Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33637730.
- Also identified by DOI 10.1038/s41467-021-21600-x and PMC identifier 7910428.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp<sup>3</sup>) fraction and avoid flat molecules. sp<sup>3</sup>-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.