 11 was obtained in 48% over all yield. It is
worth mentioning that the stereo chemical outcome of
each glycosylation steps and overall yield of the final
pentasaccharide derivative 11 in the one-pot iterative
sequence was quite satisfactory, which was confirmed
from the NMR spectroscopic analysis of compound 11
(Scheme 3). It is worth mentioning that in the one-pot
iterative reaction sequence no trace of formation of
PMB glycosides with the glycosyl donors was
observed although PMB-alcohol might have been
generated during the removal of PMB ether. The PMB-
alcohol generated in situ could have been converted
into quinonoid form during the course of reaction
resulting it’s non-availability for the glycosylation with
glycosyl donors.
Finally, compound 11 was subjected to a set of
reactions consisting of (a) hydrolytic removal of
benzylidene and isopropylidene acetals using 80% aq.
acetic acid; (b) TEMPO mediated selective oxidation
of primary hydroxyl group to carboxylic acid without
affecting the secondary hydroxyl groups;30 (c)
hydrogenolysis of benzyl ethers and azido group using
hydrogen over Pearlman catalyst;35 (d) acetylation of
amino group using acetic anhydride in methanol and
(e) de-O-acetylation using moist sodium methoxide to
give pentasaccharide 1 as p-methoxyphenyl glycoside
in 62% over all yield. The presence of signals at δ 5.53
(d, J = 3.5 Hz, H-1A), 5.32 (br s, H-1C), 5.23 (d, J =
2.0 Hz, H-1B), 5.00 (br s, H-1D), 4.74 (br s, H-1E) in the
1H NMR spectrum and at δ 101.9 (C-1D), 100.4 (C-1E),
99.7 (C-1C), 97.2 (C-1B), 95.1 (C-1A) in the 13C NMR

Tetrahedron
5
3
3 + 4
Ph
a
a
a
O
4
5
O
Ph
O
O
AcO
OAc
O
B
O
BnO
HO
A
O
O
AcO
OAc
O
BnO
N3
OPMP
HO
8
O
Ph
N3
OPMP
Ph
a
8
5
O
O
O
O
O
AcO
OAc
O
O
O
B
AcO
OAc
O
BnO
BnO
O
A
O
O
C
O
N3
OPMP
O
N3
OPMP
BnO
a
BnO
6
BnO
Ph
9
BnO
Ph
OH
9
OH
a
6
O
O
O
O
One-pot Iterative
glycosylations of
monosaccharide
derivatives with
PMB groups
O
O
O
O
AcO
OAc
O
AcO
OAc
O
B
BnO
BnO
A
O
O
O
N3
O
C
N3
OPMP
BnO
BnO
HO
OPMP
BnO
O
BnO
O
O
a
D
O
HO
7
O
O
10
O
O
10
O
Ph
a
7
O
Ph
O
AcO
OAc
O
BnO
O
O
O
O
O
N3
O
O
BnO
AcO
OAc
O
OPMP
B
BnO
BnO
O
O
O
A
O
O
C
O
O
N3
OPMP
BnO
BnO
O
PicO
BnO
11
Over all 48%
OBn
O
O
D
O
E
O
Scheme 3: (a) NIS, HClO4-SiO2, CH2Cl2, MS 4Å, −30
°C, 45 min, then 0 °C for 30 min, over all 48%.
BnO
O
O
PicO
11
OBn
4. Experimental
b, c, d, e
General methods: All reactions were monitored by
thin layer chromatography over silica gel coated TLC
plates. The spots on TLC were visualized by warming
ceric sulphate (2% Ce(SO4)2 in 2N H2SO4) sprayed
plates in hot plate. Silica gel 230-400 mesh was used
for column chromatography. NMR spectra were
recorded on Bruker Avance 500 MHz using CDCl3 as
solvent and TMS as internal reference unless stated
otherwise. Chemical shift value is expressed in δ ppm.
