PROJECT SUMMARY/ABSTRACT: The impact of synthetic chemistry on society cannot be overstated. Organic chemistry has changed our world in momentous ways, from giving women reproductive rights through the invention of contraceptives, to creating pesticides that allow us to feed the globe. It is axiomatic that innovations in medicine are invariably linked to advancements in organic chemistry as most medicines are synthesized by organic chemists. It has long been recognized that the overall shape of a small molecule is the most fundamental factor that controls its biological effects. It is fortunate that rapid developments in asymmetric synthesis have paved the way for therapeutics to reach the clinic. These triumphs can be attributed to the many innovations in the realms of enantioselective bond forming processes such as asymmetric ion pairing, organocatalysis, C–H activation, Lewis acid/base, BrØnsted acid/base, reductions/oxidations, cross-coupling reactions and many more. Despite these achievements, the state of the art still falls short in many ways from the ideal. Although each of the unique activation modes outlined above allow for high chemo-, diastero- and enantio-selectivities to be achieved, in many cases for the desired bond forming event to occur the substrate must often bear a functional group that is capable of binding or being activated by a chiral catalyst. In particular, the ability to enantioselectively convert inert C–H bonds into carbon- carbon bonds at specific locations without the aid of directing groups is highly desirable because it would further the drug discovery process. To address this challenge, our work has focused on the development of new deprotonation substitution sequences which allow for typically untargetable positions within heterocycles to be directly functionalized. Specifically, we have found that Lewis bases can extract Li cations from strong organolithium reagents allowing highly basic ion pairs to be produced and in turn for typically remote and inert C–H bonds in heterocycles to be deprotonated. Secondly, we have developed a new class of chiral phosphine ligands that enable enantioconvergent cross-couplings with racemic donor reagents. This proposal seeks to merge these concepts by developing asymmetric deprotonation cross-coupling sequences that can allow for typically inaccessible carbon centers to be functionalized. Specific goals of this proposal include: (1) the development of both organolithium reagents and Lewis bases that when combined allow for typically inert C–H bonds in alkaloids to be deprotonated; (2) the development of new chiral phosphine ligands that enable enantioconvergent Negishi cross-coupling reactions with racemic donor reagents; and (3) the development of asymmetric deprotonation cross-coupling sequences that allow for biologically relevant alkaloids to be directly functionalized in a single synthetic operation.