Recent advances in the construction of quaternary pseudoanomeric centers in gem-C,C-glycosides: from zaragozic acids to remdesivir

Abstract

Gem-C,C-glycosides—C-glycosides characterized by two carbon substituents at the pseudo-anomeric position—constitute a structurally distinctive class of glycomimetics with growing relevance in natural products and drug discovery. These motifs appear in diverse bioactive compounds such as maitotoxin, nogalamycins, zaragozic acids and remdesivir, displaying antimicrobial, anti-inflammatory, and anticancer properties. The unique architectures of gem-C,C-glycosides expand the glycochemical space and hold promise for therapeutic development. In contrast to classical C-glycosyl compounds, which benefit from a well-developed synthetic toolbox, the construction of gem-C,C-glycosides remains particularly demanding. This is primarily due to the dual requirement of forming a quaternary center while achieving stereocontrol at a highly congested site. The present review surveys current strategies for constructing quaternary pseudoanomeric centers in gem-C,C-glycosides, highlighting key advances, challenges, and opportunities in this evolving field. Particular attention is given to innovative methodologies that enable direct transformation from carbohydrate precursors, including novel approaches such as metal-hydride hydrogen atom transfer (MHAT) and C–H activation processes.