Project Summary/Abstract We wish to continue our study of a new paradigm for the selective functionalization of complex molecules. Our approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in bioactive agents. Enantio- and site-selectivity will be pursued in an integrated fashion. Importantly, bioactive analog generation by this approach spans multiple therapeutic areas, and categorizes these chemical studies as a quintessential “General Medical Science.” The main approach under study is the development of easy-to- make catalyst libraries that target a broad set of reaction types. These will include site-selective reactions of hydroxyl groups, alkenes, amines, C-H bonds and carbonyl groups. In addition, we now target a host of redox- based processes, and some of these include photochemical and electrochemical possibilities. Overwhelmingly, these processes have been developed in our laboratory, with our initial studies often focused on enantioselective catalysis – a field of high significance, with relevance to the synthesis of drugs and drug candidates. Yet, our focus is increasingly moving to the study of high-complexity molecular scaffolds, wherein enantioselectivity serves as a prelude to exploration of substrates for which stereoselectivity represents just a subset of the issues that need to be addressed. We have many preliminary results in a number of complex molecular frameworks, including those provided by some venerable natural products, such as erythromycin, vancomycin, teicoplanin geldanamycin, and thiostrepton. We wish not only to continue these studies, but also to expand them to analog generation in contexts presented by additional complex frameworks represented by emerging drug-like scaffolds. All of these objectives will require the development of new catalysts and new reactions. Foci will include high value catalytic, site-selective deoxygenation chemistry, glycosylations, amine and heteroarene functionalizations, site-selective C-H bond functionalization, various redox reactions, as well as unusual catalyst-controlled macrocyclizations – all in complex molecular scaffolds. An important parallel effort in our group includes the development of catalysts for selective control over unusual stereochemical issues, such as atropisomerism and other types of dynamic stereochemistry, which is an area of growing concern in medicinal chemistry. The significance of our overall goals may reside most in new catalysis principles, and in their application to the site- selective modification of complex, bioactive natural products. These investigations thus extend fundamental studies of enantioselectivity to the less well-studied arena of site-, regio- and chemoselectivity. Thus, we wish to expand greatly our studies of the selective derivatization of fascinating biologically active agents, with site- selective catalysts as the principal device. In all cases, we will continue to study reaction m...