Project Summary To enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic logic (the design concepts) and the synthetic tools (the chemical reactions) to assemble molecules with chiral centers and polycyclic frameworks. The proposed research program seeks to address this need through chemical research in two general areas. The first research area will focus on the synthesis of complex, highly oxidized, biologically active diterpenes. These total synthesis efforts inspire the invention of new reactions and investigate the ability of existing reactions to solve strategic bond constructions in complex settings. Synthetic access to these natural products will transform our ability to use them and their synthetic derivatives as biological probes or as lead compounds for the development of new medicines. The second research area will focus on the development of new Ni-catalyzed cross-electrophile coupling reactions. These reactions have emerged as versatile methods for carbon–carbon bond formation that are increasingly being adopted by chemists in academia and the pharmaceutical sectors. Despite recent advances, several challenges remain, particularly with respect to the development of catalyst-controlled stereoselective cross-electrophile coupling. To address these challenges, this research seeks to 1) identify new modes of electrophile activation to broaden the scope of products that can be prepared by Ni-catalyzed cross-electrophile coupling; 2) develop stereoselective cross-electrophile coupling reactions of small rings for medicinal chemistry and natural product synthesis; and 3) develop enantioselective CEC reactions of feedstock building blocks such as carboxylic acids and olefins. The expected outcomes of this research program 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. This research will be carried out by a team composed of the PI, four chemistry graduate students and one postdoctoral researcher. 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.

Project Narrative The chemical synthesis of bioactive molecules is a scientific area of fundamental importance to the discovery of new medicines. This proposal seeks to develop the synthetic logic (the design concepts) and the synthetic tools (the chemical reactions) to enable the efficient preparation of structurally complex, bioactive molecules. In doing so, this research will accelerate the discovery of new medicines and enable study and treatment of human disease.