The proposed research seeks to develop metal-catalyzed C?C and C?N bond-forming methodologies that streamline organic synthesis by leveraging the unique control that electrochemistry provides over electron trans- fer events. In particular, this work will develop synthetic methodologies based on dual-catalyst systems. One catalyst is electrochemically activated to mediate the formation of alkyl radicals, while a second catalyst selec- tively activates the complementary substrate to effect coupling with the electrogenerated radicals. The long-term goal of this program is to establish electrochemistry as a standard synthetic strategy in a way that complements the successful integration of photoredox catalysis into organic synthesis: another dual-catalyst system that relies on one catalyst to promote electron transfer and a second to mediate bond-forming reactions. The proposed research relies on the merger of multiple scientific fields to develop next-generation methodologies in organic synthesis. The Sevov team has a unique combination of expertise in synthetic methodology, mecha- nistic organometallic chemistry, and homogeneous electrochemistry that will lead to new synthetic strategies that impact both the rate of discovery and large-scale synthesis of new therapeutic agents. These strategies and the targeted transformations of the proposal are summarized below: Goal 1. to develop C?C and C?N coupling reactions with alkyl electrophiles: Electrochemically-driven cross-coupling will be developed using a dual-catalyst system that allows each substrate to be activated by a distinct catalyst. Dedicated electrocatalysts will be developed that mediate formation of alkyl radicals from alkyl halides or ethers/epoxides. The radical intermediates will be intercepted and functionalized by co-catalysts that exclusively (i) activate aryl chlorides and ethers to form alkyl arenes, (ii) mediate C?N coupling from high-valent complexes to form amines, or (iii) utilize chiral nonracemic ligands to enable enantioselective C?C/N coupling. Goal 2. to develop C(sp3)?H bond alkylation/arylation and amination: Aliphatic C?H bond activation will be accomplished via directed H-atom abstraction (HAA) from a tethered aryl radical. Aryl radicals will be generated by electroreduction of Ni(II)aryl intermediates to form low-valent organonickel(I) complexes that are susceptible to Ni?C bond homolysis. Radical relay by HAA from the aryl directing group to the alkyl side-chain provides access to an activated aliphatic site for C?X coupling. Goal 3. to develop decarboxylative functionalization of carboxylic acids: The first of two complementary approaches will investigate pulsed-electrolysis techniques to enable decarboxylation at potentials that are mild and compatible with catalysts for selective C-C/N/X of the resulting alkyl radicals. A second approach will utilize electrocatalysts that are photoactive upon oxidation at mild potentials. Photoexcitation of the oxidized species will transiently generate a high energy oxidant that can effect oxidative decarboxylation to form alkyl radicals.

Public Health Relevance

The following research proposal will develop broadly-applicable strategies for new synthetic-organic meth- odologies that are particularly suited for the preparation or late-stage modification of natural products and phar- maceuticals. These synthetic strategies all rely on electrical energy as a means to (i) promote challenging ? but desirable ? reactions, (ii) eliminate the need for expensive or hazardous reagents, and (iii) reduce the synthetic steps required to access the target molecules. As a result of streamlining synthesis, these findings will accelerate the identification of new therapeutics and allow their preparation on large scale with lower costs to the public.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Yang, Jiong
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Ohio State University
Schools of Arts and Sciences
United States
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