PROJECT SUMMARY Identifying just one new clinical candidate for the treatment of human disease usually requires the design, synthesis, testing, and redesign of thousands upon thousands of organic compounds. Improvements to synthetic technologies therefore have a major impact on the time required to identify clinical candidates by maximizing the number of compounds that can be accessed from a single precursor. In particular, adjusting key properties such as bioactivity, solubility, metabolism, and stability are best accomplished by methods that are capable of preparing a wide variety of new compounds with a minimal number of steps. Late-stage functionalization of carbon-hydrogen bonds offers medicinal chemists this coveted opportunity by facilitating the introduction of numerous types of functional groups into a given lead structure. Recent efforts have demonstrated that transition- metal catalysts can enable the diverse functionalization of strong alkyl C–H bonds within organic compounds via the intermediacy of an organoboron compound. However, methods to achieve control over the site- and stereoselectivity of alkyl C–H bond functionalization are limited by their strength and ubiquity in complex molecules. The proposed research focuses on the development of a broadly applicable strategy to achieve selectivity in the functionalization of C(sp3)–H bonds that is independent of inherent substrate preferences. The impact of this work is to enable practitioners to make precise structural edits to bioactive compounds without lengthy synthetic manipulation. The proposed approach converts a major challenge in complex molecule functionalization, the presence of potentially intervening groups, into an opportunity to localize reactivity of a transition metal catalyst to convert specific C–H bonds into C–B bonds. Specifically, the proposed research will create catalysts and reagents that bind an existing polar functional group, such an alcohol or amide, thereby guiding functionalization to an adjacent site. Synthetic routes are presented to access a suite of catalysts and reagents. In conjunction with experiments to evaluate their suitably for guided functionalization, they will be refined iteratively for application to target structures. Subsequent studies of the functionalization of complex, biologically active compounds will demonstrate the applicability and generality of the proposed method to lead optimization. To control stereoselectivity, a key consideration in alkyl C–H bond functionalization, chiral diborane reagents derived from readily available precursors will be employed. By differentiating the energies of diastereomeric intermediates and transition states en route to the alkylboronate products, new derivatives can be accessed with well-defined three-dimensional structures. An integrated component of the proposed research program are mechanistic experiments that will form the basis of informed improvements to the overall approach, as defined by ...