PROJECT SUMMARY The main goal of the proposed research is to develop new and useful transformations using carbon-hydrogen bond functionalization reactions. Use of C-H bonds as a transformable functional group is advantageous since these bonds are typically the most abundant functionality in organic molecules, and most starting materials that are available on large scale contain only carbon-carbon and carbon-hydrogen bonds. Direct conversion of these bonds to the desired functionality shortens synthetic pathways saving reagents, solvents, and labor. However, obvious problems, such as low reactivity of alkane sp3 C-H bonds and difficulty to attain regioselective functionalization of these bonds, have prevented widespread use of C-H functionalization methodology. Our efforts are directed towards addressing these issues in the context of pharmaceutically relevant transformations. Specifically, the project will focus on the auxiliary-directed alkane C-H bond functionalization and group 11 metal-catalyzed sp3 C-H bond functionalization via carbene intermediates. We have a substantial amount of preliminary data showing that proposed chemistry is viable and may lead to useful methodology. We will develop second-generation auxiliaries for sp3 C-H bond functionalization that will replace aminoquinoline directing group and address its remaining challenges. Specifically, monodentate 1- aminopyridine and pyrazole derivatives will be used to direct sp3 C-H bond functionalization. The key difference from first-generation auxiliaries is easier removal, lack or product inhibition, possibility of ligand- accelerated catalysis while matching the outstanding directing abilities of aminoquinoline, and ability to functionalize β-positions in amine derivatives. These studies will have important implications, and have already resulted in superior auxiliaries for arylation of sp3 C-H bonds. The reactions arising from C-H bond activation will complement the current methods for C-C and C-heteroatom bond formation and will have a substantial impact on synthetic methodology. We have obtained preliminary results showing that non-directed group 11 metal-catalyzed sp3 C-H bond functionalization with alkyl diazo and fluorinated diazo compounds is feasible. These unique transformations cannot be easily achieved by using other methodology. The new catalysts should allow for unprecedented late- stage functionalization of medicinally relevant molecules. The specific aims of the research are as follows: 1. New auxiliary and reaction development for directed C-H functionalization, 2. Enantioselective C-H bond functionalization, 3. Group 11 metal-catalyzed C-H functionalization via carbenoid intermediates.