# Asymmetric Catalysis with Open-Shell Intermediates Facilitated by Proton-Coupled Electron Transfer

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2020 · $15,263

## Abstract

PROJECT SUMMARY/ABSTRACT
 Over the past 30 years, a wealth of asymmetric catalytic methods from closed-shell substrates and
intermediates have revolutionized drug discovery and materials synthesis. Yet, chiral catalysis of open-shell
radical intermediates has proven to be challenging. Mild catalytic methods for radical generation have been
limited until photoredox catalysis, which has allowed for catalytic and redox tunable radical formation. However,
extending this to asymmetric catalysis has largely remained elusive due to the high reactivity and inability to
engage radical intermediates in common selectivity manifolds. This proposal applies knowledge gleaned from
the field of closed-shell enantioselective catalysis and from the emergent field of photoredox catalysis to advance
the nascent field of asymmetric catalysis with radical species, and to subsequently study the mechanisms of these
transformations to develop general principles for achieving enantioinduction in catalytic, open-shell chemistry.
 The goal of the proposed research is to leverage the ability of proton-coupled electron transfer (PCET) to
break strong bonds with polar character to drive enantioselective catalytic transformations of cyclic substrates.
This proposal overcomes two central pitfalls in enantioselective catalysis of radical intermediates: 1) racemic
background arising from rapid reactions of highly reactive radical species generated in the absence of the chiral
catalyst and 2) orchestrating stereoselective high order elementary reaction steps. PCET functions by BrØnsted
acid coordination, lowering the reduction potential of basic functional groups or BrØnsted base lowering the
oxidation potential of acidic functional groups. With redox tunable photocatalysts, and chiral acid/base catalysts,
radicals will be exclusively generated in the presence of a chiral catalyst, shutting down racemic background.
Furthermore, coupling this step to selectivity determining rapid unimolecular ring opening ensures catalyst and
radical not diffuse from each other when being held together by a weak hydrogen-bonding interaction.
 In aim 1) meso cyclic alcohols will be oxidatively desymmetrized via O-H PCET to generate alkoxy
radicals, which will rapidly ring open via β-scission, to provide aldehydes with a distal stereocenters. Dual chiral
base and photoredox catalysis will enable PCET and chirality transfer through hydrogen bonding. In aim 2) chiral
acid and photoredox mediated PCET will reductively open racemic styrene oxides, which will be subsequently
functionalized or deracemized in divergent interception of the benzylic radical intermediate. Kinetic and
computational mechanistic investigations into the origin of enantioselectivity in these mechanistically distinct
transformations will shed light onto requirements for asymmetric induction in oxidative and reductive radical
catalysis. This work will make conceptual and practical advances in the application of asymmetric catalysis to...

## Key facts

- **NIH application ID:** 10068286
- **Project number:** 1F32GM139261-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Andrew James Bendelsmith
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $15,263
- **Award type:** 1
- **Project period:** 2020-08-01 → 2020-10-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068286

## Citation

> US National Institutes of Health, RePORTER application 10068286, Asymmetric Catalysis with Open-Shell Intermediates Facilitated by Proton-Coupled Electron Transfer (1F32GM139261-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068286. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*