Ni/Chiral Phosphoric Acid Cooperative Catalysis Enabled Radical Coupling of Carboxylic Esters/Amides to C‐ Acyl Glycosides

Comprehensive Summary C ‐Acyl glycosides are versatile building blocks for diverse C ‐glycosides, including hydrazone, alcohol, CF 2 , and alkyl variants. However, the relatively late discovery of these in natural products and their overlooked medicinal value have resulted in significantly underdeveloped synthetic methodologies compared to other C ‐glycoside subtypes. Previously, the synthesis of C ‐acyl glycosides primarily depended on metal reagent‐based addition‐oxidation reactions and palladium‐catalyzed cross‐coupling reactions. As research advances, transition‐metal (TM) catalyzed cross‐coupling reactions involving glycosyl radicals have emerged as a powerful tool to access C‐ glycosides ( C ‐acyl glycosides included) due to their advantages such as mild reaction conditions and controllable stereoselectivity. While recent years have seen a boom of cooperative catalysis of transition metals (particularly Pd) and chiral phosphoric acid (CPA), the analogous cooperative catalysis employing nickel (Ni) and CPA remains underdeveloped. Herein, we report a robust Ni/CPA co‐catalyzed protocol for synthesizing diverse C ‐acyl glycosides under mild conditions. This strategy employs readily available glycosyl bromides and amides, 2‐pyridyl esters, or phosphoric anhydrides, demonstrating broad functional group compatibility. A wide range of mono‐ and disaccharides and functionalized carboxylic acid derivatives were efficiently transformed into the corresponding products with high yields (up to 98%) and excellent stereoselectivity (α : β > 19 : 1). Furthermore, the utility of the methodology was demonstrated through the C ‐acyl glycosylation of various bioactive molecules and the synthesis of C ‐acyl disaccharides. Remarkably, the cooperative Ni/CPA catalysis significantly enhanced the yield compared to reactions without CPA. Mechanistic investigations revealed that the reaction proceeds via a nickel‐catalyzed sequential addition mechanism, while DFT calculations have furnished theoretical support for the proposed pathway whereby CPA enhances the yield through hydrogen‐bonding interactions.