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(sp³) fraction and avoid flat molecules. sp³-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 ?-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.

SUBMITTER: Wang JW 

PROVIDER: S-EPMC7910428 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature