Application of dissymmetric 2,5-cyclohexadienones to the total synthesis of isariotin E, isariotin F, TK-57-164A and a fully functionalized analogue of scyphostatin

Natural products continue to supply the scientific community with a pluripotent source of unique structural architectures coupled to highly potent and selective biological profiles. Often the case, these compounds are found to act as selective agents that may correct failing biological systems, aid the natural response of the host to ward off a potentially fatal pathogen or predator, or behave as a selective toxin for cancerous cells. However, often too is the case that slight modifications to the skeletal framework are needed to obtain optimal pharmacokinetic properties. Therefore, total synthesis remains at the cornerstone for serving as not only one of the best training grounds for drug discovery, but also as a unique source for novel chemistry, which leads to new strategies and tactics that require brand new chemical methods, and ultimately culminates with the total synthesis of the target of interest and its subsequent biological profiling.;An integral component of the research carried out in the Pettus laboratories focuses on the total synthesis of naturally occurring highly oxidized and densely functionalized carbon skeletons. Perhaps more importantly, the targets that are ultimately chosen must exhibit the potential to provide solutions or insight into significant biological processes relevant to disease. Our endeavors toward the pursuit of the total synthesis of these compounds have sparked the development of several novel chemical methods, however, this dissertation will highlight the group's dearomatization chemistry and subsequent application of 2,5-cyclohexadienones to the total synthesis of three natural products and one analogue.;The first chapter of this dissertation details our studies that led to the selective manipulation of the enone portion of a dissymmetric 2,5-cyclohexadienone as well as the elucidation of a viable set of reaction conditions to control the oxidation state of the dienone scaffold. Ultimately, the fruits of our labor afforded a novel strategy to install the trienoyl amide moiety as well as generate the epoxycyclohexenone core found in scyphostatin.;The second chapter describes the extension of our strategy for our scyphostatin analogue and its application to the racemic total synthesis of three natural products: isariotin E, isariotin F and TK-57-164A. In addition, we examined the possibility of forging a diastereoselective ipso dearomatization event with a non-natural tyrosine analogue and therefore, sought access to nonracemic non-natural tyrosine analogues. These studies culminated with the implementation of a stereodivergent strategy to obtain these natural products and analogues.