Ligand-enabled next-generation glycosyl Stille cross-coupling for the stereospecific synthesis of sterically hindered aryl C-glycosides.

Sterically hindered aryl C-glycosides are biologically important, yet their stereoselective synthesis remains challenging due to severe anomeric congestion. Here we report a next-generation, ligand-enabled, stereospecific Pd-catalyzed glycosyl cross-coupling that efficiently delivers sterically hindered aryl C-glycosides with exclusive anomeric control. Two underexplored biarylmonophosphine ligands, featuring P-bound 3,5-bis(trifluoromethyl)phenyl groups and methoxy or isopropoxy substituents at the 2'- and 6'-positions of the lower aryl ring, are uniquely effective for this challenging C-glycosylation. The scope and practicality of this next-generation Stille glycosylation are demonstrated in over 65 examples, including (un)protected sugars, deoxy sugars, and oligosaccharides. Crystallography reveals that bromide-bridged dimeric Pd(II) complexes as intrinsic features of diarylbiaryl monophosphine ligands, while natural bond orbital (NBO) analysis shows that subtle ligand electronics control the selectivity between β-methoxy elimination and C-C reductive elimination. This predictable, highly chemo- and stereoselective protocol expands the glycosylation toolbox, enables glycomimetic drug discovery, and informs rational ligand design.