Chemical "Hierarchy" and "Individuality" in Oligosaccharide Synthesis

 Chemical reactions often rely on different reactivities of reactive species. It is especially important to choose the right protective groups in the synthetic scheme, as this often determines whether the synthesis is successful or not. Protective groups must stand against variety of reaction conditions to construct an organic molecule but each group must be deprotected selectively for the following reaction. Thus, selective introduction and removal of protective groups are important in organic chemistry.

Carbohydrate chemistry is sometimes referred to as the chemistry of protective group manipulation. This is partly true because such manipulations are necessary to achieve regiospecific reactions where hydroxyl functions which are not involved in the coupling must be masked. In addition to protective group manipulation, the glycosylation reaction is another essential reaction in carbohydrate chemistry. The reaction occurs between the acetal (anomeric) center and the hydroxyl group to form an exo-cyclic acetal bond, a glycosidic linkage(Fig.1).
Figure 1.
The protection of the anomeric position must be treated separately from other protections, and it can be considered as either protection of the acetal hydroxyl group or protection of the acetal, C-1, carbon. In traditional oligosaccharide synthesis, especially in the synthesis starting from reducing end to the non-reducing terminus, and also in the synthesis of the precursor of a glycosyl donor, anomeric hydroxyl group is protected as an acetal. Thus the protective group must be removed in order to introduce the leaving group at the anomeric position in this case.

The introduction of thioglycoside to carbohydrate chemistry reversed the idea of protection of the anomeric hydroxyl group. Thioglycosides as protective groups of acetal carbon are generally stable under Lewis acidic conditions used to activate other leaving groups in glycosylation reactions. Also, they can be selectively activated under oxidative conditions to give the active glycosylating agent oxocarbonium ion(Fig.2). Thioglycoside therefore is extremely useful not only as protective group of acetal carbon but also as a leaving group.
Figure 2.
Using this characteristic of thioglycoside in combination of the use of halide as a primary glycosyl donor, it has become possible to perform two sequential coupling reactions without any protective group manipulation. Basic of this selective activation strategy is the individuality of each substituent group at the anomeric center(Fig.3a)[1]. On the other hand, there is a clear difference in reactivity between methylthio-glycoside and phenylthio-glycoside(Fig.3b-1). A similar difference in reactivity can be seen by the use of different types of protective groups on hydroxyl groups (ether vs. ester)(Fig.3b-2). These differences are drawn based on hierarchy in the reactivity of leaving groups[2,3].

Efficient oligosaccharide synthesis can be achieved based on the hierarchy and individuality of reactivities of potential leaving groups[4].
Figure 3.
Osamu Kanie (Glycoscience Laboratory, Mitsubishi-Kasei Institute of Life Sciences)
References (1) (a) Koto, S, Uchida, T, Zen, S : Syntheses of isomaltose, isomaltotetraose, and isomaltooctaose. Bull. Chem. Soc. Jpn.,
46, 2520-2523, 1973
(b) Lonn, H : Synthesis of a tri- and a hepta-saccharide which contain alpha-L-fucopyranosyl groups and are part of the complex type of carbohydrate moiety of glycoproteins. Carbohydr. Res., 139, 105-113, 1985
(2) Sliedregt, LAJM, Zegelaar-Jaarsveld, K, van der Marel, GA,van Boom, JH,: Use of 4-nitrophenylthio-beta-D-glycosides in oligosaccharide synthesis: A critical evaluation. Synlett.,335-337, 1993
(3) (a) Mootoo, DR, Konradsson, P, Udodong, U, Fraser-Reid, B: "Armed" and "disarmed" n-pentenyl glycosides in saccharide couplings leading to oligosaccharides. J. Am. Chem. Soc., 110, 5583-5584, 1988
(b)Veeneman, GH, van Boom, JH : An efficient thioglycoside-mediated formation of alpha-glycosidic linkages promoted by iodonium dichollidine perchlorate. Tetrahedron Lett., 31,275-278, 1990
(4) (a) Yamada, H, Harada, T, Takahashi, T : Synthesis of an elicitor-active hexasaccharide analogue by a one-pot, two-step glycosylation procedure. J. Am. Chem. Soc., 116, 7919-920, 1994
(b) Kanie, O, Ito, Y, Ogawa, T: Orthogonal glycosylation strategy in oligosaccharide synthesis. J. Am. Chem. Soc., 116,12073-12074, 1994
(c) Grice, P, Ley, SV, Pietruszka, J, Priepke, HWM, Walther, EPE : Tuning the reactivity of glycosides: Efficient one-pot oligosaccharide synthesis.Synlett., 781-784, 1995
Sep. 15, 1999

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