This proposal focuses on uncovering new electrocatalytic technologies that facilitate the synthesis of bioactive compounds. Improving the synthetic efficiency of medicinally active organic compounds is crucial to modern biomedical research. Oxidation and reduction reactions are among the most important and frequently executed processes in organic synthesis. However, our ability to manipulate the oxidation states of functional groups in complex settings with high efficiency, precision, and minimal waste remains in a largely nascent stage. Owing to its many distinct characteristics, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis. In particular, electrocatalysis?a process that integrates electrochemistry and small-molecule catalysis?has the potential to substantially improve the scope of synthetic electrochemistry and provide a wide range of useful transformations. Despite its attractive attributes and extensive applications in energy-related fields, electrocatalysis has been used only sparingly in synthetic organic chemistry. Thus, there exists a clear impetus for inventing new catalytic strategies to improve the scope of synthetic electrochemistry and provide new platforms for reaction discovery and synthetic innovations. Toward this end, we developed a new catalytic approach that combines electrochemistry and redox-metal catalysis for the oxidative difunctionalization of alkenes to access a diverse array of vicinally functionalized structures. These promising results led us to envision that electrocatalytic strategies will ultimately emerge as powerful tools for solving a wide range of long- standing synthetic problems. Each of the projects described herein applies our general strategy of electrocatalysis to address a prominent challenge in organic synthesis. Specifically, we aim to develop reactions such as the chlorophosphonylation, chloro(hetero)arylation, and fluorotrifluoromethylation of alkenes; ring-opening functionalization of cycloalkanols to make remotely functionalized ketones; intermolecular 1,1-difunctionalization of isonitriles to make imidoyl chlorides; and C?N coupling via the activation of C?H bonds. These oxidative transformations are either currently unknown or have significant limitations in reaction scope, efficiency, or selectivity. We will also carry out in-depth studies using canonical physical organic and electrochemical techniques to gain insights into the reaction mechanisms. The development and mechanistic understanding of these proposed transformations will represent significant advances for the field of organic synthesis.

Public Health Relevance

To assemble complex molecules rapidly, efficiently, and with predictable outcomes is among the most significant challenges in the discovery of new medicinal agents. This proposal addresses several major technological gaps in the field of organic synthesis, and its successful completion will speed the preparation of novel medicinal lead structures.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Cornell University
Schools of Arts and Sciences
United States
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