复杂二萜 trichoaurantianolide C 的全合成研究

Design and construction of biologically significant and complex diterpenoids represents a challenging and active research field in organic synthesis. In this proposal, a class of antiviral and antifungal dolabellanes, namely, trichoaurantianolides, is selected as synthetic targets with the application of chemoenzymatic approach which is recently developed in this laboratory. The unprecedented fused tetracyclic ring system represents a challenge for synthetic endeavour. With the consideration of the biogenesis of trichoaurantianolides, a late-stage oxidative cleavage of the C-ring is proposed to introduce functional groups to complete the tetracyclic system. The current strategy features (a) an enzymatic kinetic resolution to access to chiral substituted cyclopentenols, (b) the construction of C-10 quaternary carbon center through Claisen rearrangement, (c) the 5-7-6 ring system established by Friedel-Crafts cyclization, (d) the second quaternary carbon center at C7 furnished by a Birch reduction/Methylation cascade, (e) a bioinspired oxidative modification of the C-ring, and (f) a double Michael addition to complete the tetracyclic ring to finish the total synthesis of the target molecule. Moreover, a 1,3-dipolar approach is also proposed to quickly establish the 5-7-6 ring system with the construction of C7 quaternary carbon center. The proposed synthetic route would allow us to efficiently synthesize the most complex member of dolabellanes and certainly provides an opportunity to access to other diterpenoids in this family.

设计和构建具有重要生理活性的复杂二萜天然产物是合成化学极具挑战性的研究领域。在本项目中，以抗病毒和抗真菌活性的海兔烷类天然产物trichoaurantianolides 作为目标分子开展研究，运用了本实验室最近发展的酶催化反应。这类二萜具有未报道过的四并环体系，是全合成实践的挑战性课题。借鉴其生源合成的假说，在合成的后期通过氧化断裂C环的方式引入不同官能团完成四环骨架。项目关键步骤包括：(a) 取代环戊烯醇的酶催化的拆分; (b) 克莱森重排反应建立C10季碳手性中心; (c) 分子内的傅克环化构建5-7-6并环; (d) 第二个C7的季碳手性中心通过Birch还原和后续的甲基化反应建立; (e) 生源合成启发的C环氧化断裂; (f) 双Michael加成完成四环体系。另外，本项目也计划采用分子内的1,3-偶极反应高效地构建海兔烷二萜的并环体系，这有助于后续开展其他活性天然产物的高效合成。

项目执行期间实现了Amano AK (Lipase AK) 对于C2-取代和C2，C3-双取代环戊烯底物优异的拆分结果，拆分反应立体选择性高，催化剂易回收。基于上述结果，设计通过化学-酶法进行guanacastepene家族三环骨架的合成研究。在关键三环体系中最有挑战性的是七元环的构建，我们设计了分子的烯反应和1,3-偶极加成反应，没有分离到目标产物结构。鉴于Williams 小组2015年发表了trichoaurantianolide C 的全合成工作，我们调整了研究内容，专注于项目支持期间发展的生物酶催化反应，用于制备关键的手性中间体，并用于天然产物的合成研究。项目支持三年内，获得了一系列有意义的研究成果，包括联烯醇和炔丙醇的高对映选择性的动力学拆分反应，用于活性多羟基聚酮类天然产物的手性片段的高效合成。