Convergent synthesis of the tetrasaccharide repeating unit related to the O-antigenic polysaccharide of Escherichia coli 78

Article abstract of DOI:10.1016/j.tet.2010.02.052

A convergent synthesis of the tetrasaccharide repeating unit of the O-antigenic cell wall polysaccharide of Escherichia coli 78, as the corresponding methyl glycoside (I), is being reported. It involved stereoselective glycosidation of a β-linked mannodis

Full text of DOI:10.1016/j.tet.2010.02.052

Tetrahedron 66 (2010) 2809–2814
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent synthesis of the tetrasaccharide repeating unit related
to the O-antigenic polysaccharide of Escherichia coli 78
,
Sajal K. Maitya, Amarendra Patra b, Rina Ghosh a
*
a Department of Chemistry, Jadavpur University, Kolkata 700 032, India
b Department of Chemistry, University College of Science and Technology, University of Calcutta, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent synthesis of the tetrasaccharide repeating unit of the O-antigenic cell wall polysaccharide
of Escherichia coli 78, as the corresponding methyl glycoside (I), is being reported. It involved stereo-
selective glycosidation of a b-linked mannodisaccharide acceptor with a b-linked glucosamine based
disaccharide thioglycoside donor, which were prepared from the corresponding functionalised mono-
saccharide based glycosyl donors and acceptors. The resulting tetrasaccharide derivative was finally
converted to (I) by selective deprotection and also by global protection and deprotection techniques.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 December 2009
Received in revised form 12 February 2010
Accepted 12 February 2010
Available online 17 February 2010
Keywords:
E. coli 78
O-Antigen
Tetrasaccharide
Cell wall polysaccharide
1. Introduction
can not meet the quantity required for their detailed biological
studies. Oligosaccharides or their modified forms are, however,
Escherichia coli, a group of gram negative bacteria generally
confined to intestinal lumen, causes human gastroenteritis;1 it may
also infect immune-suppressed host.2 Three general clinical syn-
dromes effected by pathogenic clones of E. coli are urinary tract
infection, sepsis or meningitis, and enteric or diarrheal disease.3
About one third of isolated enterotoxic strains of E. coli (ETEC) in-
clude serogroups of O6, O8, and O78. ETEC are associated with
pediatric diarrhea in developing countries, severe cholera like
disease in epidemic cholera zones and ‘travellers’ diarrhea’.
Structure of the O-antigenic cell wall polysaccharide of E. coli 78
(Fig. 1) was established by Jansson et al.4 through methylation
analysis, partial solvolysis with liquid hydrogen fluoride and also by
1D- and 2D-NMR spectroscopy.
obtainable in large quantities by chemical synthesis.
In continuation to our research based on carbohydrate syn-
thesis,5 and also as part of our ongoing research programme to the
synthesis of oligosaccharides for developing serological markers
toward a variety of bacterial strains, we present herein the conver-
gent synthesis (Schemes 1–3) of the tetrasaccharide repeating unit,
of the O-antigenic polysaccharide of E. coli 78 as its methyl glycoside
(I). To the best of our knowledge, this is the first synthesis of the
tetrasaccharide related to this strain.
Figure 1. Structure of the O-antigenic polysaccharide of E. coli 78.
Carbohydrates of bacterial cell wall play important role during
host infection and subsequent immune response in the host. Sub-
stantial amounts of bacterial polysaccharides or oligosaccharides
are necessary for extensive biological evaluation and biochemical
studies of bacterial strains. Though, oligosaccharides can be isolated
from the native sources, the meager amount obtained by isolation
Scheme 1. Reagents and conditions: (a) Ac2O (1.2 equiv), pyridine, DMAP, CH2Cl2, rt,
1 h, 99%; (b) NaCNBH3 (12 equiv), HCl/Et2O, THF, 4 Å MS, 0 ꢀC /20 ꢀC, 40 min, 94%;
(c) 1 (1.0 equiv), BSP, Tf2O, TTBP, CH2Cl2, 4 Å MS, Ar, ꢁ78 ꢀC, 30 min, 75%.
* Corresponding author. Fax: þ91 033 24146266; e-mail addresses: ghosh_rina@
hotmail.com, ghoshrina@yahoo.com.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.052

2810
S.K. Maity et al. / Tetrahedron 66 (2010) 2809–2814
glycosyl donor 6 and acceptor 9. Similarly, 5 was obtainable from its
corresponding donor 1 and acceptor 4. Throughout the synthesis
we have used thioglycoside donors as these are sufficiently stable
for protecting group manipulation and can tolerate a wide range of
reaction conditions.
