Introduction

Sialic acids are a class of nine-carbon monosaccharides found at the termini of oligosaccharides in many mammalian cellular systems [1]. This class is represented by the prototypical congener V-acetylneuraminic acid (NeuAc, 1, Scheme 1). These unique sugars are ubiquitous, and they are present as components of both glycolipids and glycoproteins. Some examples of sialic acid containing oligosaccharides are shown in Scheme 2. Sialic acids are found in variety of glycosidic linkages, some more common of which are a-2,3- or a-2,6-linkages to galactose residues. Additionally, they frequently exist as a-2,8-linked oligomers or polymers.

The lack of efficient technology to accomplish glycosylations with sialic acid is one of the long-standing deficiencies in carbohydrate chemistry [2]. Owing to the central role of sialic acids in carbohydrate recognition events, the development of high-yielding and operable methods to synthesize sialic acid glycosides has been the subject of considerable research. The development of such methods allows the construction of complex sialic acid containing glycoconjugates for the investigation of their roles in biochemical and cellular processes.

Most classical methods for synthesizing sialic acid glycosides are based on the reaction of an activated sialic acid such as 2 with an oligosaccharide glycosyl acceptor bearing a hydroxyl group nucleophile (Scheme 3) [2]. The leaving group is typically a halogen, such as a chloride or bromide, and the activator is typically a heavy metal salt [3,4]. A regioselective union of the two reacting partners of course relies on appropriate protecting group patterns for both the glycosyl donor and acceptor components. Many of the early methods are generally plagued with side reactions, low yields, and poor stereoselectivity. There are several reasons for these ho ho c02h ho oh 1

c02h ho oh 1

(NeuAc)

Scheme 1

shortcomings. The electron-withdrawing carboxylate at the anomeric carbon disfavors the formation of the oxocarbenium ion 6 (7) en route to glycoside bond formation (Scheme 4). This oxocarbenium ion intermediate is also somewhat sterically hindered, so attack of hydroxyl nucleophiles can be slow. Therefore an elimination to provide 9 can be a significant competing reaction pathway. Additionally, since the reacting carbon is insulated from the nearest stereogenic center by either O6 or C3, there is very little steric biasing of one face of this oxocarbenium ion over the other. As a consequence, the stereoselectivity commonly observed is less than desirable. Complicating the issue further, the anomeric effect causes a-glycosides to be ther-modynamically less stable than the corresponding /3 anomers. Heating a sialic acid ester in the presence of a primary alcohol and an acid catalyst results in exclusive formation of the ^-glycoside (Scheme 5) [5]. As a result of these factors, glyco-sylation reactions with sialyl donors often provide low yields of the desired sialic acid a-glycosides. Thus the synthesis challenge of efficient glycosylation with sialic acid is a daunting one indeed.

More recently, this long-standing problem has been revisited in a number of laboratories. This renewed focus was influenced significantly by the recent explosion of discoveries concerning the roles of oligosaccharides in biochemical processes of all types. Reviewed in this chapter are some selected recent advances in both chemical and enzymatic glycosylation with sialic acid.

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