Iron-catalysed reductive cross-coupling of glycosyl radicals for the stereoselective synthesis of C-glycosides

Abstract

Stereochemically defined C-glycosides are prized for their biological activity. Developing a catalytic method that comprises non-precious metals to synthesize these C-glycosides remains challenging. Here, starting from readily accessible glycosyl chlorides, we show that an Earth-abundant iron-based catalyst promotes the facile generation of glycosyl radicals, which either react directly with an unsaturated electrophile or are captured by an organonickel species to facilitate C−C bond formation under mild reductive conditions. Exploration of these two reaction pathways across a range of substrates has produced a diverse array of C-glycoside products functionalized with alkenyl, alkynyl or aromatic anomeric groups, with excellent diastereocontrol. Mechanistic control and electron paramagnetic resonance spectroscopic experiments indicate that the active catalytic species is a low-valent iron complex formed through Mn reduction. The method was applied in the stereoselective synthesis of bioactive C-glycosides and therapeutically relevant analogues. [Figure not available: see fulltext.]