The actual synthesis of the tetrasaccharide methyl glycoside (I)
was initiated from known phenyl 4,6-O-benzylidene-2-deoxy-2-
phthalimido-1-thio-
b-D
-glucopyranoside 2.6 Acetylation of
2
followed by regioselective opening of the benzylidene acetal7 of the
resulting product 3 using NaCNBH3 and ethereal hydrogen chloride
afforded 48 in excellent yield. The glucosamine derived glycosyl
acceptors containing free 4-hydroxy group are known to have re-
latively low nucleophilicity.9 Since Crich’s glycosidation technique10
has been successfully utilized for the synthesis of N-acetylglucos-
amine oligosaccharides involving less reactive glycosyl acceptors,8
we have adopted Crich’s glycosidation procedure. Preactivation of
the known 2-phthalimidoglucosamine derived thioglycoside donor
112 was done with 1-benzenesulfinylpiperidine (BSP)13 and Tf2O in
the presence of 2,4,6-tri-tert-butylpyrimidine (TTBP) at ꢁ60 ꢀC, and
subsequent reaction of the in situ generated glucosaminyl triflate
intermediate with acceptor 4 resulted in the formation of the cor-
responding disaccharide 5 in modest 55% yield, probably because of
decomposition of the triflate intermediate as side reaction at this
temperature. Similar decomposition has been observed by Hansen
et al.11 in such type of coupling reactions using related donors at
ꢁ60 ꢀC. It has also been mentioned by Yamago et al. that the
Scheme 2. Reagents and conditions: (a) NaH, DMF, 0 ꢀC, BnBr (2.4 equiv), rt, 2 h, 92%;
(b) NaCNBH3 (9 equiv), HCl/Et2O, THF, 4 Å MS, 0 ꢀC, 10 min, 83%; (c) 6 (1.0 equiv), BSP,
Tf2O, TTBP, CH2Cl2, 4 Å MS, Ar, ꢁ78 ꢀC, 1 h, 83%; (d) (i) Et3SiH (16 equiv), BF3$Et2O
(2 equiv), CH2Cl2, ꢁ5 ꢀC, 2 h; (ii) TBDPSCl (1.5 equiv), Imidazole, DMF, 12 h, 65%.
a-glucosaminyl triflate intermediate generated in situ decomposes
above ꢁ50 ꢀC.8 Preactivation of 1 at ꢁ60 ꢀC and conducting the re-
action with the acceptor 4 at ꢁ78 ꢀC followed by quenching of the
reaction mixture with triethylphosphite gave the desired
b-di-
saccharide 58 in good yield (75%, Scheme 1). Improvement of yield
using triethylphosphite as quencher has also been mentioned for
glycosidation of other glycosyl donors.11,14 Although participation of
the adjacent phthalimido group in such type of reaction was pro-
posed earlier,15 this point could not be proved by NMR.8 Probably,
O-glycosidation to give 5 proceeds by an SN2 type reaction involving
the triflate intermediate. Structure of 5 was confirmed by NMR (ID-
Scheme 3. Reagents and conditions: (a) BSP (1.1 equiv), Tf2O, TTBP, CH2Cl2, 4 Å MS, Ar,
ꢁ70 ꢀC, 1 h, 70%; (b) (i) NH2NH2$H2O, ethanol, reflux, 8 h; (ii) Ac2O, Pyridine, rt, 12 h;
(iii) 0.05 M CH3ONa–CH3OH, rt, 20 h; (iv) 10% Pd–C, CH3OH/H2O/AcOH (6:1:1 v/v), rt,
24 h; overall yield 96%.
1
0
0
and 2D-) spectroscopy. Although, the J(C1 , H1 ) value (169.0 Hz) was
higher than that expected for a
b
-linkage, but chemical shifts of H-10
(d
5.45) 0and C-10 (
d 96.9) of 5 along with the corresponding high
3
0
0
0
J(H1 ,H2 ) value (8.4 Hz) and the H1 H5 NOE correlation were in-
2. Results and discussion
dicative of a
compound.
b-linkage between the two glucosamine units in this
The convergent route depicted in Figure 2 was envisioned. The
retrosynthetic analysis indicated that I could be synthesized
through compound 12, which could be assembled from the corre-
sponding D-mannose disaccharide derived glycosyl acceptor 11 and
glucosamine disaccharide based glycosyl donor 5. Compound 11
Synthesis of the mannose disaccharide acceptor (Scheme 2) was
started from the known methyl 4,6-O-benzylidene-a-D-man-
nopyranoside 7.16 Benzylation followed by regioselective depro-
tection of 8 with NaCNBH3 using ether moistened with hydrogen
chloride7 generated the mannose-glycosyl acceptor 9. Preactivation
of the known mannose derived thioglycoside donor 65h,17 with BSP
could in turn be obtained by coupling reaction of the mannose-
and Tf2O generated in situ the corresponding
flate,10c,d,g,18 which subsequently reacted with 9 affording the cor-
responding crystalline
-mannoside 1019 in high yield (Scheme 2).
Chemical shifts of H-10 ( 4.49, br s), H-50 (
3.07, m, characteristic of
H-5 of 4,6-O-benzylidenated 102.0)
-mannoside10c–f) and C-10 (
along with the corresponding J(C1 , H1 ) (156.2 Hz) of compound 10
a-mannosyl tri-
b
d
d
b
d
1
0
0
confirmed formation of the b-glycoside. It is worthy to mention here
that synthesis of 10 has been made by Kim et al.,19 via activation of
the anomeric center through phthalic-triflic acid mixed anhydride,
and compound 10 has been reported by this group to be a colorless
20
oil showing [
a
]
þ5.2 in CHCl3, whereas, in the present synthesis
D
20
we have obtained crystalline 10 (having [
a]
ꢁ12.5 in CHCl3), which
D
was characterized by 1D- and 2D-NMR data. Regioselective opening
of the benzylidene acetal of 10 was then effected by Et3SiH in the
presence of BF3$Et2O,20 which resulted in the formation of the de-
sired glycosyl acceptor 11 (major) together with its 6-regioisomer
(minor), but the mixture was chromatographically inseparable at
Figure 2. Retrosynthesis of I.

S.K. Maity et al. / Tetrahedron 66 (2010) 2809–2814
2811
this stage. This problem was circumvented by selective silylation21
of the primary hydroxyl group of the undesired regioisomer in the
mixture followed by its facile chromatographic separation on silica
gel column, which furnished 11 in 65% yield.
