Project Summary The proposed research will uncover new radical-based methodologies that facilitate the synthesis of complex bioactive compounds. Organic radicals are highly reactive species with unique chemoselectivities that complement canonical two-electron chemistry. Recently, the emergence of new reaction strategies that leverage single-electron redox events and harness radical intermediates for the selective functionalization of organic molecules has provided chemists with useful tools for solving contemporary synthetic problems. However, the highly reactive nature of many organic radicals has made it difficult to impart catalyst-control over the regio- and stereoselectivity of these fleeting intermediates, especially when complex reaction systems are concerned. In the past funding period, we developed new catalytic strategies that leverage the unique redox features of low-valent Ti complexes to achieve redox-neutral and net-reductive transformations, and through catalyst innovation, we demonstrated that free radical-mediated reactions can be made highly enantioselective. These promising results prompted us to continue to invent novel catalytic and reaction strategies that can effectively harness radical intermediates and provide powerful tools for solving a range of longstanding synthetic problems. In the new funding cycle, we will build on our previous success while moving our research into important new areas of inquiry. In the proposed work, we aim to advance new approaches that employ radical-based catalysts or reagents to address prominent challenges in organic synthesis. The transformations targeted in each project area are either currently unknown or significantly limited in reaction scope or selectivity. Some of the specific reactions that we aim to develop are: site-selective oxidation of alcohols, enantioselective oxidation of amides and ethers, oxidative synthesis of stereogenic- at-phosphorous(V) compounds, site-selective amination, halogenation, and desaturation of alkanes, and deconstructive functionalization of alcohols. In-depth studies using canonical physical organic and electroanalytical techniques will provide insights into the reaction mechanisms that will be used to guide optimization. Ultimately, the realization of these proposed transformations will represent a significant advance for the field of organic synthesis and support innovation in the synthesis of biomedically important molecules.