Synthese des polycyclischen Naturstoffs Lingzhiol

01/04/2016 to 31/03/2019

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.