Concise synthesis of a hexasaccharide related to the adhesin receptor of Streptococcus oralis ATCC 55229

Article abstract of DOI:10.1080/07328300903261554

A concise synthesis of a hexasaccharide related to the adhesin receptor of Streptococcus oralis ATCC 55229 (previously characterized as Streptococcus sanguis H1) has been achieved in excellent yield. A general glycosylation condition has been used throughout the synthetic scheme. All glycosylation steps and protecting group functionalization steps are high yielding and suitable for scale-up preparation.

Full text of DOI:10.1080/07328300903261554

Journal of Carbohydrate Chemistry, 28:447–462, 2009
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300903261554
Concise Synthesis of a
Hexasaccharide Related to
the Adhesin Receptor of
Streptococcus oralis ATCC
55229
Samir Ghosh and Anup Kumar Misra
Division of Molecular Medicine, Bose Institute, A.J.C. Bose Centenary Campus,
P-1/12, C.I.T. Scheme VII-M, Kolkata 700054, India
A concise synthesis of a hexasaccharide related to the adhesin receptor of Streptococcus
oralis ATCC 55229 (previously characterized as Streptococcus sanguis H1) has been
achieved in excellent yield. A general glycosylation condition has been used throughout
the synthetic scheme. All glycosylation steps and protecting group functionalization
steps are high yielding and suitable for scale-up preparation.
Keywords Hexasaccharide; Streptococcus oralis; Glycosylation; Adhesin
INTRODUCTION
Most microbial infections initiate with protein-carbohydrate interactions,
which play a key role in the effective adhesion of bacteria, viruses, or proto-
zoa to the host.[1] Microbial cell-wall glycolipids,[2] glycoproteins,[3] and capsu-
lar polysaccharides[4] are known to contain receptors for carbohydrate-binding
proteins playing crucial roles at the initial stage of microbial adhesion to the
host. Dental plaque formation is a common phenomenon in the human oral en-
vironment due to the aggression of a diverse range of microbes.[5] It has been
well established that specific interactions between bacterial adhesins and car-
bohydrates play significant roles in the initiation and maturation of dental
plaque formation.[6] In the past, a number of studies have been carried out
Received May 15, 2009; accepted August 15, 2009.
Address correspondence to Anup Kumar Misra, Division of Molecular Medicine, Bose
Institute, A.J.C. Bose Centenary Campus, P-1/12, C.I.T. Scheme VII-M, Kolkata 700054,
India. E-mail: akmisra69@rediffmail.com
447

S. Ghosh & A. K. Misra
448
Figure 1: Structure of the adhesin receptor of Streptococcus oralis ATCC 55229.
for the identification and biochemical characterization of specific molecular
mediators of interbacterial aggregation responsible for plaque formations.[7]
The frequently found bacterial species acting as primary colonizers in dental
plaque are Streptococcus oralis, Actinomyces viscosis, and Actinomyces naes-
lundii.[8] To date, a few adhesin receptor polysaccharides have been identified
and characterized to study their role in dental plaque formation. A number
of carbohydrate receptor molecules having significant antigenicity have been
isolated from Streptococcus mitis 522, S. oralis ATCC 10557, S. oralis 34, and
S. oralis C104 strains, which are found in the matured dental plaque.[9] The
complete structure of an antigenic hexasaccharide repeating unit of the ad-
hesin receptor polysaccharide from S. oralis ATCC 55229 (previously char-
acterized as Streptococcus sanguis H1) has been reported by Glushka et al.
(Fig. 1).[10]
The development of glycoconjugate vaccines against microbial infections
has been of considerable interest for a long time, which has been reflected
in several reports in the recent past.[11] Although oligosaccharides can be iso-
lated from natural sources, their limited availability cannot always meet the
required quantity for their extensive biological studies. Efficient chemical syn-
thetic strategies could offer access to larger quantities of natural oligosac-
charides and its several analogs. In order to determine the relation between
structure and immunological specificity, it is quite logical to prepare oligosac-
charides related to the repeating unit of the antigenic polysaccharide. The
synthesized oligosaccharide could also be utilized as a molecular probe for
studying the immunochemical behavior of the antigen. In this report, we de-
scribe a concise chemical synthesis of a hexasaccharide related to the repeat-
ing unit of the adhesin receptor polysaccharide of S. oralis ATCC 55229 as its
Figure 2: Structure of the synthesized hexasaccharide related to the adhesin receptor of
Streptococcus oralis ATCC 55229 in which the D-Galf unit is linked through an α-linkage.

Synthesis of Streptococcus oralis-Related Hexasaccharide
449
Figure 3: Chemical structure of the synthesized hexasaccharide as 4-methoxyphenyl
glycoside.
4-methoxyphenyl glycosides (Figs. 2 and 3). A 1,2-cis linked D-galactofuranose
moiety is present in the nonreducing terminus in the synthesized hexasaccha-
ride, whereas in the natural glycan repeating unit the D-galactofuranose moi-
ety is 1,2-trans linked. The 4-methoxyphenyl group could serve as a temporary
anomeric protecting group, which could be removed easily for the preparation
of glycoconjugate molecule.
RESULTS AND DISCUSSION
The synthesis of the hexasaccharide was achieved by sequential glycosylation
of suitably protected monosaccharide derivatives prepared from commercially
available reducing sugars using literature-reported reaction conditions (Fig.
4).
4-Methoxyphenyl
(4-O-acetyl-2,6-di-O-benzyl-β-D-galactopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (2)[12] was prepared from
D-lactose following an earlier reported procedure. Ethyl 4,6-O-benzylidene-1-
Figure 4: Suitably protected mono- and disaccharide intermediates used for the synthesis of
target hexasaccharide 1.

