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

铜催化不对称炔丙基胺化/去对称策略构建含N-α-季碳中心的手性吗啉骨架

作　　者：Peng Chen Mao-Mao Zhang Li Rao Yuan-Heng Li Yue Jia Ying Tan Wen-Jing Xiao Liang-Qiu Lu 陈鹏;张毛毛;饶立;李沅恒;贾玥;谭英;肖文精;陆良秋

机构地区：[1]Engineering Research Center of Photoenergy Utilization for Pollution Control and Carbon Reduction(Ministry of Education),College of Chemistry,Central China Normal University,Wuhan 430079,China [2]State Key Laboratory of Chemical Oncogenomics,Key Laboratory of Chemical Biology,Tsinghua Shenzhen International Graduate School,Tsinghua University,Shenzhen 518055,China [3]Wuhan Institute of Photochemistry and Technology,Wuhan 430082,China [4]State Key Laboratory for Oxo Synthesis and Selective Oxidation,Lanzhou Institute of Chemical Physics(LICP),Chinese Academy of Sciences,Lanzhou 730000,China [5]School of Chemistry and Chemical Engineering,Henan Normal University,Xinxiang 453007,China

出　　处：《Science Bulletin》2024年第22期3516-3524,共9页科学通报（英文版）

基　　金：supported by the National Key R&D Program of China(2023YFE0110100);the National Natural Science Foundation of China(22271113,92256301,21822103,and 21820102003)。

摘　　要：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-a-quaternary stereocenters were produced with high efficiency and selectivity(42 examples,up to91%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 withπ-πstacking aids remote enantioinduction.

关 键 词：Chiral morpholine Copper catalysis DESYMMETRIZATION Propargylic amination 

分 类 号：O621.251[理学—有机化学]