# Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2024 · $325,997

## Abstract

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. This
work will develop novel mechanisms for generating free radical intermediates within protein active sites.
Evolution of the protein will be conducted to enhance the chemo-, regio-, and enantioselectivity of the reactions
performed within their protein active site. Building on findings in the previous funding period, we will develop
couplings reactions between nitronates and alkyl halides. These reactions have two possible products: a redox-
neutral reaction to afford chiral 𝛼-tertiary nitroalkanes and a reductive coupling to prepare cross-coupled
products. We will design catalysts to favor each outcome. Secondly, we will develop a regioselective coupling
of alkyl radicals with arenes. In this project, we will engineer the protein scaffold to favor functionalization at
positions that are untouched using existing synthetic methods. Thirdly, we will explore alkene
difunctionalization. In one manifold, we will oxidize radical intermediates to form carbocations which can be
quenched with various nucleophiles. In a second approach, we will exploit Smiles rearrangements for radical
termination. These approaches will enable the rapid synthesis of highly substituted products while also enabling
the development of catalysts to precisely control the stereochemistry of stereocenters formed in C–C bond-
forming events. In this application, we will also develop a new strategy for radical initiation using oxidative
decarboxylation. This activation mode will be applied to the synthesis of secondary amines. Finally, we will
create a biocatalytic cross-coupling reaction, where alkylated flavin adducts mimic the reactivity of
organometallic intermediates. This method will enable the coupling of carboxylic acids and alkyl halides without
using a metalloprotein. 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.

## Key facts

- **NIH application ID:** 10789985
- **Project number:** 5R01GM127703-09
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Todd Kurt Hyster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $325,997
- **Award type:** 5
- **Project period:** 2018-05-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789985

## Citation

> US National Institutes of Health, RePORTER application 10789985, Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions (5R01GM127703-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10789985. Licensed CC0.

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