Synthesis of S-Glycoside Building Blocks as Mimetics of the Repeating d-GlcN-α-1,4-d-GlcA Heparan Sulfate Disaccharide

Abstract

Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is a key regulator of biological processes. Owing to the inherent structural complexity of HS, structure-to-function studies with its ligands are required, and materials to improve the understanding of such interactions are therefore of high importance. Herein, the synthesis of novel S-linked GlcN-α(1→4)-GlcA disaccharide building blocks is detailed. Initial attempts at constructing the desired disaccharide using d-GlcN donors and d-Glc/GlcA acceptors via an S-glycosylation failed. Reversing the reactivity polarity of the monosaccharide building blocks enabled successful SN2 coupling using α-d-GlcN thiohemiacetals and d-galactosyl triflates. Subsequent C6-oxidation furnished the desired S-linked GlcN-α(1→4)-GlcA disaccharide building blocks on a gram scale. Such disaccharides offer potential for incorporation into wider synthetic HS sequences to provide glycomimetic tools.