The complete assignment of proton and carbon spectra
1
Scheme 2: (a) NIS, HClO4-SiO2, CH2Cl2, MS 4Å, −30
°C, 45 min, then 0 °C for 30 min, 75% for compound 8,
71% for compound 9, 75% for compound 10, 74% for
compound 11; (b) 80% aq. AcOH, 80 °C, 1 h; (c)
TEMPO, BAIB, CH3CN-H2O (1:1), room temperature, 3
h; (d) H2, 20% Pd(OH)2-C, CH3OH, room temperature, 24
h; (e) acetic anhydride, CH3OH, room temperature, 1 h;
(f) 0.1 M NaOCH3, CH3OH, room temperature, 3 h, 58%
yield in five steps.
was carried out by using a standard set of NMR
1
experiments, e.g. H NMR, 13C NMR, 13C DEPT 135,

Tetrahedron
6
2D COSY and 2D HSQC etc. MALDI-MS were
recorded on a Bruker mass spectrometer. Optical
product was purified over SiO2 using hexane-EtOAc
(5:1) as eluant to give pure compound 8 (4.2 g, 75%);
1
rotations were recorded in
a
Jasco P-2000
Colourless syrup; [α]D +42 (c 1.0, CHCl3); H NMR
spectrometer. Commercially available grades of
organic solvents of adequate purity are used in all
reactions. HClO4-SiO2 was prepared following the
reported method.28, 29
(500 MHz, CDCl3): δ 7.51-7.18 (m, 10 H, Ar-H), 7.02
(d, J = 9.0 Hz, 2 H, Ar-H), 6.81 (d, J = 9.0 Hz, 2 H, Ar-
H), 5.57 (d, J = 3.0 Hz, 1 H, H-4A), 5.49 (d, J = 3.5 Hz,
1 H, H-1A), 5.42 (s, 1 H, PhCH), 5.26 (d, J = 3.5 Hz, 1
H, H-1B), 4.74 (dd, J = 11.5 Hz, each, 2 H, 2 PhCH),
4.42 (dd, J = 9.5, 3.5 Hz, 1 H, H-3A), 4.35-4.30 (m, 2
H, H-3B, H-5A), 4.27-4.22 (m, 1 H, H-5B), 4.18 (d, J =
2.5 Hz, 1 H, H-4B), 4.11 (dd, J = 12.5, 5.0 Hz, 1 H, H-
6aA), 4.09-4.08 (m, 2 H, H-2B, H-6bA), 3.86-3.80 (m, 2
H, H-6abB), 3.78 (s, 3 H, OCH3), 3.69 (dd, J = 9.5, 3.0
Hz, 1 H, H-2A), 2.12 (s, 3 H, COCH3), 1.98 (s, 3
H,COCH3); 13C NMR (125 MHz, CDCl3): δ 170.8
(COCH3), 170.0 (COCH3), 155.7-114.7 (Ar-C), 100.9
p-Methoxyphenyl 4,6-di-O-acetyl-2-azido-2-deoxy-
α- -galactopyraside (3): To a solution of compound 2
D
(4 g, 10.0 mol) in DMF (10 mL) were added allyl
bromide (1.3 mL, 15.0 mmol), powdered NaOH (1.6 g,
40.0 mmol) and TBAB (100 mg) and the reaction
mixture was allowed to stir at room temperature for 2
h. The reaction mixture was diluted with H2O (100
mL) and extracted with EtOAc (100 mL). The organic
layer was dried (Na2SO4) and concentrated under
reduced pressure. The crude product was passed
through a short pad of SiO2. To a solution of the
allylated product in acetic anhydride (10 mL) was
added HClO4-SiO2 (150 mg) and the reaction mixture
was stirred at room temperature for 10 min. The
reaction mixture was filtered and concentrated under
reduced pressure. To a solution of the acetylated
product in CH3OH (15 mL) was added PdCl2 (350 mg,
1.97 mmol) and the reaction mixture was stirred at
room temp. The reaction mixture was filtered and
concentrated. The crude product was purified over
SiO2 using hexane-EtOAc (3:1) as eluant to give pure
(PhCH), 98.1 (C-1A), 97.5 (C-1B), 76.0 (C-3 ), 73.8
B
(C-4 ), 71.7 (C-2B), 71.5 (PhCH2), 69.5 (C-6B), 67.6
A
(C-3B), 67.4 (C-5A), 66.1 (C-4B), 63.8 (C-5B), 61.5 (C-
6A), 59.0 (C-2A), 55.5 (OCH3), 20.8 (COCH3), 20.6
(COCH3); HRMS [M+Na]+: Calcd. 758.2537; found,
758.2545.
