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

作者：Linqing Wang, Feiyun Gao, Xiaoyong Zhang, Tianyu Peng, Yingfan Xu, Rui Wang, Dongxu Yang · 发表于：Journal of the American Chemical Society · 年份：2022 · DOI：10.1021/jacs.2c11284 · 被引用次数：23 · 研究领域：Synthesis and Catalytic Reactions、Synthesis of β-Lactam Compounds、Synthetic Organic Chemistry Methods

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 31 P 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, 31 P 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.