Stereodivergent Access to N-Glycosyl Sulfonamides via Palladium-Catalyzed N-Glycosylation of Pyranone Donors

Abstract

Glycosylation of bioactive molecules provides an attractive and efficient strategy to modulate their biological and pharmacological properties. Catalytic stereoselective N-glycosylation of sulfonamides to access medicinally relevant N-glycosyl sulfonamides represents an appealing yet challenging strategy for the direct structural diversification of sulfonamide scaffolds. Conventional synthetic methods generally rely on strong acids and exhibit high substrate dependence, insufficient regio- and stereocontrol, and exclusive access to only one-type of anomer, significantly restricting their general applicability. Herein, we present a stereodivergent, palladium-catalyzed N-glycosylation platform for the synthesis of a broad spectrum of N-glycosyl sulfonamides with high efficiency and excellent control over regioselectivity and stereoselectivity, using readily accessible pyranones as glycosyl donors. Remarkably, this approach enables efficient access to all four diastereomers of the N-glycosyl sulfonamides in excellent yields with complete regio- and stereocontrol. This mild protocol features broad substrate generality, excellent functional group compatibility, and facile scalability. The synthetic utility of this method is further demonstrated through a range of downstream synthetic transformations of the glycoside products. Collectively, this Pd-catalyzed glycosylation platform offers a general and precise strategy for the construction of valuable N-glycosyl sulfonamides, facilitating carbohydrate-based drug discovery.