Patra Koushik, Deb Samiran, Kumar Choutipalli Venkata Surya, Mulani Sana, Mallik Sumitava, Subramanian Venkatesan, Baidya Mahiuddin
Department of Chemistry, Indian Institute of Technology Madras Chennai 600 036 Tamil Nadu India
Centre for High Computing, CSIR-Central Leather Research Institute Chennai 600020 Tamil Nadu India.
Chem Sci. 2025 Mar 26;16(17):7551-7559. doi: 10.1039/d5sc01527h. eCollection 2025 Apr 30.
Three-dimensional fused-ring frameworks, especially those incorporating heteroatoms, are fundamental to expanding chemical space and unlocking unique properties critical for drug discovery and functional materials, yet their synthesis remains a formidable challenge. Herein, we report for the first time the union of two distinct azolium salts as an efficient synthetic platform to access tertiary amine-caged frameworks under mild conditions. The strategy combines the masked nucleophilic and electrophilic properties of isoquinolinium and pyridinium salts, and avails double dearomatization guided inverse electron demand (4 + 2) or (3 + 2) annulation in a highly regio- and diastereoselective manner to construct the nitrogen caged motifs. Our methodology creates two new rings and four new bonds in a single operation and transforms flat-aromatic compounds into structurally unprecedented three-dimensional architectures with contiguous stereocenters in very high yields. DFT studies have shed light on the reaction mechanism, indicating that the annulation step is rate-limiting, with (4 + 2) annulation proceeding stepwise and (3 + 2) annulation following a concerted pathway.
三维稠环骨架，尤其是那些含有杂原子的骨架，对于拓展化学空间以及揭示对药物发现和功能材料至关重要的独特性质而言至关重要，但它们的合成仍然是一项艰巨的挑战。在此，我们首次报道了将两种不同的唑鎓盐结合起来，作为一种在温和条件下获得叔胺笼状骨架的高效合成平台。该策略结合了异喹啉鎓盐和吡啶鎓盐的掩蔽亲核和亲电性质，并以高度区域和非对映选择性的方式利用双去芳构化导向的逆电子需求（4 + 2）或（3 + 2）环化反应来构建氮笼状结构单元。我们的方法在一次操作中创建了两个新环和四个新键，并以非常高的产率将平面芳香化合物转化为具有连续立体中心的结构前所未有的三维结构。密度泛函理论研究揭示了反应机理，表明环化步骤是限速步骤，（4 + 2）环化反应是分步进行的，而（3 + 2）环化反应遵循协同途径。
