Studies on the stereoselective synthesis of a protected α-D-Gal-(1→2)-D-Glc fragment

Article abstract of DOI:10.1016/j.carres.2011.03.012

A novel 1,2-cis stereoselective synthesis of protected α-D-Gal- (1→2)-D-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O- benzylidene-α-D-galactopyranosyl-(1→2)-3-O-benzoyl-4, 6-O-benzylidene-α-D-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6- O-benzylidene-α-D-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-α- D-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-D- galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-β-D- glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α- D-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-β-D-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl- 4,6-O-benzylidene-1-thio-β-D-galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl-α-D-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O- benzylidene-β-D-glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-β- D-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis α-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of α selectivity. In particular, higher α/β stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a β-CH₃ at C-1 and benzoyl groups at C-4 and C-6.

Full text of DOI:10.1016/j.carres.2011.03.012

Carbohydrate Research 346 (2011) 1250–1256
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Studies on the stereoselective synthesis of a protected
a-D-Gal-(1?2)-D-Glc
fragment
⇑
Langqiu Chen , Shen-De Shi, Yong-Qing Liu, Qing-Jiao Gao, Xing Yi, Kai-Ke Liu, Hao Liu
College of Chemistry, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Xiangtan University, Xiangtan, Hunan
Province 411105, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2010
Received in revised form 12 February 2011
Accepted 7 March 2011
Available online 11 March 2011
A novel 1,2-cis stereoselective synthesis of protected
a-D-Gal-(1?2)-D-Glc fragments was developed.
Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
idene- -glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
(1?2)-3,4,6-tri-O-benzoyl- -glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
-galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-benzylidene-b- -glucopyranoside (17), and methyl 2-O-
acetyl-3-O-allyl-4,6-O-benzylidene- -galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-b- -glucopyran-
oside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl-4,6-O-
benzylidene-1-thio-b- -galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzyli-
dene- -glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl- -glucopyranoside (5), methyl 3-O-
benzoyl-4,6-O-benzylidene-b- -glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-b- -glucopyran-
oside (12), respectively. By virtue of the concerted 1,2-cis -directing action induced by the 3-O-allyl
and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group partic-
ipation, the couplings were achieved with a high degree of selectivity. In particular, higher /b ster-
a
-
D
-galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-benzyl-
a-
D
a-D
-galactopyranosyl-
a
-
D
a-
D
D
a
-
D
D
Keywords:
a-
D-Gal-(1?2)-
D-Glc
D
Oligosaccharide
Neighboring-group participation
Stereoselectivity
a
-
D
a-D
D
D
a
a
a
eoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12
having a b-CH3 at C-1 and benzoyl groups at C-4 and C-6.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
of the cell-wall structure of Gram-positive bacteria. Listeria mono-
cytogenes, which is ubiquitous in the environment, has important
In spite of their high structural diversity and complexity, oligo-
saccharides and glycoconjugates have demonstrated various bio-
logical specificities involved in cell–cell recognition, signal
transduction, the immune response, cellular differentiation and
development, as well as programmed cell death. It is still necessary
to clarify further their structures and biological processes. Concise
and practical chemical synthesis of oligosaccharides, glycoconju-
gates, and their analogues have been rapidly developed to effi-
ciently provide significant amounts of these materials in order to
elucidate their glycobiological activities and exploit new vaccines,
diagnostics, therapeutic agents, and vectors for targeted delivery of
therapeutic and imaging agents.1 Galactose, which is available for
biological activities3 and may lead to severe food-borne infections
by multifaceted pathological mechanisms.
a-L-Fuc-(1?2)-a-D-Gal-
(1?2)- -Glc as a schistosome-associated oligosaccharide sequence
D
is selectively recognized by a novel family of isolectins that has
been identified as part of the humoral defense mechanisms of
Biomphalaria alexandina, the snail vector of Schistosoma mansoni.2a
A stereochemically defined synthesis of the protected disaccharide
units a-D-Gal-(1?2)-D-Glc would, therefore, be helpful for prepa-
ration of the corresponding oligosaccharides3 that would enable
biological research and pharmaceutical evaluation with synthetic
oligosaccharides in lieu of those isolated from natural sources.
a
-(1?2)-, a-(1?3)-, a-(1?4)-, and a-(1?6)-glycosyl linkages to
2. Results and discussion
terminal glucopyranosyl, mannopyranosyl, or galactopyranosyl
residues, is an essential component of numerous oligosaccharides
Herein, chemical synthesis of a protected
fragment has an important significance for the possibility of inves-
tigating the potential glycobiology of deprotected -Gal-(1?2)-
-Glc and its derivatives.2,3 To the best of our knowledge, the
formation of -galactopyranosidic bonds is a key process to be
developed for 1,2-cis -galactopyranoside synthesis. The construc-
tion of 1,2-cis -galactopyranosidic bonds has often been re-
ported as a somewhat daunting task due to the lack of
a-D-Gal-(1?2)-D-Glc
and glycoconjugates.2
a
-
D
-Gal-(1?2)-
-Glc-(1?3)-acyl2Gro and
-Glc.2a,3
-Gal-(1?2)-
D
-Glc is a part of
a
a
-
-
D
D
-Gal-
-Gal-
(1?2)-
(1?2)-
a
D
-
D
a-L-Fuc-(1?2)-
a-D
a
-D
a-D
-Glc-(1?3)-acyl2Gro exists in
D
sugar-chain structures of lipoteichoic acid (LTA), which is a part
a
-D
D
a
-D
⇑
Corresponding author. Tel./fax: +86 731 58292251.
E-mail address: chengood2003@263.net (L. Chen).
a
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.012

L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
1251
workable synthetic procedure in the literature or one known
through personal experiences.4,5 Generally, it is believed that var-
ious parameters, such as temperature, solvent, concentration, the
character of the promoter, the leaving group, the nature of a donor
and/or an acceptor influence the stereochemical overcome in the
thio-b-
and obtained the stereochemically 1,2-cis
age by coupling with -glucopyranosyl acceptors.
