PROJECT SUMMARY/ABSTRACT The discovery of potent pharmaceutical agents requires expedient access to a wide range of diverse molecular architectures, and the chemical tools available to the medicinal chemist both enable and limit this venture. Over the past half century, transition metal-catalyzed cross-coupling has grown into a powerful strategy for organic synthesis. However, the use of the d-block elements presents specific disadvantages, including low acceptable metal content in pharmaceutical products and susceptibility to unproductive coordination by polar medicinally- relevant functional groups. Thus, there has been a recent surge in interest in developing cross-coupling catalysts containing the naturally abundant main group elements of the p-block. Mechanistic understanding of the reactivity of main group catalysts lags far behind that of transition metal catalysts, and synthetic applications remain limited. One particularly promising approach for main group catalysis is to utilize the P(III)⇌P(V) redox couple as one would employ the analogous redox couples of transition metal catalysts. To develop improved biphilic catalysts for phosphorus redox cycling chemistry, a more complete mechanistic understanding of the factors affecting catalyst performance is necessary. Towards this end, the proposed research will employ two distinct approaches to catalyst development: multivariate regression analysis to correlate phosphetane structure with desired redox properties, and computational modeling to guide the rational design of a novel class of boron- and silicon-containing phosphetanes with reduced frontier orbital energy gaps. The detailed study of these catalysts will provide valuable insights into the ability of phosphorus-based catalysts to facilitate carbon- heteroatom bond formation, enabling the development of an allylic amination reaction of immediate medicinal relevance. This research proposal supports and aligns with the fellowship goals by requiring new skills to be learned in inorganic synthesis, mechanistic study, and computational modeling that complement previous training in synthetic organic methods development. The Radosevich lab provides an ideal research environment uniquely suited to facilitate training in these areas, as evidenced by their pioneering efforts in the development of phosphorus-catalyzed reactions. Prof. Radosevich’s personal commitment to supporting postdoctoral researchers in their development into independent investigators ensures that the professional training goals will be achieved. Lastly, MIT, as one of the most productive research institutions in the world, provides the resources and equipment necessary to carry out the research proposed.