Azaphilones are fungal natural products that contain a highly oxygenated pyranoquinone bicyclic core. Many of these fungal pigments possess potent biologically activity including anticancer, anti-inflammatory, and antimicrobial properties. With a variety of activities reported across this class of molecules, azaphilones are interesting targets for further interrogation of their biology and potential development as pharmaceutical agents. However, their construction has proven challenging due to their densely functionalized, bicyclic structure and the presence of a congested stereocenter. The classical approach toward this class of molecules relies on the oxidative dearomatization of prefunctionalized arenes. These reactions can be mediated by hypervalent iodine reagents, copper and lead complexes, and typically require harsh reaction conditions. In contrast, Nature has evolved efficient enzyme catalysts to perform oxidative dearomatization with exquisite site- and stereoselectivity, providing an alternative to the current state-of-the-art. These enzymes can operate on a variety of substrates under mild conditions, using O<sub>2</sub> as the terminal oxidant. This work seeks to develop a stereodivergent, chemoenzymatic route toward azaphilone natural products and analogs thereof. A stereodivergent approach has been achieved in which two common synthetic intermediates can be oxidatively dearomatized by two stereo-complementary FAD-dependent monooxygenases, providing access to enantioenriched azaphilone scaffolds that can be elaborated to a variety of azaphilone natural products. These efforts have led to the structural revision of two tricyclic azaphilone natural products, trichoflectin and deflectin-1a.

Stereodivergent, chemoenzymatic synthesis of azaphilones natural products

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.