Enantioselective Carbonylative Coupling Reactions: Merging Nickel-Based Selectivity and Photoredox Reactivity

Transition metal-catalyzed carbonylative coupling reactions play a crucial role in the synthesis of functional molecules of use throughout pharmaceutical development, natural products, and material science. This utility is driven by both the efficiency of carbonylation chemistry and the broad presence of the carbonyl functionality in most synthetic materials. Unfortunately, the development of enantioselective carbonylative coupling reactions of alkyl halides and nucleophiles to access the α-chiral motif found in most drugs is, to date, not viable. This has been attributed to the inhibitory influence of carbon monoxide, which blocks the activation of C(sp³)-halides and limits the efficacy of chiral ligand environments in modulating selectivity. Here, we show how this challenge can be addressed via a conceptually alternative approach to such reactions, where the coupling of photoredox and chiral nickel catalysis can be employed to separate reactivity from stereocontrol. This combined strategy has enabled the first asymmetric carbonylative coupling of benzylic and related C(sp³)-halides with amines and the preparation of a diverse array of chiral amides with excellent enantioselectivity. These findings expand the scope of enantioselective catalysis and offer new possibilities for synthesizing chiral carbonyl-containing compounds with wide-ranging implications for drug discovery and synthetic chemistry.