Enantioconvergent Cu-catalyzed N-alkylation of aliphatic amines – Nature

Chiral amines are commonly found in the pharmaceutical and agrochemical industries¹. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods^1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version^3–5. Herein we report the use of chiral tridentate anionic ligands to enable the copper-catalyzed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals including ammonia and pharmaceutically-relevant amines into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method suggests that multidentate anionic ligands are a general solution for overcoming transition metal catalyst poisoning.