Salvinorin A的不对称全合成研究

Salvinorin A is a potent non-nitrogenous κ-opioid receptor agonist. Highly efficient synthesis of this natural occurring compound will enable the studies of relevant drugs derived from it. However, the known synthetic routes require long steps with low efficiency and thus greatly confine their application. This project is devised to develop a concise synthetic route to achieve not only the total synthesis of salvinorin A but also the collective syntheses of its analogous diterpenes. Considering the structural features of salvinorin A and its related family members as well as the established biomimetic methodologies in terpene synthesis, this project is going to investigate the tandem asymmetric Michael reaction or radical cyclization of polyenones, developing this type of asymmetric synthetic method and applying it as a key step in the total synthesis. The realization of this tandem reaction will enrich the biomimetic polyene cyclizations, establishing a distinct anion or radical based asymmetric cyclization of enones. Besides, the investigation of late-stage C-H bond oxidation to assemble the hydroxyl moieties of the target molecule will further expand the application of biomimetic C-H oxidation in terpene synthesis.

Salvinorin A是具有重要κ-阿片受体抑制活性的非含氮天然产物。对该天然分子的高效合成将有助于以该分子为先导化合物的药物研究。然而，已知的全合成路线步骤较长，效率较低，大大降低了其实用性。本课题旨在发展一条简捷高效的不对称合成策略完成对该目标分子的合成，并将该合成策略拓广到对该类其它分子的合成中去，从而实现对该类天然产物的集体合成。根据Salvinorin A及其家族分子的结构特点，结合萜类合成中固有的仿生合成方法，本项目拟以不对称串联Michael或自由基环化反应为核心合成步骤，对其展开研究与探索，发展该类不对称合成方法学，探讨其在该类二萜分子合成中的应用性，拓宽现有的用于萜类合成的多烯环化反应类型，建立新型以烯酮结构为环化前体的环合策略。此外，本项目将研究利用碳氢键氧化从分子骨架中引入目标分子中的氧化结构，该策略将有助于拓展仿生氧化步骤在实际萜类合成中的应用。

在本项目的资助下，利用串联Prins环化/多烯环化反应实现了对申请书中天然产物Salvinorin A的核心碳环骨架构建；同时，基于所发展的不对称有机阳离子催化联氧化吲哚双烷基化反应完成对二聚吲哚生物碱(-)-Chimonanthidine的不对称全合成以及利用小分子催化不对称Mannich/酰胺化/Wittig反应实现对单帖吲哚生物碱Naucleofficine I和II的不对称全合成。. 发展了1,3-二烯硼氢化/钯催化迁移型Suzuki-Miyaura偶联反应用于合成支链型烯丙基取代芳香化合物；烯丙基碳正离子促进的semipinacol重排反应用于合成α-芳基（或烷基）-α-高烯丙基取代环酮；不对称催化醛基α位通过氧化促进的semipinacol重排反应用于合成光学纯1,5-二羰基化合物。. 发表SCI论文8篇（含综述），其中一区论文7篇，三区论文1篇，联合培养在读博士6名，在读硕士1名。