S. Ghosh & A. K. Misra
450
Scheme 1: Reagents: (a) (i) Bu2SnO, CH3OH, 80◦C, 3 h; (ii) allyl bromide, CsF, DMF, rt, 12 h; (b)
benzyl bromide, NaOH, TBAB, THF, rt, 4 h, overall 92%.
thio-β-D-galactopyranoside (7),[13] derived from D-galactose, was selectively
3-O-allylated via stanylidene acetal formation to give compound 8, which was
benzylated using benzyl bromide and sodium hydroxide to furnish compound
3 in 92% overall yield (Sch. 1). Starting from L-rhamnose, compounds 4[14]
and 5[15] were prepared using similar reaction conditions reported earlier.
Compound 6[16] was prepared by mercury (II) chloride-catalyzed cyclization of
acyclic D-galactose diethyldithioacetal.
Stereoselective glycosylation of disaccharide acceptor 2 with thioglycoside
derivative 3 in the presence of N-iodosuccinimide (NIS) and trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf)[17] furnished trisaccharide derivative 9 in
89% yield. Formation of compound 9 was confirmed from its spectral analysis
[signals at δ 5.15 (d, J = 3.2 Hz, H-1C), 4.75 (d, J = 8.7 Hz, H-1A), and 4.47 (d,
1
J = 7.8 Hz, H-1B) in H and δ 102.9 (C-1A), 102.4 (C-1B), 100.8 (PhCH), and
93.6 (C-1C) in the 13C NMR spectra]. 1,2-Cis glycosylation of the D-galactose
derivative was supported by the coupling constant (J = 3.2 Hz) of the H-1 of
the D-galactose residue in compound 9. Removal of allyl group using palladium
chloride in sodium acetate buffer medium[18] afforded trisaccharide acceptor 10
in 77% yield. Stereoselective glycosylation of compound 10 with thioglycoside
derivative 4 using NIS-TMSOTf[17] furnished tetrasaccharide derivative 11 in
92% yield, which was deacetylated using sodium methoxide to give tetrasac-
charide acceptor 12 in 98% yield. Presence of signals at δ 102.8 (C-1A), 102.4
(C-1B), 100.6 (PhCH), 100.2 (C-1D), and 93.5 (C-1C) in the 13C NMR spectra con-
firmed the formation of compound 11. Exclusive formation of 1,2-trans glyco-
side was achieved due to the presence of the neighboring participating O-acetyl
group in the C-2 position of the L-rhamnosyl thioglycoside derivative. NIS-
TMSOTf-mediated[17] stereoselective glycosylation of compound 12 with thio-
glycoside derivative 5 furnished pentasaccharide derivative 13 in 83% yield.
Presence of signals at δ 102.8 (C-1B), 102.7 (C-1A), 101.4 (C-1E), 100.7 (PhCH),
99.1 (C-1D), and 95.1 (C-1C) in the 13C NMR spectra supported the formation of
compound 13. In this case also, exclusive formation of 1,2-trans glycoside was
achieved due to the presence of the neighboring participating O-acetyl group
in the C-2 position of the L-rhamnosyl thioglycoside derivative. Oxidative re-
moval of 4-methoxybenzyl group using 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ)[19] in a biphasic reaction condition resulted in the formation of

Synthesis of Streptococcus oralis-Related Hexasaccharide
451
pentasaccharide acceptor 14 in 73% yield. Stereoselective glycosylation of com-
pound 14 with thioglycoside derivative 6 using NIS-TMSOTf[17] furnished hex-
asaccharide derivative 15 in 78% yield, which was confirmed from its spectral
analysis. Presence of signals at δ 108.4 (C-1F), 102.7 (C-1A), 102.4 (C-1B), 101.3
(2 C, C-1D, C-1E), 100.5 (PhCH), and 93.8 (C-1C) in the 13C NMR spectra sup-
1
ported the formation of compound 15. Although in the H NMR spectrum of
compound 15 H-1F appeared in a multiplet, the presence of a signal at δ 108.4
in the 13C NMR spectrum unambiguously confirmed the formation of 1,2-cis
glycosylation of D-galactofuranose moiety.[16] Hydrogenolysis of the hexasac-
charide derivative 15 over Pearlman’s catalyst[20] followed by deacetylation
furnished pure hexasaccharide 1 in overall 76% yield. Formation of compound
1 was confirmed from its 1D and 2D NMR and mass spectral analysis. Pres-
ence of signals at δ 5.16 (br s, 2 H, H-1E, H-1F), 5.10 (br s, H-1C), 4.97 (d, J =
7.8 Hz, H-1A), 4.92 (br s, H-1D), and 4.47 (d, J = 7.6 Hz, H-1B) in the 1H NMR
and at δ 109.1 (C-1F), 102.8 (C-1B), 101.8 (C-1E), 101.1 (C-1A), 100.5 (C-1D), and
95.5 (C-1C) in the 13C NMR spectra unambiguously confirmed the formation of
target hexasaccharide 1 (Sch. 2).
In summary, synthesis of a hexasaccharide related to the hexasaccharide
adhesin receptor of S. oralis ATCC 55229 as its 4-methoxyphenyl glycoside has
been achieved in a concise manner using a sequential stereoselective glycosy-
lation strategy. Most of the glycosylation steps are highly stereoselective and
reproducible for scale-up preparation. The 4-methoxyphenyl group has been
chosen as the temporary protecting group at the reducing end for its easy re-
moval whenever required for the preparation of glycoconjugates.
EXPERIMENTAL
General Procedure
All reactions were monitored by thin layer chromatography over silica gel-
coated TLC plates. The spots on TLC were visualized by warming ceric sul-
phate (2% Ce(SO4)2 in 2N H2SO4)-sprayed plates in a hot plate. Silica gel
1
230–400 mesh was used for column chromatography. H and 13C NMR, 2D
COSY, and HSQC spectra were recorded on a Brucker Advance DPX 300 MHz
using CDCl3 and D2O as solvents and TMS as internal reference unless stated
otherwise. Chemical shift value is expressed in δ ppm. ESI-MS data were
recorded on a MICROMASS QUATRO II triple quadrupole mass spectrometer.
Elementary analysis was carried out on a Carlo ERBA-1108 analyzer. Optical
rotations were measured at 25◦C on a Rudolf Autopol III polarimeter. Com-
mercially available grades of organic solvents of adequate purity are used in
many reactions.

