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

Sci Bull (Beijing)

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; Wuhan Institute of Photochemistry and Technology, Wuhan 430082, China; State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China. Electronic address:

Published: November 2024

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.

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Source
http://dx.doi.org/10.1016/j.scib.2024.08.005DOI Listing

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