As outlined in Scheme 1, isopropyl 3-O-allyl-4,6-O-benzylidene-
1-thio-b- -galactose was acety-
-galactopyranoside (1)10c from
D
-galactopyranoside (2) as a novel galactopyranosyl donor
a
-galactopyranosyl link-
D
D
D
crucial
a
-
D
-galactosylation step. Basically, neighboring-group par-
lated to afford a donor 2 in satisfactory yield (85%). For the synthe-
sis of the acceptor 12, acetylation of methyl 3-O-benzoyl-4,6-O-
ticipation by acyl groups is one of the most fundamental and
widely applied concepts of carbohydrate chemistry for accom-
plishing a stereospecific synthesis of a 1,2-trans glycoside or a gly-
benzylidene-b-glucopyranoside (8)11 from
D-glucose with acetyl
chloride in dichloromethane and pyridine was carried out over-
night, giving methyl 2-O-acetyl-3-O-benzoyl-4,6-O-benzylidene-
b-glucopyranoside (9) in acceptable yield (81%). Subsequent 4,
6-O-debenzylidenation with 80% HOAc–H2O at 80 °C was carried
out smoothly to get methyl 2-O-acetyl-3-O-benzoyl-b-glucopyran-
oside (10) in good yield (82%), Benzoylation of 10 with benzoyl
chloride–pyridine gave methyl 2-O-acetyl-3,4,6-tri-O-benzoyl-b-
glucopyranoside (11) in very good yield (87%), and selective re-
moval of the 2-O-acetyl group of 11 in methanol–dichloromethane
acidified with acetyl chloride overnight afforded methyl 3,4,6-tri-
coconjugate.4–6 In contrast, donors for 1,2-cis
a
-galactosylation
-galactopyranosyl donors with an ether-type, non-
participating group at C-25 such as a per-O-benzylated
-galacto-
-galactopyranosyl fluo-
-galactopyranosyl trichloroacetimi-
-galactopyranosyl trichloroacetimi-
-galactopyranosyl trichloroace-
timidate,5e a 2-O-benzylated 1-thio- -galactopyranoside,5e a per-
O-benzylated 1-thio-
-galactopyranoside,5f,g or a 2,3-di-O-benzy-
lated 1-thio-
-galactopyranoside.5h,i However, it is rather difficult
to get stereospecific 1,2-cis -galactosylation, and the subse-
quent separation steps are not always effective in separating ano-
mers, as the desired -galactopyranoside cannot be isolated,
even by column chromatography.6 Quite by accident, a 1,2-trans
b- -galactopyranosyl linkage was achieved with a donor, per-O-
benzylated 1-thio-
-galactopyranoside in propionitrile.7 On the
other hand, it is generally easier to obtain a b- -galactopyranoside
using a
-galactopyranosyl donor with a 2-O-acyl group,5e,6a,8 such
as a per-O-acetylated
-galactopyranosyl bromide,8a per-O-ben-
zoylated
-galactopyranosyl bromide,8b,8c 2,3,4-triacetylated
galactosyl 2-O-benzoylated -galactopyranosyl
bromide,6a
fluoride,5b per-O-acetylated galactopyranosyl trichloroacetimi-
date,5b,8d 2-O-acetylated b-
-galactopyranosyl trichloracetimi-
date,8e 2,3,4-tri-O-acetylated 1-thio- -galactopyranoside,8f 2,4,6-
tri-O-acetylated 1-thio-
-galactopyranoside,8g or 2-O-benzoylated
-galactopyranoside.5b Very recently, on the basis of a
-galactosylation method reported in the literature,9 we
seem to be
D
D
pyranosyl chloride,5a a 2,3-dibenzylated
D
ride,5b a per-O-benzylated
date,5c a 2,3-di-O-benzylated
D
D
date,5d a 2,3,4-tri-O-benzylated
D
D
D
D
O-benzoyl-b-
was then coupled with methyl 3-O-benzoyl-4,6-O-benzylidene-
-glucopyranoside (4)11 under activation by the promoters NIS
and TMSOTf at low temperature to obtain methyl 2-O-acetyl-3-
O-allyl-4,6-O-benzylidene- -galactopyranosyl-(1?2)-3-O-ben-
zoyl-4,6-O-benzylidene- -glucopyranoside (13) in 56.2% yield
along with its b anomer, methyl 2-O-acetyl-3-O-allyl-4,6-O-ben-
zylidene-b- -galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-benzyli-
dene-
-glucopyranoside (14) in 18.7% yield. The 1H NMR spectra
of 13 and 14 showed that the new glycosidic bonds are -linked (d
D-glucopyranoside (12) in high yield (90%). Donor 2
a-
D
a-
D
a-D
a
-D
D
a-D
D
D
D
D
a-D
D
a
D
a
-D
-
5.41 with J1,2 3.2 Hz for H-1Gal) and b-linked (d 4.64 with J1,2 8.0 Hz
for H-1Gal), respectively, with a molar ratio of 13/14 = 3.0:1.0.
Similarly, donor 2 was coupled with methyl 3,4,6-tri-O-benzoyl-
D
D
a-D
-glucopyranoside (5)12 to afford methyl 2-O-acetyl-3-O-allyl-
D
4,6-O-benzylidene-
zoyl- -glucopyranoside (15) (52.6%) along with its b anomer,
methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-b- -galactopyr-
anosyl-(1?2)-3,4,6-tri-O-benzoyl- -glucopyranoside (16)
(26.3%). The 1H NMR spectrum of 15 showed that the new
a-D-galactopyranosyl-(1?2)-3,4,6-tri-O-ben-
D
a-D
1-thio-
cis-1,2
D
D
a-
D
a-D
have developed two applicable galactopyranosyl donors, namely,
isopropyl 3-O-allyl-2-O-benzoyl-4,6-O-benzylidene-1-thio-b-
galactopyranoside and 3-O-allyl-2-O-benzoyl-4,6-O-benzylidene-
-galactopyranosyl trichloroacetimidate, both of which have an
a-
D
-
linked glycosidic bond is characterized by a resonance at d 5.43
with J1,2 3.1 Hz for H-1Gal, while the 1H NMR spectrum of 16
showed that a new b-linked glycosidic bond is also formed by
the signal at d 4.60 with J1,2 8.0 Hz for H-1Gal. The molar ratio
of 15/16 = 2.0:1.0. Condensation of donor 2 and methyl 3-O-ben-
a-D
O-allyl group at C-3 and a benzylidene acetal at C-4–C-6. In spite
of a benzoyl group at C-2, they were both conducive to affording
1,2-cis
a
-
D
-galactopyranosides upon coupling with some monosac-
zoyl-4,6-O-benzylidene-b-
methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
anosyl-(1?2)-3-O-benzoyl-4,6-O-benzylidene-b-
D
-glucopyranoside
(8)
furnished
-galactopyr-
charide and disaccharide acceptors.10a–c Kiso and co-workers10d
and Takeda and co-workers10e have also discovered that the 4,6-
O-TDBS (di-tert-butylsilylene) group, when introduced into galac-
topyranosyl donors that bore aromatic groups (NHTroc, OBz,
a
-
D
D
-glucopyrano-
side (17) (65.5%) and its b-linked isomer, methyl 2-O-acetyl-3-O-
allyl-4,6-O-benzylidene-b- -galactopyranosyl-(1?2)-3-O-benzoyl-
4,6-O-benzylidene-b-
-glucopyranoside (18) (16.4%). Their 1H
NMR spectra showed that the new glycosidic bonds are -linked
D
OBn) at C-2, results in an
condensation of the galactopyranosyl donors and protected gluco-
a
-(1?6)-selective galactosylation in
D
a
pyranosyl acceptors with free 6-OH groups. In spite of the
(d 5.59 with J1,2 3.7 Hz for H-1Gal of 17) and b-linked (d 4.84 with
J1,2 8.1 Hz for H-1Gal of 18), respectively, with the molar ratio of
17/18 = 4.0:1.0. Donor 2 was also readily coupled with methyl
quite effective syntheses of
-(1?2)-10g
-galactosyl oligosaccharides and
ceramide,10h including -Gal,10e
-Gal-(1?6)-
-Gal-(1?4)- -Gal-(1?2)-
-GlcNAc,5b -Gal-Cer10g
Gal-Cer,10h using the 4,6-O-TDBS group on the
donors, a synthesis of -Gal-(1?2)-
a
-(1?6)-10e
,
a
-(1?4)-,10f,5b and
-galactosyl
a
a-
D
a-D
a-
D
D
a-
D-Gal-(1?4)-
a
-
-
3,4,6-tri-O-benzoyl-b-
acetyl-3-O-allyl-4,6-O-benzylidene-
3,4,6-tri-O-benzoyl-b- -glucopyranoside (19) (70.8%) along with
