Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

Abstract

To increase the reliability and success rate of drug discovery, efforts have been made to increase the C( sp ³) fraction and avoid flat molecules. sp ³-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.

Abstract

Enantiopure aliphatic amines are frequently encountered as chiral auxiliaries and synthetic intermediates for bioactive compounds. Here, the authors report a mild nickel-catalysed asymmetric reductive hydroalkylation to convert enamides and enecarbamates into α-branched chiral amines and derivatives.