Unlocking C–OH Bond Activation for Radical C-Glycosylation of Native Saccharides

C-Glycosides are valuable structural motifs in bioactive natural products and pharmaceuticals due to their enhanced metabolic stability. However, direct C-glycosylation of native saccharides remains a significant challenge due to both the inert nature of the C–OH bond and the inherent selectivity issues arising from multiple hydroxyl groups. In this SYNPACTS article, we highlight our recent development of a titanium-catalyzed radical C-glycosylation strategy that enables selective C–OH bond activation without prefunctionalization. By leveraging a Cp*TiCl₃/Zn system, this method generates glycosyl radicals under mild conditions, facilitating stereoselective C-glycosylation with electron-deficient alkenes. The approach exhibits broad substrate scope, including monosaccharides, disaccharides, and complex bioactive molecules, offering significant potential utility in glycodrug discovery. Radical stabilization and stereoelectronic effects drive the observed axial selectivity (>20:1). This work establishes a powerful and practical platform for C-glycoside synthesis, addressing long-standing challenges in carbohydrate functionalization and opening new avenues for radical-mediated glycosylation strategies.

Publikationsverlauf

Eingereicht: 03. März 2025

Angenommen nach Revision: 01. April 2025

Accepted Manuscript online:
01. April 2025