Solvent effect in glycosylation reaction on polymer support

Article abstract of DOI:10.1055/s-1998-1750

The solvent effect in glycosylation reaction on polymer support was investigated. In the presence of CH₃CN, the β product was increased.

Full text of DOI:10.1055/s-1998-1750

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Solvent Effect in Glycosylation Reaction on Polymer Support
Shino Manabe†, Yukishige Ito*, and Tomoya Ogawa*#
The Institute of Physical and Chemical Research (RIKEN), Wako, Saitama, 351-01, Japan
† Special researcher, Basic Science Program
# Alternative address: Graduate School of Agriculture and Life Science, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, 113, Japan
Fax +81-48-462-4680; yukito@postman.riken.go.jp
Received 26 March 1998
Abstract: The solvent effect in glycosylation reaction on polymer
support was investigated. In the presence of CH CN, the β product was
3
increased.
Polymer supported organic synthesis technology has firmly established
its practical utility in peptide and nucleic acid chemistry, and has
witnessed a great resurgence in recent years in connection with
combinatorial chemistry, particularly in the area of pharmaceutical
1
research. Oligosaccharide synthesis on polymer support is also
highlighted, and various types of biologically relevant oligosaccharides
2
were synthesized on polymer support.
Although the solvent effect in glycosylation reaction in solution phase
3
has been well documented, solvent effect in glycosylation reaction on
4
polymer support has not been investigated systematically. As part of
our effort aiming at the development of solid phase oligosaccharide
synthesis methodology, we report here the result of our investigation of
the solvent effect in glycosylation reaction on polymer support.
Poly(ethylene glycol)methyl ether (PEG) (M. W. ca 5000) and
Merrifield resin were chosen as soluble and insoluble polymer support,
respectively, which are previously reported as effective polymer
2
supports in glycosylation reactions. Polymer supported glucosamine
derivatives 3a, 3b, 7a, and 7b were synthesized to be used as glycosyl
acceptors as shown in Scheme 1 and 2. As polymer-bound acceptors,
phthaloyl protected glucosamine derivatives were designed, for the sake
of ease of stereocotrolled linking to the polymer sector. For relatively
unreactive and reactive acceptors, 3a/7a and 3b/7b were designed,
respectively. Polymer-free alcohols, 8a and 8b were used as acceptors in
solution phase for control experiments in order to make comparison
with the glycosylation reactions on polymer supports. Benzyl protected
methylthioglucoside 9, and corresponding fluoride 10 were chosen as a
donor so that any stereochemical perturbation due to participation from
of C2- or other positions can be eliminated.
Scheme 2
was used as a polymer support, α/β ratio was determined based upon
isolated yield after cleavage of disaccharides from resin (vide infra).
Except entry 12, all reaction gave satisfactory yield (calculation based
on weight) in glycosylation reactions, and no starting acceptors
remained. First, glycosylation with thioglycoside 9 was investigated by
use of DMTST (dimethylthiomethylsulfonium triflate) as a promoter at
6
room temperature for 24 h. In CH Cl , toluene, CH Cl -ether, and
2
2
2
2
C H CF , significant level of α selectivities were observed (entry 1, 2,
6
5
3
3, and 4), when 3a was used as a substrate. Chlorine free- C H CF is
6
5
3
known to be a potential environmentally benign substitute of CH Cl in
2
2
7
several reactions, and now it is clear that this solvent is an effective
reaction medium of glycosylation reaction (entry 2). In the presence of
CH CN, β product was favored (entry 5, 7, 8) in corroboration with
3
numerous precedents in solution phase chemistry. PhSeNPhth/
8
TMSOTf condition also gave the product on PEG. However this system
seems to be rather insensitive to β-directing nature of acetonitrile, which
was also observed in polymer-free system. This phenomenon might well
be explained assuming the participation of PhSeSMe onto the cationic
Scheme 1
8
intermediates. The glycosylation with fluoride 10 by use of AgClO /
4
SnCl gave disaccharides, and solvent effects were observed, which
2
Representative results are shown in Table 1. In the case of PEG bound
saccharides, α/β ratio of the products are determined by H-NMR
favor the formation of α- and β-isomer in ether-containing and
1
9
acetonitrile-containing media, respectively (entry 12, 13, 14, and 15).
technique relying upon integration ratios of anomeric protons without
5
cleavage of the product from polymer support. When Merrifield resin

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Scheme 3
Scheme 4
summarized in Table 1 imply that stereochemical outcomes obtained in
conventional solution phase glycosylation reaction may well be utilized
in polymer-supported chemistry.
Efficiency of cleavage from polymer support was ascertained in a
quantitative manner as follows. Liberation of disaccharide bound 12 was
possible by hydrogenation by use of Pd(OH) on carbon. After
2
acetylation of the product, 13 was easily purified by silica gel column
chromatography (Scheme 3). The overall yield from 3b (3 steps) was
67 %. In the case of Merrifield resin bound products, two types of
operations of cleavage were possible. After treatment of the
Acknowledgments
This work was supported by the Science and Technology Agency of the
Japanese Government through Special Researcher’s Basic Science
Program at RIKEN (S. M.). We thank Ms. A. Takahashi for technical
assistance.
disaccharides bound Merrifield resin 14a, 14b in CF CO H:CH Cl
2
3
2
2
1:10 for 30 min, the disaccharides were cleaved from resin as
hemiacetal. The total yield of 15 from 7(2 steps) is 92 %, which is
highly satisfactory. By hydrazine hydrate, disaccharide 16 was obtained
with simultaneous deprotection of phthaloyl group at C-2 position
(Scheme 4).
Reference and Notes
1)
For recent review; a) Früchtel, J. S.; Jung, G. Angew Chem. Int.
Ed. Engl. 1996, 35, 17. b) Hermkens, P. H. H.; Ottenheijm, H, C,
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Ottenheijm, H, C, J.; Rees, D. Tetrahedron 1997, 53, 5643.
d) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997,
1217.
In conclusion, it was demonstrated that solvent effects are also
functionalized in glycosylation reaction on polymer support. Although
minor derivatives are to be noticed in several instances, results

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2)
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4)
5)
In the literture 2j and 2k, they report 1,2-cis-glycosidic linkage
formation was increased in the presence of dioxane and ether
respectively.
The α/β ratios were determined by integration of anomeric
protons. For starting from 3a; δ 5.69 (d, J = 3.2 Hz, for α of
glucose, H-1), 5.53 (d, J = 8.6 Hz, for β of glucosamine, H-1) 5.46
(d, J = 8.6 Hz, for α of glucosamine, H-1), 5.29 (d, J = 12.4 Hz,
CH Ph of β) in C D . For starting from 3b, 5.51 (d, J = 8.3 Hz, for
β of glucosamine, H-1), 5.45 (d, J = 7.9 Hz, for α of glucosamine,
H-1), 5.36 (d, J = 3.3 Hz, α of glucose, H-1) in C D .
2
6 6
6
6
6)
In the absence of CH Cl , PEG was not dissolved at all. CH Cl
2 2 2 2
was helpful to dissolve PEG, or swell Merrifield resin.
Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
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7)
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Cp ZrCl /AgClO system did not give the product at all. Imidate
2 2 4
11 was too reactive for this reaction and did not give the product.
Cp ZrCl / AgClO system; see Suzuki, K.; Maeta, H.; Suzuki, T.;
2
2
4
Matsumoto, T. Tetrahedron Lett. 1989, 30, 6879.