Silylium Ion Enhanced Dual-Relay Glycosylation: Assembly of Tailor-Made Glycoconjugates

Catalytic glycosylation, vital for biomolecule synthesis, remains constrained by challenges in efficiency and stereoselectivity. While silylium ions stabilized by weakly coordinating anions (WCAs) are powerful in organic transformations, their catalytic potential in glycosylation has remained largely untapped. Herein, we report a mild and operationally simple catalytic glycosylation driven by silylium ion-WCA catalysis that efficiently promotes both glycosyl (ortho-[1-(p-methoxyphenyl)vinyl]benzoate (PMPVB) or ortho-(1-phenylvinyl)benzoate (PVB)) donors and broad O- and S-nucleophile acceptors, delivering diverse glycosides in high yields. Experimental mechanistic studies combined with DFT calculations identify key intermediates and transition states along the reaction route, clearly delineating a sequential dual-relay process for silylium ion-promoted glycosylation. The synthetic versatility of this method is highlighted by the orthogonal one-pot synthesis of bioactive 17β-estradiol (E2) trisaccharide derivatives and, especially, the streamlined one-pot assembly of the synthetically challenging tetrasaccharide domain of lipid IV bearing orthogonal handles, achieving substantially improved step-economy over established approaches. These findings uncover a meaningful catalytic role for silylium ion-WCA catalysis in carbohydrate chemistry and offer a conceptual blueprint for next-generation glycosylation strategies with broad applications across chemical glycoscience and pharmaceutical discovery.