Preactivation of glucosamine derived disaccharide donor 5 with
BSP and Tf2O at ꢁ60 ꢀC and its reaction with functionalized man-
nose disaccharide acceptor 11 in the presence of TTBP at ꢁ70 ꢀC
then afforded the corresponding tetrasaccharide derivative 12 in
70% yield (Scheme 3). The structure of 12 was confirmed by 1H- and
13C NMR using 1D- and 2D- (COSYGP, HMBCGP, HSQCGP, TOCSY, and
ROESY) techniques. The anomeric protons of 12, listed from the non-
obtained without further purification. Solvents were purified and
dried by standard methods prior to use. Melting points were de-
termined on a Toshniwal melting apparatus and are uncorrected.
Thin-layer chromatography (TLC) was performed on glass plates
precoated with silica gel or on Merck silica gel plates (60-F254) to
monitor the reactions. Visualization of spots was accomplished by
spraying the chromatograms with 5% ethanolic solution of sulfuric
acid and charring on a hot plate. Column chromatography was
carried out on silica gel 60–120 mesh (SRL, India) and Flash chro-
matography was performed on Merck silica gel 60 (230–400 mesh).
Proton and carbon chemical shifts (d) are expressed in ppm. NMR
reducing end, appeared at
(d), and the corresponding anomeric carbons showed respective
chemical shifts at
96.7, 97.7, 101.0, and 99.4. The 1J(C1, H1) coupling
constants from the non-reducing end were 167.0, 164.9, 156.9, and
168.3 Hz, respectively. Long-range coupling correlation (Fig. 3, vide
d
5.36 (d), 5.45 (d), 4.31 (br s), and 4.68
spectra were recorded on a Brucker DPX-300 and AV 300 spec-
trometer at ambient temperature in CDCl3 with tetramethylsilane
as internal standard and D2O [HOD (4.78 ppm, 298 ꢀK)] with 1,4
Dioxan (67.4 ppm) as internal standard, respectively and assigned
using 2D-methods (COSYGP, DEPT, HSQCGP, HBMCGP, TOCSYGP,
NOESY, and ROESY). IR spectra were recoded on FTIR-8300 in-
strument and reported in cmꢁ1. Optical rotations were measured
on a Jasco P-1020 polarimeter. Elemental analysis was done using
2400-Series II C,H,N-Analyzer, Perkin–Elmer, US from IACS, Kolkata
700032, India. HRMS measurements were made with a Q-tof-Micro
(YA-263) mass spectrometer by electron spray ionization method.
d
Electronic Supplementary data) of the tetrasaccharide derivative 12,
1
00
00
together with the coupling constants J(C1 , H1 ) (164.9 Hz) and
3J(H010,H020 ) (8.5 Hz) corresponding to the new glycosidic bond un-
equivocally proved the new linkage to be (1/4)-b. Removal of the
phthalimido groups of 12 with hydrazine hydrate followed by suc-
´
cessive N-acetylation, Zemplen deacetylation and global debenzy-
lation under catalytic hydrogenation conditions finally furnished
the corresponding tetrasaccharide as its methyl glycoside (I). A
comparison of the chemical shifts of anomeric protons and carbons
along with the values of the 1J(C1, H1) of the synthesized tetra-
saccharide glycoside (I) recorded in D2O at 22 ꢀC, with those of E. coli
78 O-antigenic polysaccharide (taken in D2O at 70 ꢀC)4 is given in
Table 1. Compound I showed anomeric proton signals, listed from
4.2. Phenyl 3-O-acetyl-4,6-O-benzylidene-2-deoxy-
2-phthalimido-1-thio-b-D-glucopyranoside (3)
To a magnetically stirred solution of the phenyl 4,6-O-benzyli-
dene-2-deoxy-2-phthalimido-1-thio- -glucopyranoside (2, 1.2 g,
b-D
2.45 mmol), DMAP (60 mg, 0.49 mmol), and pyridine (0.60 mL,
7.43 mmol) in dry CH2Cl2 (10 mL) was added acetic anhydride
(0.347 ml, 3.68 mmol) at room temperature and the reaction mix-
ture was stirred for 2 h. After completion of the reaction, the mix-
ture was concentrated under reduced pressure and then diluted
with CH2Cl2. The organic layer was successively washed with sat-
urated aqueous NaHCO3 and water, dried (Na2SO4) and concen-
trated under reduced pressure. The crude mass was purified by
column chromatography (20% EtOAc/hexane) to furnish 3 (1.29 g,
99%) as white solid; Rf (30% EtOAc/hexane) 0.4; mp 114–115 ꢀC
the non-reducing end at
d 4.53 (d, 7.8 Hz), 4.57 (d, 8.4 Hz), 4.72 (br s),
and 4.76 (d, 3 Hz), respectively, and the corresponding anomeric
carbons at d 102.3 (162.9 Hz),102.2 (162.9 Hz),100.8 (163.3 Hz), and
101.5 (173.7 Hz). These chemical shifts and the respective 1J(C1, H1)
values are consistent with those of anomeric protons and carbons of
the O-antigen of E. coli 78.4 The observed NMR spectral data indicate
the presence of two
b
-linked GlcpNAc residues, one
b-linked Manp
and one
a-linked Manp residue in I.
