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, β- S -glycosides are used as antirheumatic, anticancer, and antidiabetic drugs in clinical practice. However, the stereoselective synthesis of β- S -glycosides is still highly challenging. Herein, we report an effective β- 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 β-stereoselectivity. This method demonstrates excellent compatibility with a broad scope of various thiol acceptors and glycal donors with yields up to 87% and a β/α ratio of up to 20:1. The present β- 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 β-thioglycosides, which holds high potential in drug discovery and development.