# Radical Chaperones to Harness Remote, Selective C-H Functionalization Mechanisms

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2022 · $453,243

## Abstract

Project Summary/Abstract
 Chiral amines are prevalent motifs in nature and medicine. Conversely, alcohols are among the cheapest
and most ubiquitous molecules. This program is dedicated to the development of new, remote C-H
functionalization strategies that will streamline the synthesis of biologically relevant amines from abundant
alcohol precursors. The key innovation of the proposed approach is the design of catalysts to harness
regioselective 1,5-hydrogen atom transfer (HAT) mechanisms via imidate (β) and amidyl (δ) radicals. Through
catalyst-controlled generation of nitrogen-centered radicals, as well as newly enabled regulation of their remote
(β or δ) terminations, we seek to access new types of reactivity and selectivity. For example, the first
asymmetric examples of several radical-mediated transformations are proposed. Additionally, a series of novel,
single and double C-H functionalization cascades are described. The elucidation of these divergent
mechanisms for intercepting radical intermediates will enable new access to valuable, remote transformations,
including the synthesis of several medicinally relevant scaffolds (e.g. α-amino acids, β-amino alcohols, aza-
heterocycles) in a rapid, modular, and selective fashion.
 The significance of these strategies for radical-mediated, remote C-H functionalization is their facilitation of
the discovery of otherwise unlikely synthetic reactivity. Specifically, by employing transient imidate radical
chaperones, alcohols may be selectively converted to a family of chiral amines. Two metal-catalyzed classes
of reactivity (stereoselective HAT and termination, or desymmetrization by HAT) are proposed to facilitate
asymmetric β C-H amination and other enantioselective functionalizations. In parallel, new approaches for
metal-mediated, amidyl radical generation from amines will facilitate their more rapid and direct access, as well
as new avenues for their remote cross-coupling with arenes and other nucleophiles. The newly elucidated
mechanisms for harnessing novel δ C-H reactivity (by amidyl radicals) will also enable further developments of
chaperone-mediated β C-H functionalizations (by imidate radicals). Together, these studies will further expand
our ability to selectively control remote HAT mechanisms and enable novel, useful, and unprecedented C-H
editing of alcohols and amines found in medicinally relevant molecules.

## Key facts

- **NIH application ID:** 10404550
- **Project number:** 5R35GM119812-07
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** David A Nagib
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,243
- **Award type:** 5
- **Project period:** 2016-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404550

## Citation

> US National Institutes of Health, RePORTER application 10404550, Radical Chaperones to Harness Remote, Selective C-H Functionalization Mechanisms (5R35GM119812-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10404550. Licensed CC0.

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