S. Ghosh & A. K. Misra
452
Scheme 2: Reagents: (a) N-iodosuccinimide, trimethylsilyl trifluoromethane sulfonate, MS 4Å,
CH2Cl2, −40◦C, 1 h, 89% for 9, 92% for 11, 83% for 13, 78% for 15; (b) PdCl2, NaOAc,
AcOH-H2O, rt, 12 h, 77%; (c) CH3ONa, CH3OH, rt, 3 h, 98%; (d) DDQ, CH2Cl2, H2O, rt, 2 h, 73%;
(e) (i) CH3ONa, CH3OH, rt, 3 h; (ii) H2, 20% Pd(OH)2-C, rt, 24 h, 76%.
Ethyl 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-1-thio-β-D-
galactopyranoside (3)
To a solution of compound 7 (5 g, 16 mmol) in anhydrous CH3OH (120
mL) was added dibutyltin oxide (4.8 g, 19.3 mmol), and the reaction mixture

Synthesis of Streptococcus oralis-Related Hexasaccharide
453
was allowed to stir at 80◦C for 3 h. The solvents were removed under reduced
pressure and the crude mass was dissolved in anhydrous DMF (50 mL). To
the reaction mixture were added cesium fluoride (2.5 g, 16.45 mmol) and allyl
bromide (2.5 mL, 28.9 mmol) and the reaction mixture was allowed to stir at
rt for 12 h. The solvents were removed under reduced pressure and the crude
residue was dissolved in CH2Cl2 (150 mL). The organic layer was washed with
1 N HCl and water in succession, dried (Na2SO4), and concentrated. To a so-
lution of the crude product in anhydrous THF (70 mL) were added powdered
NaOH (1.8 g, 45 mmol), benzyl bromide (3.8 mL, 32 mmol), and tetrabuty-
lammonium bromide (200 mg, 0.62 mmol) and the reaction mixture was al-
lowed to stir briskly at rt for 4 h. The reaction was quenched by addition of
satd. NH4Cl and concentrated under reduced pressure. The crude mass was
dissolved in CH2Cl2 (150 mL) and 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 3 (6.5 g, 92%). Col-
orless oil; IR (neat): 3448, 2986, 1752, 1375, 1235, 1090, 1057, 919, 719 cm−1
;
1H NMR (300 MHz, CDCl3): δ 7.52–7.24 (m, 10 H, Ar-H), 6.0–5.88 (m, 1 H,
CH CH2), 5.50 (s, 1 H, PhCH), 5.32–5.15 (m, 2 H, CH CH2), 4.87–4.70 (2
d, J 10.2 Hz, 2 H, PhCH2), 4.42 (d, J 9.6 Hz, 1 H, H-1), 4.33 (d, J = 12.3
Hz, 1 H, H-6a), 4.22–4.18 (m, 3 H, H-4, OCH2-CH CH2), 4.0 (d, J 12.3 Hz,
H-6b), 3.81 (t, J = 9.3 Hz, 1 H, H-2), 3.50 (dd, J = 9.2, 3.4 Hz, 1 H, H-3),
3.37 (br s, 1 H, H-5), 2.86–2.70 (m, 2 H, SCH2CH3), 1.33 (t, J = 7.4 Hz, 3 H,
SCH2CH3); 13C NMR (75 MHz, CDCl3): δ 138.4–137.9 (Ar-C), 134.9 (CH CH2),
129.0–126.5 (Ar-C), 117.4 (CH CH2), 101.5 (PhCH), 84.4 (C-1), 80.9 (C-5), 76.8
(C-3), 75.6 (PhCH2), 74.2 (OCH2CH CH2), 71.2 (C-4), 69.8 (C-2), 69.4 (C-6),
23.8 (SCH2CH3), 15.0 (SCH2CH3); ESI-MS: 465.2 [M+Na]+; Anal. Calcd. for
C25H30O5S (442.18): C, 67.85; H, 6.83; found: C, 67.69; H, 7.00.
4-Methoxyphenyl (3-O-allyl-2-O-benzyl-4,6-O-benzylidene-α-D
galactopyranosyl)-(1→3)-(4-O-acetyl-2,6-di-O-benzyl-β-D-
galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
glucopyranoside (9)
To a solution of compound 2 (4 g, 4.25 mmol) and compound 3 (2.8 g, 6.33
mmol) in anhydrous CH2Cl2 (50 mL) was added MS-4 (5 g) and the reaction
mixture was allowed to stir at rt for 1 h under argon. The reaction mixture
was cooled to −40◦C and N-iodosuccinimide (NIS; 1.7 g, 7.55 mmol) and TM-
SOTf (25 µL) were added to it. After stirring at same temperature for 1 h, the
reaction mixture was quenched with Et3N (0.2 mL), filtered through a Celite
bed, and washed with CH2Cl2 (100 mL). The organic layer was washed with
aq. Na2S2O3 and water in succession, dried (Na2SO4), and concentrated under
reduced pressure to give the crude product, which was purified over SiO2 using

