Stereoselective synthesis of C-aryl glycosides via radical-enabled 1,4-Ni migration: glycosyl chlorides as coupling partners

Abstract

C-Aryl glycosides are important skeleton motifs in medicinal chemistry and biochemistry. However, the stereoselective and efficient construction of structurally complex C-aryl glycosides under mild conditions remains challenging. Herein, we report an efficient strategy for the alkenylation and ortho-glycosylation of aryl halides through a 1,4-nickel migration. This three-component protocol uniquely employs glycosyl chlorides to achieve high anomeric stereocontrol (α/β > 20 : 1), overcoming competing arylation via LiI modulation—distinct from prior Ni-migrations with alkyl electrophiles. The method not only exhibits broad substrate scope and exceptional functional-group compatibility but also enables controllable regioselectivity in alkyne insertion. Mechanistic studies revealed that the reaction proceeds through 1,4-nickel migration of Ni(II) species and involves a glycosyl radical process. Furthermore, a deprotection experiment efficiently produced free C-aryl glycosides in excellent yields. Overall, this work expands the toolbox of migratory catalysis by introducing glycosyl chlorides as novel radical precursors and offers a modular approach for stereocontrolled C-glycoside synthesis.