its b-linked isomer, methyl 2-O-acetyl-3-O-allyl-4,6-O-benzyli-
D-glucopyranoside (12) to give methyl 2-O-
D
D
a-
D
D
,
and
a
-D
a-D
-galactopyranosyl-(1?2)-
D
-galactopyranosyl
D
a-D
D-Glc or its derivatives has
not been found in the literature using the 4,6-O-TDBS protection
strategy. At the same time, it is rather difficult to remove the ben-
dene-b-D-galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-b-D-gluco-
pyranoside (20) (14.1%). The 1H NMR spectra of 19 and 20 were in
zoyl group in an
deacylation under acidic or basic conditions, which serves to re-
strict its value in the synthesis of certain 1,2-cis -galactopyran-
osyl oligosaccharides and their analogues. Therefore, it is necessary
to replace the benzoyl group with another more promising acyl
group in some instances. A simple and practical example of an acyl
group is the acetyl group, which is easier to remove. Accordingly,
we chose isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-
a
-
D
-galactopyranosyl residue by regioselective
agreement with the glycosidic bonds assigned, as there was a
doublet at d 5.62 with J1,2 3.5 Hz for the new
a-linked H-1Gal
a-
D
(19) and a doublet at d 4.69 with J1,2 8.3 Hz for the new b-linked
H-1Gal (20). The molar ratio of 19/20 is as high as 5.0:1.0. Accord-
ing to the experimental results based on glycosidations with the
galactopyranosyl donor 2 and the glucopyranosyl acceptors 4, 5,
8, and 12, one comes to the following conclusions: (1) in spite
of a C-2 O-acetyl group in donor 2, condensation of 2 with four

1252
L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
Ph
Ph
Ph
b
BzO
BzO
BzO
HO
HO
HO
O
O
O
O
O
O
a
O
O
O
c
BzO
O
O
OH
OH
OH
SPr-i
SPr-i
5
4
OCH3
OCH3
AllO
3
AllO
OCH3
OCH3
OH
OAc
1
2
Ph
Ph
HO
HO
HO
Ph
O
O
O
O
O
O
O
O
f
d
e
O
O
OCH3
OCH3
OCH3
BzO
BzO
HO
OH
OH
OAc
OH
9
8
7
6
HO
BzO
BzO
BzO
BzO
BzO
BzO
O
O
O
HO
h
i
g
OCH3
AllO: CH2=CHCH2O
SPr-i: SCH(CH3)2
OCH3
OCH3
BzO
OAc
OAc
OH
10
12
11
Ph
Ph
Ph
Ph
O
O
O
O
j
O
O
O
BzO
O
2
2
4
BzO
+
O
O
+
O
O
O
AllO
AllO
H3CO
OAc
O
H3CO
OAc
14
13
Ph
Ph
OBz
O
BzO
BzO
O
BzO
BzO
OBz
O
O
j
O
O
+
5
+
O
O
O
H3CO
AllO
AllO
OAc
O
OAc
O
H3CO
15
16
Ph
Ph
Ph
Ph
O
O
O
BzO
O
O
O
BzO
O
j
OCH3
2
O
+
+
8
O
O
+
O
O
AllO
AllO
OAc
OAc
BzO
O
18
OCH3
17
Ph
OBz
Ph
BzO
BzO
OBz
O
O
O
j
BzO
O
O
O
2
12
OCH3
+
O
O
O
AllO
AllO
OAc
O
OCH3
OAc
20
19
Scheme 1. Reagents and conditions: (a) AcCl, Pyr, rt; (b) (i) PhCHO, TsOH, HC(OEt)3, (ii) PhCOCl, Pyr; (c) (i) Ac2O, Pyr, (ii) 80% HOAc–H2O, reflux, (iii) PhCOCl, Pyr, (iv) AcCl–
MeOH; (d) PhCHO, TsOH, HC(OEt)3; (e) PhCOCl, Pyr; (f) AcCl, Pyr; (g) 80% HOAc–H2O, 80 °C; (h) PhCOCl, Pyr; (i) 2% AcCl–MeOH. (j) NIS, TMSOTf.
glucopyranosyl acceptors (4, 5, 8, and 12) with free 2-OH groups
afforded predominantly the -linked disaccharides (13, 15, 17,
and 19); (2) the nature of the acceptor obviously influences the
ocation 21, which is then changed into an oxacarbenium ion 22.
Intermediate 22 is further converted into twisted boat form cations
24 and 25 via internal nucleophilic substitution (SNi) by attack of
O-6 and O-4, respectively. Both intermediates take active roles in
the stability of the newly produced positive charge at C-1 of 22
by so-called ‘through-space electron donation’ with O-6 and O-
4.13a Intermediates 24 and 25 are apparently different from 22 in
their structures, as O-6 and O-4 are closely linked to C-1 in 24
and 25, rather than to O-5 in 22. C-1 and O-5 are, therefore, twisted
up and down, respectively, resulting in more exposure of the
a
stereoselectivity in the coupling reaction. Coupling of donor 2
and acceptor 12 was observed to achieve higher 1,2-cis
a-galac-
tosylation (19) than the coupling of the three other acceptors
(4, 5, and 8).
A great number of mechanisms have been proposed to elucidate
the coupling reactions leading to stereoselective construction of
1,2-trans and/or 1,2-cis glycosides with monofunctional and/or
non-cyclic/cyclic bifunctional protecting groups including acyl, al-
kyl, benzylidene, carbonate, oxazolidione, cyclic silyl groups, and
others.4,7,13a,b A mechanism was proposed to explain the di-tert-
empty space of the
a-face to nucleophilic attack; moreover, 25 is
more strained and labile than 24 in its
a-directing activity. It is
of course impossible for both 24 and 25, having steric hindrance
at their b-faces, to be attacked by the nucleophilic secondary OH
of glucopyranosides (ROH: 4, 5, 8, and 12). However, such highly
hindered glucopyranosides (4, 5, 8, and 12) could readily attack
butylsilylene (DTBS)-directed a-predominant galactosylation with
galactosyl and galactosaminyl donors with ether and ester protect-
ing groups, as well as for those with participating groups on the C-
2 oxygen or nitrogen, such as benzoyl, Troc, and Phth groups, all of
which have appeared since the work by Kiso and co-workers.10d,13a
Based on the experimental results of the aforementioned benzyli-
the anomeric center of either of 24 and 25 from the
achieve 1,2-cis -galactosylation. On another hand, 22 would
be attacked by same glucopyranosides (4, 5, 8, and 12) from either
the - or b-face to get 1,2-cis and 1,2-trans galactosylation, respec-
a-face to
a-D
dene-directed stereoselective
a-D
-galactosylation shown in
a
Scheme 1, we suggest a probable mechanism as shown in Scheme
tively. However, the molar ratio of 1,2-cis galactosylation to 1,2-
2. Compound 2 is initially reacted with promoter NIS to give a thi-
trans galactosylation is absolutely higher than 1:1, indicating that

L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
1253
Ph
Ph
Ph
O
O
O
O
O
O
O
I
N
I
O+
O
O
S+-Pr-i
H+O
SPr-i
AllO
AllO
AllO
Ph
OAc
OAc
OAc
22
2
21
Ph
Ph
O
steric hindrance
O
O
R
O
O
O
O+
O
O
O
O
AllO
H
OR
AllO
AllO
O+
CH3
OAc
1,2-trans
O
CH3
22
26
O
23
Ph
Ph
middle steric hindrance
O
O
O
O
R
O+
+
O
26
O
H
AllO
AllO
1,2-cis
OAc
OR
OAc
27
22
strong steric hindrance
Ph
Ph
R
O+
O
O
O
O
H
27
O+
O
AllO
AllO
OAc
OAc
24
22
very strong steric hindrance
Ph
Ph
R
O
O
O
O+
O
27
H
O+
O
AllO
AllO
OAc
ROH: glucopyranosides 4, 5, 8, 12
OAc
25
22
Scheme 2. Proposed mechanism of 1,2-cis a-galactosylation.
the attack is rather hindered for approach on the b-face, and giving
credence to the effect of the benzylidene group and its axial C-4–O-
4 bond. In contrast, 22 would be changed by cyclization into a cyc-
lic oxonium ion 23, which would subsequently be attacked by the
lation. In addition, 12 could readily actually attack 22, 24, or 25
at the -face without steric hindrance due to 12’s 1,2-trans b-ano-
meric form, resulting in an :b ratio that is as high as 5.0:1.0 for
this coupling reaction. However, it is highly sensitive to 5’s 1,2-
cis -anomeric form for 5 to attack 22, 24, or 25 so that the ,b
-galactosylation ratio is as low as 2.0:1.0 for the coupling reaction.
