Glycosidation Reactions Capitalizing on Phosphorus-containing Leaving Groups

 Due to the rapidly recognized biological significance of saccharide residues of carbohydrate-containing biomolecules, the rational design and development of stereocontrolled glycosidation reactions are of growing importance not only in carbohydrate chemistry but also in medicinal chemistry. As alternatives to the classical Koenigs-Knorr process, there have recently been developed glycosyl fluoride, glycosyl trichloroacetimidates, and thioglycosides as new glycosylating agents.

Considering that the leaving group of glycosyl donors is one of the most fundamental parameters responsible for the selectivity and yield of glycosidation reactions, our interest has led to the design of the leaving groups of glycosyl donors allowing excellent shelf-lives, as well as their activation without resorting to precious, explosive, or toxic heavy-metal salts as promoters. We were intrigued by the feasibility of the use of phosphorus-containing leaving groups, with the prospect that a number of variations of substituents on the phosphorus atom could make "tailor-made glycosyl donors" readily available. We have recently devised new glycosyl donors incorporating diphenyl phosphate, phosphorodiamidate, diphenylphosphinimidate, phosphorodiamidimidothioate, and phosphite as leaving groups, the glycosidations of which constitute mild and efficient methods for the highly stereocontrolled construction of 1,2-trans-beta- and 1,2-cis-alpha-glycosidic linkages. Several notable features of the present glycosidation methods are described below.

The diphenyl phosphate method and the phosphorodiamidate method: Coupling of benzyl-protected glycosyl diphenyl phosphates with a variety of alcohols in propionitrile in the presence of trimethylsilyl triflate (TMSOTf) at -78 proceeds to completion within 5 to 10 min, affording 1,2-trans-linked glycosides in high yields and with high degrees of beta-selectivity. It is worthy of note that the alcohols bearing the acid-sensitive groups such as epoxy, acetal, or O-tert-butyldimethylsilyl groups are safely glycosylated. The corresponding phosphorodiamidates with excellent shelf-lives exhibit reactivities and stereoselectivities comparable to those of the diphenyl phosphates in TMSOTf-promoted glycosidation. An additional feature of benzyl-protected glycosyl phosphorodiamidates is the fact that they can be activated by boron trifluoride etherate at -10 to provide the predominant formation of 1,2-trans-beta-linked steroidal glycosides, whereas glycosidation of the corresponding diphenyl phosphates are promoted by this reagent at 10 to give an anomeric mixture of products. TMSOTf-promoted glycosidation of benzoyl-protected glycosyl diphenyl phosphates as well as that of the corresponding phosphorodiamidates uneventfully leads to the exclusive formation of 1,2-trans-linked glycosides or disaccharides, as might be anticipated from the anchimeric assistance by O-2 benzoyl group.

The diphenylphosphinimidate method: Coupling of benzoyl-protected glycosyl diphenylphosphinimidates with alcohols in dichloromethane in the presence of boron trifluoride etherate proceeds smoothly at -30 to -10 to afford exclusively 1,2-trans-linked glycosides. The efficiency of the method has been well verified by the first successful glycosylations of highly acid-sensitive podophyllum lignans and digitoxigenin.

The phosphorodiamidimidothioate method: Coupling of benzyl-protected glycosyl phosphorodiamidimidothioates with alcohols in toluene in the presence of 2,6-lutidinium p-toluenesulfonate (LPTS) and tetrabutylammonium iodide (TBAI) proceeds under kinetic control to lead to the preferential formation of 1,2-cis-alpha-linked glycosides in high yields.

The phosphite method: The Schmidt and Wong groups independently demonstrated the effectiveness of the phosphite method through high-yield and alpha-selective sialylation using sialyl phosphite as a donor and TMSOTf as a promoter. As yet another advantage of glycosyl phosphites, we have recently found that coupling of benzyl-protected glycosyl diethyl phosphites with alcohols could be effected by the aid of boron trifluoride etherate at -78 to exhibit the highest 1,2-trans-beta-selectivity known to date for glycosidations without neighboring group participation, whereas glycosidations of the same glycosyl phosphites in the presence of 2,6-di-tert-butylpyridinium iodide (DTBPI) and TBAI provides a highly stereoselective entry to 1,2-cis-alpha-linked glycosides. Furthermore, a direct glycosidation for the stereocontrolled construction of beta-mannnosides, a long-standing and formidable problem, has been achieved by exploiting 4,6-O-benzylidene-protected mannopyranosyl diethyl phosphites in the presence of TMSOTf, though the method is limited to primary alcohols.

The major challenge to a convergent block synthesis of oligosaccharides is a facile construction of saccharide building blocks as well as their high-yield and stereocontrolled assembly wherein an anomeric protective group of glycosyl acceptors, after each glycosidation, has heretofore been converted into a leaving group for the next coupling under conditions that leave other protective groups on a saccharide block unaffected. In this context, we have recently developed chemoselective glycosidation methods based on glycosyl donors and acceptors carrying phosphorus-containing leaving groups, wherein the anomeric reactivity of glycosyl donors and acceptors can be regulated by varying the type of leaving groups as well as the nature of protective groups. The phosphorodiamidate group plays a pivotal role as an anomeric protective group as well as a leaving group. As an application of our glycosidation method for the synthesis of biologically important oligosaccharides, we have recently accomplished stereocontrolled syntheses of globotriaosylceramide Gb3 and ganglioside GM3.
Shunichi Hashimoto, Seiichi Nakamura (Graduate School of Pharmaceutical Sciences, Hokkaido University)
References (1) Toshima, K, Tatsuta, K : Recent progress in O-glycosylation methods and its application to natural products synthesis. Chem. Rev. 93, 1503-1531, 1993
(2) Hashimoto, S, Honda, S, Yanagiya, Y, Nakajima, M, Ikegami, S : Highly selective glycosidation reactions capitalizing on phosphorus-containing leaving groups. J. Synth. Org. Chem. Jpn. 53, 620-632, 1995
(3) Boons, G.-J : Strategies in oligosaccharide synthesis. Tetrahedron 52,1095-1121, 1996
(4) Tanaka, H, Sakamoto, H, Sano, A, Nakamura, S, Nakajima, M, Hashimoto, S : An extremely mild and stereocontrolled construction of 1,2-cis-alpha-glycosidic linkages via benzyl-protected glycopyranosyl diethyl phosphites. Chem. Commun. 1259-1260, 1999
(5) Hashimoto, S, Sakamoto, H, Honda, T, Abe, H, Nakamura, S, Ikegami,S : "Armed-disarmed" glycosidation strategy based on glycosyl donors and acceptors carrying phosphoroamidate as a leaving group: a convergent synthesis of globotriaosylceramide. Tetrahedron Lett. 38, 8969-8972, 1997
Sep. 15, 1999

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