基于电化学氧化下碘催化策略合成多环苯并氮杂环化合物

Due to good biological activities of indole, quinoline or isoquinoline-containing polycyclic alkaloids which are belong to nitrogen-containing polycyclic benzo-heterocycles, they have been widely studied in recent years. However, current methods for these alkaloids synthesis are characterized by complicated multi-step synthesis, rigorous reaction conditions, remaining of metallic catalysts in products, and being environmentally unfriendly. Electrochemical synthesis with high-efficiency, green and mild conditions has getting more and more attention. And it would be an ideal tactic to solve the above issues by the combination of electrochemical synthesis and iodine catalysis. Based on our previous works, this project will focus on the electrochemical synthesis of indole, quinoline or isoquinoline-containing polycyclic alkaloids such as carbolines, quinolone fused five (six)-membered ring derivatives, isoquinoline fused five-membered ring derivatives, triazole-containing indolin-2-ones, indeno[1,2-b]indoles, pyrrolo[2,3-b]indoles through the iodine-catalyzed cyclization reactions from available starting materials. At the same time, the reaction mechanisms including the formation of nitrogen radical, hypervalent iodine, iodonium cation, 1-iodoacetylene, and acyl radical intermediates will be investigated to illuminate the general characters of these reactions. And all the synthetic compounds will be subjected to pharmacological activity screening to seek three to five promising lead compounds in drug discovery. In brief, this project will not only afford a new approach for iodine-catalyzed electrochemical synthesis but also lay the foundation for the further research of the above indole, quinoline or isoquinoline-containing polycyclic alkaloids.

多环吲哚、喹啉和异喹啉类生物碱作为具有良好生物活性的多环苯并氮杂环是近年的研究热点，但已报道的合成方法存在路线长、反应条件苛刻、金属残留和环境污染等诸多缺点。电化学合成具有高效、绿色和温和等特点，其与碘催化相结合的方法是解决上述问题的理想策略。本项目基于前期研究基础，拟在电化学氧化下开展碘催化有机新反应合成多环吲哚、喹啉和异喹啉类生物碱的研究，探索反应中氮自由基、高价碘、碘鎓离子、炔碘和酰基自由基等活性中间体的形成过程，解析反应机理，阐明其基本特征，获得以简单原料高效构筑咔啉、喹啉并五（六）元杂环、异喹啉并五元杂环、三唑-吲哚酮、茚并吲哚和吡咯并吲哚等多环苯并氮杂环的碘催化电化学合成方法，并对所合成化合物进行药理活性筛选，从中发现3-5个活性强、药用开发前景好的先导化合物。项目的实施既可提供碘催化电化学合成拓展应用的新思路，也可为多环吲哚、喹啉和异喹啉类生物碱的深入研究与开发应用奠定基础。

研究了在电化学条件下碘鎓离子、炔碘、氮自由基和碳自由基等活性中间体的形成规律及其反应机制。在此基础上，获得了在电化学条件下高效、简便地合成喹唑啉酮、1,2,4-噻二唑类化合物、1,2,3-噻二唑类化合物、多环异喹啉酮类化合物、硫化咪唑并吡啶、四氢异喹啉并氮杂环、吴茱萸次碱、脱氧鸭嘴花酮碱、氨基甲酸酯、硫化脒类化合物、次膦酸酯、1-萘酚、多取代呋喃、含硫N-烷基唑类化合物、芳族偶氮化合物、苯并异噁唑类化合物、N-酰基对氨基苯酚类化合物、β-硒基唑类衍生物、硒环醚、硒内酯、偕二芳基硫代烯胺、炔砜类化合物、不对称硫代磺酸酯、磺酰基肼基吲哚化合物和α‒苯基硫代酮等系列化合物的新方法，发展了电化学条件下酮α位甲氧基甲基化和胺甲基化反应、醛和醇氧化酯化反应、吲哚去芳构化反应，并开展了电化学条件下的异相合成化学研究。发现了12个抗肿瘤活性突出（IC50 < 10 μM）、结构新颖的抗肿瘤化合物，并明确了其中6个抗肿瘤化合物的作用机制。