2-(Dimethyloctylsilyl)ethyl lactoside: a versatile intermediate for chemical and enzymic ganglioside synthesis

Abstract

The discovery that glycoconjugates containing sialic acid fulfill a number of important biological functions [ 1 ] has led to an increased interest in the synthesis of sialosides. Yet despite significant advances in methodology, chemical synthesis of the naturally occurring a-sialosides remains a major challenge. Interest in antibodies that bind the carbohydrate epitopes of gangliosides such as GD3 prompted the synthesis of an oligosaccharide that could be either deprotected or subjected to further reactions at the anomeric center. This led us to adopt a potentially general method for the combined chemical-enzymic preparation of gangliosides. A new 2-(dimethyloctylsilyl)ethyl [DMOSEt] protecting group for the anomeric center is introduced, and unlike its 2-(trimethylsilyl)ethyl [TMSEt] counterpart [2], DMOSEt can be used as a hydrophobic anchor to simplify oligosaccharide isolation from enzyme-catalyzed reactions, while maintaining the ease of subsequent synthetic transform~ition at the reducing terminus of complex oligosaccharides. The versatility of TMSEt glycosides has been well demonstrated since they are readily converted under mild conditions to glycosyl donors, either directly [ 3,4 ] or via the anomeric hemiacetal [4,5]. The resulting glycosyl donor can then be coupled to a ceramide derivative to form the ganglioside [ 6 ]. In synthesizing the oligosaccharide portion, the use of activated derivatives of N-acetylneuraminic acid (Neu5Ac) as glycosyl donors under standard glycosylation conditions often gives both poor yields and anomeric mixtures of sialosides [ 7]. In order to promote the formation of natural ot-sialosides and to in ,ease the yields in glycosylation of secondary alcohols, more complex derivatives of Neu5Ac, such as xanthates, [ 8 ] thioglycosides [ 9], and glycosyl donors with a C-3 stereocontrolling auxiliary