笼状石松生物碱Palhinine A和Lycopalhine A的不对称全合成研究

Palhinine alkaloids, a novel class of Lycopodium alkaloids with more complicated structure, were isolated from Lycopodium by our research groups. There are six members of family. They possess a caged, rigid, sterically congested ring system and continuous tertiary and quaternary stereogenic centers, which have attracted broad attention from the synthetic chemists. Only two asymmetric total synthesis of Lycopalhine A to date have been achieved. The samples of Palhinine alkaloids from separation and purification of natural products were not sufficient for biological activity screaning. . This topic aims at the total synthesis of Palhinine alkaloid Palhinine A and Lycopalhine A. A divergent strategy based on a common intermediate will be applied in our syntheses. The key reactions of synthetic route involve an asymmetric Pauson-Khand reaction, a tandem conjugate addition/aldol reaction, SmI2-mediated intramolecular cyclization, and construction of nitrogen-containing nine-membered ring. These studies are expected to facilitate the systematic synthetic and biological investigations of the members of Palhinine family.

Palhinine类生物碱是从石松中分离出的结构最为复杂的一类新型石松生物碱，目前共有六个家族成员。笼状、刚性、空间拥挤的环系以及连续的叔、季碳手性中心使其成为合成化学家们的关注热点。目前只有两例Lycopalhine A不对称全合成的研究报道。由于在天然石松中含量极低，分离提纯的样品不足以进行充分的生物活性实验，因此对其进行化学合成就显得尤为重要。. 本课题以Palhinine石松生物碱Palhinine A和Lycopalhine A为研究对象，拟运用发散性的合成策略，通过共用中间体分别完成两个天然产物的全合成。路线涉及不对称Pauson-Khand环化反应、串联的Michael加成/Aldol缩合、SmI2催化的分子内环化以及氮杂九元环的构建等关键反应。本课题为笼状立体结构Palhinine类石松生物碱的全合成提供了方法和借鉴，并为后续的生物活性研究做好了前期准备。

在本项目主要是对Palhinine 生物碱进行合成，在本项目资助下，我们开展了以下的研究工作：.1. 以二碘化钐介导的环化和光诱发的自由基-碎片化作为关键步骤发展了Palhinine 生物碱的三环癸烷笼状母核的合成新方法。.2. 以丙炔酸和炔丙醇为原料，实现了铑催化的区域选择性和立体选择性的碳-碳键脱羧偶联反应。.3. 在室温和免金属条件下通过醋酸碘苯和2-硝基丙烷创建不稳定的甲基自由基的新方法实现菲啶和异喹啉的甲基化。.4. 我们发展了在自由基条件下用环己醇进行银催化的芳杂环C-2位立体选择性的烷基化。.5. 我们报道了第一例在免金属条件下用非保护的氨基酸作为稳定的烷基/酰基自由基前体构建碳-碳键的反应。