Automated parallel synthesis of a protected oligosaccharride library based upon the structure of dimeric Lewis X by one-pot sequential glycosylation

Article abstract of DOI:10.1055/s-2005-863751

An efficient synthesis of a protected dimeric Lewis X epitope by two sequential one-pot glycosylations is described. Combinatorial synthesis of the dimeric Lewis X epitope derivatives by the one-pot glycosylation was accomplished utilizing an automated synthesizer to provide 12-protected oligosaccharides.

Full text of DOI:10.1055/s-2005-863751

824
LETTER
Automated Parallel Synthesis of a Protected Oligosaccharide Library Based
upon the Structure of Dimeric Lewis X by One-Pot Sequential Glycosylation
A
utomated Paralle
i
l
Synth
r
e
sis of
a
o
Protected
O
s
ligosaccha
h
r
ide
L
ibraryi Tanaka, Nobuatsu Matoba, Hirokazu Tsukamoto,1 Hisami Takimoto, Haruo Yamada,2 Takashi Takahashi*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama,
Meguro, Tokyo 152-8552, Japan
E-mail: ttak@apc.titech.ac.jp
Received 16 December 2004
Ph
Ph
Abstract: An efficient synthesis of a protected dimeric Lewis X
epitope by two sequential one-pot glycosylations is described.
Combinatorial synthesis of the dimeric Lewis X epitope derivatives
by the one-pot glycosylation was accomplished utilizing an auto-
mated synthesizer to provide 12-protected oligosaccharides.
O
OBn
O
OBn
O
O
BnO
O
O
OBn
O BnO
OPiv
O
O
O
OBn
O
O
ClAcO
O
O
O
OBn
O
O
OBz
OBz
PhtN
OBn
OBn
PhtN
Me
O
Me
O
OBn
OBn
OBn
BnO
BnO
Key words: automated synthesis, glycosyl fluoride, Lewis X, one-
pot glycosylation, thioglycoside
1
Ph
Ph
O
OBn
O
O
O
BnO
HO
Oligosaccharides on cell surface play important roles in
many biological processes.3 Most biologically active
oligosaccharides are rare, and are difficult to purify. Ad-
ditionally, their structural diversity based upon stereo- and
regioisomers makes it difficult to determine their structure
in comparison with that of oligopeptides and oligonucle-
otides. Therefore, the chemical synthesis of such oli-
gosaccharides would strongly assist one in the elucidation
of their structure–activity relationships. Recent develop-
ments of the chemical synthesis of oligosaccharide in-
volving automated solid-phase synthesis, allows the high
speed synthesis of a single target oligosaccharide.4,5
Furthermore, combinatorial chemistry enables one to
synthesize oligosaccharide libraries containing tri- or tet-
rasaccharides.6,7,8d However, preparation of biologically
active and complex natural product-based oligosaccharide
libraries is still difficult to accomplish.
OBn
OPiv
O
O
O
O
O BnO
F
ClAcO
OBn
O
O
O
O
OBn
OBz
PhtN
OBn
OBn
BzO
i
ii
Me
O
OBn
O
HO
HO
4
SPh
OBn
BnO
PhtN
2
iii
3
SPh
OBn
Me
O
OBn
BnO
5
Ph
Ph
O
OBn
O
O
O
O
O
O
ClAcO
HO
SPh
F
HO
HO
BzO
iv
Br
PhtN
BzO
v
6
vi
3
SPh
OBn
7
Me
O
OBn
BnO
5
Scheme 1 Strategy for the one-pot synthesis of dimeric Lewis X
derivative 1.
One-pot glycosylation, involving sequential activation of
glycosyl donors in a single vessel, is effective not only for
the high speed synthesis of a single target oligosaccharide,
but also for the parallel synthesis of oligosaccharide li-
braries.7c,8,9 We have investigated the one-pot glycosyla-
tion based on the chemoselective activation of glycosyl
donors attached with different leaving groups with appro-
priate activators,9 and have already reported a one-pot six-
step synthesis of a di-branched heptasaccharide composed
of a b(1,6) linked pentasaccharide backbone using seven
independent building blocks.9f If the requisite manipula-
tions in the one-pot glycosylation are adaptable to an au-
tomated synthesizer, it would be an attractive way to
synthesize structurally complex oligosaccharides.
