武汉大学王春江及南方科技大学钟龙华团队揭示了过双激活策略β-取代烯基杂芳烃作为亲偶极分子，在Cu（I）催化的偶氮甲基叶立德不对称1,3-偶极环加成反应中应用的立体选择性和机理分析。 相关研究成果发表在2021年3月1日出版的《美国化学会杂志》。

甲亚胺叶立德与各种缺电子烯烃的不对称1，3-偶极环加成反应为有机合成中制备对映体富集的吡咯烷提供了最直接的方法。然而，利用共轭烯基杂芳烃作为亲偶极分子来提供药物化学中一类特别重要的分子仍然是一个巨大的挑战。

该文报道了在Cu（I）催化的偶氮甲基叶立德不对称1,3-偶极环加成反应中，各种β-取代的烯基杂芳烃，在没有强吸电子取代基的情况下，首次成功地用作亲偶极分子。该反应提供了大量的多对映体杂环化合物，这些杂环化合物结合了生物上重要的吡咯烷和杂芳烃骨架，产率高，具有独特的非对映选择性和优良的对映体选择性。

通过DFT计算给出了该反应方法中立体化学结构产生的原因，验证了该过程中具有三重-同轴手性的单齿亚磷酰胺配体，为催化剂中心金属提供了手性口袋结构，实现了较高的对映选择性。同时双极性亲偶极体底物中的杂原子配位到Cu同样对反应机理中的对映选择性、提高反应性非常重要。亲偶极基质中的杂原子与铜的配位也对非对映选择性和反应活性的提高起着关键作用。

研究人员通过计算还预测了相应底物与单环杂芳烃的反向和高对映体诱导，以及一个相关的亲偶极二烯底物的低反应性内部C═C键的区域特异性环加成。实验验证了这种独特的空间效应导致的对映体转换和配位导向的区域选择性。

附：英文原文

Title: β-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight

Author: Xin Chang, Yuhong Yang, Chong Shen, Kun-Shan Xue, Zuo-Fei Wang, Hengjiang Cong, Hai-Yan Tao, Lung Wa Chung, Chun-Jiang Wang

Issue&Volume: March 1, 2021

Abstract: The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various β-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C═C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

DOI: 10.1021/jacs.0c12911

Source: https://pubs.acs.org/doi/10.1021/jacs.0c12911