p-Methoxyphenyl
rhamnopyranosyl)-(1→2)-(3-O-benzyl-4,6-O-
benzylidene-α- -galactopyranosyl)-(1→3)-4,6-di-O-
acetyl-2-azido-2-deoxy-α- -galactopyranoside (9):
(3,4-di-O-benzyl-α-
L
-
D
D
Glycosylation of compound 8 (3.5 g, 4.76 mmol) and
compound 5 (1.9 g, 3.73 mmol) was carried out in the
presence of NIS (880 mg, 3.91 mmol) and HClO4-SiO2
(50 mg) following the similar reaction condition as
mentioned in the preparation of compound 8. The
crude product was purified over SiO2 using hexane-
compound 3 (3.4 g, 86% in three steps); Colourless
1
syrup; [α]D −25 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3): δ 7.05 (d, J = 9.0 Hz, 2 H, Ar-H), 8.83 (d, J =
9.0 Hz, 2 H, Ar-H), 5.48 (d, J = 3.5 Hz, 1 H, H-1), 5.42
(d, J = 3.0 Hz, 1 H, H-4), 4.48-4.44 (dd, J = 9.0, 3.0
Hz, 1 H, H-3), 4.36-4.33 (m, 1 H, H-5), 4.17 (d, J =
12.5, 3.0 Hz, 1 H, H-6a), 4.09 (d, J = 12.5, 5.0 Hz, 1 H,
H-6b), 3.77 (s, 3 H, OCH3), 3.62 (dd, J = 9.0 Hz, 3.0
Hz, 1 H, H-2) 2.19 (s, 3 H, COCH3), 2.00 (s, 3 H,
COCH3); 13C NMR (125 MHz, CDCl3): δ 171.3
(COCH3), 170.5 (COCH3), 155.6-114.6 (Ar-C), 98.1
(C-1), 70.0 (C-3), 67.6 (C-4), 67.1 (C-5), 62.0 (C-6),
60.0 (C-2), 55.6 (OCH3), 20.8 (COCH3), 20.6
(COCH3); HRMS [M+Na]+: Calcd. 418.1227; found,
418.1220.
EtOAc (4:1) as eluant to give pure compound 9 (3.6 g,
1
71%); Colourless syrup; [α]D −17 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3): δ 7.51-7.24 (m, 20 H, Ar-H),
7.00 (d, J = 9.0 Hz, 2 H, Ar-H), 6.78 (d, J = 9.0 Hz, 2
H, Ar-H), 5.53 (d, J = 3.0 Hz, 1 H, H-4A), 5.45 (d, J =
3.5 Hz, 1 H, H-1A), 5.43 (s, 1 H, PhCH), 5.24 (d, J =
1.5 Hz, 1 H, H-1C), 5.21 (d, J = 3.0 Hz, 1 H, H-1B),
4.81 (d, J = 11.5 Hz, 1 H, PhCH), 4.68-4.59 (m, 5 H, 5
PhCH), 4.36 (dd, J = 10.5 Hz, 3.0 Hz, 1 H, H-2B),
4.30-4.25 (m, 3 H, H-3A, H-5A, H-6Aa), 4.19 (d, J = 3.5
Hz, 1 H, H-4B), 4.50-3.95 (m, 5 H, H-2C, H-3B, H-6abB
,
H-6aA), 3.85 (dd, J = 10.5 Hz, 3.5 Hz, 1 H, H-3C), 3.80
(br s, 1 H, H-5B), 3.77 (dd, J = 10.5 Hz, 3.0 Hz, 1 H,
H-2A), 3.76-3.74 (m, 1 H, H-5C), 3.73 (s, 3 H, OCH3),
p-Methoxyphenyl (3-O-benzyl-4,6-O-benzylidene-α-
D
-galactopyranosyl)-(1→3)-4,6-di-O-acetyl-2-azido-
2-deoxy-α-
D
-galactopyranoside (8): To a solution of
3.40 (t, J = 9.5 Hz, each, 1 H, H-4 ), 2.00 (s, 3 H,
C
compound 3 (3 g, 7.58 mmol) and compound 4 (4.47 g,
8.33 mmol) in anhydrous CH2Cl2 (25 mL) was added
MS 4Å (5 g) and the reaction mixture was cooled to
−30 °C under argon. To the cooled reaction mixture
was added NIS (2 g, 8.88 mmol) followed by HClO4-
SiO2 (150 mg) and the reaction mixture was allowed to
stir at same temperature for 45 min. The temperature of
the reaction was raised to room temperature and stirred
for another 30 min. The reaction mixture was filtered
and washed with CH2Cl2 (100 mL). The combined
organic layer was successively washed with 5% aq.