Dimeric Lewis X is an important tumor-associated anti-
gen, and is composed of a b(1,3) and b(1,4) linked hexa-
saccharide backbone attached with two a(1,3) linked
branching saccharides.10,11 Owing to the biological signif-
icance and the complexity of the structure, it has served as
a synthetic target for the development of the new method-
ologies. There have already been reported several synthe-
ses of dimeric Lewis X derivatives using a polymer-
supported synthesis and a solid-phase synthesis.12 Herein
we report an automated parallel solution-phase synthesis
of a protected dimeric Lewis X library by one-pot glyco-
sylation.
At first, the synthesis of the protected octasaccharide 1 by
one-pot glycosylation was conducted. Based on our previ-
ous report, the di-branched structure could be prepared by
one-pot six-step glycosylation. In this approach, MeOTf
would be used for selective activation of ethyl thioglyco-
sides. However, this glycosylation conditions would not
SYNLETT 2005, No. 5, pp 0824–0828
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863751; Art ID: U34604ST
© Georg Thieme Verlag Stuttgart · New York
2
1.
0
3.
2
0
0
5

LETTER
Automated Parallel Synthesis of a Protected Oligosaccharide Library
825
Ph
ride at the C3 position. Activation of the resulting thiogly-
coside for coupling with the glycosyl acceptor 4, followed
by a-selective glycosylation of the remaining C3 hydrox-
yl group of the glucosamine unit with thiofucoside 5 pro-
vides the protected octasaccharide 1 in one pot. The N-
phthaloyl group reduces the reactivity of the C3 hydroxyl
group of the glucosamine 3 to promote regioselectively
glycosylation at the C4 hydroxyl group due to steric hin-
drance, and generates the 1,2-trans-glycosidic bond in the
second glycosylation.13 The branched tetrasaccharide 2
can be prepared by one-pot three-step glycosylation in
the same manner using the glycosyl bromide 6, the N-
phthaloyl thioglucosamine 3, the galactosyl fluoride 7,
and thiofucoside 5 (iv → v → vi). Various glycosyl
halides, glycosyl acceptors and thioglycosides would be
adaptable to the one-pot glycosylation instead of building
blocks 2, 4, and 5 to provide combinatorial oligosaccha-
ride libraries based on the structure of dimeric Lewis X.
Ph
O
O
O
O
OBn
d
OBn
O
O
O
O
HO
HO
SPh
NPht
O
F
ClAcO
O
O
BzO
BzO
NPht
Me
O
OBn
3
Ph
OBn
BnO
O
O
2
O
a
ClAcO
Ph
SPh
OBn
Me
O
OBn
BzO
c
Br
O
O
BnO
6
O
F
5
HO
BzO
Ph
Ph
Ph
b
7
O
O
O
O
O
O
OBn
O
OBn
O
O
O
O
O
ClAcO
SPh
NPht
O
HO
F
ClAcO
O
NPht
HO
BzO
BzO
BzO
8
9
Scheme 2 Reagents and conditions: a) 6 (1.2 equiv), AgOTf
(1.5 equiv), CH2Cl2, MS 4 Å, –40 °C, 92%; b) 7 (1.0 equiv), DMTST
(1.5 equiv), CH2Cl2, MS 4 Å, 0 °C, 85%; c) 5 (2.0 equiv), DMTST
(2.5 equiv), CH2Cl2, MS 4 Å, 0 °C, 96%; d) 6 (1.2 equiv), AgOTf
(1.6 equiv), CH2Cl2–toluene, MS 4 Å, –40 °C, then 7 (1.2 equiv),
DMTST (5.0 equiv), CH2Cl2, 0 °C, then 5 (2.0 equiv), CH2Cl2, 56%
based on 3.
Stepwise synthesis of the protected dimeric Lewis X
epitope 1 was investigated. Regio- and chemoselective
glycosylation of thioglycoside 3 with glycosyl bromide 6
by AgOTf provided disaccharide 8 in 92% yield
(Scheme 2). Glycosidation of the resulting thioglycoside
8 at the C3 position of glycosyl fluoride 7 by DMTST
[dimethyl(methylthio)sulfonium triflate] proceeded
smoothly to provide the linear trisaccharide 9 in 85%
yield. DMTST was effective for activation with thiogly-
coside without decomposition of glycosyl fluoride 9. Gly-
cosylation of the remaining hindered hydroxyl group at
C3 position on glucosamine in 9 was accomplished by us-
ing excess thiofucoside 5 and DMTST to provide tetrasac-
charide 2 in 96% yield with complete a-selectivity. The
glycosyl fluoride 2 underwent chemo- and regioselective
glycosylation of thioglycoside 3 at the C4 position by
HfCp2Cl2/2AgOTf to afforded heptasaccharide 10 in 99%
be suitable for glycosylation of hindered hydroxyl groups.
