Chemical Synthesis of Chiral Bioactive Molecules



 DESCRIPTION (provided by applicant): The overarching goal of this research program is to develop new chemical reactions and synthetic strategies for the preparation and study of chiral bioactive small molecules. Over the past decade, researchers in the pharmaceutical industry have begun to recognize the benefit of structural complexity in drug candidates, wherein molecules with greater complexity exhibit higher success rates as the proceed through the process of clinical testing and FDA approval. In order to enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic tools - new chemical reactions - and the synthetic logic for assembling molecules with chiral centers and polycyclic frameworks. The proposed research program will seek to address this need through chemical research in two general areas. The first research area will focus on the development of new Nickel-catalyzed enantioselective reductive cross-coupling reactions. These reactions tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as catalysts and stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. Preliminary results obtained for a series of new asymmetric reductive cross-coupling reactions provide compelling evidence for the feasibility of this research. The second research area will focus on the synthesis of complex, polycyclic natural products of the epidithiodiketopiperazine and alkaloid diterpenoid families. The expected outcomes of this research are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives, which could serve as lead compounds in drug discovery efforts. This research will be carried out by a team composed of the PI, five chemistry graduate students and three postdoctoral researchers. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.