Sailer Joshua K, Ly Duc, Wang Andrew, Musaev Djamaladdin G, Davies Huw M L
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
Cherry L. Emerson Center for Scientific Computation, Emory University, Atlanta, Georgia 30322, United States.
ACS Catal. 2025 Aug 19;15(17):15253-15260. doi: 10.1021/acscatal.5c04199. eCollection 2025 Sep 5.
Spirocyclopropanes have become a prevalent structural motif in drug discovery campaigns. However, methods to generate these spirocyclopropanes stereoselectively are scarce, highlighting the need for efficient synthetic methods. In this report, we describe the synthesis of various azaspiro-[n.2]-alkanes by means of a dirhodium tetracarboxylate catalyzed cyclopropanation of exocyclic olefins using donor/acceptor carbenes. The optimum chiral dirhodium tetracarboxylate catalyst, Rh(-PhTPCP), results in highly enantioselective cyclopropanation of symmetrical azacyclomethylidenes and highly enantioselective and diastereoselective cyclopropanation of nonsymmetrical azacyclomethylidenes and can achieve up to 83,000 turnovers. Computational studies reveal that the stereoselectivity is controlled by the way the substrate can fit into the chiral pocket generated by the ligands.
螺环丙烷已成为药物研发活动中普遍存在的结构基序。然而，立体选择性生成这些螺环丙烷的方法很少，这凸显了高效合成方法的必要性。在本报告中，我们描述了通过使用供体/受体卡宾的四羧酸二铑催化环外烯烃环丙烷化反应来合成各种氮杂螺[n.2]烷烃。最佳的手性四羧酸二铑催化剂Rh(-PhTPCP)能使对称氮杂环亚甲基发生高度对映选择性环丙烷化反应，使非对称氮杂环亚甲基发生高度对映选择性和非对映选择性环丙烷化反应，并且可以实现高达83000次的转化。计算研究表明，立体选择性是由底物适配配体产生的手性口袋的方式所控制的。