Our strategy for the synthesis of 1 involves two sequential
one-pot three-step glycosylations involving one-pot gly-
cosylation using four building blocks 3, 5, 6, and 7 (iv →
v → vi) to provide glycosyl fluoride 2, and one pot
glycosylation using four building blocks 2, 3, 4, and 5
(i → ii → iii) to provide 1 (Scheme 1). The second
one-pot glycosylation for the synthesis of 1 was initiated
by chemo- and regioselective glycosylation of the 2-N-
phthaloyl thioglucosamine 3 at the C4 position with the
galactosyl fluoride 2 attached with a branched trisaccha-
Ph
Ph
Ph
Ph
O
O
O
O
O
O
O
d
BnO
O
O
OBn
O
OBn
O
OBn
O BnO
OBn
O
OPiv
O
O
O
O
O
F
ClAcO
OBn
O
O
O
ClAcO
O
O
O
O
O
OBn
BzO
O
BzO
BzO
Me
NPht
BzO
NPht
OBn
NPht
O
OBn
Me
O
OBn
Me
O
OBn
OBn
BnO
OBn
OBn
BnO
BnO
2
1
OBn
O
SPh
OBn
Me
O
OBn
HO
HO
a
SPh
c
NPht
BnO
BnO
OBn
O BnO
3
OPiv
5
OBn
HO
O
O
OBn
Ph
Ph
Ph
Ph
OBn
O
O
O
O
O
O
BnO
O
O
4
OBn
O
OBn
O
OBn
b
OPiv
OBn
OBn
O
O
O
O BnO
O
O
OBn
O
O
O
O
ClAcO
O
O
O
O
O
ClAcO
O
OBn
O
NPht
O
SPh
HO
O
H
BzO
Me
BzO
NPht
OBn
NPht
BzO
Me
BzO
NPht
O
OBn
O
OBn
OBn
OBn
BnO
BnO
10
11
Scheme 3 Reagents and conditions: a) 3 (1.0 equiv), HfCp2Cl2/2AgOTf (2.0 equiv), CH2Cl2, MS 4Å, –40 °C, 99%; b) 4 (1.2 equiv), NIS
(1.5 equiv), TfOH (0.1 equiv), CH2Cl2, MS 4 Å, 0 °C, 75%; c) 5 (2.0 equiv), NIS (2.5 equiv), TfOH (0.1 equiv), CH2Cl2, MS 4 Å, 0 °C,
87%; d) 2 (1.4 equiv), 3 (1.2 equiv), HfCp2Cl2/2AgOTf (2.0 equiv), CH2Cl2, MS 4 Å, –40 °C, then 4 (1.0 equiv), NIS (5.0 equiv), TfOH (0.1
equiv), –40 °C, then, 5 (2.5 equiv), 75% based on 4.
Synlett 2005, No. 5, 824–828 © Thieme Stuttgart · New York

826
H. Tanaka et al.
LETTER
yield. The thioglycoside 10 was activated with NIS/TfOH the following procedure: (1) selective removal of the N-
in the presence of the glycosyl acceptor 4 to provide hep- phthaloyl groups with hydrazines, followed by acetylation
tasaccharide 11 in 75% yield. Glycosylation of the re- of the resulting amines to acetamide groups, (2) hydroly-
maining hindered hydroxyl group of 11 was accomplished sis of ester groups, and (3) reductive cleavage of the ben-
by using excess thioglycoside 5 and NIS/TfOH to provide zyl ethers and reduction of the azido group to amine by
the protected octasaccharide 1 in 87% yield with complete hydrogenolysis. The 6 oligosaccharides 15a,b, 16a,b,
a-selectivity. It should be noted that in each reaction, any 16e,f would be prepared by linear type one-pot glycosyla-
regio- and stereoisomers were not detected.
tion using the three glycosyl donors 2, 6, and 12,15 glu-
cosamine 3 and two acceptors 13 and 14. Further
incorporation of fucoside 5 to the oligosaccharides 15a,b,
16a,b, 16e,f at the remaining hydroxyl group affords 6
branched oligosaccharides 15c,d, 16c,d,g,h. (Scheme 3
and Table 1). Scheme 4 shows the program schedule for
the parallel synthesis of twelve oligosaccharides 15a–d
and 16a–h utilizing an automated synthesizer (L-
COSTM).16,17 It took eight hours to finish the program after
set-up of all reagents. Purification of the twelve crude
compounds using silica gel chromatography and a gel per-
meability chromatography provided twelve protected oli-
gosaccharides 15a–d and 16a–h in 22–46% overall yields
based on 13 or 14.
