Catalyst-Tuned Regiodivergent and Enantioselective Formal Hydroaminations of Acryamides to α-Tertiary-α-Aminolactam and β-Aminoamide Derivatives.

Abstract

Enantioenriched α-tertiary-α-aminoacid and α-chiral-β-aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable yet remains challenging. Herein, an unprecedented catalyst-controlled regiodivergent and enantioselective formal hydroamination of 1,1-disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives. Conceptually, sterically-disfavoured and electronically-disfavoured enantioselective hydroamination of electron-deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely steric congested aliphatic α-tertiary-α-aminolactam derivatives were synthesized by Cu-H catalyzed asymmetric forge of C-N bond with tertiary alkyl species for the first time. Enantioenriched α-chiral-β-aminoamide derivatives have been accessed by Ni-H catalyzed anti-Markovnikov-selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives in good yields with high levels of enantioselectivity.