In a similar way, the /b -galactosylation ratio is 4.0:1.0 for cou-
pling of 8 due to the 1,2-trans b-anomeric form of 8. This result is
higher than that of the coupling of 4 ( /b = 3.0:1.0), where 4 is
locked in the 1,2-cis -anomeric form. In a structural comparison
a
a
hindered
through an SN2 pathway leading solely to the formation of 1,2-
trans b- -galactopyranosides; however, this SN2 pathway would
D-glucopyranosides (4, 5, 8, and 12) from the b-face
a
a
D
D
a
D
be partially restrained since there is a conformation-constraining
benzylidene group that restricts the flexibility of 23, destabilizes
it, and even shields especially its b-face to a certain extent. Cations
22, 23, 24, and 25 could be considered capable of interchanging
with each other, and 23 would hereby return to 22, and convert
a
a
of 4 and 5, the benzylidene group in 4 has been replaced with
two benzoyl groups at C-4 and C-6 of 5 to reduce the electron-
withdrawing effect and allow 4 to attack more readily the interme-
further to 24 and 25, which would lead to more 1,2-cis a-D-galac-
tosylation in the case of 23 being attacked by rather hindered
glucopyranosides (4, 5, 8, and 12) from the b-face. It could be con-
diates 22, 24, or 25 from a point of less steric hindrance at their
face. In another aspect, for 8 and 12 the b configuration of the
methoxy group at C-1 shows a larger effect on -stereoselectivity
than the change of substituents at C-4 and C-6. Thus it is more
favorable to obtain 1,2-cis -galactosylation with the b methoxy
group at C-1. This fact is shown in the experimental results: the
/b ratio is 5.0:1.0 for the coupling of 12 and 4.0:1.0 for the cou-
pling of 8.
In summary, an operationally simple and efficient procedure
has been developed for a rational stereochemical 1,2-cis -galac-
a-
cluded that the main reason for
due to the formation of intermediates 22, 24, and 25 and their
strong -directing effect on coupling with the hindered glucopyr-
anosides 4, 5, 8, and 12.
The molar ratios of
a-
D-galactosylation is probably
a
a
a
a,b-
D-galactosidic linkages of the acceptors
a
4, 5, 8, and 12 have been determined as 3.0:1.0 (13 and 14),
2.0:1.0 (15 and 16), 4.0:1.0 (17 and 18), and 5.0:1.0 (19 and 20),
respectively. Thus the
a-directing galactosylation order is summed
a-D
up as 12 > 8 > 4 > 5, which is perhaps at first perplexing. However,
the repulsion of the three benzoyl groups at C-3, C-4, and C-6 of 12
tosylation by using 3-O-allyl and 4,6-O-benzylidene groups with a
C-2-acetyl group that is capable of neighboring-group participation
by each of the
at the b-face, and this is probably helpful for coupling at the
thus there is a steric assistance effect leading to 1,2-cis galactosy-
D
-galactosyl cations 22, 23, 24, or 25 is considerable
in a
(1?2)-
acceptor 12 with a b methoxy group at C-1 and three benzoyl
D
-galactopyranosyl donor to obtain all four protected
a-D-Gal-
a
-face,
D-Glc compounds. In particular, the coupling of donor 2 and

1254
L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
groups at C-3, C-4 and C-6 gave higher 1,2-cis
a
-galactopyranosyl
cooling in an ice bath. The mixture was stirred overnight, at the
end of which time TLC (3:1 petroleum ether–EtOAc) indicated that
the reaction was complete. The mixture was diluted with CH2Cl2,
and washed with N HCl, satd aq NaHCO3, and satd aq NaCl. The or-
ganic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by flash column chromatography (3:1 petroleum
ether–EtOAc) gave 9 as a white foamy solid (0.18 g, 81%): mp
stereoselectivity. The new donor 2 may be readily available to pro-
vide other protected 1,2-cis -galactopyranosyl oligosaccharides
and to construct complex glycosides as well. Furthermore, the syn-
thetic, protected -Gal-(1?2)- -Glc intermediates as novel
a
a-
D
D
building blocks will be conveniently available to synthesize corre-
sponding oligosaccharides and glycoconjugates.
186–188 °C; [
a]
ꢁ124.7 (c 1.0, CHCl3); 1H NMR (CDCl3): d 8.02
D
(2H, d, J 7.6 Hz, Ar-H), 7.56 (1H, t, J 7.3 Hz, Ar-H), 7.40–7.45 (4H,
m, Ar-H), 7.31–7.32 (3H, m, Ar-H), 5.60 (1H, dd, J2,3 = J3,4 = 9.6 Hz,
H-3), 5.52 (1H, s, PhCH), 5.20 (1H, dd, H-2), 4.59 (1H, d, J1,2
3. Experimental
3.1. General methods
0
7.8 Hz, H-1), 4.42 (1H, dd, J5,6 4.9 Hz, J6,6 10.4 Hz, H-6), 3.82–3.88
(2H, m, H-4, H-60), 3.60–3.66 (1H, m, H-5), 3.55 (3H, s, CH3O),
1.98 (3H, s, CH3CO). HRESIMS: calcd for C23H24NaO8, m/z
451.13634; found, m/z 451.13536.
Melting points were measured on an X-4 micro melting point
apparatus (Yuhua Instruments Co., Ltd) and are uncorrected. Opti-
cal rotations were determined with a Perkin–Elmer model 341-MC
automatic polarimeter for solutions in a 1-dm, jacketed cell. 1H and
13C NMR spectra were recorded on a Bruker Avance-400 spectrom-
eter at 400 and 100.6 MHz, respectively. All chemical shifts are
quoted on the d-scale in parts per million downfield from TMS.
Mass spectra were recorded on a Bruker Esquire-LC electrospray-
ionization mass spectrometer, on a Bruker Daltonics autoflex III
TOF/TOF mass spectrometer, or on a Bruker Apex IV FTMS. The pro-
gress of all reactions was followed by thin-layer chromatography
(TLC) that was performed on silica gel HF254 with detection by
charring with 30% (v/v) sulfuric acid in MeOH or by UV detection.
Purification by chromatography was conducted by elution of a col-
umn (8 ꢀ 100 mm, 16 ꢀ 240 mm, 18 ꢀ 300 mm, or 35 ꢀ 400 mm)
of silica gel (100–200 mesh) with EtOAc–petroleum ether as the
eluent. HPLC was performed with a Gilson apparatus consisting
of a pump (model 306), a stainless steel column packed with silica
gel (Spherisorb SiO2, 10 ꢀ 300 mm or 4.6 ꢀ 250 mm), a differential
refractometer (132-RI Detector), and a UV–vis detector (model
118). EtOAc–petroleum ether (bp 60–90 °C) was used as the eluent
at a flow rate of 1–4 mL/min. Solutions were concentrated at 60 °C
under diminished pressure.