S. Ghosh & A. K. Misra
454
hexane-EtOAc (5:1) as eluant to furnish pure 9 (5 g, 89%). Colorless solid; m.p.
110–112◦C; IR (KBr): 3018, 2925, 2361, 1742, 1505, 1453, 1364, 1217, 1099,
1062, 758, 668 cm−1; [α]D +140 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): δ
25
7.36–7.06 (m, 35 H, Ar-H), 6.90 (d, J 9.0 Hz, 2 H, Ar-H), 6.66 (d, J = 9.0 Hz,
2 H, Ar-H), 5.94–5.81 (m, 1 H, CH CH2), 5.42 (d, J = 2.9 Hz, 1 H, H-4B), 5.20
(s, 1 H, PhCH), 5.15 (d, J = 3.2 Hz, 1 H, H-1C), 5.26–5.06 (m, 2 H, CH CH2),
4.94–4.83 (m, 3 H, PhCH2), 4.75 (d, J = 8.7 Hz, 1 H, H-1A), 4.70–4.49 (m, 6
H, PhCH2), 4.47 (d, J = 7.8 Hz, 1 H, H-1B), 4.39–4.32 (m, 2 H, PhCH2), 4.21
(d, J = 12.0 Hz, 1 H, PhCH2), 4.10–4.06 (m, 2 H, OCH2-CH = CH2), 4.01–3.93
(m, 2 H, H-3A, H-6aC), 3.86 (dd, J = 9.2, 3.4 Hz, 1 H, H-2C), 3.77–3.69 (m, 4
H, H-4C, H-5C, H-6abA), 3.68–3.62 (m, 2 H, H-3B, H-3C), 3.66 (s, 3 H, OCH3),
3.55–3.48 (m, 3 H, H-2A, H-2B, H-5A), 3.45–3.36 (m, 3 H, H-4A, H-5B, H-6bC),
3.29–3.20 (m, 2 H, H-6abB), 1.58 (s, 3 H, COCH3); 13C NMR (75 MHz, CDCl3):
δ 169.7 (COCH3), 155.3–137.9 (Ar-C), 135.4 (CH CH2), 128.7–118.5 (Ar-C),
116.6 (CH CH2), 114.5 (Ar-C), 102.9 (C-1A), 102.4 (C-1B), 100.8 (PhCH), 93.6
(C-1C), 82.7 (C-5A), 81.4 (C-2B), 79.3 (C-2A), 76.1 (C-3A), 75.5 (2 C, C-4A, C-5C),
75.4 (2 C, 2 PhCH2), 75.3 (C-3C), 75.2 (PhCH2), 74.5 (C-4C), 74.1 (PhCH2), 73.6
(2 C, 2 PhCH2), 73.1 (C-2C), 72.3 (C-5B), 70.9 (OCH2CH CH2), 69.2 (C-6C),
68.4 (C-6A), 67.7 (C-6B), 64.8 (C-4B), 62.2 (C-3B), 55.5 (OCH3), 20.3 (COCH3);
ESI-MS: 1343.5 [M+Na]+; Anal. Calcd. for C79H84O18 (1320.57): C, 71.80; H,
6.41; found: C, 71.64; H, 6.58.
4-Methoxyphenyl (2-O-benzyl-4,6-O-benzylidene-α D-
galactopyranosyl)-(1→3)-(4-O-acetyl-2,6-di-O-benzyl-β-D-
galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
glucopyranoside (10)
To a solution of compound 9 (4 g, 3.03 mmol) in AcOH-H2O (60 mL; 20:1
v/v) were added NaOAc·3H2O (1.6 g, 16 mmol) and PdCl2 (380 mg, 2.14 mmol)
and the reaction mixture was allowed to stir at rt for 12 h. The solvents were
removed under reduced pressure and the crude product was purified over SiO2
using hexane-EtOAc (4:1) as eluant to give pure 10 (3 g, 77%). Colorless oil; IR
(neat): 3423, 3020, 2359, 1741, 1593, 1504, 1426, 1368, 1216, 1058, 761, 670
cm−1; [α]D +118 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3): δ 7.41–7.14 (m,
35 H, Ar-H), 6.97 (d, J = 9.0 Hz, 2 H, Ar-H), 6.75 (d, J = 9.0 Hz, 2 H, Ar-H), 5.50
(d, J = 3.0 Hz, 1 H, H-4B), 5.27 (d, J = 3.1 Hz, 1 H, H-1C), 5.23 (s, 1 H, PhCH),
5.01–4.89 (m, 3 H, PhCH2), 4.83–4.80 (m, 2 H, H-1A, PhCH2), 4.77–4.70 (m,
2 H, PhCH2), 4.65–4.51 (m, 4 H, H-1B, PhCH2), 4.48–4.41 (m, 2 H, PhCH2),
4.30 (d, J = 12.0 Hz, 1 H, PhCH2), 4.10–3.92 (m, 3 H, H-3A, H-6aA, H-6aC),
3.85–3.83 (m, 2 H, H-4C, H-6bA), 3.78–3.68 (m, 3 H, H-2C, H-3B, H-3C), 3.73 (s,
3 H, OCH3), 3.62–3.57 (m, 4 H, H-2A, H-2B, H-5A, H-5C), 3.51–3.41 (m, 3 H,
H-4A, H-5B, H-6bC), 3.34–3.28 (m, 2 H, H-6abB), 1.72 (s, 3 H, COCH3); 13C NMR
25
1

