Palladium catalysis enables cross-coupling-like S_N2-glycosylation of phenols.

Abstract

Despite their importance in life and material sciences, the efficient construction of stereo-defined glycosides remains a challenge. Studies of carbohydrate functions would be advanced if glycosylation methods were as reliable and modular as palladium (Pd)-catalyzed cross-coupling. However, Pd-catalysis excels in forming sp²-hybridized carbon centers whereas glycosylation mostly builds sp³-hybridized C-O linkages. We report a glycosylation platform through Pd-catalyzed S_N2 displacement from phenols toward bench-stable, aryl-iodide-containing glycosyl sulfides. The key Pd(II) oxidative addition intermediate diverges from an arylating agent (Csp² electrophile) to a glycosylating agent (Csp³ electrophile). This method inherits many merits of cross-coupling reactions, including operational simplicity and functional group tolerance. It preserves the S_N2 mechanism for various substrates and is amenable to late-stage glycosylation of commercial drugs and natural products.