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 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.
Highlights
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
Enantiopure amines are frequently encountered as chiral auxiliaries and synthetic intermediates for pharmaceutical agents and bioactive natural products (Fig. 1a
In the aforementioned classical methods, especially the hydrogenation and hydroamination of unsaturated bonds, chiral amines with circumscribed skeleton structures could be successfully synthesised; typically, the chiral carbon centre should be adjacent to an auxiliary aryl13 or ester group22
Summary
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. We report a reductive hydroalkylation of generalised organic unsaturated bonds, namely, the reductive hydroalkylation process of enamides and enecarbamates (Fig. 1c)37–40 This reaction involves in situ hydrometallation of enamide or enecarbamate to generate prospective enantioenriched alkylnickel intermediates, which subsequently react with alkyl halides to form C(sp3)–C(sp3) bonds, representing an enantioselective control mode different from the well-known nickel-catalysed electrophile–nucleophile cross-coupling reactions developed by Fu at Caltech. This reaction involves in situ hydrometallation of enamide or enecarbamate to generate prospective enantioenriched alkylnickel intermediates, which subsequently react with alkyl halides to form C(sp3)–C(sp3) bonds, representing an enantioselective control mode different from the well-known nickel-catalysed electrophile–nucleophile cross-coupling reactions developed by Fu at Caltech41,42 This reaction enables the construction of structurally complex and multifunctional amides and β-aminoboronates with excellent functional-group compatibility suitable for late-stage elaboration applications. NiLn O N aldehyde, alkyne, amide enamide, enecarbamate alkyl halide protected amine bulk chemicals facile synthesis enantioselective drug-like molecules
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