College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, People's Republic of China.
State Key Laboratory of of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People's Republic of China.
J Am Chem Soc. 2021 Mar 10;143(9):3519-3535. doi: 10.1021/jacs.0c12911. Epub 2021 Mar 1.
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.
氮丙啶亚胺与各种缺电子烯烃的催化不对称 1,3-偶极环加成反应为有机合成中手性吡咯烷的制备提供了最直接的方法。然而，在这些方案中使用共轭烯基杂芳烃作为偶极子，以提供一类在药物化学中特别重要的分子，仍然是一个巨大的挑战。在此，我们报告了各种β-取代的烯基杂芳烃，作为没有强吸电子取代基的内部烯烃底物，首次成功地用作氮丙啶亚胺的铜（I）催化不对称 1,3-偶极环加成的偶极子。该反应以优异的对映选择性和高收率，以独特的非对映选择性提供了大量包含生物重要吡咯烷和杂芳环骨架的多立体中心杂环。我们广泛的密度泛函理论（DFT）计算提出了一个工作模型，以解释立体化学结果的起源，并阐明了金属对偶极子和偶极子底物的不常见双重活化/配位，其中空间位阻大、刚性、单齿膦酰胺配体具有三重同轴向手性，在金属中心周围提供有效的手性口袋，从而实现高对映选择性。偶极子底物中杂原子与 Cu 的额外配位对于独特的非对映选择性和增强的反应性也至关重要。我们的计算还预测了相应的单环杂芳烃底物的相反和高对映诱导以及相关偶极子二烯底物的反应性较低的内部 C═C 键的区域特异性环加成。这种独特的空间位阻定向的对映选择性切换和配位定向的区域选择性通过实验得到了验证。
