Glycosyltransferase-catalyzed synthesis of thiooligosaccharides.

Abstract

BACKGROUND Oligosaccharide analogues in which the interglycosidic oxygen atom(s) have been replaced by sulfur are known as thiooligosaccharides. These molecules are metabolically stable analogues of their naturally occurring counterparts, since the rate of hydrolysis of the thioglycosidic bond by glycosylhydrolases is several orders of magnitude slower than that of the corresponding Oglycosides and the conformational space sampled by S-linked glycosides is similar to that of O-glycosides. In combination, these properties suggest that S-linked carbohydrates may be attractive antigens with extended in vivo activity,1 and the ability of glycosyltransferases to create such linkages has significant potential. Considerable attention has been focused on the synthesis of complex oligosaccharides containing S-linked residues and a variety of chemical approaches are available to construct this linkage.2 Most thiooligosaccharide syntheses take advantage of the reduced basicity and enhanced nucleophilicity of sulfur compared to oxygen, employing a sugar thiol or thiolate anion in a reaction with another carbohydrate bearing an electrophilic leaving group. Recently active site mutants of glycosylhydrolases, termed “thioglycoligases” have been shown to transfer a glycosyl residue to sugar thiols.3 The development of a glycosyltransferase-based approach to the synthesis of thiooligosaccharides does not obviate the considerable effort required for the construction of thiosugar acceptors. However, this method demonstrates the high yields, stereo-, and regio-selectivities characteristic of glycosyltransferase catalyzed reactions, and renders a final deprotection step unnecessary