3.4. Methyl 2-O-acetyl-3-O-benzoyl-b-D-glucopyranoside (10)
To compound 9 (0.20 g, 0.47 mmol) was added 80% HOAc
(6.3 mL) and the mixture was stirred for 4 h at 80 °C, at the end
of which time TLC (2:1 petroleum ether–EtOAc) indicated that
the reaction was complete. The mixture was concentrated in va-
cuo. Purification of the crude product by flash column chromatog-
raphy (2:1 petroleum ether–EtOAc) gave 10 as a white solid
(0.13 g, 82%): mp 18–20 °C; [
a]
+51.3 (c 1.0, CHCl3); 1H NMR
D
(CDCl3): d 8.02 (2H, d, J 7.5 Hz, Ar-H), 7.60 (1H, t, J 7.4 Hz, Ar-H),
7.46 (2H, dd, J 7.7 Hz, Ar-H), 5.24 (1H, dd, J2,3 = J3,4 = 9.4 Hz, H-3),
5.14 (1H, dd, H-2), 4.51 (1H, d, J1,2 7.9 Hz, H-1), 3.98 (1H, dd, J5,6
2.2 Hz, J6,6 11.6 Hz, H-6), 3.87–3.90 (2H, m, H-4, H-60), 3.54 (3H,
0
s, CH3O), 3.50–3.54 (1H, m, H-5), 3.30 (1H, br s, OH), 2.20 (1H, br
s, OH), 1.98 (3H, s, CH3CO). HRESIMS: calcd for C16H20NaO8: m/z
363.10504; found, m/z 363.10569.
3.5. Methyl 2-O-acetyl-3,4,6-tri-O-benzoyl-b-D-glucopyranoside
(11)
To a solution of compound 10 (1.20 g, 3.53 mmol) in 30.0 mL
CH2Cl2 was added pyridine (2.27 mL, 27.8 mmol). A solution of
benzoyl chloride (2.04 mL, 17.7 mmol) in CH2Cl2 (20.0 mL) was
added dropwise with cooling in an ice bath. The mixture was stir-
red overnight at rt, at the end of which time TLC (3:1 petroleum
ether–EtOAc) indicated that the reaction was complete. The mix-
ture was diluted with CH2Cl2 and washed with N HCl, water, satd
aq NaHCO3, and satd aq NaCl. The organic layer was dried (Na2SO4),
filtered, and concentrated in vacuo. Purification of the crude prod-
uct by flash column chromatography (3:1 petroleum ether–EtOAc)
3.2. Isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-thio-b-
D-galactopyranoside (2)
Compound 110c (2.50 g, 6.82 mmol) was dissolved in pyridine
(12 mL) and AcCl (0.97 mL, 13.6 mmol) was added dropwise. The
reaction mixture was stirred overnight at rt, at the end of which
time TLC (2:1 petroleum ether–EtOAc) indicated that the reaction
was complete. The reaction mixture was diluted with CH2Cl2, and
washed with N HCl, water, and satd aq NaHCO3. The organic layers
were combined, dried (Na2SO4), filtered, and concentrated in va-
cuo. Purification by flash column chromatography (2:1 petroleum
ether–EtOAc) gave 2 as a foamy solid (2.37 g, 85%): mp 182–
gave 11 as a white foamy solid (1.69 g, 87%): mp 167–169 °C; [a]
D
ꢁ69.0 (c 1.0, CHCl3); 1H NMR (CDCl3): d 8.01 (2H, d, J 7.5 Hz, Ar-H),
7.88–7.91 (4H, m, Ar-H), 7.48–7.56 (3H, m, Ar-H), 7.33–7.42 (6H,
m, Ar-H), 5.71 (1H, dd, J2,3 = J3,4 = 9.6 Hz, H-3), 5.61 (1H, dd, H-2),
5.27 (1H, dd, J4,5 8.8 Hz, H-4), 4.64 (1H, d, J1,2 7.8 Hz, H-1), 4.61
184 °C; [a]
+3.95 (c 2.0, CHCl3); 1H NMR (CDCl3): d 7.50–7.52
D
(2H, d, J 6.1 Hz, Ar-H), 7.34–7.36 (3H, m, Ar-H), 5.83–5.92 (1H, m,
CH2@CHCH2O), 5.53 (1H, s, PhCH), 5.40 (1H, dd, J2,3 9.7 Hz, H-2),
5.17–5.30 (2H, dd, Jtrans 17.3 Hz, Jcis 10.3 Hz, CH2@CHCH2O), 4.49
0
0
(1H, d, J5,6 3.0 Hz, H-6), 4.47 (1H, dd, J5,6 5.2 Hz, J6,6 12.1 Hz, H-
60), 4.06–4.11 (1H, m, H-5), 3.56 (3H, s, CH3O), 1.99 (3H, s, CH3CO).
HRESIMS: calcd for C30H28NaO10, m/z 571.15747; found, m/z
571.15644.
0
(1H, d, J1,2 9.9 Hz, H-1), 4.33 (1H, d, J6,6 12.4 Hz, H-6), 4.30 (1H,
0
br s, H-4), 4.08–4.19 (2H, m, CH2@CHCH2O), 4.02 (1H, d, J6,6
12.4 Hz, H-60), 3.59 (1H, dd, J3,4 2.2 Hz, H-3), 3.44 (1H, br s, H-5),
3.29–3.36 (1H, m, -SCH(CH3)2), 2.10 (3H, s, CH3CO), 1.39 (3H, d, J
6.5 Hz, –SCH(CH3)2), 1.26 (3H, d, J 6.7 Hz, –SCH(CH3)2). HRESIMS:
calcd for C21H28NaO6S, m/z 431.14988; found, m/z 431.14956.
3.6. Methyl 3,4,6-tri-O-benzoyl-b-D-glucopyranoside (12)
To a solution of compound 11 (1.10 g, 2.01 mmol) in 8.0 mL
CH2Cl2 was added a solution of 2% AcCl in MeOH (60.0 mL). The
mixture was stirred overnight at rt, at the end of which time TLC
(2:1 petroleum ether–EtOAc) indicated that the reaction was com-
plete. The mixture was concentrated in vacuo. Purification by flash
column chromatography (2:1 petroleum ether–EtOAc) gave 12 as a
3.3. Methyl 2-O-acetyl-3-O-benzoyl-4,6-O-benzylidene-b-D-
glucopyranoside (9)
To a solution of compound 811 (0.20 g, 0.52 mmol) in 10.0 mL
CH2Cl2 was added pyridine (0.2 mL, 2.5 mmol). A solution of AcCl
(0.11 mL, 1.5 mmol) in 10.0 mL of CH2Cl2 was added dropwise with
white foamy solid (0.92 g, 90%): mp 62–64 °C; [
a]
ꢁ74.6 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 7.96–8.01 (4H, m, Ar-H), 7.90 (2H, d, J

L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
1255
7.5 Hz, Ar-H),7.47–7.56 (3H, m, Ar-H), 7.32–7.41 (6H, m, Ar-H),
5.61 (1H, dd, J2,3 = J3,4 = 8.1 Hz, H-3), 5.59 (1H, dd, J4,5 8.0 Hz, H-
20.1 Hz, Jcis 10.5 Hz, CH2@CHCH2O), 5.04(1H, dd, J2,3 10.6 Hz,
GalH-2), 4.91 (1H, d, J1,2 3.1 Hz, GlcH-1), 4.55 (1H, dd, J5,6 2.0 Hz,
0
0
0
4), 4.61 (1H, J5,6 3.0 Hz, J6,6 12.0 Hz, H-6), 4.50 (1H, d, J1,2 7.7 Hz,
J6,6 11.9 Hz, GlcH-6), 4.44 (1H, dd, J5,6 5.3 Hz, GlcH-6), 4.31–4.35
(1H, m, GlcH-5), 4.04–4.09 (3H, m, GlcH-2, CH2@CHCH2O), 3.81–
3.84 (2H, m), 3.76 (1H, dd, J3,4 3.0 Hz, GalH-3), 3.50 (3H, s, CH3O),
3.36–3.39 (2H, m), 2.14 (3H, s, CH3CO). HRESIMS: calcd for
H-1), 4.47 (1H, dd, J5,6 5.4 Hz, H-60), 4.04–4.09 (1H, m, H-5),
3.79–3.84 (1H, m, H-2), 3.62 (3H, s, CH3O), 2.74 (1H, d, JOH,2
2.6 Hz, OH). HRESIMS: calcd for C28H26NaO9, m/z 529.14690;
found, m/z 529.14585.