Synthesis of Streptococcus oralis-Related Hexasaccharide
455
(75 MHz, CDCl3): δ 169.9 (COCH3), 155.2–114.4 (Ar-C), 102.8 (C-1A), 102.4
(C-1B), 100.8 (PhCH), 93.1 (C-1C), 82.7 (C-5A), 81.5 (C-2B), 79.3 (C-2A), 76.5
(C-3A), 76.1 (C-4A), 75.9 (C-5C), 75.6 (C-4C), 75.5 (PhCH2), 75.3 (PhCH2), 75.1
(PhCH2), 73.6 (3 C, 3 PhCH2), 73.2 (C-2C), 72.3 (C-5B), 69.0 (C-6C), 68.5 (C-3C),
68.4 (C-6A), 67.6 (C-6B), 64.9 (C-4B), 62.0 (C-3B), 55.5 (OCH3), 20.4 (COCH3);
ESI-MS: 1303.5 [M+Na]+; Anal. Calcd. for C76H80O18 (1280.53): C, 71.23; H,
6.29; found: C, 71.05; H, 6.50.
4-Methoxyphenyl (2-O-acetyl-3,4-di-O-benzyl-α-L-
rhamnopyranosyl)-(1→3)-(2-O-benzyl-4,6-O-benzylidene-α-
D-galactopyranosyl)-(1→3)-(4-O-acetyl-2,6-di-O-benzyl-β-D
galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
glucopyranoside (11)
To a solution of compound 10 (2.8 g, 2.18 mmol) and compound 4 (1.2 g, 2.79
mmol) in anhydrous CH2Cl2 (30 mL) was added MS-4 (3 g) and the reaction
mixture was allowed to stir at rt for 1 h under argon. The reaction mixture
was cooled to −40◦C and NIS (750 mg, 3.33 mmol) and TMSOTf (20 µL) were
added to it. After stirring at same temperature for 1 h, the reaction mixture
was quenched with Et3N (0.2 mL) and filtered through a Celite bed and washed
with CH2Cl2 (100 mL). The organic layer was washed with aq. Na2S2O3 and
water in succession, dried (Na2SO4), and concentrated under reduced pressure
to give the crude product, which was purified over SiO2 using hexane-EtOAc
(4:1) as eluant to furnish pure 11 (3.3 g, 92%). Colorless solid; IR (neat): 3461,
2924, 2856, 2362, 1744, 1605, 1505, 1454, 1368, 1232, 1063, 739, 697 cm−1
;
25
1
[α]D +212 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3): δ 7.42–7.16 (m, 45 H,
Ar-H), 6.97 (d, J = 9.0 Hz, 2 H, Ar-H), 6.76 (d, J = 9.0 Hz, 2 H, Ar-H), 5.47
(d, J = 2.9 Hz, 1 H, H-4B), 5.44–5.43 (m, 1 H, H-2D), 5.24 (s, 1 H, PhCH), 5.22
(d, J = 3.1 Hz, 1 H, H-1C), 5.06 (br s, 1 H, H-1D), 5.02–4.90 (m, 4 H, PhCH2),
4.86–4.80 (m, 2 H, H-1A, PhCH2), 4.78–4.58 (m, 5 H, PhCH2), 4.56–4.45 (m, 5
H, H-1B, PhCH2), 4.40–4.25 (m, 2 H, PhCH2), 4.10–3.96 (m, 4 H, H-3A, H-5D,
H-6aA, H-6aC), 3.91–3.80 (m, 5 H, H-2C, H-3D, H-4C, H-6bA, H-6bC), 3.77–3.70
(m, 2 H, H-3B, H-3C), 3.74 (s, 3 H, OCH3), 3.65–3.57 (m, 3 H, H-2A, H-2B, H-5A),
3.54–3.46 (m, 2 H, H-4A, H-5C), 3.39 (t, J = 9.3 Hz each, 1 H, H-4D), 3.35–3.24
(m, 3 H, H-5B, H-6abB), 2.15, 1.59 (2 s, 6 H, 2 COCH3), 1.25 (d, J = 6.1 Hz, 3
H, CCH3); 13C NMR (75 MHz, CDCl3): δ 169.9, 169.8 (2 COCH3), 155.3–114.5
(Ar-C), 102.8 (C-1A), 102.4 (C-1B), 100.6 (PhCH), 100.2 (C-1D), 93.5 (C-1C), 82.6
(C-5A), 81.4 (C-2B), 79.8 (C-2A), 79.2 (C-4D), 77.7 (C-3C), 77.4 (C-3D), 76.3 (C-
4A), 75.9 (C-5C), 75.5 (PhCH2), 75.4 (C-4C), 75.2 (PhCH2), 75.0 (PhCH2), 74.7
(PhCH2), 74.6 (C-2C), 74.2 (PhCH2), 73.5 (2 C, 2 PhCH2), 73.1 (C-5D), 72.3
(C-5B), 71.6 (PhCH2), 69.1 (C-2D), 68.9 (C-6C), 68.4 (C-6A), 68.0 (C-3A), 67.6 (C-
6B), 64.6 (C-4B), 61.8 (C-3B), 55.4 (OCH3), 21.0, 20.3 (2 COCH3), 18.1 (CCH3);

S. Ghosh & A. K. Misra
456
ESI-MS: 1671.7 [M+Na]+; Anal. Calcd. for C98H104O23 (1648.70): C, 71.34; H,
6.35; found: C, 71.18; H, 6.50.
4-Methoxyphenyl (3,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1→3)-
(2-O-benzyl-4,6-O-benzylidene-α-D-galactopyranosyl)-
(1→3)-(2,6-di-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-
tri-O-benzyl-β-D-glucopyranoside (12)
A solution of compound 11 (3 g, 1.82 mmol) in 0.1 M CH3ONa in CH3OH
(60 mL) was allowed to stir at rt for 4 h and neutralized with Dowex-50W X8
(H+) resin. The reaction mixture was filtered and concentrated under reduced
pressure to give the crude product, which was purified over SiO2 using hexane-
EtOAc (2:1) as eluant to give pure 12 (2.8 g, 98%). White solid, m.p. 96–98◦C;
IR (KBr): 3486, 3032, 2924, 2858, 2363, 1507, 1454, 1365, 1225, 1065, 828, 748,
698 cm−1; [α]D +68 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3): δ 7.44–7.21
(m, 45 H, Ar-H), 6.98 (d, J = 9.0 Hz, 2 H, Ar-H), 6.74 (d, J = 9.0 Hz, 2 H, Ar-
H), 5.29 (s, 1 H, PhCH), 5.05 (br s, 1 H, H-1D), 5.02–4.88 (m, 3 H, PhCH2), 4.84
(d, J = 8.7 Hz, 1 H, H-1A), 4.80–4.76 (m, 3 H, H-1C, PhCH2), 4.73–4.57 (m, 6
H, PhCH2), 4.51–4.36 (m, 6 H, H-1B, PhCH2), 4.07–4.02 (m, 2 H, H-3A, H-5D),
3.98–3.96 (m, 1 H, H-2D), 3.94–3.90 (m, 3 H, H-4B, H-6abA), 3.88–3.79 (m, 5
H, H-2C, H-3D, H-4C, H-6abC), 3.73 (s, 3 H, OCH3), 3.71–3.68 (m, 1 H, H-3C),
3.63–3.57 (m, 3 H, H-2A, H-2B, H-5A), 3.52–3.45 (m, 4 H, H-3B, H-4A, H-4D, H-
5C), 3.42–3.32 (m, H-5B, H-6abB), 1.25 (d, J = 6.3 Hz, 3 H, CCH3); 13C NMR (75
MHz, CDCl3): δ 155.3–114.5 (Ar-C), 102.8 (C-1B), 102.6 (C-1A), 101.9 (C-1D),
100.7 (PhCH), 95.1 (C-1C), 82.8 (C-5A), 81.5 (C-2B), 79.9 (C-4D), 79.7 (C-2A),
78.8 (C-3C), 78.1 (C-3D), 77.9 (C-4A), 76.4 (2 C, C-4C, C-5C), 75.6 (PhCH2), 75.5
(C-2C), 75.3 (PhCH2), 75.1 (PhCH2), 74.8 (PhCH2), 74.5 (PhCH2), 74.3 (C-5D),
73.5 (PhCH2), 73.4 (PhCH2), 73.0 (C-5B), 72.2 (PhCH2), 69.0 (C-6C), 68.9 (C-
2D), 68.5 (C-6A), 68.2 (C-6B), 67.8 (C-3A), 64.6 (C-4B), 62.5 (C-3B), 55.4 (OCH3),
18.0 (CCH3); ESI-MS: 1587.7 [M+Na]+; Anal. Calcd. for C94H100O21 (1564.68):
C, 72.10; H, 6.44; found: C, 71.93; H, 6.65.
25
1
4-Methoxyphenyl [2-O-acetyl-4-O-benzyl-3-O-(4-
methoxybenzyl)-α-L-rhamnopyranosyl]-(1→2)-(3,4-di-O-
benzyl-α-L-rhamnopyranosyl)-(1→3)-(2-O-benzyl-4,6-O-
benzylidene-α-D-galactopyranosyl)-(1→3)-(2,6-di-O-benzyl-
β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
glucopyranoside (13)
To a solution of compound 12 (2.5 g, 1.6 mmol) and compound 5 (900 mg,
1.95 mmol) in anhydrous CH2Cl2 (30 mL) was added MS-4 (3 g) and the reac-
tion mixture was allowed to stir at rt for 1 h under argon. The reaction mixture
was cooled to −40◦C and NIS (500 mg, 2.22 mmol) and TMSOTf (10 µL) were