Na2S2O3 (50 mL), satd. NaHCO3 (50 mL) and H2O (50
mL), dried (Na2SO4) and concentrated. The crude
COCH3), 1.88 (s, 3 H, COCH3), 1.30 (d, J = 6.5 Hz, 3
H, CCH3); 13C NMR (125 MHz, CDCl3): δ 170.0
(COCH3) 169.4 (COCH3), 155.7-114.6 (Ar-C), 100.8
(C-1C), 100.7 (PhCH), 98.1 (C-1A), 97.7 (C-1B), 80.0
(C-4C), 79.8 (C-3C), 76.2 (C-3B), 75.1 (PhCH2), 73.7
(C-4B), 72.0 (C-3A), 71.7 (PhCH2), 71.5 (PhCH2), 71.4
(C-2B), 69.3 (C-6B), 68.3 (C-2C), 68.1 (C-5A), 67.9 (C-
5C), 66.6 (C-4A), 63.7 (C-5B), 61.8 (C-6A), 59.3 (C-2A),
55.5 (OCH3), 20.6 (COCH3), 20.5 (COCH3), 18.0
(CCH3); HRMS [M+Na]+: Calcd. 1084.4055; found,
1084.4064.

Tetrahedron
7
p-Methoxyphenyl
rhamnopyranosyl)-(1→2)-(3,4-di-O-benzyl-α-
rhamnopyranosyl)-(1→2)-(3-O-benzyl-4,6-O-
(2,3-O-isopropylidene-α-
L
-
Hz, 3.0 Hz, 1 H, H-3E), 4.88-4.78 (m, 4 H, 4 PhCH),
4.71 (br s, 1 H, H-1E), 4.68-4.53 (m, 6 H, 6 PhCH),
4.35-4.32 (m, 2 H, H-2B, H-3A), 4.28-4.24 (m, 3 H, H-
5A, H-5E, H-6aA), 4.16-4.14 (m, 1 H, H-3D), 4.12-4.06
(m, 3 H, H-2D, H-2E, H-4B), 4.00-3.93 (m, 5 H, H-2C,
H-3B, H-6bA, H-6abB), 3.85-3.84 (m, 3 H, H-2A, H-5B,
H-5D), 3.77 (s, 3 H, OCH3), 3.76-3.70 (m, 2 H, H-3C,
H-5C), 3.45-3.36 (m, 3 H, H-4C, H-4D, H-4E), 1.98 (s, 3
H, COCH3), 1.90 (s, 3 H, COCH3), 1.50 (s, 3 H, CH3),
1.40 (d, J = 6.5 Hz, 3 H, CCH3), 1.33 (s, 3 H, CH3),
1.31 (d, J = 6.0 Hz, 3 H, CCH3); 13C NMR (125 MHz,
CDCl3): δ 169.9 (COCH3), 169.5 (COCH3), 164.0
(COpic), 155.7-114.6 (Ar-C), 108.6 C(CH3)2 100.9 (C-
1E), 100.8 (PhCH), 100.6 (C-1C), 98.1 (2 C, C-1A, C-
1B), 97.1 (C-1D), 82.9 (C-4C), 80.7 (C-4D), 78.5 (2 C,
C-5B, C-5D), 77.4 (C-3E), 76.6 (C-3A), 76.2 (C-3D),
75.9 (2 C, C-2D, C-3C), 75.6 (C-4B), 75.5 (C-2E), 75.2
(2 C, 2 PhCH2), 74.6 (PhCH2), 73.9 (C-3B), 71.9 (C-
4E), 71.8 (PhCH2), 71.5 (PhCH2), 69.2 (C-6B), 68.1 (2
C, C-5A, C-5E), 66.1 (C-4A), 64.6 (2 C, C-2B, C-2C),
63.6 (C-5C), 61.8 (C-6A), 59.4 (C-2A), 55.5 (OCH3),
28.2 (CH3), 26.4 (CH3), 20.6 (COCH3), 20.5 (COCH3),
18.0 (CCH3), 17.8 (CCH3); HRMS [M+Na]+:
Calcd.1701.6680; found, 1701.6690.
