Unnatural α-amino acid synthesis enabled by nickel-catalysed enantioselective hydrocarbamoylation of enamides via C‒H functionalisation

Enantioselective construction of unnatural α-amino acids is highly desirable due to their widespread applications across biochemistry, medicinal industry and materials science. Herein, we report a straightforward and efficient method for the assembly of structurally diverse enantioenriched α-amino acid derivatives from readily accessible enamides and N,N-dimethylformamide (DMF) by merging nickel hydride catalysis and hydrogen atom transfer (HAT). The protocol affords good yields and high enantioselectivities of products which easily can be converted into unprotected unnatural α-amino acids and other valuable chiral building blocks. Notably, the enantiopurity of the products can be further enhanced by normal flash chromatography on silica gel, providing a practical platform for enantiopurification of both oily and solid products. This radical cross-coupling reaction proceeds under mild conditions, tolerates a broad range of functional groups and is amenable to the construction of enantioenriched α-amino amides bearing active pharmaceutical ingredients on the sidechain. Enantioselective construction of unnatural α-amino acids is highly desirable due to their widespread applications across biochemistry, medicinal industry and materials science. Herein, the authors report a straightforward and efficient method for the assembly of structurally diverse enantioenriched α-amino acid derivatives from readily accessible enamides and N,N-dimethylformamide by merging nickel hydride catalysis and hydrogen atom transfer.