Synthesis of Streptococcus oralis-Related Hexasaccharide
457
added to it. After stirring at same temperature for 1 h, the reaction mixture
was quenched with Et3N (0.1 mL) and filtered through a Celite bed and washed
with CH2Cl2 (80 mL). The organic layer was washed with aq. Na2S2O3 and wa-
ter in succession, dried (Na2SO4), and concentrated under reduced pressure to
give the crude product, which was purified over SiO2 using hexane-EtOAc (3:1)
as eluant to furnish pure 13 (2.6 g, 83%). Colorless oil; IR (neat): 3453, 3020,
2360, 1596, 1424, 1216, 1050, 762, 670 cm−1; [α]D +191 (c 1.2, CHCl3); H
NMR (300 MHz, CDCl3): δ 7.41–7.20 (m, 52 H, Ar-H), 6.98 (d, J = 9.0 Hz, 2 H,
Ar-H), 6.81–6.73 (m, 4 H, Ar-H), 5.51–5.47 (m, 1 H, H-2E), 5.27 (s, 1 H, PhCH),
5.04 (d, J = 12.1 Hz, 1 H, PhCH2), 4.99–4.95 (m, 3 H, H-1D, H-1E, PhCH2),
4.90–4.79 (m, 5 H, H-1A, PhCH2), 4.73–4.66 (m, 3 H, H-1C, PhCH2), 4.64–4.55
(m, 5 H, PhCH2), 4.53–4.31 (m, 8 H, H-1B, PhCH2), 4.06–3.95 (m, 1 H, H-3A),
3.98–3.87 (m, 5 H, H-2D, H-5D, H-5E, H-6abA), 3.86–3.76 (m, 6 H, H-2C, H-3E,
H-4B, H-4C, H-6abC), 3.75, 3.73 (2 s, 6 H, 2 OCH3), 3.71–3.68 (m, 1 H, H-3C),
3.66–3.54 (m, 4 H, H-2A, H-2B, H-3D, H-5A), 3.52–3.44 (m, 3 H, H-4A, H-4D,
H-4E), 3.41–3.36 (m, 3 H, H-3B, H-5B, H-5C), 3.33–3.27 (m, 2 H, H-6abB), 2.13
(s, 3 H, COCH3), 1.28–1.24 (m, 6 H, 2 CCH3); 13C NMR (75 MHz, CDCl3): δ
169.8 (COCH3), 159.3–113.8 (Ar-C), 102.8 (C-1B), 102.7 (C-1A), 101.4 (C-1E),
100.7 (PhCH), 99.1 (C-1D), 95.1 (C-1C), 82.9 (C-5A), 81.5 (C-2B), 80.0 (C-4D),
79.9 (C-4E), 79.6 (C-2A), 78.9 (C-3E), 77.9 (C-3C), 77.3 (2 C, C-3D, C-4A), 76.4
(2 C, C-4C, C-5C), 75.7 (PhCH2), 75.6 (PhCH2), 75.5 (C-2C), 75.4 (PhCH2), 75.1
(PhCH2), 74.9 (PhCH2), 74.7 (C-5E), 74.6 (PhCH2), 74.5 (C-5D), 73.6 (PhCH2),
73.5 (PhCH2), 73.1 (C-5B), 72.3 (PhCH2), 71.4 (PhCH2), 69.0 (C-6C), 68.9 (C-
2D), 68.6 (C-6A), 68.5 (C-2E), 68.4 (C-3A), 68.3 (C-6B), 64.5 (C-4B), 62.5 (C-
3B), 55.5 (OCH3), 21.1 (COCH3), 18.2 (CCH3), 18.1 (CCH3); ESI-MS: 1985.8
[M+Na]+; Anal. Calcd. for C117H126O27 (1962.85): C, 71.54; H, 6.47; found: C,
71.37; H, 6.70.
25
1
4-Methoxyphenyl (2-O-acetyl-4-O-benzyl-α-L-rhamnopyranosyl)-
(1→2)-(3,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1→3)-(2-O-
benzyl-4,6-O-benzyli-dene-α-D-galactopyranosyl)-(1→3)-
(2,6-di-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-
benzyl-β-D-glucopyranoside (14)
To a solution of compound 13 (2.2 g, 1.12 mmol) in CH2Cl2 and water (50
mL, 1:1) was added DDQ (380 mg, 1.67 mmol) and the reaction mixture was
allowed to stir at rt for 2 h. The reaction mixture was diluted with CH2Cl2 (100
mL) and the organic layer was washed successively with satd. aq NaHCO3
and water, dried (Na2SO4), and concentrated under reduced pressure to give
the crude product, which was purified over SiO2 using hexane-EtOAc (5:1) to
furnish pure 14 (1.5 g, 73%). Colorless oil; IR (neat): 3468, 2935, 2370, 1736,
1721, 1394, 1232, 1076, 769 cm−1; [α]D +126 (c 1.2, CHCl3); H NMR (300
25
1

