几个活性二萜类海洋天然产物的不对称全合成研究

Clavulactone和Clavirolides A～F是由中国化学家从中国南海软珊瑚Clavularia viridis中分离出来的结构复杂的dolabellane二萜天然产物。这些天然产物具有细胞毒性、钙离子通道抑制、降低肌肉收缩力、降低心率、降低血压等重要生理活性。结构方面，除了拥有dolabellane家族特有的trans-bicyclo[9.3.0]tetradecane骨架外，这些分子还具有一个不饱和内酯环，全合成相当具有挑战性。本项目拟发展新颖的全合成策略，完成这一组天然产物的发散式全合成。为此，首先以D'Angelo反应、RCM、Grob裂解以及pinacol-type重排为关键反应完成Clavulactone和Clavirolide B的不对称全合成，再通过后期加工完成另几个分子的全合成。该项目将丰富dolabellane全合成研究，并为相关药物化学研究打下基础。

Clavulactone and Clavirolides A～F are structurally complex diterpenoids isolated by Chinese scientists from Clavularia viridis, a soft coral collected off Xi'Sha Islands in South China Sea. These natural products possess significant biological activities, including potent cytotoxicity toward Ehrlich Ascites Carcinoma (EAC), blockage of Ca2+ channels, negative inotropic activity, bradycardia effect, and hypotensive activity. Structurally, these molecules possess a common trans-bicyclo[9.3.0]tetradecane skeleton featured by the dolabellane family along with an unsaturated lactone ring, posing significant synthetic challenges. This project aims to develop a novel synthetic strategy that allows a unified total synthesis of the whole collection of these natural products. To this end, Clavulactone and Clavirolide B have been selected as the direct synthetic targets, and the proposed late-stage elaborations may serve as bridge between Clavulactone/Clavirolide B and the other molecules. The synthetic routes leading to Clavulactone and Clavirolide B feature key steps including a D'Angelo reaction, a RCM reaction, a Grob fragmentation, and a pinacol-type rearrangement. The late-stage elaborations include selective C-H oxidation and olefin manipulations. This research will enrich the strategic arsenal for dolabellane synthesis while providing an scientific basis for relevant medicinal chemistry explorations.