Synthesis of Polycyclic Terpenoids enabled by C-H Oxidation

In nature, complex terpenoid natural products are constructed via a two-step process. First, a three- dimensional molecule is generated via the cyclization of a linear carbon precursor. The decoration (functional groups) of the natural product is then introduced via an enzyme-catalyzed CH oxidation sequence. Chemists have mimicked this powerful process in the chemical laboratory for simple substrates, but the application to more complex molecules is still in its infancy. This project wants to address this limitation by investigating and applying modern CH oxidation methods for the synthesis of complex terpenoid natural products. In the first phase, we will develop a flexible route to the undecorated trachylobane framework. Having gained access to this framework, we will initiate the second phase: investigation of chemical methods for selective CH oxidation. This will lead to detailed insights pertaining the biosynthetic hypothesis and will also produce highly oxidized trachylobanes that have eluded their synthesis so far. The results will provide valuable information about the inherent substrate selectivity and will allow us to study the biological activity of several artificial molecules in detail. In the second part of this project, we will investigate the application of this concept to the synthesis of the recently isolated anti-cancer natural products merosterol A and B.