Copper-Mediated Radical Transformation of Protection-Free Glycosylsulfonohydrazide for Access to Diverse Glycosides

Protecting-group-free glycosides, which serve as fundamental scaffolds for numerous therapeutic agents, present significant synthetic challenges due to the difficulties in stereocontrol and the reliance on multistep protection-deprotection sequences. Herein, we report a unified and concise strategy that enables the highly stereoselective synthesis of diverse protecting-group-free glycosides─including alkenyl C-glycosides with multiple stereocenters, alkyl C-glycosides, aryl thioglycosides, and aryl selenoglycosides─that were previously difficult to access from unprotected glycosyl donors. The process involves generating glycosyl radicals from readily accessible glycosylsulfonohydrazides under copper/ligand/base mediation, which then undergo addition to various radicals or unsaturated bonds with high stereoselectivity. Notably, nitrogen-containing ligands are key to achieving highly stereoselective alkenyl glycosides and alkyl thioglycosides. The utility of this approach is demonstrated by the concise synthesis of an anti-inflammatory drug, highlighting its potential to accelerate the development of glycoside-based therapeutics.