L
-
benzylidene-α-
D
-galactopyranosyl)-(1→3)-4,6-di-O-
-galactopyranoside (10):
acetyl-2-azido-2-deoxy-α-
D
Glycosylation of compound 9 (2.5 g, 2.35 mmol) and
compound 6 (950 mg, 2.58 mmol) was carried out in
the presence of NIS (610 mg, 2.71 mmol) and HClO4-
SiO2 (30 mg) following the similar reaction condition
as mentioned in the preparation of compound 8. The
crude product was purified over SiO2 using hexane-
EtOAc (4:1) as eluant to give pure compound 10 (2.2
g, 75%); Colourless syrup; [α]D +80 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3): δ 7.50-7.24 (m, 20 H, Ar-H),
6.97 (d, J = 9.0 Hz, 2 H, Ar-H), 6.78 (d, J = 9.0 Hz, 2
H, Ar-H), 5.55 (d, J = 3.0 Hz, 1 H, H-4A), 5.44 (d, J =
3.0 Hz, 1 H, H-1A), 5.35 (s, 1 H, PhCH), 5.24 (d, J =
2.0 Hz, 1 H, H-1C), 5.21 (d, J = 3.5 Hz, 1 H, H-1B),
5.11 (s, 1 H, PhCH), 4.81-4.57 (m, 6 H, 6 PhCH), 4.36
(dd, J = 9.5 Hz, 3.0 Hz, 1 H, H-2B), 4.28-4.22 (m, 3 H,
H-3A, H-5A, H-6aA), 4.15 (dd, J = 9.0 Hz, 2.5 Hz, 1 H,
H-3B), 4.11 (br s, 1 H, H-2D), 4.05 (d, J = 2.5 Hz, 1 H,
H-4B), 4.02-3.92 (m, 5 H, H-2C, H-3B, H-6bA, H-6abB),
3.83 (dd, J = 9.0 Hz, 3.0 Hz, 1 H, H-3C), 3.79-3.76 (m,
2 H, H-2A, H-5B), 3.75 (s, 3 H, OCH3), 3.74-3.70 (m, 2
H, H-5C, H-5D), 3.43 (t, J = 9.5 Hz, 1 H, H-4C), 3.35 (t,
J = 9.5 Hz, 1 H, H-4D), 1.99 (s, 3 H, COCH3), 1.90 (s,
3 H, COCH3), 1.49 (s, 3 H, CH3), 1.35 (s, 3 H, CH3),
1.26 (d, J = 6.5 Hz, 3 H, CCH3), 1.21 (d, J = 6.5 Hz, 3
H, CCH3); 13C NMR (125 MHz, CDCl3): δ 169.9
(COCH3), 169.5 (COCH3), 155.7-114.6 (Ar-C), 109.1
C(CH3)2, 100.7 (C-1C), 100.6 (PhCH), 98.3 (C-1A),
98.0 (C-1D), 97.0 (C-1B), 80.7 (C-4C), 78.1 (C-3C), 76.2
(C-3B), 75.7 (C-3D), 74.4 (C-2D), 74.3 (C-2C, C-4D, C-
5D), 73.8 (C-4B), 71.9 (2 C, 2 PhCH2), 71.8 (C-3A),
71.3 (PhCH2), 70.9 (C-2B), 69.2 (C-6B), 68.2 (C-2C),
68.1 (C-5A), 66.5 (C-5C), 66.1 (C-4A), 63.6 (C-5B), 61.8
(C-6A), 59.4 (C-2A), 55.5 (OCH3), 28.0 (CH3), 26.3
(CH3), 20.6 (COCH3), 20.5 (COCH3), 18.3 (CCH3),
17.2 (CCH3); HRMS [M+Na]+: Calcd. 1270.4948;
found, 1270.4940.
