# Controlling Radicals via Sulfonium Activation and Anion Binding Catalysis

> **NIH NIH F32** · HARVARD UNIVERSITY · 2021 · $71,062

## Abstract

Project Summary/Abstract
The reactivity of organic radicals endows these species with the potential to mediate otherwise inaccessible
transformations. This potential, however, has not been fully met in synthetic applications because the
selectivity of these fleeting intermediates is exceedingly difficult to control. Nature, on the other hand, has
evolved a strategy for generating and controlling a single radical to carry out a dizzying variety of challenging
bond activations within the largest known enzyme superfamily, radical S-adenosyl-methionine (SAM) enzymes.
This chemistry is enabled by activation of a redox-inert electrophile (adenosine triphosphate) with a Lewis base
(methionine) to generate a sulfonium cofactor (SAM). This cofactor binds in tightly regulated environment such
that, upon sulfonium reduction, the resulting radical is poised to react in a manner dictated by weak
interactions in the enzyme active site. The research proposed in this application aims to mimic this method of
generating and controlling these reactive species to harness the full potential of radical intermediates in
synthetic chemistry. The proposed means of achieving this outcome involves activation of mild and readily
available electrophiles (alkyl-carboxylates) by cooperative Lewis-base activation and anion-abstraction to
generate ion-paired sulfonium intermediates in a pre-organized, chiral environment. Upon single-electron
reduction, the resulting radical will react with selectivity controlled by attractive non-covalent interactions that
were templated in the sulfonium precursor. By mimicking the mechanism that enables radical SAM enzymes to
tame reactive intermediates, the proposed catalysts will provide an unprecedented degree of catalyst control
over the reactivity of organic radicals.

## Key facts

- **NIH application ID:** 10180986
- **Project number:** 5F32GM133068-03
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Joseph Jeffery Gair
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $71,062
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180986

## Citation

> US National Institutes of Health, RePORTER application 10180986, Controlling Radicals via Sulfonium Activation and Anion Binding Catalysis (5F32GM133068-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180986. Licensed CC0.

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