0
C
46H50NO15, m/z 856.31750; found, m/z 856.31867.
Compound 16: yield 26.3%; mp 97–98 °C; [ +44.5 (c 1.0,
D
a]
3.7. Typical procedure for the coupling reaction of the acceptors
4, 5, 8 and 12 with donor 2
CHCl3); 1H NMR (CDCl3): d 8.02 (2H, d, J 7.7 Hz, Ar-H), 7.94 (2H,
d, J 7.6 Hz, Ar-H), 7.90 (2H, d, J 7.6 Hz, J 7.8 Hz, Ar-H), 7.47–7.56
(5H, m, Ar-H), 7.32–7.42 (9H, m, Ar-H), 5.97(1H, dd,
J2,3 = J3,4 = 9.8 Hz, GlcH-3), 5.66–5.75 (1H, m, CH2@CHCH2O), 5.51
(1H, s, PhCH), 5.49 (1H, dd, J2,3 9.7 Hz, GalH-2), 5.25 (1H, dd, J4,5
8.3 Hz, GlcH-4), 5.12 (1H, d, J 3.5 Hz, GlcH-1), 5.04–5.12 (2H, dd,
Jtrans 14.5 Hz, Jcis 10.3 Hz, CH2@CHCH2O), 4.60 (1H, d, J1,2 8.0 Hz,
Donor 2 (0.4–0.5 g, 2.0 equiv) and the acceptor (4,11 5,12 11 and
8
12) (1.0 equiv) were dried together under high vacuum for 2 h,
then dissolved in anhyd CH2Cl2 (25 mL). Then NIS (2.0 equiv) was
added, and TMSOTf (0.2 equiv) was added dropwise at ꢁ20 °C un-
der an N2 atmosphere. The reaction mixture was stirred for 2 h, at
the end of which time TLC (2:1 petroleum ether–EtOAc) indicated
that the reaction was complete. Then the mixture was neutralized
with Et3N and concentrated in vacuo. Purification of the crude
product by flash column chromatography (2:1 petroleum ether–
0
GalH-1), 4.54 (1H, dd, J5,6 2.3 Hz, J6,6 12.0 Hz, GlcH-6), 4.43 (1H,
0
dd, J5,6 5.4 Hz, GlcH-6), 4.34–4.39 (1H, m, GlcH-5), 4.28 (1H, d,
0
J6,6 12.2 Hz, GalH-6), 4.18 (1H, dd, J4,5 0.6 Hz, GalH-4), 4.07 (1H,
d, J6,6 12.2 Hz, GalH-60), 4.01 (1H, dd, Glc-2), 3.90–4.01 (2H, m,
0
CH2@CHCH2O), 3.53 (3H, s, CH3O), 3.40 (1H, s, GalH-5), 3.31 (1H,
dd, J3,4 3.2 Hz, GalH-3), 1.63 (3H, s, CH3CO). HRESIMS: calcd for
EtOAc) gave a- and b-linked disaccharides as white solids.
C46H46NaO15, m/z 861.27289; found, m/z 861.27091.
3.7.1. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-benzylidene-
glucopyranoside (13) and methyl 2-O-acetyl-3-O–allyl-4,6-O-
benzylidene-b- -galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-
benzylidene- -glucopyranoside (14)
Compound 13: yield 56.2%; mp 153–155 °C; [
a-D-
a
-
D-
3.7.3. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-benzylidene-b-
glucopyranoside (17) and methyl 2-O-acetyl-3-O-allyl-4,6-O-
a-D-
D
-
D
a
-D
benzylidene-b-
benzylidene-b-
D
-galactopyranosyl-(1?2)-3-O-benzoyl-4,6-O-
a]
+117.1 (c 1.0,
D-glucopyranoside (18)
D
CHCl3); 1H NMR (CDCl3): d 8.05 (2H, d, J 7.6 Hz, Ar-H), 7.61 (1H, t, J
7.3 Hz, Ar-H), 7.47 (2H, t, J 7.6 Hz, Ar-H), 7.39–7.43 (4H, m, Ar-H),
7.30–7.31 (6H, m, Ar-H), 5.81–5.92 (1H, m, CH2@CHCH2O), 5.83
(1H, dd, J2,3 = J3,4 = 9.6 Hz, GlcH-3), 5.51 (1H, s, PhCH), 5.41 (1H,
d, J1,2 3.2 Hz, GalH-1), 5.31 (1H, s, PhCH), 5.14–5.29 (2H, dd, Jtrans
17.6 Hz, Jcis 10.4 Hz, CH2@CHCH2O), 5.04 (1H, dd, J2,3 10.4 Hz,
GalH-2), 4.84 (1H, d, J1,2 3.1 Hz, GlcH-1), 4.33 (1H, dd, J5,6 4.7 Hz,
Compound 17: yield 65.5%; mp 174–177 °C; [a] +69.2 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 8.08 (2H, d, J 7.4 Hz, Ar-H), 7.62 (1H,
t, J 7.5 Hz, Ar-H), 7.49 (2H, t, J 7.7 Hz, Ar-H), 7.28–7.42 (10H, m,
Ar-H), 5.84–5.93 (1H, m, CH2@CHCH2O), 5.63 (1H, dd,
J2,3 = J3,4 = 9.4 Hz, GlcH-3), 5.59 (1H, d, J1,2 3.7 Hz, GalH-1), 5.50
(1H, s, PhCH), 5.27 (1H, s, PhCH), 5.21 (1H, dd, J2,3 10.7 Hz, GalH-
2), 5.16–5.31 (2H, m, Jtrans 18.1 Hz, Jcis 10.6 Hz, CH2@CHCH2O),
0
0
J6,6 10.0 Hz, GlcH-6), 4.07–4.15 (2H, m, CH2@CHCH2O), 3.95–4.00
4.53 (1H, d, J1,2 7.5 Hz, GlcH-1), 4.41 (1H, dd, J5,6 5.0 Hz, J6,6
(2H, m), 3.88 (1H, m, GalH-4), 3.75–3.82 (4H, m), 3.45(3H, s,
CH3O), 3.38–3.42 (2H, m), 2.14 (3H, s, CH3CO). HRESIMS: calcd
for C39H46NO13, m/z 736.29639; found, m/z 736.29800.
10.5 Hz, GlcH-6), 4.11 (2H, d, J 5.5 Hz, CH2@CHCH2O), 3.94 (1H,
0
d, J3,4 2.7 Hz, GalH-4), 3.75–3.87 (4H, m), 3.66 (1H, d, J6,6 12.4 Hz,
GalH-6), 3.56–3.62 (1H, m, GlcH-5), 3.51 (3H, s, CH3O), 3.36 (1H,
br s, GalH-5), 3.13 (1H, dd, J5,6 0.9 Hz, J6,6 12.4 Hz, GalH-60), 2.13
0
Compound 14: yield 18.7%; mp 287–289 °C; [
a
]
+35.9 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 8.07 (2H, d, J 7.7 Hz, Ar-H), 7.57 (1H,
t, J 7.2 Hz, Ar-H), 7.35–7.52 (9H, m, Ar-H), 7.28–7.29 (3H, m, Ar-
H), 5.83 (1H, dd, J2,3 = J3,4 = 9.7 Hz, GlcH-3), 5.66–5.76 (1H, m,
CH2@CHCH2O), 5.51 (1H, s, PhCH), 5.46 (1H, s, PhCH), 5.25 (1H,
dd, J2,3 9.0 Hz, GalH-2), 5.04–5.13 (2H, dd, Jtrans 17.2 Hz, Jcis
9.8 Hz, CH2@CHCH2O), 5.04 (1H, d, J1,2 3.5 Hz, GlcH-1), 4.64 (1H,
(3H, s, CH3CO). HRESIMS: calcd for C39H46NO13, m/z 736.29639;
found, m/z 736.29821.
