复杂二倍半萜类天然产物astellatol的全合成

Natural terpenoids, such as taxol and artemisinin, represent as one of the most important resources for drug discovery. Within the terpenoid family, sesterterpenoids probably form the smallest class, but often show significant biological activity, such as anti-cancer, antibacteria, anti-viral, anti-inflammatory and anti-cardiovascular diseases. With their comparatively large size, structural complexity, and bioactivity diversity, sesterterpenoids represent highly attractive targets for total synthesis. In 1989, an unusual fungal sesterterpenoid, astellatol, was isolated from the metabolite of Aspergillus stellatus. It possesses a complex, caged, pentacyclic scaffold and ten contiguous stereocenters. However, the biological profiles of astellatol have not been illustrated. Due to its intriguing architectures and undefined biological profiles, herein we propose a novel and highly efficient strategy for the total synthesis of astellatol. The key steps would include a RCM reaction, an intramolecular Pauson-Khand reaction and a SmI2-mediated reductive radical cyclization. We hope to achieve the first total synthesis of astellatol and illustrate its biological activity.

天然萜类化合物长期以来是小分子创新药物的最重要来源之一，其中有代表性的包括二萜类化合物紫杉醇、倍半萜类化合物青蒿素等。二倍半萜是萜类化合物中数目相对较少的一组，但它们中很大一部分物质具有显著的抗肿瘤、抗菌、抗病毒、抗炎以及抗心血管疾病等生物活性。近几十年来，由于二倍半萜类化合物独特的多环结构以及多样的生物活性引起了合成化学家浓厚的兴趣。astellatol是一种从真菌次级代谢产物中分离得到的二倍半萜类天然产物，具有复杂的五环笼状结构，并且有十个连续的手性中心，但遗憾的是该分子并没有得到很完善的生物活性测试。由于其复杂的骨架结构和尚未阐明的生物活性，本课题计划发展出一条针对astellatol的高效合成路线，分别利用RCM反应，分子内Pauson-Khand反应以及二碘化钐介导的环化反应作为环系构建关键步骤，以期望完成astellatol的首次全合成，并测定其生物活性。

Astellatol是一种从真菌次级代谢产物中分离得到的二倍半萜类天然产物，具有复杂的五环笼状结构，并且有十个连续的手性中心，高密度稠环体系、高度取代的反式六氢茚满结构以及带环外双键的大张力四元环，合成挑战十分巨大。在本项目的资助下，我们成功地完成了astellatol的首次全合成工作，该工作的成果发表在Angewandte Chemie International Edition杂志上。该工作的关键步骤包括一个分子内的Pauson-Khand反应、一个二碘化钐介导的还原1,6-自由基加成反应和一个创新的大位阻反式六氢茚满合成策略。此项目的开展也为其它二倍半萜类天然产物的全合成提供了一个可借鉴的合成策略。