Total Synthesis of Complex Alkaloid Natural Products

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Seth B. Herzon of Yale University develops novel synthetic routes toward bioactive complex molecules derived from living organisms known as natural products. The syntheses and structural analyses of natural products play an essential role in the chemical industries as well as in the development of new chemical methods. Moreover, natural products form the basis for a large proportion of pharmaceuticals. Access to natural products by synthetic chemistry allows for systematic evaluation of their molecular properties, including bioactivity, thereby providing the foundation for new medicines. Until now, the marine natural products known as chartellamides have remained relatively inaccessible, limiting our understanding of the properties of these molecules. During the last funding period, a synthesis of the related isolates known as securamines and securines was developed, and this will form the foundation of the approach to chartellamides. To access chartellamides, the development of novel synthetic transformations, which may be of general utility, will be required. To access chartellamide, a biomimetic strategy based upon direct introduction of the indolenine–imidazole bond, peripheral oxidative cyclization, and alkene bromoamination will be pursued. The total synthesis of chartellamide B will permit rigorous structural analysis and potential structural revision using computational, crystallographic, and spectroscopic techniques. The unknown cytotoxicity profile of chartellamide B will be assessed following completion of the proposed synthesis. The researchers involved in this project participate in the Pathways to Science Program through Yale University, focused on STEM education and mentorship for secondary school students in the New Haven area. Additionally, researchers on this project will serve as mentors in the Yale–GSK Scholars program, which provides summer research opportunities for undergraduate students. The researchers involved in this project are involved in the Yale Joint Safety Team, focused on chemical and biological safety education and career development for the broader Yale community. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.