Compound 18: yield 16.4%; mp 222–225 °C; [
a
]
ꢁ2.2 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 8.06 (2H, d, J 7.5 Hz, Ar-H), 7.58 (1H,
t, J 7.4 Hz, Ar-H), 7.44–7.52 (4H, m, Ar-H), 7.29–7.40 (8H, m, Ar-
H), 5.71–5.81 (1H, m, CH2@CHCH2O), 5.52 (1H, s, PhCH), 5.51
(1H, s, PhCH), 5.44 (1H, dd, J2,3 6.4 Hz, J3,4 8.9 Hz, GlcH-3), 5.28
(1H, dd, J2,3 9.6 Hz, GalH-2), 5.08–5.18 (2H, dd, Jtrans 17.1 Hz, Jcis
10.3 Hz, CH2@CHCH2O), 4.84 (1H, d, J1,2 8.1 Hz, GalH-1), 4.72 (1H,
0
d, J1,2 8.0 Hz, GalH-1), 4.32 (1H, dd, J5,6 4.8 Hz, J6,6 10.2 Hz, GalH-
0
6), 4.27 (1H, d, J6,6 12.6 Hz, GlcH-6), 4.19 (1H, d, J 3.0 Hz, GalH-
4), 4.06 (1H, d, J6,6 12.6 Hz, GlcH-60), 3.96–4.05 (2H, m,
0
0
CH2@CHCH2O),
3.91–3.97
(2H,
m),
3.76
(1H,
dd,
d, J1,2 5.7 Hz, GlcH-1), 4.40 (1H, dd, J5,6 4.5 Hz, J6,6 10.1 Hz, GlcH-
J5,6 = J6,6 = 10.3 Hz, GalH-60), 3.69 (1H, dd, J4,5 9.6 Hz, GlcH-4),
3.48 (3H, s, CH3O), 3.40 (1H, br s, GalH-5), 3.33 (1H, dd, J2,3
10.0 Hz, J3,4 3.2 Hz, GalH-3), 1.68 (3H, s, CH3CO). HRESIMS: calcd
for C39H42NaO13, m/z 741.25176; found, m/z 741.25034.
6), 4.31 (1H, d, J6,6 12.1 Hz, GalH-6), 4.20 (1H, d, J3,4 3.2 Hz,
0
0
0
GalH-4), 4.05 (1H, d, J6,6 12.1 Hz, GalH-60), 3.95–4.04 (2H, m,
0
CH2@CHCH2O), 3.92–3.99 (2H, m, GlcH-2, GlcH-4), 3.75 (1H, dd,
J5,6 10.1 Hz, GlcH-60), 3.64–3.70 (1H, m, GlcH-5), 3.55 (3H, s,
0
CH3O), 3.41–3.44 (2H, m, GalH-3, GalH-5), 1.85 (3H, s, CH3CO).
HRESIMS: calcd for C39H42NaO13, m/z 741.25176; found, m/z
741.25051.
3.7.2. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-
glucopyranoside (15) and methyl 2-O-acetyl-3-O–allyl-4,6-O-
benzylidene-b- -galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-
-glucopyranoside (16)
Compound 15: yield 52.6%; mp 85–88 °C; [ ] +101.6 (c 1.0,
D
a-D-
a-D-
D
a-
3.7.4. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-
galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-b-
glucopyranoside (19) and methyl 2-O-acetyl-3-O–allyl-4,6-O-
benzylidene-b- -galactopyranosyl-(1?2)-3,4,6-tri-O-benzoyl-b-
-glucopyranoside (20)
a-D-
D
D-
a
CHCl3); 1H NMR (CDCl3): d 8.03 (2H, d, J 7.6 Hz, Ar-H), 7.90–7.95
(4H, m, Ar-H), 7.49–7.56 (3H, m, Ar-H), 7.29–7.43 (11H, m, Ar-H),
5.96 (1H, dd, J2,3 = J3,4 = 9.7 Hz, GlcH-3), 5.82–5.92 (1H, m,
CH2@CHCH2O), 5.55 (1H, dd, J4,5 9.7 Hz, GlcH-4), 5.43 (1H, d, J1,2
3.1 Hz, GalH-1), 5.30 (1H, s, PhCH), 5.14–5.30 (2H, dd, Jtrans
D
D
Compound 19: yield 70.8%; mp 95–97 °C; [a] +117.9 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 7.99 (2H, d, J 7.6 Hz, Ar-H), 7.95 (2H,
d, J 8.1 Hz, Ar-H), 7.88 (2H, d, J 7.8 Hz, Ar-H), 7.29–7.59 (14H, m,

1256
L. Chen et al. / Carbohydrate Research 346 (2011) 1250–1256
Angata, T.; Narimatsu, H.; Hirabayashi, J. Glycobiology 2008, 18, 789–798; (f)
Elbein, A. D.; Pan, Y. T.; Pastuszak, I.; Carroll, D. Glycobiology 2003, 13, 17R–27R.
3. (a) Fischer, W.; Leopold, K. Int. J. Syst. Bacteriol. 1999, 49, 653–662; (b) Ryu, Y.
H.; Baik, J. E.; Yang, J. S.; Kang, S.-S.; Im, J.; Yun, C.-H.; Kim, D. W.; Lee, K.; Chung,
D. K.; Ju, H. R.; Han, S. H. Int. Immunopharmacol. 2009, 9, 127–133; (c) Schirner,
K.; Marles-Wright, J.; Lewis, R. J.; Errington, J. EMBO J. 2009, 28, 830–842; (d)
Toledo-Arana, A.; Dussurget, O.; Nikitas, G.; Sesto, N.; Guet-Revillet, H.;
Balestrino, D.; Loh, E.; Gripenland, J.; Tiensuu, T.; Vaitkevicius, K.;
Barthelemy, M.; Vergassola, M.; Nahori, M.-A.; Soubigou, G.; Régnault, B.;
Coppée, J.-Y.; Lecuit, M.; Johansson, J.; Cossart, P. Nature 2009, 459, 950–956;
(e) Roethlisberger, P.; Iida-Tanaka, N.; Hollemeyer, K.; Heinzle, E.; Ishizuka, I.;
Fischer, W. Eur. J. Biochem. 2000, 267, 5520–5530; (f) Fischer, W.; Arneth-
Seifert, D. J. Bacteriol. 1998, 180, 2950–2957.
