Beng Timothy K, Johnsen Ailan, Gitonga Alan, Kaur Jasleen
Department of Chemistry, Central Washington University Ellensburg WA 98926 USA
RSC Adv. 2025 Jun 19;15(26):20810-20814. doi: 10.1039/d5ra03502c. eCollection 2025 Jun 16.
Polysubstituted pyrrolidines and azonanes bearing at least two (vicinal) stereocenters constitute the core of several pharmaceuticals or advanced intermediates that directly lead to marketed drugs. Here, we leverage our recently developed 1,3-azadiene-succinic anhydride annulation protocol to produce vicinally functionalized allylic pyrrolidine methanols and explore their amenability to four-carbon homologation. The success of the aza-Cope rearrangement hinges on the use of hexafluoroisopropanol (HFIP) as the reaction medium. The method provides rapid, modular, and efficient access to highly customized azonines. The ring expansion reaction of these sterically-imposing and vicinally functionalized α-styrenyl pyrrolidine methanols proceeds with complete control of the / geometries of the enamine and alkene C[double bond, length as m-dash]C double bonds resident in the 9-membered ring. Additionally, the approach furnishes sp-rich nine-membered nitrogen heterocycles bearing at least two tetrahedral stereocenters, including a remote benzylic stereocenter.
带有至少两个（邻位）立体中心的多取代吡咯烷和氮杂环壬烷构成了几种药物或直接通向上市药物的高级中间体的核心。在此，我们利用我们最近开发的1,3-氮杂二烯-琥珀酸酐环化反应方案来制备邻位官能化的烯丙基吡咯烷甲醇，并探索它们进行四碳同系化反应的适用性。氮杂-Cope重排反应的成功取决于使用六氟异丙醇（HFIP）作为反应介质。该方法能够快速、模块化且高效地获得高度定制的氮杂环壬烷。这些空间位阻较大且邻位官能化的α-苯乙烯基吡咯烷甲醇的扩环反应能够完全控制九元环中烯胺和烯烃C=C双键的/几何构型。此外，该方法还能提供富含sp的九元氮杂环，其带有至少两个四面体立体中心，包括一个远程苄基立体中心。
