Chemoselective elaboration of O-linked glycopeptide mimetics by alkylation of 3-thioGalNAc.

Abstract

A critical branch point in mucin-type oligosaccharides is the beta 1-->3 glycosidic linkage to the core alpha-N-acetylgalactosamine (GalNAc) residue. We report here a strategy for the synthesis of O-linked glycopeptide analogues that replaces this linkage with a thioether amenable to construction by chemoselective ligation. The key building block was a 2-azido-3-thiogalactose-Thr analogue that was incorporated into a peptide by fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Higher order oligosaccharides were readily generated by alkylation of the corresponding 3-thioGalNAc with N-bromoacetamido sugars. The rapid assembly of "core 1"and "core 3" O-linked glycopeptide mimetics was accomplished in this fashion.