Efficient synthesis of S-linked glycopeptides in aqueous solution by a convergent strategy

In naturally occurring glycopeptides and glycoproteins the glycan residues generally possess N- and O-linkages to the peptide backbone. Here we report the synthesis of the corresponding S-linked glycopeptides by a convergent strategy to provide compounds which should be quite stable to glycosidases. To this end, peptides that contain beta-bromoalanine and gamma-bromohomoalanine were generated either directly by bromination of serine and homoserine residues, respectively, or by standard ligation of the corresponding amino acids. 1-Thiosugars of O-acetyl protected GalNAc, GlcNAc, and lactose were prepared by known procedures. Reaction of the thiosugars with these peptides in an ethyl acetate/water two-phase system, which contained TBAHS and NaHCO(3), or in a one-phase system that consists of DMF/water and which contains NaHCO(3), led to the desired S-linked glycopeptides cleanly and in almost quantitative yield. This reaction also worked well for O-unprotected 1-thiosugars.