Confined Acids Catalyze a Broadly Applicable β-Selective O-Glycosylation

Glycans are fundamental components of biological systems, composed of monosaccharides linked through glycosidic bonds. The stereogenic nature of these glycosidic bonds plays a decisive role in the structure and biological function of the glycan. Achieving precise, stereocontrolled formation of glycosidic linkages has therefore been a long-standing objective and an ongoing challenge for chemists. To date, general catalytic β-selective glycosylations have been limited to S_N2-like reactions with competing S_N1-like pathways via oxocarbenium ions eroding the selectivity. Here we report an alternative approach: confined acids catalyze a broadly applicable β-selective O-glycosylation, including 2-deoxyglucosylation, glucosylation, and mannosylation, that we suggest proceeds via an S_N1-like pathway. Mechanistic and theoretical studies support this view.