20
25
(EtOAc/hexane) (lit.22, 115 ꢀC); [
a]
þ23.0 (c 1.0, CHCl3); lit.22
[a]
D
D
Table 1
þ18.3 (c 1.5, CHCl3); nmax (KBr plate) 3630, 2882, 1775, 1734, 1717,
Comparison of chemical shifts and coupling constants of anomeric protons and
carbons of compound I and O-antigen of E. coli 78
1383, 1225, 1098, 1067, 725 cmꢁ1
; dH (300 MHz, CDCl3) 7.87–7.74
H-1 (3J)
H-10 (3J)
H-100 (3J)
H-1% (3J)
(4H, m, ArH), 7.45–7.29 (10H, m, ArH), 5.90 (1H, t, J 9.5, 9.1 Hz, H-3),
5.84 (1H, d, J 10.6 Hz, H-1), 5.54 (1H, s, CHPh), 4.44 (1H, d, J 5.9 Hz,
H-4), 4.36 (1H, t, J 10.2, 10.1 Hz), 3.84–3.76 (3H, m, H-5, H-6a, H-6b),
1.88 (3H, s, COCH3); dC (75 MHz, CDCl3) 170.1 (C]O), 167.8 (C]O),
167.2 (C]O), 136.8, 134.4, 134.2, 133.0 (2C), 131.6, 131.1, 129.1, 129.0
(2C),128.3, 128.2 (2C),126.2 (2C),123.7, 123.6, 101.6, 83.8, 79.0, 70.6,
70.5, 68.5, 54.3, 20.5.
Compound I
O-Antigen
4.76 (3)
5.25
4.72
4.70
4.57 (8.4)
4.63
4.53 (7.8)
4.55
of E. coli 784
C-1 (1J)
C-10 (1J)
C-100 (1J)
C-1% (1J)
Compound I
O-Antigen
101.5 (173.7) 100.8 (163.3) 102.2 (162.9) 102.3 (162.9)
101.4 (174) 100.9 (162) 101.9 (164) 102.2 (164)
of E. coli 784
3J¼3J(H1–H2) Hz and 1J¼1J(C1–H1) Hz; Chemical shifts in
d (ppm).
4.3. Phenyl 3-O-acetyl-6-O-benzyl-2-deoxy-2-phthalimido-
1-thio-b-D-glucopyranoside (4)
3. Conclusion
To a solution of phenyl 3-O-acetyl-4,6-O-benzylidene-2-deoxy-
2-phthalimido-1-thio- -glucopyranoside (3, 1.7 g, 3.20 mmol) in
In summary, the first synthesis of the methyl glycoside of the
tetrasaccharide repeating unit (I) of O-antigenic polysaccharide of
E. coli 78 has been achieved following a convergent strategy that
exploits Crich’s glycosidation technique. The glycosidation steps
proceeded well with generation of the corresponding glycosides in
b-D
freshly dried THF (40 mL) was added sodium cyanoborohydride
(2.42 g, 38.42 mmol), 4 Å molecular sieves and a pinch of methyl
orange. After stirring at 0 ꢀC for 15 min, a saturated solution of
hydrogen chloride in diethyl ether was added slowly until the color
of the solution became permanently pink. The mixture was allowed
to stir at 20 ꢀC for another 40 min. Then the reaction mixture was
diluted with CH2Cl2, filtered through a Celite bed and the filtrate
was washed successively with saturated aqueous NaHCO3 solution,
brine and water. The organic layer was separated, dried and con-
centrated under reduced pressure. Purification of the crude product
good yields and excellent
b-selectivities.
4. Experimental
4.1. General methods
Unless otherwise stated, all the glass-wares were flame-or oven
dried before use. All the commercial reagents were used as
by silica gel column chromatography (30% EtOAc/hexane) afforded
4 (1.6 g, 94%) as colorless foam; Rf (50% EtOAc/hexane) 0.41; [a]
D
25

2812
S.K. Maity et al. / Tetrahedron 66 (2010) 2809–2814
þ22.5 (c 2.0, CHCl3); nmax (KBr plate) 3474, 2916, 1777, 1746, 1717,
1385, 1230, 1074, 719 cmꢁ1
dH (300 MHz, CDCl3) 7.87–7.82 (2H, m,
1.2, CHCl3), lit.24
2866, 1454, 1126, 1101, 1057, 750, 698 cmꢁ1
; dH (300 MHz, CDCl3)
[a]
þ29.6 (c 1.1, CHCl3); nmax (neat) 3030, 2909,
D
;
ArH); 7.72–7.66 (2H, m, ArH), 7.43–7.38 (2H, m, ArH), 7.36–7.30 (5H,
m, ArH), 7.26–7.20 (3H, m, ArH), 5.81 (1H, d, J 10.5 Hz), 5.71 (1H, dd,
J 10.2, 8.3 Hz), 4.61 (2H, m), 4.31 (1H, t, J 10.3 Hz), 3.85 (2H, br s),
3.82 (2H, br s), 3.13 (1H, d, J 4.0 Hz), 1.9 (3H, s, COCH3); dC (75 MHz,
CDCl3) 171.1 (C]O), 167.8 (C]O), 167.2 (C]O), 137.8, 134.4, 134.2,
132.7 (2C), 131.7, 131.6, 131.2, 128.8 (2C), 128.4 (2C), 128.0, 127.8,
127.7 (2C), 123.7, 123.6, 83.1, 78.5, 74.3, 73.7, 70.9, 70.1, 53.6, 20.6;
HRMS (ESI-TOF) (m/z): [MþNa]þ, found 556.1403. C29H27NO7SNa
requires 556.1406.
7.53–7.50 (2H, m, ArH), 7.41–7.26 (13H, m, ArH), 5.65 (1H, s, CHPh),
4.85–4.80 (2H, m), 4.76–4.64 (3H, m), 4.29–4.22 (2H, m), 3.97–3.83
(3H, m), 3.78 (1H, m), 3.37 (3H, s, OMe); dC (75 MHz, CDCl3) 138.7,
138.2, 137.8, 128.8, 128.4 (2C), 128.3 (2C), 128.2 (2C), 128.1 (2C), 127.8,
127.5 (3C),126.1 (2C),101.5,100.1, 79.2, 76.4, 73.6, 73.1, 68.9, 64.1, 54.8.
