Preparation of ketonyl <i>C</i>-glycosides from designed glycosyl sulfides and styrenes by a radical pathway.

Abstract

Ketonyl <i>C</i>-glycosides, a vital subclass of alkyl <i>C</i>-glycosides, play essential roles in drug discovery, biochemistry, and materials sciences. However, a practical strategy that merges bench-stable glycosyl donors with styrenes-a ubiquitous class of synthetic building blocks-remains elusive. Herein, we report a simple and general approach for synthesizing ketonyl <i>C</i>-glycosides. The transformation uses designed glycosyl sulfides as air- and moisture-stable precursors to glycosyl radicals, styrenes as aglycone sources, and dimethyl sulfoxide as both an oxidant and solvent, proceeding under photoredox catalysis. Glycosyl radicals are generated from glycosyl sulfides via efficient unimolecular homolytic substitution. This approach obviates harsh conditions for donor activation and the use of activated aglycone precursors, accommodating extensive functional groups and heterocycles. The reaction also exhibits high stereoselectivity across various glycosyl units. Demonstrating synthetic versatility, this method enables efficient access to diverse drug-sugar conjugates and complex <i>C</i>-glycopeptidomimetics. Mechanistic studies reveal key intermediates, suggesting a radical-polar crossover pathway. This study offers a broadly applicable approach to valuable sugar-containing structures.