Total synthesis of salvinorin A

本项目的主要目标是利用分子内Diels-Alder反应(IMDA)作为关键的转化反应，完成新十字烷二萜萨尔维诺菌素A的全合成。作为一种选择性kappa-阿片受体(KOR)激动剂，salvinorin A是开发治疗中枢神经系统疾病的新药物的一个有吸引力的先导结构。我们概念上新颖的合成的完成将提供与已发表的全合成相比更短的途径来获得这种新的甾烷，并另外开辟了从天然产品中无法获得或仅有困难地获得结构类似物的新途径。在这项研究项目的先前工作中，我们已经为新十字烷BC子系统开发了一条通往双环构筑块的短路线。由于它已经实现了氧化裂解烯烃，现在它可以快速转化为所需的三烯，用于关键的分子内[4+2]环加成，从而得到新的十字烷骨架。除了为这种高级中间体转化为二萜萨尔维诺菌素A建立适当的条件外，还将研究我们的新十字花烷BC构建块到与萨尔维诺菌素A相关的具有生物活性的二萜查斯曼素和柱状物的简明转化。

The main objective of this project is the completion of the total synthesis of the neoclerodane diterpene salvinorin A using an intramolecular Diels-Alder reaction (IMDA) as the key transformation. As a selective kappa-opioid receptor (KOR) agonist, salvinorin A represents an attractive lead structure for the development of new agents for the treatment of disorders of the central nervous system. The completion of our conceptually novel synthesis would provide a shortened access to this neoclerodane compared to the published total syntheses and additionally open new avenues to structural analogs, which are not available, or only with difficulty, from the natural product. In previous work on this research project, we have developed a short route to a bicyclic building block for the neoclerodane BC subsystem. Since its oxidative olefin cleavage was already achieved, it can now be transformed rapidly into the desired triene for the crucial intramolecular [4+2] cycloaddition to give the neoclerodane framework. Next to establishing appropriate conditions for the conversion of this advanced intermediate into the diterpene salvinorin A, a concise transformation of our neoclerodane BC building block into the bioactive diterpenes chasmanthin and columbin related to salvinorin A is to be examined as well.