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  • Title: Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.
    Author: Chen JJ, Fang JH, Du XY, Zhang JY, Bian JQ, Wang FL, Luan C, Liu WL, Liu JR, Dong XY, Li ZL, Gu QS, Dong Z, Liu XY.
    Journal: Nature; 2023 Jun; 618(7964):294-300. PubMed ID: 36940729.
    Abstract:
    Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. 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 version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed 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 indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.
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