华中师范大学陆良秋团队报道了通过铜催化的不对称炔丙基胺化/不对称化策略获得N-α-季手性吗啉。相关研究成果发表在2024年8月8日出版的国际知名学术期刊《科学通报》。

吗啉类化合物广泛存在于许多生物和催化活性剂中，因此是制药和合成化学家的重要对象。然而，催化不对称合成具有密集立体中心的手性吗啉的有效策略仍然难以捉摸。

该文中，研究人员报道了一种铜催化的不对称炔丙基胺化/不对称化策略，以解决这一挑战。因此，研究人员高效地选择性地制备了两种结构多样的具有丰富的官能团和N-α-季立体中心的手性吗啉（42个实例，高达91%的收率，97:3er和>19:1dr）。

此外，还进行了一系列转换，以证明这种方法的综合效用。特别是，通过细胞评估确定了一种新的抗肿瘤药物的关键化合物。此外，机理研究表明，关键的亚烯丙基铜中间体中的氢键与π-π堆叠有助于远程对映体诱导。

附：英文原文

Title: Access to N-α-quaternary chiral morpholines via Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy

Author: Peng Chen,Mao-Mao Zhang,Li Rao,Yuan-Heng Li,Yue Jia,Ying Tan,Wen-Jing Xiao,Liang-Qiu Lu

Issue&Volume: 2024/08/08

Abstract: Morpholines are widespread in many biologically and catalytically active agents, thus being an important aim of pharmaceutical and synthetic chemists. However, efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive. Herein, we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge. As a result, two kinds of structurally various chiral morpholines bearing rich functional groups and N-α-quaternary stereocenters were produced with high efficiency and selectivity (42 examples, up to 91% yield, 97:3 er and >19:1 dr). In addition, a series of transformations were performed to demonstrate the synthetic utility of this methodology. In particular, a hit compound for new antitumor drugs was identified through cellular evaluation. Furthermore, mechanistic investigations reveal that, hydrogen bonding in the key copper-allenylidene intermediate together with π-π stacking aids remote enantioinduction.

DOI: 10.1016/j.scib.2024.08.005

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927324005644