Tao Xiangzhang, Han Hyeonsoo, Jeong Jinwook, Kim Dongwook, Hong Sungwoo
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea.
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
J Am Chem Soc. 2025 Jun 18;147(24):21143-21152. doi: 10.1021/jacs.5c06469. Epub 2025 Jun 6.
Skeletal editing of heteroarenes in complex molecules represents a transformative synthetic strategy that transcends the limitations of conventional peripheral functionalization, enabling the profound structural diversification of molecular frameworks. Here, we demonstrate a powerful metal-free approach for converting pyridines into planar (2D) and three-dimensional (3D) fused bicyclic heterocycles through a precisely orchestrated process of nucleophilic addition, 6π-electrocyclic ring opening/ring closure, and fused ring formation. This methodology exploits the unique reactivity of -pyridinium salts with hydrazine nucleophiles, accommodating diverse functional groups in a sequential one-pot protocol. In addition, a modified procedure enabled the synthesis of C3-brominated heterocyclic scaffolds. The synthetic utility is further demonstrated by successful late-stage modifications of structurally complex bioactive molecules. Comprehensive mechanistic investigations, including the isolation of key intermediates and computational studies, offer critical insights into the reaction pathway. Our findings establish a versatile platform for the strategic reconstruction of pyridine cores, significantly expanding the accessible chemical space. Notably, the newly synthesized pyrazolopyridazine scaffolds exhibit low-micromolar inhibitory activity over JNK1, positioning them as promising candidates with a substantial medicinal chemistry value for further optimization. This bioactivity validation underscores how our findings establish a versatile platform for the strategic reconstruction of pyridine cores, considerably expanding the accessible chemical space for drug discovery.
复杂分子中杂芳烃的骨架编辑代表了一种变革性的合成策略，它超越了传统外围功能化的限制，能够实现分子框架的深度结构多样化。在此，我们展示了一种强大的无金属方法，通过精心编排的亲核加成、6π-电环化开环/闭环以及稠环形成过程，将吡啶转化为平面（二维）和三维（三维）稠合双环杂环。该方法利用了吡啶鎓盐与肼亲核试剂的独特反应性，在连续的一锅法方案中容纳多种官能团。此外，一种改进的方法能够合成C3-溴代杂环支架。通过对结构复杂的生物活性分子进行成功的后期修饰，进一步证明了该合成方法的实用性。全面的机理研究，包括关键中间体的分离和计算研究，为反应途径提供了关键见解。我们的研究结果建立了一个用于吡啶核心战略重建的通用平台，显著扩展了可及的化学空间。值得注意的是，新合成的吡唑并哒嗪支架对JNK1表现出低微摩尔级的抑制活性，使其成为具有重大药物化学价值的有前景的进一步优化候选物。这种生物活性验证强调了我们的研究结果如何建立了一个用于吡啶核心战略重建的通用平台，大大扩展了药物发现的可及化学空间。