S. Ghosh & A. K. Misra
458
MHz, CDCl3): δ 7.42–7.13 (m, 50 H, Ar-H), 6.98 (d, J = 9.0 Hz, 2 H, Ar-H), 6.76
(d, J = 9.0 Hz, 2 H, Ar-H), 5.32–5.29 (m, 1 H, H-2E), 5.23 (s, 1 H, PhCH), 5.18 (d,
J = 2.7 Hz, 1 H, H-1C), 5.02 (br s, 1 H, H-1E), 5.0–4.85 (m, 4 H, H-1D, PhCH2),
4.83–4.76 (m, 3 H, H-1A, PhCH2), 4.75–4.54 (m, 7 H, PhCH2), 4.53–4.40 (m, 6
H, H-1B, PhCH2), 4.28 (d, J = 12.0 Hz, 1 H, PhCH2), 4.22–4.13 (m, 1 H, H-3A),
4.12–4.04 (m, 1 H, H-5D), 4.02–3.89 (m, 5 H, H-5E, H-6abA, H-6abC), 3.87–3.80
(m, 6 H, H-2A, H-2C, H-2D, H-3E, H-4B, H-4C), 3.75 (s, 3 H, OCH3), 3.78–3.72
(m, 2 H, H-2B, H-3C), 3.70–3.67 (m, 1 H, H-3D), 3.66–3.57 (m, 3 H, H-4A, H-4D,
H-4E), 3.56–3.42 (m, 3 H, H-3B, H-5A, H-5C), 3.40–3.26 (m, 3 H, H-5B, H-6abB),
2.06 (s, 3 H, COCH3), 1.25–1.22 (m, 6 H, 2 CCH3); 13C NMR (75 MHz, CDCl3):
δ 169.6 (COCH3), 102.9 (C-1A), 102.5 (C-1B), 101.5 (C-1E), 101.1 (PhCH), 100.6
(C-1D), 93.7 (C-1C), 82.8 (C-5A), 81.7 (C-2B), 81.5 (C-4D), 80.2 (C-4E), 80.0 (C-
2A), 79.8 (C-3E), 79.5 (C-3C), 79.2 (C-3D), 79.1 (C-4A), 77.2 (C-5C), 76.4 (C-4C),
75.9 (C-2C), 75.5 (PhCH2), 75.4 (2 C, C-5D, C-5E), 75.1 (PhCH2), 73.9 (PhCH2),
73.6 (2 C, 2 PhCH2), 73.4 (C-5B), 72.8 (PhCH2), 72.5 (PhCH2), 72.4 (PhCH2),
72.0 (PhCH2), 70.4 (C-2D), 69.7 (C-6C), 69.0 (C-6A), 68.4 (C-2E), 68.0 (C-3A),
67.7 (C-6B), 64.9 (C-4B), 61.9 (C-3B), 55.5 (OCH3), 20.3 (COCH3), 18.3, 18.2 (2
CCH3); ESI-MS: 1865.8 [M+Na]+; Anal. Calcd. for C109H118O26 (1842.79): C,
70.99; H, 6.45; found: C, 70.82; H, 6.61.
4-Methoxyphenyl (2,3,5,6-tetra-O-benzyl-α-D-galactofuranosyl)-
(1→3)-(2-O-acetyl-4-O-benzyl-α-L-rhamnopyranosyl)-(1→2)-
(3,4-di-O-benzyl-α-L-rhamnopyranosyl)-(1→3)-(2-O-benzyl-
4,6-O-benzylidene-α-D-galactopyranosyl)-(1→3)-(2,6-di-O-
benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
glucopyranoside (15)
To a solution of compound 14 (1.2 g, 0.65 mmol) and compound 6 (450
mg, 0.77 mmol) in anhydrous CH2Cl2 (20 mL) was added MS-4 (2 g) and the
reaction mixture was allowed to stir at rt for 1 h under argon. The reaction
mixture was cooled to −40◦C and NIS (200 mg, 0.88 mmol) and TMSOTf (5
µL) were added to it. After stirring at same temperature for 1 h, the reaction
mixture was quenched with Et3N (0.1 mL) and filtered through a Celite bed
and washed with CH2Cl2 (100 mL). The organic layer was washed with aq.
Na2S2O3 and water in succession, dried (Na2SO4), and concentrated under re-
duced pressure to give the crude product, which was purified over SiO2 using
hexane-EtOAc (3:1) as eluant to furnish pure 15 (1.2 g, 78%). Colorless oil; IR
(neat): 3460, 3030, 2400, 1572, 1447, 1234, 1076, 792, 680 cm−1; [α]D +96 (c
25
1
1.2, CHCl3); H NMR (300 MHz, CDCl3): δ 7.42–7.13 (m, 70 H, Ar-H), 7.02 (d,
J = 9.2 Hz, 2 H, Ar-H), 6.78 (d, J = 9.2 Hz, 2 H, Ar-H), 5.48–5.47 (m, 1 H,
H-2E), 5.44 (d, J = 3.4 Hz, 1 H, H-1F), 5.25 (s, 1 H, PhCH), 5.17 (d, J = 3.2
Hz, 1 H, H-1C), 5.05–5.03 (m, 2 H, H-1D, H-1E), 4.99–4.92 (m, 2 H, PhCH2),

