兰州大学杨东旭团队报道了镁催化剂介导亚胺协同对映选择性[2+2]环加成反应。相关研究成果发表在2022年12月20日出版的《美国化学会杂志》。

亚胺和碳-碳双键之间的对映体选择性[2+2]环化是构建手性氮杂环丁烷的通用策略。然而，α-支链二烯酸酯从未成功地应用于与亚胺的[2+2]环化反应，因为在以前的催化方法中，它们总是经历Kwon的[4+2]环化反应。

该文中，研究人员首次使用简单的原位生成的镁催化剂成功地实现了DPP亚胺和α-支化二烯酸酯的对映选择性[2+2]环化反应。包括KIE实验、对照实验、Hammett图分析和初始中间体的³¹P NMR研究表明，亚胺的当前[2+2]环化最可能涉及异步协同过渡状态。通过结合动力学研究、ESI实验、配位配合物的³¹P NMR研究以及不同催化剂负载量下反应速率的控制实验，进一步的机理研究为DPP亚胺和α-支链烯丙酸酯之间的[2+2]环化反应提供了配位细节。

该新方法被应用于各种手性氮杂杂环的合成，包括对映体选择性合成降脂剂Ezetimibe的关键中间体。

附：英文原文

Title: Concerted Enantioselective [2+2] Cycloaddition Reaction of Imines Mediated by a Magnesium Catalyst

Author: Linqing Wang, Feiyun Gao, Xiaoyong Zhang, Tianyu Peng, Yingfan Xu, Rui Wang, Dongxu Yang

Issue&Volume: December 20, 2022

Abstract: Enantioselective [2 + 2] cyclization between an imine and a carbon–carbon double bond is a versatile strategy to build chiral azetidines. However, α-branched allenoates have never been successfully applied in [2 + 2] cyclization reactions with imines, as they always undergo Kwon’s [4 + 2] annulation in previous catalytic methods. Herein, a simple in situ generated magnesium catalyst was employed to successfully achieve the enantioselective [2 + 2] cyclization reaction of DPP-imines and α-branched allenoates for the first time. Insightful experiments including KIE experiments, controlled experiments, Hammett plot analysis, and 31P NMR studies of initial intermediates indicate that the current [2 + 2] cyclization of imine most likely involves an asynchronous concerted transition state. Further mechanistic investigations by combining kinetic studies, ESI experiments, 31P NMR studies of coordination complexes, and controlled experiments on reaction rates under different catalyst loading amounts provided the coordination details for this [2 + 2] cyclization reaction between DPP-imines and α-branched allenoates. This new approach was applied to the synthesis of various chiral aza-heterocycles, including the enantioselective synthesis of the key intermediate of a lipid-lowering agent Ezetimibe.

DOI: 10.1021/jacs.2c11284

Source: https://pubs.acs.org/doi/10.1021/jacs.2c11284