Total synthesis of salvinorin A

• Applicant: Professor Dr. Peter Metz
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2010 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190136453

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.

• DFG Programme: Research Grants