Synthetic Strategies

Three major strategies have been explored for the solid support synthesis of oligosaccharides and glycoconjugates. In one variation, the first carbohydrate is anchored to the support via its "reducing" end (see Scheme 1, Case 1). The carbohydrate bound to the solid support functions as an acceptor in the coupling event to a solution-based donor (D). In the cycle, a unique acceptor hydroxyl must be exposed

Scheme 1 Glycosyl acceptor (Case 1) and donor (Case 2) bound to the solid support, and bidirectional synthesis (Case 3): S, solid support; P, unique protecting group; X, activating group; asterisk, uniquely differentiated hydroxyl group.

in the now elongated, resin-bound carbohydrate construct. In Case 1, this strategy virtually demands for the donor (D) employed in the preceding glycosidation step a uniquely removable blocking group at the site of the next proposed elongation. The need to expose the unique hydroxyl group in the context of the polymer support will necessitate multiple functional group manipulations in synthesizing D.

Alternatively, the carbohydrate that is to undergo elongation may be mounted to the support somewhere in a ''nonreducing'' region, thereby making the reducing end available as a glycosyl donor for coupling with solution based acceptor A (Case 2). The use of A, of course, demands that the precise acceptor site be properly identified. In anticipation of the next coupling event, the reducing end of acceptor A is so functionalized that a new donor capability can be installed at the anomeric carbon of the elongated construct. This approach necessitates in the acceptor an anomeric group that does not serve as a glycosyl donor itself but rather may be converted in a straightforward manner into a glycosyl-donating moiety.

A hybrid of both strategies is the bidirectional synthesis approach (Case 3), which is based on the orthogonal glycosylation concept. The first monosaccharide (A/D) may serve as glycosyl donor as well as glycosyl acceptor and is attached to the support matrix through a position other than the anomeric center. This glycoside contains an anomeric leaving group (as for Case 2), and in addition exhibits an uniquely distinguished acceptor site (analogous to Case 1). During the initial phase of the synthesis the support-bound sugar functions as a glycosyl acceptor A without compromising the chemical integrity of the anomeric moiety. In this fashion, oli-gosaccharide synthesis following the Case 1 paradigm may be carried out. If an orthogonal set of glycosylating conditions is used, the support-bound sugar may be activated to serve as a glycosyl donor in chain elongation to follow a Case 1 synthetic scheme.

This chapter discusses the different approaches to solid phase oligosaccharide synthesis developed to date, grouped by the overall synthetic paradigm they obey.

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