新型二萜atropurpuran和二萜生物碱arcutin及其天然衍生物的仿生不对称全合成

Atropurpuran is a rare non-alkaloidal diterpene isolated from the genus Aconitum. The structure of atropurpuran features an unprecedented cage-like skeleton bearing two fused bicyclo[2.2.2]octane moieties. Of interesting, atropurpuran shares the carbon skeleton with three known alkaloids arcutin, arcutinine and arcutinidine, isolated from the related plant Aconitum arcuatm. Until now, there is no successful total synthesis reported in the literature yet. Intrigued by the sttructural complexity and potential biological activities of these compounds, we proposed a biogenitically patterned strategy for total synthesis of these compounds based on our own comprehensive biogenitic pathway that atropurpuran might be derived from hetidane-type diterpene via a Wagner-Meerwein rearrangment. This biosynthetic strategy involve several key transformations, including a cascade retro-Diels-Alder/ IMDA reaction to construct BCD ring system,ruthenium catalyzed enye cycloisomerzation reaction to constuct A ring, SmI2 promoted intramolecular reductive cyclization of lactone and alkene to form hetidane backbone, and Wagner-Meerwein rearrangement involving a rare 1,2-acyl shift to achieve atropurpuran and arcutin. Finally, the asymmetric synthetic access to atropurpuran by application of Sharpless asymmetric epoxidation to form optical chiral side chain at early synthetic stage has been designed.

Atropurpuran 是分离自乌头属植物的罕见的非生物碱二萜，与二萜生物碱arcutin、 arcutinine 和arcutinidine共同具有由五个六元碳环组成的独特的笼状骨架结构体系。迄今文献未见有这类化合物的成功的全合成报道。我们在分析其可能生物合成途径的基础上，提出了一条仿生全合成路线。路线涉及以下可能的关键反应：通过串联的retro-D-A反应和分子内D-A反应高效实现BCD环系的构建，金属钌催化的烯炔环异构化反应构建功能化的ABCD环系，SmI2促进的烯-内酯还原偶联反应仿生构建五环hetidane-型骨架；1,2-酰基迁移的Wagner-Meerwein重排实现从hetidane-型骨架到atropurpuran和 acutin的仿生转化。最后，通过不对称Sharpless环氧化在路线开始阶段合成手性侧链，设计完成了上述目标分子的不对称全合成。

绣线菊醇、绣线菊内酯B、绣线菊碱C 和D 是中国科学院昆明植物研究所郝小江课题组从蔷薇科绣线菊属植物(Spiraea japonica L.f)分离出的代表性的阿替生型二萜和阿替生型二萜生物碱. 该类成分多具有抗炎、抗血小板聚集、神经保护作用以及潜在的抗肿瘤活性. 其全合成未见报道。本研究 (两年计划）在模型构建的基础上，以集合式的方式首次成功实现了绣线菊醇、绣线菊内酯B、绣线菊碱C、D 和dihydroajaconine 消旋体的全合成. 其关键步骤涉及：1）氧化去芳香化Diels-Alder反应高效构建BCD三环中间体 2）钌催化的烯炔环异构化反应高立体选择性地构建阿替生型四环骨架；3）跨环内酯化构建绣线菊内酯E五环骨架；4）形式内酯迁移构建绣线菊内酯B五环骨架 ； 5） Mislow-Evans 重排逆转羟基构型合成绣线菊内酯B； 6）仿生转化合成绣线菊醇、绣线菊碱C、D. 和dihydroajaconine. 本研究为进一步合成其它类型的hitisine型和acutine型二萜和二萜生物碱奠定了重要基础。本研究共培养博士研究1名，硕士研究生6名；发表SCI文章六篇。