Applicant: Andrea Bucknam Project Summary/Abstract Natural product synthesis contributes significantly to the identification and development of potential therapeutics. Retrosynthetic analysis of a natural product target demands innovation at all levels of study, giving rise to the design of novel reaction technology and creative application of established reactivity to provide access to structures with pharmaceutical potential. Tetracyclic triterpenoid natural products present a challenging landscape for synthetic organic chemists to explore novel chemical transformations. More than one hundred FDA-approved drugs are tetracyclic triterpenoids. Cardenolides are a class of tetracyclic triterpenoid natural products with many members having demonstrated medically-relevant biological activity, but further investigation of their pharmaceutical potential is hindered by limited access to natural sources and a lack of reported approaches to synthesis of the cardenolide carbon framework. The research project proposed herein would report a solution to key challenges to cardenolide synthesis—C10 and C13 quaternary centers, C14 tertiary alcohol, and C17 substitution (steroid numbering)—thus establishing an asymmetric de novo synthesis of a cardenolide natural product, sarmentogenin. A novel oxidative dearomatization/Wagner-Meerwein rearrangement, in which a 1,2-methyl shift from C9 to C10 would establish the quaternary center at C10 and oxidation in the C-ring. This synthesis would be an application of a recently reported methodology from the Micalizio group to install C17 substitution, a historically significant challenge to completing the total synthesis of cardenolide natural products. The long-term success of the project proposed herein would be a report of a cardenolide total synthesis, paving the way for future investigations of pharmaceutically-relevant cardenolide bioactivity. The fellowship award would support continued graduate research and training in the Micalizio laboratory at Dartmouth College. The Micalizio group has a well-established program for developing novel reaction technology to concisely synthesize complex natural product targets. The research supported by the award would take place in an established organic synthesis laboratory with all necessary equipment for the preparation, purification, and characterization of organic compounds.