Ni/Photoredox-Catalyzed Enantioselective Acylation of α-Bromobenzoates with Aldehydes: A Formal Approach to Aldehyde-Aldehyde Cross-Coupling.

The catalytic cross-coupling of identical or similar functional groups is a cornerstone strategy for carbon-carbon bond formation, as exemplified by renowned methods, such as olefin cross-metathesis, Kolbe electrolysis, and various cross-electrophile couplings. However, similar methodologies for coupling aldehydes─fundamental building blocks in organic synthesis─remain underdeveloped. While the benzoin-type condensation, first reported in 1832, offers a reliable route for aldehyde dimerization, the chemo- and enantioselective cross-coupling of nonidentical yet similar aldehydes remains an unsolved challenge. Herein, we report a unified platform enabling highly chemo- and enantioselective cross-coupling of aldehydes. By leveraging nickel photoredox catalysis in tandem with discrete activation strategies for each aldehyde, this mechanistically distinct approach facilitates the enantioselective union of an aldehyde-derived α-oxy radical with an acyl radical, photocatalytically generated from a distinct aldehyde. This novel strategy enables modular access to enantioenriched α-oxygenated ketones with two minimally differentiated aliphatic substituents, a feat not achievable with existing chemocatalytic or biocatalytic techniques. The synthetic utility of this method is demonstrated by its application in the streamlined asymmetric synthesis of various medicinally relevant molecules. Additionally, mechanistic investigations rationalize the versatility of nickel photoredox catalysis to exploit new pathways for addressing long-standing synthetic challenges.