Ni-catalyzed enantioselective three-component reductive alkylacylation of alkenes: modular access to structurally complex α-amino ketones

Abstract

Chiral alpha-amino ketones have found extensive applications as functional molecules. A nickel-catalyzed, enantioselective, and fully intermolecular three-component 1,2-alkylacylation of N-acyl enamides has been realized with tertiary alkyl bromides and carboxylic acid-derived electrophiles as the coupling reagents. This reductive coupling strategy is operationally simple, exhibiting broad substrate scope and excellent functional group tolerance using readily available starting materials and allowing rapid access to structurally complex α-amino ketone derivatives in high enantioselectivity. A suitable chiral biimidazoline ligand together with additional chelation of the amide carbonyl group in a Ni alkyl intermediate facilitates the enantioselective control by suppressing the background reaction, accounting for the excellent enantioselectivity. Mechanistic studies indicated intermediacy of radical species.

Scheme 1. Chiral α-amino ketones and enantioselective carboacylation of olefins.

Scheme 2. Gram-scale experiment and synthetic transformations.

Scheme 3. Mechanistic studies.