Direct and Enantioselective Acylation of Diverse C(sp³)-H Bonds with Aldehydes

Chiral ketones containing α-aryl, α-amino, or α-oxy stereocenters are unique structural motifs found in numerous important natural products and pharmaceuticals, but their enantioselective synthesis remains a challenge. We report a synthetic method for the enantioselective acylation of diverse C(sp³)-H bonds by combining peroxide photosensitization and nickel catalysis. This method utilizes abundant and readily available aldehydes as an acyl source and is capable of acylating a variety of C(sp³)-H bonds, including benzylic, α-amino, and α-alkoxy C(sp³)-H bonds, with excellent enantioselectivity and atom economy. The practicability of this strategy is demonstrated in the enantioselective synthesis of chiral building blocks as well as biologically active natural products and pharmaceuticals. This method provides an unprecedented solution to the challenging problem of stereoselective control in various radical-radical direct cross-coupling reactions. Mechanistic studies revealed that visible light triplet energy transfer promotes the mild decomposition of peroxides to generate alkoxy radicals, which act as hydrogen atom transfer reagents to generate acyl radicals and substrate radicals, respectively, while chiral nickel catalysis is responsible for the asymmetric cross-coupling of these two radicals to generate C(sp³)-H acylated products.