Project Summary/Abstract Progress in pharmaceutical development is often limited by the advancement of innovative chemical transformations that enable the expedient synthesis of drug molecules. The improvement of methods for selectively forming C–C bonds in the construction of complex small molecules remains an ongoing challenge for the field of synthetic chemistry. The Nozaki-Hiyama-Kishi (NHK) reaction has historically been an essential tool for chemoselectively forging C–C bonds in both academic and industrial synthesis of natural products and natural product derivatives. Although substantial progress has been made in developing NHK methodologies that avoid superstoichiometric amounts of Cr and facilitate valuable stereoselective transformations, scarce mechanistic knowledge of NHK chemistry has hindered any further improvements of this transformations over the past two decades. Therefore, the goal of this proposal is to examine the hypothesis that thorough physical organic understanding of known electrocatalytic NHK methodologies, guided by kinetics-based mechanistic investigations, can empower the advancement of robust and versatile electrochemically driven NHK chemistries, thereby expanding current knowledge of Cr-catalysis and enabling the synthesis of complex molecular scaffolds. This work will first focus on investigating the reaction mechanism of electrocatalytic NHK methodologies by utilizing chemical kinetics in concert with other mechanistic tools such as in-situ spectroscopy and electroanalytical chemistry. This comprehensive physical organic understanding of electrochemical NHK chemistry will then be leveraged towards the development of robust and versatile electrocatalytic NHK methodologies that enable new selectivity and reactivity. Finally, these improved electrocatalytic NHK methods will enable the first example of an electrochemical NHK chemistry utilized in total synthesis and empower a novel retrosynthetic disconnection strategy for the synthesis of a densely functionalized polycyclic natural product, Scabrolide A. This research will ultimately enable the synthesis of a wide range of pharmaceuticals, as well as probes for biological systems. The Reisman group at the California Institute of Technology creates innovative retrosynthetic strategies and develops novel synthetic methodologies towards efficient synthesis of natural products with important medicinal properties. The proposed research will complement their ongoing efforts in advancing novel methodologies, demonstrating innovative retrosynthesis strategies, and take advantage of the world-class facilities at Caltech, such as their automated screening facility that enables extensive access to high-throughput experimentation. This fellowship training position in Prof. Reisman’s group will not only improve my expertise in synthetic organic chemistry, but will enhance my prior training as a physical organic chemist, collectively preparing me for a future career in academ...