2-烯基吡啶的分子内环加成反应及其在石松定类生物碱合成中的应用

Polycyclic alkaloids containing heteroaromatic subunits represent a large family of bioactive natural products. Lycodine and its structurally related alkaloids, due to their unique polycyclic skeleton and their extroadinary biological activity, have become excellent targets for the synthetic community.In the current application, a concise synthetic strategy toward this family of natural products has been devised, mainly based on a newly designed intramolecular [4+2] cycloaddition reaction of a 2-alkenylpyridine and an electron-rich alkene.The disign is based on comprehensive analysis of 2-alkenylpyridine and enamine's reactivity. Preliminary study of a structurally analogous model substrate has provided promising results, affording the expected cycloaddition product in high stereoselectivity. This reaction offers a rapid and stereoselective method for construction of complex N-containing polycyclic skeletons. Based on this reaction,total syntheses of lycodine and related alkaloids will be developed.Among them are complanadine A and B, important leads in developing agents for treatment of neurodegenerative diseases. All of these synthetic approaches are designed to be unified, concise and flexible, that is, amenable to syntheses of various structural analogs. Thus, a series of natural and unnatural lycodine alkaloids will be prepared and submitted to biological studies. In collaboration with the neurobiology team in FIST, Xi'an Jiaotong University, the aim of these synthetic and biological studies is for searching valuable small molecule probes for neuroscience study and leads for drug discovery.

含有芳香氮杂环的多环生物碱是一大类具有多种生物活性的天然产物。石松定碱类生物碱由于其独特的多环骨架和突出的生物活性，成为其中具有挑战性的重要合成目标。受这类天然结构的启发，本申请书设计出一个2-烯基吡啶的分子内【4+2】环加成反应，利用该反应可以简洁地合成石松定碱类天然产物。反应的设计是基于对2-烯基吡啶和烯胺的详细反应性分析。前期实验已经从一个结构相关的模型底物得到预期的环加成产物,证明了该设计的有效性。该反应提供了一种既方便快捷又具有立体选择性的构建复杂含氮杂环骨架的方法。据此，本项目致力于发展石松定碱类天然产物的通用、简洁、灵活的全合成策略，其中包括具有重要神经系统药用研究价值的complanadine A和B。本项目将合成一系列天然和非天然的石松定生物碱，并与神经生物学研究队伍合作，进行生物活性研究，以期寻找有价值的小分子探针和药物先导结构。

本项目内容属于有机合成新方法及其在生物活性分子合成中的应用研究。本项目主要研究内容分为三个部分。第一，采用新颖的N-B配位键做为桥梁实现了非活化烯烃和二烯的【4+2】环加成反应，且通过辅基的设计得到极高的exo-立体选择性。该反应原料易得，操作简单，所得产物为复杂多环笼状结构，含多个连续立体中心，因此是一个快速提高分子复杂性的有效方法。第二，为了发展高效有机硼制备和转化反应，本项目通过设计新型配体获得目前活性最高的芳烃硼化催化体系；通过易得单硼原料制备了多用途芳基多硼试剂并用于复杂结构合成；通过对硼中心自由基的电子结构和反应性研究探讨了自由基型C-B键形成的可能性。第三，采用新颖成环方法和去芳化反应，简洁高效地构建了巴豆烷和瑞香烷天然二萜的共同三环骨架，且正确形成多个连续立体中心。这些研究结果从多个方面为快速提高分子复杂性提供了合成方法，对解决挑战性的成环反应、惰性键转化等基本化学问题提供了新颖研究思路，对均相催化中配体设计也开辟了新颖视角。