# Ligand-promoted Enantioselective C-H Activation Reactions

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $244,226

## Abstract

Project Summary
Desymmetrizing activation of prochiral C–H bonds via metal insertion has emerged as a
potentially transformative approach for the rapid and divergent synthesis of chiral compounds.
However, a significant challenge prohibiting the broad utility of this approach is the poor reactivity
of native substrates in the absence of externally-appended directing groups. This proposal directly
addresses this challenge by developing two approaches to achieve the enantioselective C–H
activation of a range of native substrates commonly found in organic synthesis and drug
discovery—carboxylic acids, ketones, aldehydes and amines: (A) Development of chiral bidentate
L,X-type ligands containing N-acetyl or pyridone motifs to accelerate C–H cleavage; (B)
Development of chiral transient directing groups (TDGs) to enable enantioselective C–H
activation of ketones, aldehydes and amines. Following initial discoveries of chiral ligands and
TDGs, we will then develop various catalytic cycles to enable the enantioselective C–H activation
of diverse native substrates, forming a range of carbon–carbon and carbon–heteroatom bonds
asymmetrically.
These novel reactions will provide a versatile platform for the construction of α-, β-, and γ-
stereocenters. These technologies will be applied to drug discovery in collaboration with the
pharmaceutical industry and academic laboratories. Specifically, the one-step access to the
atypical chiral β-lactones and lactams via enantioselective C–H activation will be applied to the
discovery of covalent inhibitors for serine hydrolases and cysteine-dependent proteins using
activity-based protein profiling.

## Key facts

- **NIH application ID:** 11101033
- **Project number:** 3R01GM084019-17S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jin-Quan Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $244,226
- **Award type:** 3
- **Project period:** 2008-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11101033

## Citation

> US National Institutes of Health, RePORTER application 11101033, Ligand-promoted Enantioselective C-H Activation Reactions (3R01GM084019-17S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11101033. Licensed CC0.

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