Nickel-catalyzed stereo-controlled C–F activation for the synthesis of monofluoroalkenyl C-glycosides

Abstract

The monofluoroalkene moiety serves as a metabolically stable bioisostere of amide bonds, and C-glycosides offer improved pharmacokinetic properties compared to glycan mimetics. Consequently, monofluoroalkenyl C-glycosides, which merge the benefits of both structural motifs, have emerged as highly valuable scaffolds in medicinal chemistry. However, stereocontrolled synthetic access to monofluoroalkenyl C-glycosides still remains challenging. Herein, we report a nickel-catalyzed asymmetric C–F bond activation strategy for the direct and stereocontrolled synthesis of these valuable scaffolds via the coupling of glycosyl bromides with gem-difluoroalkenes. This method leverages an ester directing group to govern stereoselective C–F cleavage, affording monofluoroalkenyl glycosides in good yields with excellent E-selectivity and high α-selectivity. The reaction exhibits broad substrate compatibility, accommodating diverse glycosyl donors and a wide range of gem-difluoroalkenes. Its synthetic utility is demonstrated through the late-stage functionalization of complex pharmaceuticals and natural product derivatives. Mechanistic investigations support a pathway involving a Ni(I)/Ni(II)/Ni(III) catalytic cycle with the glycosyl radical intermediates. This work establishes a general and stereocontrolled catalytic approach to monofluoroalkene-based C-glycosidic linkages, providing a new avenue for selective fluorinated modification in drug discovery.