Chemical synthesis of syndecan-3 glycopeptides bearing two heparan sulfate glycan chains.

Despite the ubiquitous presence of proteoglycans in mammalian systems, methodologies to synthesize this class of glycopeptides with homogeneous glycans are not well developed. Herein, we report the first synthesis of a glycosaminoglycan family glycopeptide containing two different heparan sulfate chains, namely the extracellular domain of syndecan-3. With the large size and tremendous structural complexity of these molecules, multiple unexpected obstacles were encountered during the synthesis, including high sensitivity to base treatment and the instability of glycopeptides with two glycan chains towards catalytic hydrogenation conditions. A successful strategy was established by constructing the partially deprotected single glycan chain containing glycopeptides first, followed by union of the glycan-bearing fragments and cleavage of the ester-type protecting groups. This work lays the foundation for preparing other members of this important class of molecules.