4.6. Methyl 2,3,6-tri-O-benzyl-
a-D-mannopyranoside (9)
To a solution of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-
a-D-
mannopyranoside (8, 2.3 g, 4.98 mmol) in freshly dried THF (70 mL)
was added sodium cyanoborohydride (2.82 g, 44.87 mmol), 4 Å
molecular sieves and a pinch of methyl orange. After stirring at 0 ꢀC
for 15 min, a saturated solution of hydrogen chloride in diethyl ether
was added slowly until the color of the solution became perma-
nently pink. The reaction mixture was stirred for 10 min at 0 ꢀC. It
was then diluted with CH2Cl2, filtered through Celite bed and the
filtrate was washed successively with saturated aqueous NaHCO3
solution, brine and water. The organic layer was separated, dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
Purification of the crude product by silica gel column chromatog-
4.4. Phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-
b-D
-glucopyranosyl-(1/4)-3-O-acetyl-6-O-benzyl-2-deoxy-
2-phthalimido-1-thio- -glucopyranoside (5)
b-D
A solution of donor 1 (525 mg, 0.996 mmol), BSP (229 mg,
1.096 mmol), TTBP23 (495 mg, 1.99 mmol) and activated 4 Å pow-
dered molecular sieves in dried CH2Cl2 (12 mL) was stirred at
ꢁ60 ꢀC under Ar atmosphere for 30 min, then was added Tf2O
(218 mL, 1.295 mmol). After 30 min, the temperature was brought
down to ꢁ78 ꢀC, and then a cold solution of acceptor 4 (796.5 mg,
1.49 mmol) in CH2Cl2 (3 mL) was slowly added. The reaction mix-
ture was stirred at ꢁ78 ꢀC for further 30 min and then quenched by
the addition of triethylphosphite (0.52 mL, 3.03 mmol). The mix-
ture was stirred at ꢁ78 ꢀC for another 30 min, after which it was
warmed up to room temperature. The molecular sieves were fil-
tered off, and the filtrate was washed successively with saturated
aqueous NaHCO3 solution, brine and dried over Na2SO4. The or-
ganic layer was concentrated under reduced pressure. Purification
by silica gel column chromatography (32% EtOAc/hexane) afforded
5 (711.4 mg, 75%) as white foam, which on crystallization from
raphy (14% EtOAc/hexane) afforded 9 (1.92 g, 83%) as colorless
25
syrup; Rf (20% EtOAc/hexane) 0.38; [
a]
þ5.1 (c 1.1, CHCl3), lit.24
[a]
D
D
þ4.5 (c 1.68, CHCl3); nmax (neat) 3462, 2910, 2872, 1454, 1138, 1109,
1057, 737, 698 cmꢁ1
; dH (300 MHz, CDCl3) 7.38–7.27 (15H, m, ArH),
4.81 (1H, br s), 4.70 (1H, s), 4.69 (1H, s), 4.64–4.59 (3H, m,), 4.52 (1H,
d, J 11.7 Hz), 4.06 (1H, dt, J 9.3, 1.5 Hz), 3.84–3.79 (3H, m), 3.76–3.70
(2H, m,), 3.37 (3H, s, OMe), 2.55 (1H, s, OH); dC (75 MHz, CDCl3)
138.3, 138.2 (2C), 128.5 (2C), 128.4 (2C), 128.3 (2C), 127.9 (2C), 127.8,
127.75 (2C), 127.7, 127.6 (2C), 127.5, 99.2, 79.7, 73.9, 73.6, 72.7, 71.8,
71.5, 70.5, 67.8, 54.9.
EtOAc/hexane gave white crystals; Rf (50% EtOAc/hexane) 0.39; mp
25
193–194 ꢀC; [
a
]
D
þ10.1 (c 2.0, CHCl3); nmax (KBr plate) 3480, 2936,
1778, 1748, 1717, 1389, 1233, 1071, 1042, 723 cmꢁ1
;
dH (300 MHz,
4.7. Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-b-D-manno-
CDCl3) 7.85–7.82 (7H, m, ArH), 7.74–7.71 (4H, m, ArH), 7.39–7.30
(7H, m, ArH), 7.21–7.12 (3H, m, ArH), 5.74–5.66 (2H, m, H-3, H-30),
5.59 (1H, d, J 10.6 Hz, H-1), 5.45 (1H, d, J 8.4 Hz, H-10), 5.09 (1H, t, J
9.7, 9.6 Hz, H-40), 4.51 (1H, d, J 11.8 Hz, CH2Ph), 4.44 (1H, d, J 11.8 Hz,
CH2Ph), 4.37 (1H, dd, J 12.4, 3.9 Hz, H-6a0), 4.23 (1H, t, J 10.5, 9.2 Hz,
H-2), 4.20–4.09 (2H, m, H-20, H-4), 3.93 (1H, dd, J 12.3, 1.7 Hz, H-
6b0), 3.61–3.44 (4H, m, H-5, H-5’, H-6a, H-6b), 2.03 (3H, s, COCH3),
1.99 (3H, s, COCH3), 1.90 (3H, s, COCH3), 1.81 (3H, s, COCH3); dC
(75 MHz, CDCl3) 170.5 (C]O), 170.1 (C]O), 169.9 (C]O), 169.4
(C]O), 167.7 (C]O, 2C), 167.2 (C]O, 2C), 138.3, 134.4, 134.1, 133.1,
131.7, 131.3, 131.2, 128.8, 128.3, 128.1, 127.5, 127.4, 123.6, 123.5, 96.9
pyranosyl-(1/4)-2,3,6-tri-O-benzyl- -mannopyranoside (10)
a-D
To a stirred solution of donor 6 (1.44 g, 2.67 mmol), BSP (614 mg,
2.94 mmol), TTBP (1.33 g, 5.35 mmol), and 4 Å molecular sieves in
CH2Cl2 (50 mL), at ꢁ60 ꢀC under an Ar atmosphere, was added Tf2O
(0.54 mL, 3.21 mmol). After 30 min, the temperature was brought
down to ꢁ78 ꢀC, and then acceptor 9 (1.48 g, 0.60 mmol) in CH2Cl2
(3 mL) was slowly added. The reaction mixture was stirred for 1 h at
ꢁ78 ꢀC and then allowed to warm up over 1 h to 0 ꢀC. The reaction
mixture was poured into aq NaHCO3 solution, diluted with CH2Cl2,
and filtered through Celite. The organic layer was separated from
the filtrate, washed with brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by flash column chroma-
tography (hexane/EtOAc/CH2Cl2, 6:2:1, v/v) on silica gel to give 10
1
1
0
0
[ J(C1 ,H1 )¼169.0 Hz], 82.9 [ J(C1,H1)¼160.4 Hz], 78.5, 73.8, 72.7,
71.9, 71.6, 70.6, 68.4, 67.8, 61.4, 54.9, 53.9, 20.6, 20.5, 20.4, 20.3;
HRMS (ESI-TOF) (m/z): [MþNa]þ, found 973.2463. C49H46N2O16SNa
requires 973.2466.