One-pot iterative reaction condition for the
synthesis of compound 11: To a solution of
compound 3 (500 mg, 1.26 mmol) and compound 4
(680 mg, 1.26 mmol) in anhydrous CH2Cl2 (10 mL)
was added MS 4Å (1 g) and the reaction mixture was
cooled to −30 °C under argon. To the cooled reaction
mixture was added NIS (290 mg, 1.28 mmol) followed
by HClO4-SiO2 (50 mg) and the reaction mixture was
allowed to stir at same temperature for 45 min. The
temperature of the reaction was raised to 0 °C and
stirred for another 30 min. After consumption of the
starting materials and formation of a new major spot in
TLC (hexane-EtOAc 2:1), the reaction mixture was
cooled to −30 °C and compound 5 (640 mg, 1.25
mmol) followed by NIS (270 mg, 1.20 mmol) were
added to it and allowed to stir for 45 min at same
temperature. The temperature of the reaction mixture
was raised to 0 °C and stirred for 30 min. After
checking the TLC (hexane-EtOAc 2:1), the reaction
mixture was cooled to −30 °C and compound 6 (440
mg, 1.19 mmol) followed by NIS (270 mg, 1.20 mmol)
were added to it and allowed to stir for 45 min at same
temperature. The temperature of the reaction mixture
was raised to 0 °C and stirred for 30 min. Again, after
checking the TLC (hexane-EtOAc 1:1), the reaction
mixture was cooled to −30 °C and compound 7 (540
mg, 1.09 mmol) followed by NIS (250 mg, 1.11 mmol)
were added to it and allowed to stir for 45 min at same
temperature. The temperature of the reaction mixture
was raised to 0 °C and stirred for 30 min. The reaction
mixture was filtered and washed with CH2Cl2 (50 mL).
The combined organic layer was successively washed
with 5% aq. Na2S2O3 (50 mL), satd. NaHCO3 (50 mL)
and H2O (50 mL), dried (Na2SO4) and concentrated.
The crude product was purified over SiO2 using
p-Methoxyphenyl (2,4-di-O-benzyl-3-O-picoloyl-β-
rhamnopyranosyl)-(1→4)-(2,3-O-isopropylidene-α-
-rhamnopyranosyl)-(1→2)-(3,4-di-O-benzyl-α-
rhamnopyranosyl)-(1→2)-(3-O-benzyl-4,6-O-
benzylidene-α- -galactopyranosyl)-(1→3)-4,6-di-O-
acetyl-2-azido-2-deoxy-α- -galactopyranoside (11):
L
-
L
L
-
D
D
Glycosylation of compound 10 (1.5 g, 1.2 mmol) and
compound 7 (625 mg, 1.26 mmol) was carried out in
the presence of NIS (300 mg, 1.33 mmol) and HClO4-
SiO2 (25 mg) following the similar reaction condition
as mentioned in the preparation of compound 8. The
crude product was purified over SiO2 using hexane-
EtOAc (3:1) as eluant to give pure compound 11 (1.5
g, 74%); Colourless syrup; [α]D −110 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3): δ 8.80-8.78 (m, 1 H, Ar-
H), 7.96-6.75 (m, 37 H, Ar-H), 5.55 (d, J = 2.5 Hz, 1
H, H-4A), 5.44 (d, J = 3.5 Hz, 1 H, H-1A), 5.32 (s, 1 H,
PhCH), 5.22 (d, J = 1.5 Hz, 1 H, H-1C), 5.18 (d, J = 3.5
Hz, 1 H, H-1B), 5.05 (br s, 1 H, H-1D), 5.03 (dd, J = 9.5

Tetrahedron
8
hexane-EtOAc (5:1) as eluant to give pure compound
11 (1 g, 48%).
New Delhi (Project No. EMR/2015/000282 dated
17.09.2015) and Bose Institute.
