A Unified Approach to Chiral α-Aryl Ketones and Aldehydes via Ni-Catalyzed Asymmetric Reductive Cross-Coupling

We disclose a highly enantioselective protocol for the facile preparation of protected tertiary alpha-aryl ketones and aldehydes, enabled by chiral Ni/Biox-catalyzed reductive coupling of readily accessible alpha-iodoacetals and -ketals with (hetero)aryl halides. The generality of the method is demonstrated by its excellent performance across a broad range of (hetero)cyclic and acyclic carbonyl scaffolds. The reaction is thought to proceed through unactivated acetal/ketal alpha-carbon radicals, overcoming challenges related to the ancillary steric bulkiness of the acetal/ketal moieties and the lack of stabilizing and directing factors. Experimental and density functional theory (DFT) studies reveal a plausible radical chain mechanism and elucidate the observed enantioselectivity. This method avoids the postreaction epimerization issue often encountered in unprotected tertiary alpha-aryl ketones and aldehydes. Thus, it holds great promise for the rapid synthesis of a wide array of important natural products and drug molecules based on tertiary alpha-aryl ketones and aldehydes by leveraging earth-abundant nickel catalysts.