(1.98 g, 83%) as white solid; Rf (hexane/EtOAc/CH2Cl2, 6:2:1, v/v)
25
0.30; mp 116–117 ꢀC (EtOAc/hexane); [
a]
ꢁ12.5 (c 1.24, CHCl3),
D
20
4.5. Methyl 2,3-di-O-benzyl-4,6-O-benzylidene-
lit.19
[
a]
þ5.2 (c 0.5, CHCl3); nmax (KBr plate) 3028, 2893, 2870,
D
a
-D-mannopyranoside (8)
1142, 1111, 1088, 1061, 735 cmꢁ1
; dH (300 MHz, CDCl3) 7.52–7.17
(30H, m, ArH), 5.50 (1H, s, CHPh), 4.84–4.74 (3H, m, CH2Ph), 4.73
(1H, d, J 2.1 Hz, H-1), 4.71–4.63 (4H, m, CH2Ph), 4.57–4.53 (2H, m,
CH2Ph), 4.49 (1H, s, H-10), 4.40 (1H, d, J 12.0 Hz, CH2Ph), 4.18 (1H, t, J
8.9 Hz, H-4), 4.09–4.00 (2H, m, H-40, H-6a0), 3.84 (1H, dd, J 8.5, 3.0,
Hz, H-3), 3.74 (1H, t, J 2.6, 2.5 Hz, H-2), 3.68 (1H, d, J 3.0 Hz, H-20),
3.66–3.57 (4H, m, H-5, H-6a, H-6b, H-6b0), 3.39 (1H, dd, J 9.9, 2.9 Hz,
H-30), 3.34 (3H, s, OMe), 3.07 (1H, m, H-50); dC (75 MHz, CDCl3)
139.2, 138.7, 138.6, 138.4, 138.2, 137.7, 128.8, 128.4, 128.3, 128.23,
128.18, 128.14, 128.12, 128.0, 127.8, 127.7, 127.5, 127.4, 127.2, 127.1,
126.1, 102.0 [ J(C1 ,H1 )¼156.2 Hz], 101.3, 99.5 [ J(C1,H1)¼167.5 Hz],
78.7, 78.4, 78.0, 77.2, 76.2, 75.8, 74.9, 73.5, 72.9, 72.6, 72.5, 71.2, 69.2,
68.6, 67.3, 54.9; HRMS (ESI-TOF) (m/z): [MþNa]þ, found 917.3880.
C55H58O11Na requires 917.3877.
Sodium hydride (1.7 g, 60% suspension) was added to a solution
of methyl 4,6-O-benzylidene- -mannopyranoside (7, 4.0 g,
a-D
14.18 mmol) in dry DMF (20 mL) at 0 ꢀC with constant stirring fol-
lowed by dropwise addition of benzyl bromide (4.05 mL, 34.0 mmol).
The reaction mixture was allowed to warm gradually to room tem-
perature, and stirred for 2 h. The excess of sodium hydride was
decomposed with methanol, the mixture was evaporated to syrup,
which was then dissolved in CH2Cl2, washed with water, dried over
anhydrous Na2SO4, and concentrated. The crude product was then
purified on a column of silica gel (10% EtOAc/hexane) to give methyl
1
1
0
0
2,3-di-O-benzyl-4,6-O-benzylidene-
92%) as colorless syrup; Rf (20% EtOAc/hexane) 0.50; [
a-D-mannopyranoside (6.05 g,
25
a]
D
þ28.5 (c

S.K. Maity et al. / Tetrahedron 66 (2010) 2809–2814
2813
4.8. Methyl 2,3,6-tri-O-benzyl-
b
-
D
-mannopyranosyl-(1/4)-
6b0), 2.03 (3H, s, COCH3),1.98 (3H, s, COCH3),1.81 (6H, s, 2ꢂCOCH3); dC
(75 MHz, CDCl3) 170.6 (C]O), 170.1 (C]O), 169.9 (C]O), 169.4
(C]O), 168.0 (C]O), 167.8 (C]O), 139.0, 138.98, 138.7, 138.6, 138.5,
138.4, 138.3, 134.3, 134.1, 133.7, 131.7, 131.5, 131.4, 128.3 (2C), 128.19
(3C), 128.17 (3C),128.0 (3C),127.93 (2C),127.88,127.8 (2C), 127.7 (3C),
2,3,6-tri-O-benzyl- -mannopyranoside (11)
a-D
To a mixture of 10 (614.4 mg, 0.687 mmol) and 4 Å molecular
sieves in CH2Cl2 (14 mL) at 0 ꢀC under Ar atmosphere triethylsilane
(1.75 mL, 10.96 mmol) was added slowly, followed by boron tri-
fluoride diethyletherate (0.175 mL, 1.38 mmol). After stirring the
mixture for 2 h at ꢁ5 ꢀC, molecular sieves were filtered off and the
filtrate was poured into cold saturated aqueous NaHCO3 solution and
extracted with CH2Cl2 (3ꢂ30 mL). The combined organic extracts
were washed with brine (50 mL), dried over Na2SO4, filtered and
concentrated.
