Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines

Ji-Jun Chen, Jia-Heng Fang, Xuan-Yi Du, Jia-Yong Zhang, Jun-Qian Bian, Fu-Li Wang, Cheng Luan, Wei-Long Liu, Ji-Ren Liu, Xiao-Yang Dong, Zhong-Liang Li, Qiang-Shuai Gu, Zhe Dong and Xin-Yuan Liu ()
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Ji-Jun Chen: Southern University of Science and Technology
Jia-Heng Fang: Southern University of Science and Technology
Xuan-Yi Du: Southern University of Science and Technology
Jia-Yong Zhang: Southern University of Science and Technology
Jun-Qian Bian: Southern University of Science and Technology
Fu-Li Wang: Southern University of Science and Technology
Cheng Luan: Southern University of Science and Technology
Wei-Long Liu: Southern University of Science and Technology
Ji-Ren Liu: Southern University of Science and Technology
Xiao-Yang Dong: Southern University of Science and Technology
Zhong-Liang Li: Southern University of Science and Technology
Qiang-Shuai Gu: Southern University of Science and Technology
Zhe Dong: Southern University of Science and Technology
Xin-Yuan Liu: Southern University of Science and Technology

Nature, 2023, vol. 618, issue 7964, 294-300

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05950-8

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