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(sp3)-C(sp2) 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.