# Dual Electrocatalytic Enantioselective C-O Bond Formation via Benzylic C-H Functionalization

> **NIH NIH F32** · CORNELL UNIVERSITY · 2021 · $65,610

## Abstract

Project Summary
Benzylic ethers are prominent motifs in pharmaceuticals and biologically active molecules.
Previous methods for enantioselective synthesis of these motifs have relied on asymmetric
reduction of a carbonyl compound with a hydride or carbon nucleophile, requiring pre-
functionalized starting materials and therefore additional chemical steps. Ideally, C–O bond
formation would occur through direct C–H/O–H cross-coupling, while avoiding solvent quantities
of the alcohol coupling partner and tolerating a broad range of both coupling partners. Although
C–H oxygenation methods have recently been developed, an enantioselective variant remains
elusive.
In this research strategy, we propose directly accessing optically active benzylic ethers using
readily available alkyl arenes and alcohol coupling partners through dual electrocatalysis. This
strategy will enable us to effectively merge hydrogen-atom transfer (HAT) mediated by
phthalimide N-oxyl (PINO) radicals with copper-promoted radical alkoxylation, two established
radical processes. Replacing a conventional chemical oxidation with electrochemistry will not only
improve sustainability and scalability of the proposed transformation but will also address the key
overoxidation problem associated with enantioselective Cu-mediated C–O bond formation. If
successful, this reaction would provide the first example of enantioselective benzylic ether
synthesis via C–H functionalization. This project has three specific aims: 1) investigating organic
mediators such as N-hydroxyphthalimide (NHPI) for generating benzylic radicals under mild
electrochemical oxidation conditions; 2) identifying conditions and chiral ligands for
enantioselective C–O bond formation by Cu-catalyzed radical trapping; 3) accessing sterically
hindered dialkyl ethers from racemic substrates in an enantioconvergent manner.

## Key facts

- **NIH application ID:** 10235455
- **Project number:** 1F32GM142264-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Minsoo Ju
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,610
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235455

## Citation

> US National Institutes of Health, RePORTER application 10235455, Dual Electrocatalytic Enantioselective C-O Bond Formation via Benzylic C-H Functionalization (1F32GM142264-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235455. Licensed CC0.

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