Synthesis of the polycyclic Natural Product Lingzhiol

该项目的目标是全合成多环天然产物灵芝醇。这种天然产品，从蘑菇灵芝中分离出来，具有保护肾脏的特性。初步研究表明，灵芝醇能够增加抗氧化反应蛋白Nrf2的mRNA浓度。此外，在慢性肾脏疾病中起关键作用的蛋白smad3的磷酸化被抑制。这可能是灵芝醇能够抑制额外的激酶。这也将在本项目中进行研究。对于灵芝醇的合成，我们提出了两种策略。在四酮路线方案中，四酮衍生物38通过还原自由基环化反应转化为灵脂醇核心结构37。为了达到环化底物38，提出了几种途径，这些途径也可以制备光活性灵芝醇。第二种方案称为环戊酮路线，其特点是分子内环氧化物开口带有一个富电子的芳基环。这可能模拟了生物合成的关键步骤。本文还提出了几种到达关键环化反应底物的途径。在一种情况下，可以从2-氧环戊烷羧酸58开始通过烷基化和烯烃化将其转化为酮酯，生成亚甲基环戊烷羧酸衍生物55。然后该中间体将被转化为底物54进行关键的阳离子环化。作为一种替代方法，可通过分子内Conia反应获得与59相似的亚甲基环戊烷羧酸盐。一方面，这个项目可以支持关于生物合成的假设。另一方面，它可以为进一步的生物学研究提供重要的灵芝醇衍生物。

The goal of the project is the total synthesis of the polycyclic natural product lingzhiol. This natural product, isolated from the mushroom Ganoderma lucidum is attributed with kidney protecting properties. Initial studies indicate that lingzhiol is able to increase mRNA concentrations of Nrf2, which is an antioxidant response protein. In addition, phosphorylation of smad3, a protein which has a key role in chronic kidney disease, is inhibited. It could be that lingzhiol is able to inhibit additional kinases. This will be studied in this project as well.For the synthesis of lingzhiol we suggest two strategies. In the first plan, called tetralone route, tetralone derivative 38, which contains a spiro epoxide and an alkyne will be converted to the lingzhiol core structure 37 via a reductive radical cyclization reaction. In order to reach cyclization substrate 38, several routes are suggested, that also might allow preparation of optically active lingzhiol.A second plan, called cyclopentanone route, features an intramolecular epoxide opening with an electron-rich aryl ring. This possibly mimics a biosynthetic key step. Here also several routes are suggested to reach the substrates for the key cyclization reaction. In one case, one would start with an alkyl 2-oxocyclopentanecarboxylate 58 and convert this keto ester via alkylation and olefination to methylenecyclopentanecarboxylate derivative 55. This intermediate will then be converted to substrate 54 for the key cationic cyclization. As an alternative, a methylenecyclopentanecarboxylate comparable to 59 might be obtained by an intramolecular Conia en reaction. On one hand this project could support hypotheses regarding the biosynthesis. On the other hand it could provide important lingzhiol derivatives for further biological studies.