Stereoselective Synthesis of β-S-Glycosides via Palladium Catalysis

S-Glycosides are more resistant to enzymatic and chemical hydrolysis and exhibit higher metabolic stability than common O-glycosides, demonstrating their widespread application in biological research and drug development. In particular, beta-S-glycosides are used as antirheumatic, anticancer, and antidiabetic drugs in clinical practice. However, the stereoselective synthesis of beta-S-glycosides is still highly challenging. Herein, we report an effective beta-S-glycosylation using 3-O-trichloroacetimidoyl glycal and thiols under mild conditions. The C3-imidate is designed to guide Pd to form a complex with glucal from the upper face, followed by Pd-S (thiols) coordination to realize beta-stereoselectivity. This method demonstrates excellent compatibility with a broad scope of various thiol acceptors and glycal donors with yields up to 87% and a beta/alpha ratio of up to 20:1. The present beta-S-glycosylation strategy is used for late-stage functionalization of drugs/natural products such as estrone, zingerone, and thymol. Overall, this novel and simple operation approach provides a general and practical strategy for the construction of beta-thioglycosides, which holds high potential in drug discovery and development.