Project Summary/Abstract The efficient and stereoselective preparation of chiral organic molecules is vitally important to the development of new therapeutic agents. However, despite significant progress, many desirable complex 2D and 3D molecular scaffolds remain difficult to access or are inefficiently prepared. Consequently, development of new transformations that provide synthetic chemists with strategic bond disconnections that facilitate de novo approaches to organic synthesis is of great importance. In addition, such methods should be robust, practical, allow the preparation of useful amounts of material, and ideally employ readily available starting materials. The aim of this MIRA grant is the conversion of an NIGMS funded project with a long-term goal that broadly seeks to develop and exploit new, practical, and efficient stereoselective new technologies for organic synthesis of molecular scaffolds of biological importance that are otherwise difficult to access, or inefficiently prepared via current processes. To this end, we are interested in developing transformations that leverage the broad chemical reactivity of boron-stabilized chemical synthons for complex molecule synthesis. This approach is attractive because reactions of such intermediates permit novel bond constructions and simultaneous installation of a synthetically desirable boron moiety. The proposed studies described in this program will further our expanding studies of catalytic stereoselective C–C bond forming reactions with organoboron reagents. These readily accessible reagents merge powerful bond forming reactivity with broad synthetic utility, to deliver versatile organic compounds of notable significance for fragment-based drug discovery. Building off our previous work, we are developing new catalytic C–C, C–N, and C–X bond forming methods for the synthesis of chiral amines, alcohols, and aromatic structures, with a particular focus on examples that contain quaternary carbon stereogenic centers. We envision that chiral metal nucleophiles can be accessed by enantioselective transmetalation of readily accessible achiral organodiboron reagents. The resultant nucleophilic species can engage in a number of enantioselective reactions with various C=O, C=N, C–X electrophiles. We also aim to target the generation and utility of novel boron-functionalized synthons by metal-free Lewis base catalysis for reactions with electrophiles that are difficult to achieve via transition metal catalysis. Importantly, enantioselective variants of these unknown reactions will herein be explored. Furthermore, new nucleophilic aromatic substitution reactions of aromatic and heteroaromatic compounds with organoboron carbon nucleophiles will be developed that operate under metal-free conditions. Overall, by exploring synthetic reactions of organoborons, these studies in methods development will introduce new transformations and strategies that will streamline synthetic chemists' approaches to ...