Synthesis of Streptococcus oralis-Related Hexasaccharide
459
4.90–4.80 (m, 4 H, H-1A, PhCH2), 4.78–4.70 (m, 3 H, PhCH2), 4.68–4.58 (m,
5 H, PhCH2), 4.57–4.38 (m, 12 H, H-1B, PhCH2), 4.36–4.22 (m, 4 H, H-3F, H-
6aF, PhCH2), 4.16–4.13 (m, 1 H, H-3A), 4.12–4.04 (m, 3 H, H-2D, H-5D, H-5E),
4.03–3.98 (m, 2 H, H-4F, H-6bF), 3.97–3.90 (m, 2 H, H-2F, H-5F), 3.88–3.80 (m,
7 H, H-2C, H-3B, H-3E, H-6abA, H-6abC), 3.75 (s, 3 H, OCH3), 3.74–3.71 (m, 2
H, H-2A, H-4B), 3.68–3.60 (m, 5 H, H-2B, H-3C, H-3D, H-4A, H-4C), 3.56–3.44
(m, 3 H, H-4D, H-4E, H-5A), 3.38–3.29 (m, 4 H, H-5B, H-5C, H-6abB), 2.05 (s, 3
H, COCH3), 1.28–1.23 (m, 6 H, 2 CCH3); 13C NMR (75 MHz, CDCl3): δ 169.7
(COCH3), 155.2–113.5 (Ar-C), 108.4 (C-1F), 102.7 (C-1A), 102.4 (C-1B), 101.3
(2 C, C-1D, C-1E), 100.5 (PhCH), 93.8 (C-1C), 89.2 (C-3F), 83.6 (C-2F), 82.8 (C-
2B), 82.7 (C-5A), 81.4 (2 C, C-4D, C-4E), 80.9 (C-3D), 80.5 (C-4A), 80.1 (C-2A),
80.0 (C-3E), 78.9 (C-3C), 77.2 (C-5C), 76.3 (C-4C), 75.8 (C-2C), 75.3 (2 C, C-5E,
PhCH2), 75.1 (PhCH2), 74.7 (C-5D), 73.7 (PhCH2), 73.5 (4 C, 4 PhCH2), 73.4
(C-4F), 73.2 (PhCH2), 73.1 (PhCH2), 72.3 (2 C, C-5B, C-5F), 72.0 (PhCH2), 71.9
(PhCH2), 71.5 (PhCH2), 71.4 (PhCH2), 70.6 (C-6F), 69.0 (C-6C), 68.5 (C-2D),
68.3 (C-6A), 68.2 (C-2E), 68.1 (C-3A), 67.8 (C-6B), 64.9 (C-4B), 61.9 (C-3B), 55.6
(OCH3), 20.3 (COCH3), 18.0, 17.9 (2 CCH3); ESI-MS: 2387.0 [M+Na]+; Anal.
Calcd. for C143H152O31 (2365.03): C, 72.57; H, 6.47; found: C, 72.38; H, 6.70.
4-Methoxyphenyl (α-D-galactofuranosyl)-(1→3)-(α-L-
rhamnopyranosyl)-(1→2)-(α-L-rhamnopyranosyl)-(1→3)-(α-D-
galactopyranosyl)-(1→3)-(β-D-galactopyranosyl)-(1→4)-β-D-
glucopyranoside (1)
A solution of compound 15 (1 g, 0.42 mmol) in 0.1 M CH3ONa in CH3OH
(20 mL) was allowed to stir at rt for 2 h and neutralized with Amberlite IR-120
(H+) resin. The reaction mixture was filtered and evaporated to dryness. To a
solution of the crude product in CH3OH (20 mL) was added 20% Pd(OH)2-C
(200 mg) and the reaction mixture was allowed to stir at rt under a positive
pressure of hydrogen for 24 h. The reaction mixture was filtered through a
Celite bed and then washed with CH3OH-H2O (60 mL; 3:1 v/v). The combined
filtrate was evaporated under reduced pressure to furnish compound 1, which
was purified through a Sephadex LH-20 column using CH3OH-H2O (4:1) as
25
eluant to give pure compound 1 (340 mg, 76%). Glassy solid; [α]D +3.3 (c 1.0,
H2O); IR (KBr): 1605, 1472, 1357, 1046, 699 cm−1; 1H NMR (300 MHz, D2O): δ
7.06 (d, J = 9.0 Hz, 2 H, Ar-H), 6.93 (d, J = 9.0 Hz, 2 H, Ar-H), 5.16 (br s, 2 H,
H-1E, H-1F), 5.10 (br s, 1 H, H-1C), 4.97 (d, J = 7.8 Hz, 1 H, H-1A), 4.92 (br s,
1 H, H-1D), 4.47 (d, J = 7.6 Hz, 1 H, H-1B), 4.30–4.09 (m, 4 H, H-2E, H-2F, H-
3F, H-4F), 4.08–4.0 (m, 4 H, H-2D, H-3C, H-4B, H-4C), 3.98–3.87 (m, 4 H, H-3D,
H-5C, H-5F, H-6aA), 3.86–3.61 (m, 15 H, H-2C, H-3A, H-3B, H-3E, H-4A, H-5B,
H-5D, H-5E, H-6bA, H-6abB, H-6abC, H-6abF), 3.75 (s, 3 H, OCH3), 3.60–3.37 (m,
5 H, H-2A, H-2B, H-4D, H-4E, H-5A), 1.25–1.21 (m, 6 H, 2 CCH3); 13C NMR (75

S. Ghosh & A. K. Misra
460
MHz, D2O): δ 154.7, 150.9, 118.2 (2 C), 114.9 (2 C) (Ar-C), 109.1 (C-1F), 102.8
(C-1B), 101.8 (C-1E), 101.1 (C-1A), 100.5 (C-1D), 95.5 (C-1C), 82.9 (2 C, C-3F, C-
4F), 80.9 (C-2F), 78.6 (C-2D), 78.3 (C-4A), 77.3 (C-3E), 75.9 (C-3C), 74.9 (C-2A),
74.8 (3 C, C-3A, C-5A, C-5B), 74.3 (C-4D), 72.6 (2 C, C-4E, C-5F), 72.1 (C-3B),
70.7 (C-3D), 70.5 (2 C, C-5D, C-5E), 69.5 (C-5C), 69.1 (C-2B), 68.8 (C-2E), 67.8
(C-4B), 64.8 (C-2C), 62.8 (C-4C), 62.5 (C-6C), 60.9 (C-6F), 60.7 (C-6B), 59.9 (C-
6A), 55.6 (OCH3), 16.7, 16.6 (2 CCH3); ESI-MS: 1087.3 [M+Na]+; Anal. Calcd.
for C43H68O30 (1064.38): C, 48.49; H, 6.44; found: C, 48.30; H, 6.70.
ACKNOWLEDGEMENTS
S.G. thanks UGC, New Delhi, for providing a Senior Research Fellowship. This
work was supported by Ramanna Fellowship (AKM), Department of Science
and Technology, New Delhi (SR/S1/RFPC-06/2006).
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