Effective one-pot synthesis of H type 1 and 2 trisaccharide derivatives using glycal epoxide

Article abstract of DOI:10.1246/cl.2005.400

We describe an efficient synthesis of H type 1 and 2 trisaccharides by one-pot glycosylation involving glycosidation of glycal epoxide. Copyright

Full text of DOI:10.1246/cl.2005.400

400
Chemistry Letters Vol.34, No.3 (2005)
Effective One-pot Synthesis of H type 1 and 2 Trisaccharide Derivatives Using Glycal Epoxide
Hiroshi Tanaka, Nobuatsu Matoba, and Takashi TakahashiÃ
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-2 Ookayama, Meguro, Tokyo 152-5882
(Received December 21, 2004; CL-041577)
We describe an efficient synthesis of H type 1 and 2 trisac-
charides by one-pot glycosylation involving glycosidation of
glycal epoxide.
synthesis of various C2 glycosylated oligosaccharides is re-
quired. Herein we report the one-pot synthesis of H Type 1
and 2 trisaccharide units using a glycal epoxide.
Our strategy for the one-pot synthesis of H Type 1 and 2 tri-
saccharide units 1 is based on the preparing glycosyl acceptors 5
by glycosylation of acceptor 3 with glycal epoxide 2. The glycal
epoxides are known to undergo stereoselective glycosidation to
provide glycosides 5 bearing a hydroxy group at the C2 position
linked through a 1,2-trans-glycosidic bond.5 Subsequent glyco-
sylation of the hydroxy group with glycosyl donor 4 would pro-
vide the protected H Type 1 and 2 trisaccharides 1.
We first conducted the one-pot synthesis of H type 1 trisac-
charide 9aA bearing a primary amino group using the three
building blocks 2, 3a, and 4A (Scheme 2). Our initial investiga-
tion involves the stepwise synthesis of the protected trisacchar-
ide 7aA as shown in Scheme 2. Treatment of glucosamine 3a
with 1.2 equiv. of the glycal epoxide 2 in the presence of ZnCl2
in CH2Cl2 provided the desired disaccharide 6 in 74% yield with
complete ꢀ-selectivity. Use of TMSOTf as an activator resulted
in a significant amount of silylated products. Fucosylation of the
resulting disaccharide 6 with thiofucoside 4A smoothly proceed-
ed in stereoselective manner to provide ꢁ-fucoside 7aA in good
yield with complete ꢁ-selectivity.
Oligosaccharides play important roles in biological process-
es on cell surface and have served as important tumor markers.
ꢀ-Galactoside 1 attached with ꢁ-fucoside at the C2 position
(H-disaccharide) is often found in biologically active oligosac-
charides such as H type 1 and 2 epitopes (1a) and (1b), and is
known to be an appropriate tumor antigen (Scheme 1).1 In order
to develop chemical probes based on the structure of the H-dis-
accharide, an effective methodology for the synthesis of glyco-
conjugates containing the H-disaccharide is required.2
I
OR
O
RO
RO
OH
O
HO
HO
O
O
OR
O
OR
HO
2: R = Bn
O
O
3
II
O
X
OR
OH
O
1
OH
HO
OR
RO
4
H-disaccharide
O
OR
=
OBn
O
BnO
BnO
OR
O
1.2 equiv.
RO
RO
HO
HO
HO
O
O
O
HO
OR
O
OR'
O
2
OR'
ZnCl , CH Cl
2
2
2
AcHN
OH
o
AcHN
H type 2 (1b)
OBn
–78 to –20
C
H type 1 (1a)
BnO
Ph
O
5
Ph
O
O
O
O
O
O
O
O
74%
N3
HO
N3
O
BnO
NPhth
NPhth
Scheme 1.
OH
3a
6
One-pot sequential glycosylation to form two and more gly-
cosidic bonds, is an effective approach for the liquid-phase
oligosaccharide synthesis.3 This approach involves sequential
chemo- and regio-selective glycosylations without any protect-
ing group manipulations and purification of each intermediate.
