# Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $298,016

## Abstract

7. Project Summary
 The work described in this proposal aims to address the longstanding challenge of controlling the
enantioselectivity and regioselectivity of synthetically valuable reactions mediated by radical intermediates. In
this work, broadly substrate permissive flavoenzymes are coupled with three novel mechanisms for radical
formation to achieve substrate-centered radicals bound within protein active sites. The first mechanism
involves electron transfer from a prosthetic flavin cofactor to substrates located within the protein active site.
This approach enables the formation of α-acyl radicals for use in various C–C bond-forming reactions
enabling the selective synthesis of carbocyclic and heterocyclic motifs of biological importance. The second
involves exploiting the impact that binding has on the redox potential of a chosen substrate. In substrates
bearing Lewis basic functional groups, binding within the protein active site makes the substrate easier to
reduce. We have found that when weak reductants are used, selective radical formation can be localized to
substrates bound to the protein active site. This reactivity enables the formation of ketyl radicals for coupling
with electron poor partners such as medicinally valuable heterocycles. Finally, using hydrophobic dyes
capable of binding to proteins, we found that radical formation can be selectively localized to enzyme bound
substrates. This method enables the selective formation of C–C bonds. Together, these methods and the
goals proposed in the Specific Aims have the potential to streamline the synthesis of biological probes and
drug targets, creating a significant benefit to human health and associated biomedical sciences.
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## Key facts

- **NIH application ID:** 10115077
- **Project number:** 5R01GM127703-05
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Todd Kurt Hyster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $298,016
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115077

## Citation

> US National Institutes of Health, RePORTER application 10115077, Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions (5R01GM127703-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115077. Licensed CC0.

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