References
p-Methoxyphenyl
(α- -rhamnopyranosyl)-(1→2)-(α-
syl)-(1→2)-(α- -galactopyranosyl uronic acid)-
(1→3)-2-acetamido-2-deoxy-α- -galactopyranoside
(β-
L
-rhamnopyranosyl)-(1→4)-
L
L
-rhamnopyrano-
1. (a) Motarjemi, Y.; Käferstein, F. K. World Health Statistics
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D
D
(1): A solution of compound 11 (1 g, 0.59 mmol) in
80% aq. AcOH (25 mL) was allowed to stir at 80 °C
for 1 h. The solvents were removed under reduced
pressure and the product was dissolved in CH3CN-H2O
(10 mL; 1:1). To the reaction mixture was added
TEMPO (200 mg, 1.28 mmol) followed by BAIB (500
mg, 1.55 mmol) and the reaction mixture was allowed
to stir for 3 h. The reaction mixture was concentrated
under reduced pressure to give the oxidized product,
which was passed through a short pad of SiO2. To a
solution of the oxidized product in CH3OH (10 mL)
was added 20% Pd(OH)2-C (100 mg) and the reaction
mixture was stirred under a positive pressure of
hydrogen for 24 h. The reaction mixture was filtered
through a Celite bed and acetic anhydride (2 mL) was
added to it. The solvents were removed under reduced
pressure and a solution of the hydrogenolized product
in 0.1 M NaOCH3 (10 mL) was stirred at room
temperature for 3 h. The reaction mixture was
neutralized with Dowex 50W X8 (H+) resin and
concentrated to a solid mass, which was passed
through a column of Sephadex LH-20 column using
methanol-H2O (4:1) as eluant to give pure compound 1
(320 mg, 58% in five steps). White powder; [α]D −20
(c 1.0, H2O); 1H NMR (500 MHz, D2O): δ 7.15 (d, J =
9.0 Hz, 2 H, Ar-H), 7.01 (d, J = 9.0 Hz, 2 H, Ar-H),
5.53 (d, J = 3.5 Hz, 1 H, H-1A), 5.32 (br s, 1 H, H-1C),
5.23 (d, J = 2.0 Hz, 1 H, H-1B), 5.00 (br s, 1 H, H-1D),
4.74 (br s, 1 H, H-1E), 4.56 (dd, J = 10.0 Hz, 3.5 Hz, 1
H, H-2A), 4.27-4.24 (m, 2 H, H-3A, H-4B), 4.16 (br s,
H, H-2D), 4.13-4.11 (m, 1 H, H-5B), 4.10 (d, J = 3.0
Hz, 1 H, H-4A), 4.09 (br s, 1 H, H-2C), 4.08 (br s, 1 H,
H-2E), 4.07-4.06 (m, 2 H, H-2B, H-5A), 3.97-3.94 (m, 1
H, H-3D), 3.93-3.90 (m, 2 H, H-3B, H-3C), 3.82 (s, 3 H,
OCH3), 3.80-3.76 (m, 3 H, H-5D, H-6abA), 3.74-3.69
(m, 1 H, H-5C), 3.63-3.61 (m, 2 H, H-3E, H-4C), 3.55-
3.50 (m, 1 H, H-4E), 3.48-3.44 (m, 1 H, H-5E), 3.42 (t,
J = 9.5 Hz, 1 H, H-4D), 2.09 (s, 3 H, COCH3), 1.35-
1.30 (m, 9 H, 3 CCH3); 13C NMR (125 MHz, CDCl3):
δ 175.4 (COCH3), 174.2 (COOH), 154.6-115.0 (Ar-C),
101.9 (C-1D), 100.4 (C-1E), 99.7 (C-1C), 97.2 (C-1B),
95.1 (C-1A), 82.5 (C-4D), 78.1 (C-2C), 73.2 (C-3E), 72.7
(C-2B), 72.5 (2 C, C-4C, C-5E), 72.2 (C-5B), 71.9 (C-
3A), 71.8 (C-4B), 71.4 (C-4E), 71.3 (C-5A), 70.5 (C-3C),
69.8 (C-3B), 69.6 (C-2D), 69.5 (C-5C), 69.3 (C-3D), 68.8
(C-5D), 67.6 (C-2E), 65.3 (C-4A), 61.0 (C-6A), 55.7
(OCH3), 47.9 (C-2 A), 22.2 (COCH3), 17.0 (CH3), 16.9
(CCH3), 16.8 (CCH3); HRMS [M+Na]+: Calcd.
964.3274; found, 964.3285.
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P.S. thanks CSIR, New Delhi for providing Senior
Research Fellowship. The work is supported by SERB,

Tetrahedron
9
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Research Highlights
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Pentasaccharide of the O-antigen of Shigella boydii type 18 A was synthesized.
A combination of NIS and HClO4-SiO2 as glycosylation activator.
p-Methoxybenzyl (PMB) was used as in situ removable protecting groups.
A one-pot reaction sequence applying iterative glycosylation steps has been developed.
HClO4-SiO2 has been used as a solid acid catalyst.

Conflicts of Interest
There are no conflicts to declare.