Project Summary ? Michael C. Young ? University of Toledo Developing more general strategies for late stage functionalization of complex molecules is an important and much needed area of research. Using natural products that can be produced via sustainable fermentation technology is the most expedient method to prepare complex therapeutic agents, and although semi-synthesis can be a viable strategy to further derivatize these natural products to achieve new and potentially more useful drugs, the majority of unreactive C?H bonds on these molecules are not able to be selectively functionalized with current technology. To circumvent this challenge to producing next generation antibiotic, anticancer, and other much needed drugs, we propose using a simple hydrogen bonding interaction to position reactive transition metal catalysts in close proximity to a single C?H bond on complex substrates bearing a hydrogen bond acceptor. By installing a tunable linker between the hydrogen bond recognition domain and that of the metal catalyst, we anticipate that a library of different catalysts can be accessed that will allow functionalization at a defined distance from the directing handle of the substrate. The long term goal of this research is to develop libraries of different transition metal catalysts to achieve C?C, C?N, C?O, C?S, and C?B bond formation from inert C?H bonds on complex steroid and macrolide structures, thereby allowing rapid access to new therapeutic targets, especially new antibiotics and anticancer agents. During the funding period, we intend to demonstrate proof of principle by performing iron-based C?H amination and rhodium-based C?H alkylation, and using piano stool complexes we intend to expand towards photochemical-mediated C?borylation. Using a hydrogen bond-directing approach to performing biomimetic C?H activation is expected to revolutionize late stage functionalization by providing a more general strategy for directed C?H activation, and will dramatically increase the types of semi-synthetic procedures that can be performed on complex molecules. Furthermore, the catalyst and product libraries will be made readily available to members of the scientific community, ensuring maximum adoption of the catalysts as well as increasing the likelihood of quickly demonstrating the viability of the approach to access new biologically active molecules.