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

Abstract

C-Acyl glycosides are versatile building blocks for diverse C-glycosides, including hydrazone, alcohol, CF₂, 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.

Keywords

C-Acyl glycoside / Nickel / Chiral phosphoric acid / Synergy catalysis / Amides / Esters / Cross-coupling / Glycosyl radical

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