UC Berkeley

Angucycline natural products are one of the largest classes of polyketide natural products, and by far the largest class of type II PKS derived aromatic polyketides. They display a wide variety of structural complexities, as well as seemingly ubiquitous antibacterial, antifungal, and cytotoxic biological activities. This dissertation reviews the structures of many of the angucyclines which have been isolated to date, with intentional comparison of similar structures which may have been isolated from different sources or sub-families. Next, the biosynthesis of several angucyclines is covered with special attention given to the non-enzymatic sulfur incorporation proposed for many thioangucyclines to provide important context for the retrosynthetic strategy employed toward grisemycin. Additionally, a broad overview of both traditional and recent chemical synthesis of angucycline natural products is discussed. The chemical syntheses are organized by the key synthetic strategies employed to further contextualize both the exact work done as well as the broader methodology and disconnections applied to the synthesis of this class of natural products. In chapter 2, we discuss the growing field of research into the biosynthesis of thioangucyclines, and highlight many proposals include non-enzymatic sulfur incorporation. While it seems likely grisemycin may also biosynthetically incorporate sulfur via non-enzymatic means, prior to our work there existed no such proposal or experimental evidence to support it. We then give an overview of the first-generation retrosynthetic analysis, which paves the groundwork for an important Diels-Alder reaction that is later used in the complete synthesis. In the final section of chapter 2, we discuss the retrosynthetic logic and the forward route for the catalytic asymmetric total synthesis of grisemycin. We highlight a key thia-Michael cascade, which supports a non-enzymatic sulfur incorporation for the biosynthesis of grisemycin as has been proposed for the structurally related neogrisemycin, among other thioangucyclines.