Supramolecular Dual Substrate Activation: Synthetic Methods via Coencapsulation

Project Summary Pharmaceutical technologies are inherently limited by the synthetic methods available to medicinal chemists. Novel transformations in organic chemistry have the potential to enhance human well-being through the prevention of human suffering through pharmaceutical therapies. Modern innovations in synthesis have shown the ability to furnish new molecular scaffolds, especially through the employment of catalytic methods. Past efforts in supramolecular catalysis have offered strategies to more traditional methods by enabling orthogonal selectivity through non-covalent interactions which are imparted via encapsulation. In this way, supramolecular hosts behave similarly to enzymes, inspiring further study due to the allure of the rate enhancements offered by nature’s catalysts. Utilizing supramolecular hosts pioneered by the Raymond, Bergman, and Toste groups, we plan to enable several transformations relevant to the production of pharmaceuticals. Previous work with these privileged clusters has shown powerful reactivity through the coencapsulation of two reagents within the host cavity. Trends in these reactions have shown the ability to enhance the electrophilicity of electrophiles through protonation and increased reactivity from nucleophiles through p-p stacking interactions. These motifs will be leveraged for various pharmaceutically relevant transformations, including N-heterocycle reduction and functionalization, regio- and diasteroselective olefin epoxidation. Through the combination of supramolecular catalysis and Pt catalysis we also hope to provide methods for an enantioselective C(sp3)-H oxidation of alkanes. These methods all involve the use of widely available or readily synthesized reagents that may be rapidly constructed into valuable pharmacores for use in drug discovery investigations with the ultimate goal of improving human health. The specific aims in this proposal provide a detailed plan for the production of these potent technologies. Under the tutelage of Professors Toste, Bergman, and Raymond I will develop these methods with expert guidance in asymmetric reactivity, physical organic chemistry, and organometallic cluster synthesis. Conducting this research at the University of California Berkeley provides an optimal environment for both the success of this project and for my personal and professional development as a researcher. Providing the tutelage of brilliant faculty, ambitious colleagues, and stunning state-of-the-art facilities, Berkeley offers no limit to the resources for the practicing scientist.