石松生物碱类天然产物集成合成策略研究

Natural products and natural product-like molecules have been important sources for the discovery and development of new medicines and agricultural agents. Efficient construction of natural products and natural product-like compound libraries for their studies of biological activity and structure-activity relationship is a new challenge for synthetic chemists nowadays. Lycopodium alkaloids are structurally diverse group of natural products with high complex polycyclic skeletons and a dense stereochemical array, which have attracted great interest as challenging targets for chem- and bio-synthetic studies..This project aims to explore collective synthesis strategies for the Lycopodium alkaloids and Lycopodium alkaloid-like componds by using the clean oxidation degradation products of basic industrial raw material-steroidal sapogenin as new chiral materials. Based on the analysis of the interconnectedness of the biogenesis of various types of the Lycopodium alkaloids, this project demonstrates the feasibility of total syntheses of types of Lycopodium alkaloids from a common precursor. First utilizing the coupling reaction of enamine/imine triflates as a key step to build the containing C/D ring common intermediates, then by controlling the direction of the A/B ringcyclization, asymmetric synthesis of various Lycopodium alkaloids will be achieved in less than 10 linear steps. The short and efficient synthesis features readily available raw materials and considerations on step-economy, and therefore is expected to provide adequate samples for the studies of biochemical properties of Lycopodium alkaloids.

天然产物一直是发现和发展新医药、新农药的重要源泉。有效构建结构复杂、骨架多样性的“类天然产物化合物库”进行生物学相关研究是当今天然产物合成化学面临的新挑战。石松生物碱因骨架复杂多变、手性中心密集、合成难度大等特点成为近年来化学和生物合成研究的热点。. 本申请项目以我国甾体药物工业基本原料—甾体皂甙元的洁净氧化降解产物为手性源，探索石松生物碱家族化合物的集成合成策略。在对各类石松生物碱生源合成的系统分析基础上，本项目提出利用几类石松生物碱的共同中间体开展针对不同类型的石松生物碱的不对称全合成研究。首先以烯胺/亚胺三氟甲磺酸酯的偶联反应为关键步骤，构建含有C/D环的共同中间体，再通过控制A/B环的关环方向，仅需不到10步线性步骤，便可实现几类不同骨架石松生物碱的不对称合成。本合成路线简洁高效、原料价廉易得，因此有望为石松生物碱的化学生物学性质研究提供足够样品支持。

鉴于同一家族天然产物在化学结构和生物合成途径上的相关性，2011年MacMillan等提出利用相同或相似的关键中间体快速高效合成天然产物家族化合物的集体合成策略，近年来该策略被应用于多个家族天然产物的合成中。.本项目以我国甾体药物工业基本原料甾体皂体皂甙元洁净氧化降解产物（原为工业废弃物）为新的手性原料，开展了石松生物碱和类石松生物碱的集成合成策略研究。主要进展及结果如下：（1）探索出一种从甾体降解废料中大量回收手性小分子的清洁方法；（2）以手性小分子原料、二氢吡喃、丙酮等廉价易得的原料出发，经硫缩醛化，1, 3-二噻烷负离子的亲核取代，Wittig反应等步骤完成了关键中间体的大量制备；（3）从关键中间体出发，完成了Lycodine型石松生物碱的骨架构建，其他几类石松生物碱的合成尚在进行中。本合成的完成将丰富石松生物碱的合成方法学，为其类似物的合成提供参考；对石松生物碱类天然产物的化学生物学研究提供物质基础。