C-Glycosides are critical motifs embedded
in many
bioactive natural products. The inertC-glycosides
are privileged structures for developing therapeutic agents owing
to their high chemical and metabolic stability. Despite the comprehensive
strategies and tactics established in the past few decades, highly
efficientC-glycoside syntheses via C–C coupling
with excellent regio-, chemo-, and stereoselectivity are still needed.
Here, we report the efficient Pd-catalyzed glycosylation of C–H
bonds promoted by weak coordination with native carboxylic acids without
external directing groups to install various glycals to the structurally
diverse aglycon parts. Mechanistic evidence points to the participation
of a glycal radical donor in the C–H coupling reaction. The
method has been applied to a wide range of substrates (over 60 examples),
including many marketed drug molecules. Natural product- or drug-like
scaffolds with compelling bioactivities have been constructed using
a late-stage diversification strategy. Remarkably, a new potent sodium-glucose
cotransporter-2 inhibitor with antidiabetic potential has been discovered,
and the pharmacokinetic/pharmacodynamic profiles of drug molecules
have been changed using our C–H glycosylation approach. The
method developed here provides a powerful tool for efficiently synthesizingC-glycosides to facilitate drug discovery.