The one-pot glycosylation for the synthesis of 1 was ex-
amined. Sequential coupling reaction of the four building
blocks 3, 5, 6 and 7 with the appropriate activators such as
AgOTf and DMTST provided the glycosyl fluoride 2 in
56% overall yield based on 3.14 The following one-pot
glycosylation using the four building blocks 2, 3, 4, and 5
with the appropriate activators such as HfCp2Cl2/2AgOTf
and NIS/TfOH afforded the protected octasaccharide 1 in
75% yield based on 4. Analytical data of the octasaccha-
ride 1 were identical with those of authentic sample syn-
thesized by the stepwise synthesis.
Ph
O
Me
O
O
OBn
OBn
O
3
α-Bn3Fu =
15a: R = H
O
OBn
BnO
O
ClAcO
O
N3
5
O
OBz
NPht
6
a
6
a
6
a
6
a
12
e
12
b
12
b
12
b
2
b
2
b
2
b
2
b
R
15c: R = α-Bn3Fu
Ph
Ph
13
c
14
c
13
c
14 13
14
c
13
c
14
c
13
c
14
c
13
c
14
c
O
c
5
d
c
O
O
O
OBn
O
5
d
5
d
5
d
5
d
5
d
O
O
O
ClAcO
15b: R = H
15d: R = α-Bn3Fu
O
O
N3
5
O
BzO
BzO
NPht
R
e
e
e
e
e
e
e
e
e
e
e
e
Ph
Ph
16g
22%
15a 15b 15c 15d 16a 16b 16c 16d 16e 16f
16h
O
O
O
O
46% 44% 38% 43% 24% 28% 21% 23% 29% 26%
22%
OBn
OBn
O
O
O
O
O
O
ClAcO
O
N3
5
O
Ph
O
O
Ph
Ph
BzO
BzO
NPht
NPht
R2
O
R1
O
OBn
O
O
O
O
O
16a: R1 = Ac, R2 = H
O
O
O
HO
N3
5
O
F
ClAcO
O
N3
5
O
NPht
HO
16c: R1 = Ac, R2 = α-Bn3Fu
16e: R1 = α-Bn3Fu, R2 = H
16g: R1 = R2 = α-Bn3Fu
AcO
BzO
OBz
OBz
14
13
12
Ph
Ph
Ph
Scheme 4 Reagents and conditions: a) 6 (1.4 equiv), 3 (1.2 equiv),
AgOTf (2.0 equiv), CH2Cl2, MS 4 Å; b) 12 or 2 (1.4 equiv), 3 (1.2
equiv), HfCp2Cl2/2AgOTf (2.0 equiv), CH2Cl2; c) 13 or 14 (1.0
equiv), NIS (1.0 equiv), TfOH (0.01 equiv), CH2Cl2–MeCN (1.2:1);
d) 5 (4.0 equiv), NIS (3.0 equiv), CH2Cl2–MeCN (1.2:1); e) Et3N.
O
O
O
O
O
O
OBn
O
OBn
O
O
O
O
O
O
ClAcO
O
O
NPht
O
N3
5
O
O
BzO
BzO
NPht
BzO
R1
R2
16b: R1 = Ac, R2 = H
16d: R1 = Ac, R2 = α-Bn3Fu
16f: R1 = α-Bn3Fu, R2 = H
16h: R1 = R2 = α-Bn3Fu
In conclusion, we describe an automated parallel synthe-
sis of a protected branched oligosaccharide library based
upon the structure of dimeric Lewis X by one-pot sequen-
tial glycosylation. One-pot glycosylation utilizing
chemoselective activation of glycosyl donors attached
with different leaving groups by appropriate activators, is
effective not only for the synthesis of oligosaccharide
libraries, but also for the preparation of the requisite
building blocks. Using this methodology, the synthesis of
various combinatorial oligosaccharide libraries is in
progress.