In the one-pot glycosylation, reagents and resulting products
should not interfere any following glycosylations. We have in-
vestigated one-pot glycosylation based on the chemoselective
activation of various glycosyl donors with an appropriate activa-
tor, and recently reported the synthesis of a protected linear and
branched trisaccharide libraries by the one-pot glycosylation
method.4 Most of synthetic strategies are based on the in situ
synthesis of oligosaccharides with a leaving group. Therefore,
the synthesis of the trisaccharides 1 based on the one-pot glyco-
sylation strategy requires the glycosidation of glycosyl donor at-
tached with saccharide at the C2 position to from 1,2-trans-gly-
cosidic bonds. However, the absence of the participating sub-
stituents of the glycosyl donors at the C2 position makes it dif-
ficult to stereoselectively form the 1,2-trans-glycosidic bond.
Therefore, an effective one-pot glycosylation method for the
2 (1.2 equiv.), ZnCl (2.5 equiv.),
CH Cl , –78 C to 0 C,
then 4A (2.5 equiv.), NIS (3.0 equiv.),
TfOH (0.1 equiv.), 0 C, 46% based on 3a
2
o
o
2
2
SPh
OBn
o
O
OBn
BnO
OBn
BnO
BnO
Ph
O
O
O
1.5 equiv
O
X
4A
O
O
N3
O
NIS 2.0 equiv.
TfOH 0.1 equiv.
0 °C, 83%
O
OBn
OBn
BnO
•
7aA : X = NPhth
8aA : X = NHAc
1) NH NH H O, EtOH
2) Ac O, Py, 70% in 2 steps
2
2
2
2
HO
HO
HO
O
Pd/C, H , MeOH
2
HO
O
O
then H O, 86%
2
O
NH2
HO
NHAc
O
O
OH
OH
9aA
HO
Scheme 2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.3 (2005)
401
Next, we examined one-pot glycosylation using 2, 3a, and
4A. To glucosamine 3a was added 1.2 equiv. of the glycal epox-
ide 2 and 2.5 equiv. of ZnCl2 at À78 ꢀC. The reaction mixture
was stirred at 0 ꢀC for 2 h. Subsequently, 2.5 equiv. of thiofuco-
side 4A, 3.0 equiv. of NIS, and a catalytic amount of TfOH at
0 ꢀC were added to the reaction mixture. After stirring at the
same temperature for 2 h, the reaction mixture was quenched.
After removal of the solvent, the residue was purified by silica
gel chromatography and gel permeable chromatography to pro-
vide trisaccharide 7aA in 46% yield based on 3a. The analytical
data of trisaccharide 7aA, synthesized by one-pot glycosylation
were identical with those of trisaccharide 7aA by the stepwise
synthesis.
the library synthesis.
The parallel synthesis of the 6 oligosaccharides 7 by one-pot
glycosylation was performed utilizing CaruselÒ, which controls
the reaction temperature and the stirring rate in 10 reaction ves-
ꢀ
sels. The six reaction vessels were set up with activated MS-4A.
Each acceptor 3a–3c was added to the two reaction vessels, re-
spectively and the reaction vessels were cooled to À78 ꢀC. The
glycal epoxide 2 (1.2 equiv.) and ZnCl2 (2.5 equiv.) were added
to all the vessels at À78 ꢀC. The reaction mixtures were warmed
to À20 ꢀC and stirred for 2 h at the same temperature. Subse-
quently, 2.5 equiv. of thiofucoside 4A (2.5 equiv.) or thiortham-
noside 4B (2.5 equiv.), NIS (3.0 equiv.), and a catalytic amount
of TfOH at 0 ꢀC were added to the reaction mixture. After stir-
ring for 2 h at the same temperature, the reaction mixture was
quenched with NEt3. The residues were purified by silica gel
chromatography, followed by gel permeable chromatography
to provide trisaccharide 7aA-bC in moderate yields (42–60%
yields) based on 3.
In conclusion, we have demonstrated one-pot synthesis of H
type 1 and 2 trisaccharides 7 using the glycal epoxide 2. The gly-
cosydation of glycal epoxide 2 with ZnCl2 provided disaccharide
possessing the hydroxy-free C2. The secondary hydroxy group
subsequent undergo glycosylation to provide trisaccharide in
good yield in one-pot. The one-pot sequential glycosylation
should be useful to prepare oligosaccharides containing the
H-disaccharide moiety.
