天然产物Vinigrol的高效不对称全合成研究

Vinigrol is a novel diterpenoid isolated from fungus strain Virgaria nigra F-5408. An evaluation of the biological activity of vinigrol shows promising properties. it was demonstrated that this natural product decreased arterial blood pressure and inhibited platelet activating factor and epinephrine induced platelet aggregation. In addition, it was found that it is a powerful tumor necrosis factor (TNF) antagonist. From a chemical standpoint, vinigrol provides a particularly difficult challenge, as it is the only natural product to contain the decahydro-1,5-butanonaphthalene carbon skeleton. Due to its unusual chemical architecture combined with its promising biological activity, vinigrol has attracted a significant attention from the synthetic community. Despite considerable synthetic efforts, there are only two racemic total synthesis of vinigrol has been reported which required tens of steps. . We plan to develop a high efficient method to finish the total synthesis of Vinigrol enantioselectively. From simple commercially available starting material, the molecule could be finished in only 8 steps without using chiral auxiliaries or protecting groups. The carbon skeleton could be constructed in one step with a cascade reaction containing a nucleophilic substitution and two Michael additions.

天然产物Vinigrol是由霉菌Virgaria nigra F-5408中提取出来的一种活性化合物，生物实验发现，其具有非常好的抗高血压和抑制血小板凝聚活性，并可以作为肿瘤坏死因子（TNF）拮抗剂。从合成角度来说，Vinigrol给化学家提出了全新的挑战，十氢-1,5-丁基萘结构首次在天然产物中出现，还没有成熟的方法合成此类结构。到目前为止，虽然有十几篇的合成报道，但是只有两个课题组完成了消旋全合成，并且合成步骤较长；而且至今还没有对Vinigrol不对称全合成的报道。本项目将建立一种高效简洁的天然产物Vinigrol的不对称合成方法，应用Lewis酸催化的三个串联反应，实现一步构建Vinigrol主体骨架，计划利用八步反应完成天然产物Vinigrol的不对称全合成。整个路线无保护基与手性助剂，由简单的底物出发，利用底物的手性，通过合理的设计，和优势的构象来控制整个分子的手性。