复杂二萜天然产物Ryanodol的全合成研究

Ryania diterpene natural product were isolated from ryania speciosa in the Central/South American, structurally which have a cage-type pentacyclic core, eleven contiguous stereocenters, and five free hydroxyl functional groups. As a major member, ryanodine has allowed the identification of a family of intracellular calcium release channels, termed Ryanodine Receptors (RyRs). Since only a limited number of molecules have been reported to act by modifying the receptor, ryanodine and its derivatives are potential therapeutic agents for treating cardiovascular diseases. On the other hand, the chemical synthesis of ryanoids has proven challenging, and the current two synthetic sequences are both over 35 steps, which are not efficient and useful. In this proposal, we intend to select ryanodol as our synthetic target, and develop a palladium-catalyzed tandem Heck/carbonylic esterificaiton reaction to build up [6,5,5] tricyclic complex system. We also want to setup highly functionalized six-membered ring via an intramolecular dearomatization of phenol analogues. Based on the above key steps, hopefully we can develop a general, and more efficient synthetic strategy for this diterpene family.

尼亚那属天然产物是从中／南美洲大枫子科灌木中分离得到的二萜类天然产物，是一类具有五环笼状结构、多个连续立体中心，高度氧化的二萜天然产物。生物学研究发现，其成员ryanodine对心肌钙离子通道(PyR)具有专一的调节作用，是迄今发现的少数几个具有调节功能的有机小分子之一，对心血管疾病的治疗具有潜在药用价值。然而，复杂的化学结构使得对这类天然产物的合成充满了挑战，目前，有关这类天然产物的合成仅有两条合成路线报道，且均在35步之上，缺乏实用性和简洁性。本项目拟选取这类天然产物中的ryanodol作为合成研究目标，尝试采用钯催化的分子间串联Heck/羰酯化反应一步构建分子中[6,5,5]的三环体系，通过分子内苯酚衍生物去芳香化的策略来实现分子中高度官能团化六元环的合成。通过以上关键反应的设计和尝试，期望能为这类天然产物的合成发展一种通用、简洁的合成路线。

本项目对若干多环二萜类天然产物的化学合成开展了研究，针对目标分子中多环体系的快速构建，尝试采用钯催化串联环化反应，一步构建目标分子中多环核心骨架单元。在此过程中，发展了一类新型分子内钯催化串联Heck/羰化/环化反应，并将其成功应用于三尖杉降碳二萜天然产物的合成，实现了其代表性成员cephanolde B和C的首次化学合成。在此基础上，对钯催化串联环化反应的底物普适性、反应机制及其在其它多环天然产物合成中的应用做了深入拓展，建立了以钯催化串联反应为关键步骤的多环天然产物高效化学合成新方法。同时，在项目部分经费支持下，实现了灵芝科酚醌型二萜天然产物的首次发散性仿生全合成。