Deprotection of the protected trisaccharide 7aA was inves-
.
tigated. Treatment of 7aA with NH2NH2 H2O in EtOH at reflux
for 18 h, followed by acetylation of the amine provided acet-
amide 8aA in 70% yield. Hydrogenolysis of both benzyl ethers
and an azido group with H2 in the presence of Pd/C provided the
H type 1 trisaccharide 9aA bearing with an amino alkyl chain at
the reducing end in quantitative yield.
In order to demonstrate the feasibility of the method, we
planned the combinatorial synthesis of a small oligosaccharide
library 7aA-cB based on the structure of H type 1 and 2 trisac-
charide by one-pot glycosylation. (Figure 1 and Scheme 3).
Six building blocks 2, 3a–3c, and 4A–4B were designed for
BnO
OBn
O
Sugar I
References
1
N3
a) S. Hakomori and Y. Zhang, Chem. Biol., 4, 97 (1997).
b) D. S. Newburg, Curr. Med. Chem., 6, 117 (1999).
Sugar II
O
O
O
BnO
BnO
BnO
OBn
O
OBn
BnO
OBn
2
a) S. J. Danishefsky, V. Behar, J. T. Randolph, and K. O.
Lloyd, J. Am. Chem. Soc., 117, 5701 (1995). b) K. R. Love,
R. B. Andrade, and P. H. Seeberger, J. Org. Chem., 66, 8165
(2001).
Sugar I
A
B
7
Sugar II
3
4
a) S. Raghavan and D. Kahne, J. Am. Soc. Chem., 115, 1580
(1993). b) S. V. Ley and H. W. M. Pripke, Angew. Chem.,
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J. Org. Chem., 65, 2410 (2000).
BnO
O
O
O
O
O
Ph
Ph
O
O
O
O
O
OAc
O
NPhth
O
O
AcO
NPhth
a
c
b
Figure 1.
a) H. Yamada, T. Harada, and T. Takahashi, J. Am. Chem. Soc.,
116, 7919 (1994). b) H. Yamada, T. Harada, T. Miyazaki, and
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H. Takimoto, T. Ikeda, H. Tsukamoto, T. Harada, and T.
Takahashi, Synlett, 2001, 1751. f) H. Tanaka, M. Adachi, H.
Tsukamoto, T. Ikeda, H. Yamada, and T. Takahashi, Org.
Lett., 4, 4213 (2002). g) H. Tanaka, M. Adachi, and T.
Takahashi, Tetrahedron Lett., 45, 1433 (2004). h) M. Adachi,
H. Tanaka, and T. Takahashi, Synlett, 2004, 609. i) H. Tanaka,
M. Adachi, and T. Takahashi, Chem.—Eur. J., (2005), in press.
a) J. T. Randolph and S. J. Danishefsky, Angew. Chem., Int.
Ed., 33, 1470 (1994). b) M. T. Bilodeau, T. K. Park, S. Hu,
J. T. Randolph, S. J. Danishefsky, P. O. Livingston, and
S. Zhang, J. Am. Chem. Soc., 114, 7840 (1995). c) S. J.
Danishefsky and M. T. Biodeau, Angew. Chem., Int. Ed., 35,
1380 (1996). d) D. Sames, X.-T. Chen, and S. J. Danishefsky,
Nature, 389, 587 (1997). e) J. T. Randolph, K. F. McClure, and
S. J. Danishefsky, J. Am. Chem. Soc., 117, 5712 (1995).
2
a
a
a
a
a
a
3a
3a
3b
3b
3c
3c
b
b
b
b
b
b
4A
4B
4A
4B
4A
4B
7aA
46%
7aB
42%
7bA
7bB
7cA
60%
7cB
52%
SPh
57%
47%
5
OBn
O
O
O
Ph
O
O
HO
AcO
O
O
BnO
N3
N3
HO
OAc
OBn
NPhth
OBn
3b
3c
3B
Scheme 3. Reagents and conditions: a) ZnCl2, CH2Cl2, À78 to
À20 ꢀC, 2.0 h; b) NIS, TfOH, CH2Cl2, 0 ꢀC, 2.0 h.
Published on the web (Advance View) February 12, 2005; DOI 10.1246/cl.2005.400