Nickel-Catalyzed Multicomponent Coupling: Synthesis of α-Chiral Ketones by Reductive Hydrocarbonylation of Alkenes

A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed. This modular multicomponent hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes to produce a wide variety of unsymmetrical dialkyl ketones bearing a functionalized alpha-stereocenter, including enantioenriched chiral alpha-aryl ketones and alpha-amino ketones. It uses chiral bisoxazoline as a ligand, silane as a reductant, chloroformate as a safe CO source, and a racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected alpha-amino acid as the alkylation reagent. The benign nature of this process renders this method suitable for late-stage functionalization of complex molecules.

Automated summary

A nickel-catalyzed, multicomponent regio- and enantioselective coupling method has been developed for synthesizing unsymmetrical dialkyl ketones with a functionalized alpha-stereocenter. This strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes and is suitable for late-stage functionalization of complex molecules.