# Photoredox-enabled deracemization: method development and mechanistic studies

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2024 · $78,892

## Abstract

Project Summary/Abstract. Deracemization reactions are a rare but powerful means of obtaining enantioenriched material
from racemic or scalemic mixtures. The limited number of known deracemization methods are primarily due to challenges
that arise from thermodynamic and kinetic considerations. The conversion of a racemic mixture to an enantiopure one causes
a loss in entropy and is endergonic. Moreover, because enantiomers have identical potential energies, the barriers for
enantiomer interconversion in a thermal reaction are equal for both the forward and reverse steps, which is a consequence
of microscopic reversibility. Thus, the formation of enantioenriched material from a racemate is both thermodynamically
unfavorable and kinetically difficult. However, a light-driven deracemization protocol can surmount these challenges. The
input of light overcomes the endergonic penalty of this transformation, and as photochemical reactions traverse multiple
potential energy surfaces, the forward and reverse reactions of a light-driven deracemization can be judiciously engineered
to have unequal kinetic barriers to circumvent microscopic reversibility.
 Herein, we describe a photocatalytic strategy to deracemize organic compounds containing benzylic moieties
commonly found in pharmaceuticals and studies on its mechanism. This reaction deracemizes α-aryl carbonyl compounds
and involves a photocatalytic stereoablation process to generate an achiral intermediate that undergoes asymmetric
protonation by a proton transfer catalyst. This proposed pathway involves oxidation of the aromatic substrate to the aryl
radical cation by the excited state of the photocatalyst. The benzylic C–H bonds of the aryl radical cation are significantly
acidified and engage in proton transfer with a chiral base co-catalyst to furnish an α-carbonyl, benzylic radical. This open-
shell species undergoes reduction to the corresponding enolate by the reduced state of the photocatalyst, and the enolate
reacts with the conjugate acid of the chiral base co-catalyst to preferentially generate one enantiomer of product. Continued
iterations of these steps through catalysis leads to enantioenrichment, and we demonstrate the feasibility of this proposal
by describing a preliminary substrate scope. The degree of enantioenrichment (up to 97:3 er) and mass balance (≥90%) is
high. We also provide preliminary mechanistic data on this system, and this investigation is ongoing. We have found that
the rate of deprotonation of the radical cation intermediate and the rate of back electron transfer (BET) from the oxidized
substrate to the reduced photocatalyst affect the overall degree of enantioenrichment obtained, and we provide a rationale
for this behavior. Should ongoing studies support our hypotheses, this study will demonstrate how the ground state reduction
potential of a catalyst, which governs the rate of BET, and the concentration of a chiral proton transfer catalyst modulate
the degree of en...

## Key facts

- **NIH application ID:** 10899023
- **Project number:** 1F32GM154402-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Justin Wang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $78,892
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899023

## Citation

> US National Institutes of Health, RePORTER application 10899023, Photoredox-enabled deracemization: method development and mechanistic studies (1F32GM154402-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10899023. Licensed CC0.

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