Bis-S-Glycosylation of Disulfides.

Carbohydrates play essential roles throughout biology, making them key targets in biological research and drug development. While multivalent presentation of carbohydrates is widely recognized as crucial for high-affinity target binding (the glycoside cluster effect), most existing methods focus on installing one glycosidic bond and lack robust strategies for attaching multiple carbohydrate units to a functional group. Here we report a mild, operationally simple protocol for the direct, stereoselective bis-S-glycosylation of dialkyl disulfide bonds in an open-flask aqueous solution. This transformation installs two unprotected glycosyl units onto disulfide bonds, affording fully unprotected S-linked glycopeptides. The reaction employs bench-stable, readily accessible glycosyl sulfinates as donors and tert-butyl hydroperoxide (tBuOOH) as oxidant, forging cysteine-glycosyl linkages via a radical pathway. Mixed disulfides derived from thiols partook in this reaction as well, allowing installation of one sugar unit onto peptide backbones. We applied this method to synthesize glycosylated peptides with liver-targeting capabilities and to generate sugar-linked affibody-radionuclide conjugates. DFT calculations informed the reaction design and rationalized the observed selectivity of this transformation.