This proposal focuses upon the development of a concise, efficient route for the enantioselective total synthesis of the recently isolated, potent, cytostatic natural product cortistatin A. The strategy will rely upon the advancement of an asymmetric pyrrole Diels-Alder cycloaddition that could be used to construct one of the requisite rings of the pentacyclic core. This transformation should prove useful for accessing a variety of azanorbornenes and their derivatives. Additionally, a rare 6-endo Heck reaction is envisioned to provide the central diene of cortistatin A. As this could represent the first synthetic route to the cortistatins, unnatural analogs could be prepared in an effort to better understand the structure-activity relationships of these natural products and potentially deliver a more promising biologically relevant molecule. PUBLIC HEALTH RELEVANCE Often, natural sources provide small quantities of biologically important molecules, which can be used as a template to construct biologically relevant compounds utilizing chemical synthesis. The cortistatins are recently isolated natural products showing promise for the treatment of cancer due to their high activity and selectivity against this disease. This proposal is devoted to the first total synthesis of cortistatin A and hinges upon the development and use of several new chemical transformations to efficiently prepare this natural product. [unreadable] [unreadable] [unreadable]