铜催化下分子内杂D-A反应在环烯醚萜类天然产物全合成中的应用

Iridoids constitute the largest family of cyclopentanoid monoterpene derivatives, including Iridoid glycosides and Non-glycosidic Iridoids. most of them have important bioactivities, such as antiviral, antitumor, and antibacterial properties. The chemical structure of Iridoids feactures cyclopentane[c]pyran monoperoid. The unique structure and the broad important biological activities has generated much interest for their synthesis world widely. How to build the unique structure with efficiency and high stereoselectivity remain as the challenges. But until now there are no report about how to synthesis different types of Iridoids through an general proceed. Here we report this project about a novel strategy to afford different Iridoids in similar way based on the [3,4-c]pyran as the key intermediate. Copper-catalyzed intramolecular hetero-Diels-Alder reactions will be adopt to build the core skeleton of Iridoids, cis fused cyclopenta[c]pyran ring system, then we can enantioselective synthesis of Loganin thought simple transformations, such as oxymercuration/reduction to introduce C-1 glycoside, reduction to get hydroxy moity, and oxidation to produce ester at C-11. In the other aspect, the non-glycosidic Iridoid, such as Gelsemide, which has C-6 and C-7 cis vicinal diols can be functionalize based on the newly formed double bonds in the core skeleton, which are very rare in series non-glycoside Iridoids. Finally Gelsemide will be first accomplished when C-9 hydroxyl group was introduced by hydroboration/oxidation sequence. The advantage of this method over previous approaches is the ability to prepare variety both non-glycoside Iridoids and glycoside Iridoids from the product of Copper-catalyzed intramolecular hetero Diels-Alder reaction in a facile process. Therefore, this project has a very broad scientific and practical application value.

环烯醚萜类天然产物（分苷类和非苷类两种），数目庞大，结构独特且具有多种重要的生物活性（抗炎、抗菌、抗肿瘤等），是一类非常重要的天然产物，因此受到国内外化学家的广泛关注。目前现有的关于环烯醚萜合成的报道，存在缺乏通用性的问题，难以达到从同一关键骨架出发同时合成多种苷类和非苷类环烯醚萜天然产物的目的。因此，申请人设计采用铜催化下的炔与不饱和醛的分子内杂D-A反应合成[3,4-c]吡喃骨架，在这个骨架的基础上实现同时进行多种苷类及非苷类环烯醚萜天然产物的灵活合成。通过对[3,4-c]吡喃进行羟汞化/还原、选择性成苷、酯化等操作可以合成苷类产物Logenin，还能在骨架中引入环烯醚萜家族中非常少见的C-6，C-7位顺式邻二醇结构，再通过硼氢化/氧化、酯化等反应完成非苷类天然产物Gelsemide的首次全合成。本项目将发展一种较通用的环烯醚萜类天然产物合成新方法，为合成化学和药物化学提供新的选择。

环烯醚萜类天然产物存在于多种中草药植物中，近年来，随着越来越多的环烯醚萜类天然产物被分离鉴定，非苷环烯醚萜的种类和数目有所增加。Gelsemide和Loganin因其含有新颖独特的C-6，C-7位顺式邻二醇的结构，而吸引了众多化学家的兴趣，但目前还没有将这类杂D-A反应应用到环烯醚萜类全合成中的报道。. 目前为止，我们已经高效的完成了Gelsemide和Loganin重要关环反应前体的合成工作，其中成功构建连续三个手性中心(2S,3S,4R)，Gelsemide的全合成工作已经进入收数据阶段，Loganin的全合成工作正在进行中。除了项目书中的内容之外，我们又完成了与新型药物骨架合成相关的三个分支课题，(+)-石杉碱甲的形式合成: Michael/Aldol环化反应催化双环[3.3.1]中间体；[3+2]偶极环加成反应和钯催化的分子内芳基化反应合成三环异恶唑类的研究；合成一系列新型T-705的1,3-氧硫杂环戊烷核苷类衍生物及其抗甲型流感病毒和抗HIV病毒活性研究。. 本项目已经发表带有本项目基金号(21402078)的SCI论文5篇，分别为Synthesis (IF: 2.65)一篇，J. Iran. Chem. Soc. (IF: 1.407)一篇，Soft. Matt. (IF: 3.889)一篇，Medicinal Chemistry (IF: 2.331)一篇，J. Org. Chem. (IF: 4.849)一篇，其中项目申请人为通讯作者的3篇。. 本课题主要成就和科学意义在于为合成D-A反应前体时引入不同的基团及手性构型，可以灵活高效的合成一系列结构新颖或者药理活性突出的环烯醚萜天然产物，并能对环烯醚萜苷类天然产物进行结构修饰，从而进一步为药物化学家提供原料以进行更深入的生物活性研究。