Figure 1 The structure of a protected oligosaccharide library 15 and
16.
Next, we conducted an automated parallel synthesis of a
small combinatorial library containing the protected azi-
do-bearing di- to heptasaccharides 15 and 16 varying in
the number of the branched fucoses and the length of the
backbone (Figure 1). The protected oligosaccharides
could be converted to amino bearing oligosaccharides by
Synlett 2005, No. 5, 824–828 © Thieme Stuttgart · New York

LETTER
Automated Parallel Synthesis of a Protected Oligosaccharide Library
827
Table 1 Program Schedule for the Automated Synthesis of the
Protected Oligosaccharide Library 15a–d and 16a–h
References
(1) Current address: Graduate School of Pharmaceutical
Step
01
For compounds
Procedure
Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai
980-8578, Japan; e-mail:
hirokazu@mail.pharm.tohoku.ac.jp.
all
all
Cooling reaction vessel at –20 °C
(2) Current address: Department of Chemistry, Faculty of
Science Okayama University of Science, Okayama, Ridai 1-
1, Okayama 700-0005, Japan; e-mail:
02
Addition of 0.2 M solution of 3 in
CH2Cl2 (0.7 mL)
yamada@high.ous.ac.jp.
(3) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Dwek, R. A.
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03
all
Addition of 0.4 M solution of 2, 6, or
12 in CH2Cl2 (0.3 mL)
04
all
Stirring for 20 min at –20 °C
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10, 3085.
05-1
15
Addition of 0.2 M solution of AgOTf
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05-2
16
Addition of 0.2 M solution of
HfCp2Cl2/2AgOTf in CH2Cl2 (0.3
mL)
06
all
Stirring for 60 min at –20 °C
07
all
Warming reaction vessels at 0 °C
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08-1
15a,c, 16a,c,e,g
Addition of 0.2 M solution of 13 in
CH2Cl2 (0.5 mL)
08-2
15b,d, 16b,d,f,h
Addition of 0.2 M solution of 14 in
CH2Cl2 (0.5 mL)
09
10
all
all
Stirring for 20 min at 0 °C
Addition of 0.2 M solution of NIS in
MeCN (0.5 mL)
11
12
all
all
Stirring for 60 min at 0 °C
Addition of 0.01 M solution of TfOH
in CH2Cl2 (0.1 mL)
(9) (a) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc.
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13
14
15
all
Stirring for 60 min at 5 °C
all
Cooling reaction vessels at 0 °C
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15c,d, 16c,d,g,h
Addition of 0.2 M solution of 5 in
CH2Cl2 (2.0 mL)
16
17
all
Stirring for 20 min at 0 °C
15c,d, 16c,d,g,h
Addition of 0.2 M solution of NIS in
MeCN (0.5 mL)
18
19
20
all
all
all
Stirring for 60 min at 0 °C
Stirring for 60 min at 5 °C
Addition of Et3N (1.5 mL)
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Acknowledgement
We thank Mr. Tamotsu Yamamoto (Asahi Chemical Industry Co.,
Ltd.) for mass spectral analysis, and Dr. Ichiro Hijikuro and Dr.
Masaatsu Adachi for their kindly discussion.
Synlett 2005, No. 5, 824–828 © Thieme Stuttgart · New York

828
H. Tanaka et al.
LETTER
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1995, 270, C15. (b) Zhang, Y.; Brodzky, A.; Sinay, P.;
Uzabiaga, F.; Pocard, C. Carbohydr. Lett. 1996, 2, 67.
(c) Ellervik, U.; Magnusson, G. J. Org. Chem. 1998, 63,
9314.
(14) Activation of the glycosylated thioglycoside using NIS/
TfOH instead of DMTST resulted in decomposition of the
resulting glycosyl fluoride 8.
(15) The trisaccharide 12 was prepared by a linear type one-pot
glycosylation using 3, 6, and 7, followed by acetylation of
the resulting hydroxyl group.
(16) L-COS® is purchased from Moritex Corporation, Japan.
(17) We have already reported the utility of the automated
synthesizer for the parallel synthesis of oligosaccharides
based on the structure of a phytoalexin elicitor in rice cells
(ref. 7d).
Synlett 2005, No. 5, 824–828 © Thieme Stuttgart · New York