Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated alpha-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.

Automated summary

A nickel-catalyzed hydroalkylation method has been developed to assemble a wide range of chiral alkyl amines with high regio- and enantioselectivity from enecarbamates and alkyl halides. The method is suitable for both nonactivated and activated alkyl halides, producing enantiomerically enriched amines with high functional group tolerance.