127.62 (2C),127.55 (3C),127.54 (3C),127.4 (2C),127.3,127.2 (2C),127.0
1
0
0
(2C),126.8,126.3 (2C),123.6,123.4,123.1,101.0 [ J(C1 ,H1 )¼156.9 Hz],
99.4 [1J(C1,H1)¼168.3 Hz], 97.7 [1J(C100,H100)¼164.9 Hz], 96.7
[1J(C%1,H%1)¼167.0 Hz], 81.0, 77.9, 77.2, 75.6, 75.3, 75.2, 75.1, 74.1, 74.0,
73.5, 73.4, 73.3, 72.8, 72.63, 72.6, 72.4, 71.5, 71.2, 71.0, 70.7, 69.4, 68.5,
68.4, 66.7, 61.5, 55.8, 54.9, 54.8, 20.61, 20.55, 20.5, 20.4.
The crude product was dissolved in DMF (6 mL) and stirred
overnight with tert-butyldiphenylchlorosilane (TBDPSCl, 0.18 mL,
0.69 mmol) and imidazole (24 mg, 0.35 mmol). After removal of
solvent, 11 (401 mg, colorless foam, 65%) was isolated by silica gel
4.10. Methyl 2-acetamido-2-deoxy-
(1/4)-2-acetamido-2-deoxy - -glucopyranosyl-(1/4)-
-mannopyranosyl-(1/4)- -mannopyranoside (I)
b-D-glucopyranosyl-
b-D
a-D
b-D
flash column chromatography (15% EtOAc/toluene); Rf (20% EtOAc/
To a solution of 12 (155 mg, 0.089 mmol) in ethanol (10 mL) was
25
toluene) 0.25; [
a]
ꢁ22.1 (c 2.3, CHCl3); nmax (neat) 3030, 2916,
added hydrazine hydrate (6 mL). The mixture was heated to reflux
for 8 h and then concentrated under reduced pressure. The residual
moisture was co-evaporated with toluene (3ꢂ5 mL) and the crude
product was dissolved in pyridine (24 mL) and acetic anhydride
(12 mL). After stirring at room temperature for 12 h, the solvent was
removed under vacuum. The crude product was purified by silica gel
column chromatography (EtOAc/hexane, 3:2). The resulting product
was dissolved in dry methanol (19 mL), and NaOMe (1 M in MeOH,
1 mL) was added. The mixture was stirred for 20 h and then neu-
tralized with DOWEX-50 W cation exchange resin (Hþ). The resin
was filtered off and the filtrate was evaporated under reduced
pressure. A mixture of the residue, 10% Pd–C (100 mg) in AcOH
(3 mL), MeOH (9 mL), and H2O (1 mL) was stirred under H2 atmo-
sphere for 24 h. The catalyst was then removed by filtration through
D
2868, 1452, 1105, 1061, 750, 739, 698 cmꢁ1
; dH (300 MHz, CDCl3)
