南方科技大学刘心元团队报道了对映会聚铜催化脂肪胺的N-烷基化反应。相关研究成果发表在2023年3月20日出版的《自然》。

手性胺常见于制药和农药领域。对非天然手性胺的强烈需求推动了催化不对称方法的发展。尽管脂族胺与烷基卤化物的N-烷基化已经被广泛采用了100多年，但催化剂中毒和不受限制的反应性一直阻碍着催化剂控制的对映选择性的发展。

该文中，研究人员报道了手性三齿阴离子配体的使用，以实现铜催化的脂肪族胺与α-羰基烷基氯化物的化学选择性和对映转化N-烷基化。该方法可以在温和和稳健的条件下，将包括氨和药物相关胺在内的原料化学品直接转化为非天然手性α-氨基酰胺。观察到优异的对映选择性和官能团耐受性。该方法的能力在许多复杂的环境中得到了证明，包括后期功能化和多种胺药物分子的快速合成。目前的方法表明，多齿阴离子配体是克服过渡金属催化剂中毒的通用解决方案。

附：英文原文

Title: Enantioconvergent Cu-catalyzed N-alkylation of aliphatic amines

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

Issue&Volume: 2023-03-20

Abstract: 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 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. 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.

DOI: 10.1038/s41586-023-05950-8

Source: https://www.nature.com/articles/s41586-023-05950-8