Liu Wenfeng, Li Wei, Xu Weipeng, Wang Minyan, Kong Wangqing
The Institute for Advanced Studies (IAS), Wuhan University, Wuhan, 430072, China.
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
Nat Commun. 2024 Apr 4;15(1):2914. doi: 10.1038/s41467-024-47200-z.
Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only exo-cyclization/cross-coupling products can be obtained, while endo-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes cis-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves exo-cyclization followed by Dowd-Beckwith-type ring expansion to form endo-cyclization products.
碳环和杂环常用于天然产物、精细化学品以及生物和药物活性化合物中，作为关键骨架。过渡金属催化的1,6-烯炔环化反应已成为构建功能化碳环和杂环的有力策略。尽管取得了显著进展，但炔烃官能化的区域选择性完全取决于底物。并且只能得到外环化/交叉偶联产物，而内环选择性环化/交叉偶联仍然难以实现，仍然是一个巨大的挑战。在本研究中，我们揭示了一种镍催化的1,6-烯炔可切换芳基化/环化反应，其中配体的性质决定了炔烃芳基化的区域选择性，而亲电捕获试剂则决定了环化模式的选择性。具体而言，使用市售的1,10-菲咯啉作为配体有利于反式芳基化/环化以获得七元环产物，而2-萘基取代的双恶唑啉配体促进顺式芳基化/环化以得到六元环产物。还开发了非对映选择性环化反应来合成对映体富集的哌啶和氮杂环庚烷，它们是具有重要生物活性的药物和天然产物的核心结构单元。此外，实验和密度泛函理论研究表明，炔烃芳基化过程的区域选择性完全由配体的空间位阻控制；反应机理涉及外环化，随后是Dowd-Beckwith型扩环以形成内环化产物。
