Project Summary/Abstract Fundamentally, a major bottleneck in the drug discovery process across all medical indications is the difficulty of synthesizing topologically complex small molecules for biological testing. This, in turn, points back to limitations in the synthetic toolkit, specifically the paucity of reactions that can be deployed to rapidly synthesize families of structurally intricate compounds from simple starting materials. My research laboratory seeks to solve this problem by developing a collection of novel reactions to expedite organic synthesis. Central to our approach is the use of transition metal catalysts, which offer orthogonal reactivity to main group elements and can enable modes of bond construction that are otherwise impossible. Moreover, we strive to develop catalytic reactions that are both synthetically enabling and sustainable, in line with goals of green chemistry. Our perspective is unique in that we are a reaction discovery group operating in a research ecosystem focused on biomedical problems, and we collaborate closely with researchers in immunology, chemical biology, and drug discovery to identify unmet needs in synthetic methodology and to deploy newly developed reactions to prepare small molecule libraries for biological screening. The overall goal of this research proposal is to develop a mechanistically unified and inherently combinatorial catalytic cycle that enables 1,2-difunctionaliztion of alkene and alkynes, two classes of highly abundant and inexpensive starting materials. We propose a π-Lewis acid activation approach, whereby a transition metal catalyst coordinates to the carbon–carbon π-bond of the substrate and facilitates addition of a nucleophile. Next, the resulting organometallic intermediate is intercepted with an electrophile to form the final bond and close the catalytic cycle. During our first 17 months in operation, we have developed a removable directing group strategy for alkene and alkyne hydrofunctionalization and have recently succeeded in trapping a nucleopalladated alkylpalladium(II) intermediate with a carbon electrophile to achieve 1,2-difunctionalization. These results, as described in 4 research publications to date, establish a firm foundation for future work during the NIH R35 funding period. During the next five years, we intended to build this research program along three lines of inquiry: (1) expanding the scope of substrates, reaction partners, and modes of bond construction, (2) pursuing new strategies for controlling regioselectivity and promoting reactivity, including the design of removable tridentate directing groups, catalytic directing groups, and ligands to promote non-directed reactions, and (3) studying the mechanism of the nucleopalladation through computation and kinetics. This research program is significant because it involves the invention of new reactions to synthesize products that are otherwise difficult or impossible to prepare, including completely...