Ar-H), 5.84–5.93 (1H, m, CH2@CHCH2O), 5.75 (1H, dd,
J2,3 = J3,4 = 9.5 Hz, GlcH-3), 5.62 (1H, d, J1,2 3.5 Hz, GalH-1), 5.54
(1H, dd, J4,5 9.7 Hz, GlcH-4), 5.25 (1H, s, PhCH), 5.17–5.31 (3H, m,
0
CH2@CHCH2O, GalH-2), 4.60 (1H, dd, J5,6 3.0 Hz, J6,6 12.1 Hz,
0
GlcH-6), 4.55 (1H, d, J1,2 7.7 Hz, GlcH-1), 4.46 (1H, dd, J5,6 5.4 Hz,
GlcH-60), 4.10–4.11 (2H, m, CH2@CHCH2O), 4.03–4.08 (1H, m,
GlcH-5), 3.93 (1H, dd, GlcH-2), 3.87 (1H, dd, J4,5 0.3 Hz, GalH-4),
0
3.77 (1H, dd, J2,3 10.6 Hz, J3,4 3.1 Hz, GalH-3), 3.71 (1H, d, J6,6
12.5 Hz, GalH-6), 3.52 (3H, s, CH3O), 3.28 (1H, s, GalH-5), 3.10
(1H, d, J6,6 12.5 Hz, GalH-60), 2.12 (3H, s, CH3CO). HRESIMS: calcd
0
4. Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
5. (a) Matsuoka, K.; Terabatake, M.; Esumi, Y.; Terunuma, D.; Kuzuhara, H.
Tetrahedron Lett. 1999, 40, 7839–7842; (b) Koizumi, A.; Hada, N.; Kaburaki, A.;
Yamano, K.; Schweizer, F.; Takeda, T. Carbohydr. Res. 2009, 344, 856–868; (c)
Cid, M. B.; Alfonso, F.; Martín-Lomas, M. Carbohydr. Res. 2004, 339, 2303–2307;
(d) Alya, M. R. E.; Rochaix, P.; Amessou, M.; Johannes, L.; Florent, J.-C.
Carbohydr. Res. 2006, 341, 2026–2036; (e) Panchadhayee, R.; Misra, A. K.
Tetrahedron: Asymmetry 2009, 20, 1550–1555; (f) Weïwer, M.; Sherwood, T.;
Linhardt, R. J. J. Carbohydr. Chem. 2008, 27, 420–427; (g) Lafont, D.; Carrière, F.;
Ferrato, F.; Boullanger, P. Carbohydr. Res. 2006, 341, 695–704; (h) Yoon, S.; Shin,
Y.; Chun, K. H.; Shin, J. E. N. Bull. Korean Chem. Soc. 2004, 25, 289–292; (i)
Ghosh, S.; Misra, A. K. Tetrahedron: Asymmetry 2010, 21, 725–730.
for C46H50NO15, m/z 856.31750; found, m/z 856.31974.
Compound 20: yield 14.1%; mp 119–121 °C; [a] +15.1 (c 1.0,
D
CHCl3); 1H NMR (CDCl3): d 7.99 (2H, d, J 7.2 Hz, Ar-H), 7.94 (2H,
d, J 7.4 Hz, Ar-H), 7.87 (2H, d, J 7.4 Hz, Ar-H), 7.45–7.54 (5H, m,
Ar-H), 7.30–7.40 (9H, m, Ar-H), 5.67–5.77 (1H, m, CH2@CHCH2O),
5.70 (1H, dd, J2,3 = J3,4 = 9.2 Hz, GlcH-3), 5.56 (1H, dd, J4,5 9.6 Hz,
GlcH-4), 5.51 (1H, s, PhCH), 5.24 (1H, dd, J2,3 10.0 Hz, GalH-2),
3
3
5.04–5.15 (2H, m, Jtrans 17.4 Hz, Jcis 10.3 Hz, 2J 1.4 Hz,
CH2@CHCH2O), 4.69 (1H, d, J1,2 8.3 Hz, GalH-1), 4.67 (1H, d, J1,2
0
6. (a) Szabó, Z. B.; Herczeg, M.; Fekete, A.; Batta, G.; Borbás, A.; Lipták, A.; Antus, S.
Tetrahedron: Asymmetry 2009, 20, 808–820; (b) Daniellou, R.; Palmer, D. R. J.
Carbohydr. Res. 2006, 341, 2145–2150.
7. Ueki, A.; Hirota, M.; Kobayashi, Y.; Komatsu, K.; Takano, Y.; Iwaoka, M.;
Nakahara, Y.; Hojo, H.; Nakahara, Y. Tetrahedron 2008, 64, 2611–2618.
8.2 Hz, GlcH-1), 4.57 (1H, dd, J5,6 3.2 Hz, J6,6 12.1 Hz, GlcH-6),
4.44 (1H, dd, J5,6 5.2 Hz, GlcH-60), 4.33 (1H, d, J6,6 12.2 Hz, GalH-
6), 4.18 (1H, dd, J4,5 0.4 Hz, GalH-4), 3.92–4.08 (2H, m,GalH-60,
GlcH-5), 3.92–4.08 (3H, m, CH2@CHCH2O, GlcH-2), 3.59 (3H, s,
CH3O), 3.37 (1H, br s, GalH-5), 3.33 (1H, dd, J3,4 3.4 Hz, GalH-3),
0
0
ˇ
8. (a) Ruttens, B.; Kovác, P. Carbohydr. Res. 2006, 341, 1077–1080; (b) Rösch, A.;
Kunz, H. Carbohydr. Res. 2006, 341, 1597–1608; (c) Nemati, N.; Karapetyan, G.;
Nolting, B.; Endress, H.-U.; Vogel, C. Carbohydr. Res. 2008, 343, 1730–1742; (d)
Malleron, A.; Hersant, Y.; Narvor, C. L. Carbohydr. Res. 2006, 341, 29–34; (e)
Allevi, P.; Colombo, R.; Giannini, E.; Anastasia, M. Tetrahedron: Asymmetry 2007,
18, 1750–1757; (f) Mukherjee, C.; Misra, A. K. Tetrahedron: Asymmetry 2009, 20,
473–477; (g) Guchhait, G.; Misra, A. K. Tetrahedron: Asymmetry 2009, 20, 1791–
1797.
1.67 (3H, s, CH3CO). HRESIMS: calcd for C46H46NaO15
, m/z
861.27289; found, m/z 861.27170.
Acknowledgment
9. (a) Yang, F.; He, H.; Du, Y.; Lü, M. Carbohydr. Res. 2002, 337, 1165–1169; (b)
Demchenko, A. V.; Rousson, E.; Boons, G.-J. Tetrahedron Lett. 1999, 40, 6523–
6526; (c) Chen, L.; Kong, F. Carbohydr. Res. 2002, 337, 1373–1380.
10. (a) Chen, L.; Zhao, X.-E.; Lai, D.; Song, Z.; Kong, F. Carbohydr. Res. 2006, 341,
1174–1180; (b) Chen, L.; Kong, F. Tetrahedron Lett. 2003, 44, 3691–3695; (c)
Chen, L.-Q.; Lai, D.; Guo, Q.; Cai, J. Nat. Sci. J. Xiangtan Univ. 2008, 30, 89–93; (d)
Imamura, A.; Ando, H.; Korogi, S.; Tanabe, G.; Muraoka, O.; Ishida, H.; Kiso, M.
Tetrahedron Lett. 2003, 44, 6725–6728; (e) Hada, N.; Oka, J.; Nishiyama, A.;
Takeda, T. Tetrahedron Lett. 2006, 47, 6647–6650; (f) Hada, N.; Oka, J.;
Hakamata, K.; Yamamoto, K.; Takeda, T. Carbohydr. Res. 2008, 343, 2315–
2324; (g) Veerapen, N.; Brigl, M.; Garg, S.; Cerundolo, V.; Cox, L. R.; Brenner, M.
B.; Besra, G. S. Bioorg. Med. Chem. Lett. 2009, 19, 4288–4291; (h) Veerapen, N.;
Leadbetter, E. A.; Brenner, M. B.; Cox, L. R.; Besra, G. S. Bioconjugate Chem. 2010,
21, 741–747.
The project was supported by the Natural Science Foundation of
Hunan Province, China (Grant No. 10JJ6023 and 05JJ40054).
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