Synthesis of oligosaccharides corresponding to biological repeating units of Shigella flexneri variant Y polysaccharide. Part 1. Overall strategy, synthesis of a key trisaccharide intermediate, and synthesis of a pentasaccharide

Abstract

The overall strategy for the synthesis of penta-up to octa-saccharides, representing the biological repeating unit of the Shigella flexneri serogroup Y lipopolysaccharide, is described. The key intermediate, the common terminal trisaccharide, α-L-Rhap-(1 → 2)-α-L-Rhap(1 → 3)-α-L-Rhap, has been synthesised by a series of Königs–Knorr reactions. A selectively protected rhamnose intermediate has been developed for the synthesis of this trisaccharide as its allyl glycoside. Allyl α-L-rhamnopyranoside was converted into the corresponding 2-O-benzoyl-4-O-benzyl derivative via a 2,3-orthobenzoate. Königs–Knorr reaction between this partially blocked rhamnoside and 2-O-acetyl-3,4-di-O-benzyl-α-L-rhamnopyranosyl chloride afforded the blocked disaccharide. Selective transesterification of the 2′-Oacetyl group in the presence of the 2-O-benzoate yielded the disaccharide, selectively deblocked at the C-2′ position. Reaction with the same rhamnopyranosyl chloride gave the fully blocked trisaccharide. Deallylation, followed by treatment with NN-dimethyl(chloromethylene)ammonium chloride, then gave the corresponding trisaccharide chloride. In conjunction with the disaccharide methyl 2-O-(2′acetamido-4′,6′-O-benzylidene-2′-deoxy-β-D-glucopyranosyl)-3,4-di-O-benzyl-α-L-rhamnopyranoside, the synthesis of the blocked pentasaccharide was accomplished. Transesterification, followed by hydrogenolysis in aqueous acetic acid, afforded the pure pentasaccharide hapten, α-L-Rhap-(1 → 2)α-L-Rhap-(1 → 3)-α-L-Rhap-(1 → 3)-β-D-GlcpNAc-(1 → 2)-α-L-Rhap, as its methyl glycoside, for use in binding studies and n.m.r. studies.