# New Synthetic Methods Utilizing Radical Cation Intermediates Enabled by Visible Light Photocatalysis

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2024 · $74,284

## Abstract

Project Summary/Abstract: The development of catalytic reactions to selectively transform ubiquitous
functional groups to value-added products can enable the efficient synthesis of medicinally relevant molecules.
The facile generation of classical reactive intermediates such as radicals, cations, and anions via photoredox
catalysis and proton-coupled electron transfer (PCET) have shifted the way chemists construct complex
molecules and enabled novel bond-forming logic. However, the application of these mild photocatalytic manifolds
towards the generation of alkene-derived radical cation intermediates still relies on strongly oxidative conditions
to facilitate alkene oxidation. The ambiphilic nature of alkene radical cation intermediates renders these species
valuable synthetic linchpins capable of rapidly building molecular complexity and streamlining the development
of pharmaceutically relevant molecules. The goal of the proposed research is the development of a novel
synthetic platform for the photocatalytic formation of alkene radical cation intermediates from non-canonical
alcohol starting materials. This proposal seeks to leverage the mechanistic insights gleaned from the intracellular
formation of alkene radical cation intermediates in concert with the capabilities of excited state redox chemistry,
to generate radical cations under synthetically advantageous conditions. The development of this methodology
will address three fundamental limitations of radical cation chemistry: 1) the use of harsh oxidative conditions for
alkene oxidation 2) the constraint of alkenes as radical cation progenitors and 3) the use of oxidatively labile
reaction partners. The research strategy outlines a rigorous approach for establishing a mechanistically distinct
method to access classical alkene-radical cations from non-canonical precursors, and the development of new
synthetic methods outside the scope of conventional radical cation chemistries. In aim 1, we will leverage
established principles of photoredox catalysis for the development of a reductive platform for the catalytic
generation and subsequent functionalization of classical alkene radical cations intermediates from non-canonical
halohydrin precursors. The reductive generation of alkene radical cations will initially be applied to the
development of annulative carbofunctionalizations reactions. This reductive platform will then be expanded to
enable formal access to non-classical vicinal di-cation reactivity which is inaccessible via conventional alkene
radical cation chemistries. In aim 2, C–H PCET will be applied for the selective homolytic activation of strong C–
H bonds of simple alcohols for the direct generation of alkene radical cation intermediates. PCET generated
alkene radical cations will then be applied to the direct generation and functionalization of nucleotide-derived
radical cations for the expedient synthesis of nucleotide analog libraries. This work will provide a novel and
synthet...

## Key facts

- **NIH application ID:** 10884207
- **Project number:** 5F32GM151832-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Danny Thach
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884207

## Citation

> US National Institutes of Health, RePORTER application 10884207, New Synthetic Methods Utilizing Radical Cation Intermediates Enabled by Visible Light Photocatalysis (5F32GM151832-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10884207. Licensed CC0.

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