Stereoretentive and Regioselective Late-Stage C–H Glycosylation

Glycosylation of drug molecules offers an effective strategy to modulate pharmacological properties, and late-stage C–H glycosylation represents an appealing yet challenging strategy for direct molecular diversification. Current chemical and enzymatic methods often exhibit strong substrate dependence and limited control over site- and stereoselectivity, restricting their general applicability. Here, we describe a general platform that integrates highly site-selective aromatic C–H thianthrenation with stereoretentive palladium-catalyzed glycosyl cross-coupling, enabling access to both α- and β- C -glycosylated drug derivatives, including direct coupling with fully unprotected sugars. By exploiting complementary direct C–H and C–B thianthrenation pathways, this strategy enables regiodivergent synthesis of a broad range of C -glycosylated drug analogs. Within the context of organothianthrenium chemistry, this work establishes a stereospecific C(sp 3 )–C(sp 2 ) cross-coupling mode for glycosyl nucleophile. In vivo studies in Caenorhabditis elegans reveal that C- glycosylation of small-molecule drugs can substantially modulate antitumor efficacy and neuroprotection. Moreover, glycosyl stannanes are shown to exhibit intrinsic antitumor activity and therapeutic potential in Huntington’s disease models. Collectively, this late-stage C–H glycosylation platform provides a general and precise strategy for drug glycodiversification, accelerating sugar-based drug discovery and expanding the toolbox for late-stage functionalization of pharmaceutical molecules.