7.39–7.24 (30H, m, ArH), 4.87–4.79 (2H, m), 4.75 (1H, d, J 2.3 Hz),
4.71–4.66 (4H, m), 4.63–4.37 (7H, m), 4.24 (1H, t, J 8.8, 8.6 Hz),
3.97–3.89 (2H, m), 3.78–3.68 (5H, m), 3.66–3.57 (2H, m), 3.35 (3H,
s, OMe), 3.24 (1H, m), 3.15 (1H, dd, J 9.4, 2.8 Hz), 2.71 (1H, s, OH); dC
(75 MHz, CDCl3) 139.2, 138.9, 138.4, 138.3, 138.1 (2C), 128.4 (2C),
128.34 (2C),128.23 (2C),128.18 (2C),128.09 (2C),128.03 (2C),127.80
(2C), 127.7 (8C), 127.6 (2C), 127.5, 127.4, 127.3 (2C), 127.2, 127.1, 101.4,
99.5, 81.7, 78.1, 75.7, 75.6, 74.8, 74.7, 74.2, 73.7, 73.4, 72.7, 72.6, 71.4,
71.3, 71.1, 69.5, 68.7, 54.9; HRMS (ESI-TOF) (m/z): [MþNa]þ, found
919.4034. C55H60O11Na requires 919.4033.
4.9. Methyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-
b
-
D
-glucopyranosyl-(1/4)-3-O-acetyl-6-O-benzyl-2-deoxy-
2-phthalimido- -glucopyranosyl-(1/4)-2,3,6-tri-O-benzyl-
-mannopyranosyl-(1/4)-2,3,6-tri-O-benzyl-
mannopyranoside (12)
Celite bed and the filtrate, after passing through a 0.45
mm Millipore
b-D
membrane, was lyophilized to give I (65.5 mg, 96%) as a white solid;
25
b-
D
a-D-
Rf (30% H2O/CH3CN) 0.30; [
a
]
D
þ9.6 (c 1.62, H2O); IR (KBr plate)
3397, 2938, 1651, 1559, 1377, 1317, 1065, 615 cmꢁ1
;
dH (300 MHz,
D2O) 4.76 (1H, d, J 3.0 Hz, H-1), 4.72 (1H, br s, H-10), 4.57 (1H, d,
J 8.4 Hz, H-100), 4.53 (1H, d, J 7.8 Hz, H-1%), 4.09 (1H, d, J 2.7 Hz, H-2),
3.98 (1H, br s, H-20), 3.93–3.84 (6H, m), 3.76–3.68 (9H, m), 3.65–3.53
(4H, m), 3.47–3.45 (3H, m), 3.40 (3H, s, OMe), 2.06 (3H, s, NCOCH3),
2.05 (3H, s, NCOCH3); dC (75 MHz, D2O) 175.4 (C]O), 174.1 (C]O),
102.3 [1J(C%1 ,H1%)¼162.9 Hz], 102.2 [1J(C100,H100)¼162.9 Hz], 101.5
[1J(C1,H1)¼173.7 Hz], 100.8 [1J(C10,H10)¼163.3 Hz], 80.1, 77.9, 77.4,
76.7, 75.8, 75.3, 74.2, 72.9, 72.4, 71.8, 70.8, 70.6, 70.3, 70.0, 61.4, 61.3,
60.9, 56.4, 55.8, 55.6, 23.0, 20.5; HRMS (ESI-TOF) (m/z): [MþNa]þ,
found 785.2802. C29H50N2O21Na requires 785.2804.
A mixture of thioglycoside 5 (247.4 mg, 0.26 mmol), BSP (60 mg,
0.287 mmol), TTBP (130 mg, 0.52 mmol), and 4 Å molecular sieves in
dry CH2Cl2 (10 mL) was stirred under Ar for 30 min. The mixture was
cooled to ꢁ60 ꢀC and trifluoromethanesulfonic anhydride (53
mL,
0.315 mmol) was added. After 30 min, the temperature was brought
down to ꢁ70 ꢀC, and then a cold solution of acceptor 11 (280 mg,
0.313 mmol)inCH2Cl2 (4 mL)wasslowlyadded. The reaction mixture
was stirred at ꢁ70 ꢀC for further 1 h and then quenched by the ad-
dition of triethylamine (0.40 mL). The reaction mixture was warmed
to room temperature, diluted with CH2Cl2 and filtered through
a Celite bed. The organic phase was washed subsequently with sat-
urated aqueous NaHCO3 and brine, dried with anhydrous Na2SO4 and
the solvent was evaporated to dryness. The crude product was puri-
fied by flash column chromatography (EtOAc/CH2Cl2/hexane, 3:1:4,
v/v) over silica-gel to give 12 (317 mg, 70%) as colorless foam; [Found:
Acknowledgements
The authors are grateful to CSIR, New Delhi, India for providing
fellowship (SRF) to SKM and funding of project (No. 01/1951/04/
EMR-II) to RG. Supports from CAS-UGC, India and FIST-DST, India to
the Department of Chemistry, Jadavpur University, Kolkata are also
acknowledged.
C, 67.36;H, 5.67. C98H100N2O27 requiresC, 67.73; H, 5.80%]; Rf (hexane/
25
EtOAc/CH2Cl2, 3:1:4 v/v) 0.28; [
a
]
þ8.6 (c 1.98, CHCl3); IR (KBr plate)
D
3474, 3428, 2872, 1777, 1749, 1719, 1387, 1368, 1229, 1051, 723, cmꢁ1
;
dH (300 MHz, CDCl3) 7.90–7.87 (3H, m, ArH), 7.82–7.74 (3H, m, ArH),
7.61–7.59 (3H, m, ArH), 7.31–7.07 (28H, m, ArH), 6.98–6.96 (3H, m,
ArH), 6.91–6.83 (3H, m, ArH), 5.66 (1H, dd, J 10.5, 9.1 Hz, H-3%), 5.56
(1H, dd, J 10.5, 9.1 Hz, H-300), 5.45 (1H, d, J 8.5 Hz, H-100), 5.36 (1H, d, J
8.4 Hz, H-1%), 5.06 (1H, t, J 9.8, 9.4 Hz, H-4%), 4.68 (1H, d, J 2.1 Hz, H-1),
4.66–4.54 (6H, m, 3ꢂCH2Ph), 4.44, 4.42 (2H, d each, J 12.0 Hz, CH2Ph),
4.38–4.32 (5H, m, H-6a%, 2ꢂCH2Ph), 4.31 (1H, br s, H-10), 4.15 (1H, m,
H-2%), 4.13 (1H, m, H-200), 4.11–4.07 (4H, m, H-4, H-40, H-400, CHaHbPh),
4.03 (1H, d, J 12.0 Hz, CHaHbPh), 3.90 (1H, dd, J 12.4, 1.6 Hz, H-6b%),
3.79(1H, dd, J 8.4, 3.0 Hz, H-3), 3.66 (2H, m, H-2, H-500), 3.59(3H, m, H-
20, H-6a00, H-6b00), 3.43 (1H, m, H-5%), 3.28 (5H, m, H-6a, H-6b, OMe),
3.18 (1H, dd, J 9.1, 2.7 Hz, H-30), 3.00–2.91 (4H, m, H-5, H-50, H-6a0, H-
Supplementary data
Copiesof1H-and13C spectra (1Dand2D)andlong-rangecoupling
correlation of 12 (Fig. 3). Supplementary data associated with this
articlecanbefound inonlineversionatdoi:10.1016/j.tet.2010.02.052.
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