Project Summary This program is focused on the discovery, application, and mechanistic elucidation of catalytic reactions that are stereoselective, environmentally friendly, and useful for the preparation of chiral, bioactive compounds. We seek to develop novel concepts in catalytic reactivity and selectivity, and apply them to important problems in chemical synthesis. The premise underlying our current and proposed work is that new classes of small-molecule, chiral organic catalysts can promote challenging bond constructions, controlling the absolute and/or relative stereochemistry of the reactions through networks of attractive non-covalent interactions. The overarching goal is to identify simple organic catalysts that are readily accessible, inexpensive, and bear the minimal structural features necessary for inducing high levels of stereocontrol in synthetically interesting transformations. We will pursue several distinct catalytic concepts over the next five-year period, with each of the proposed reactivity manifolds based on firm mechanistic hypotheses gleaned from extensive preliminary investigations. We will apply precisely designed chiral ureas, thioureas, and squaramides to catalysis of enantioselective carbon-carbon and carbon-heteroatom bond-forming reactions. These dual hydrogen-bond donors can abstract or bind weakly basic anions, such as halides, sulfonates, phosphate, and carboxylates, to promote concerted substitution reactions or generate chiral ion pairs that remain tightly associated during subsequent enantioselectivity- determining reactions of the prochiral cations. We discovered that the combination of hydrogen-bond donors with achiral Lewis or BrØnsted acids generates highly reactive complexes that promote activation of weakly electrophilic substrates to access highly reactive cationic species. This new principle will be directed to creative applications involving atom-economical carbonyl addition reactions and additions to alkenes. The principle of anion-binding catalysis will also be examined in pathways where the catalyst-bound anion acts as the nucleophile in the enantiodetermining bond construction. Activation of polar reagents is applied in desymmetrizing ring- opening reactions and generation of stereogenic-at-phosphorus compounds. We will also pursue a new strategy aimed at applying anion binding by chiral H-bond donors to enhance the reactivity and control the stereochemical outcome of transition-metal catalyzed reactions, and separately in the context of stereoselective and site- selective glycosylation reactions. We have found that precisely tailored bisthiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl phosphates via cooperative activation of both the nucleophile and the electrophile. This cooperative mechanism provides a new approach to achieving control over the site of reaction in minimally protected sugars and other polyfunctional substrates. We also aim to u...