# Chaperones for Radical Relays: Enabling Directed C-H Functionalizations

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2020 · $365,557

## Abstract

Project Summary/Abstract
 Regioselective C-H functionalization of biologically relevant molecules, including medicinal candidates and
biochemical probes, enables access to targeted analogs with potentially improved biomedical value. A strategy
that employs radical relay mechanisms to invent pharmacologically valuable C-H functionalization methods is
proposed. The key innovation in this approach is the design and use of radical precursor tethers that may
serve as temporary chaperones to effect targeted manipulation of C-H bonds. These tethers allow the
application of robust, regioselective 1,5 hydrogen atom transfer (HAT) mechanisms for the manipulation of
varying positions in a molecule. As a proof of concept, β and δ C-H functionalizations of alcohols are proposed,
since these are ubiquitous motifs in organic chemistry, and also because such synthetic transformations are
both valuable and challenging to perform using known methods. The independent research goals include:
Goal 1: To develop a tethered radical relay strategy for the β C-H amination of alcohols.
 Direct conversion of alcohols to their biologically valuable β-amino analogs via C-H amination will be
pursued via three parallel design strategies with tethered amine-containing, radical precursors.
Goal 2: To develop a tethered radical relay strategy for alcohol β C-H functionalizations.
 Interrupted Barton reactions may also be harnessed within this tether strategy to enable the invention of
valuable C-H functionalization methods, such as β C-H deuteration, fluorination, oxygenation, and alkylation.
Goal 3: To develop a catalytic, radical relay strategy to enable δ C-H functionalizations.
 Iron-catalyzed initiation and interruption of the Barton reaction will facilitate the invention of unprecedented
functionalizations of remote C-H bonds, such as δ C-H deuteration, arylation, and methylation.
 Importantly, tandem development of the directing group tethers (for β C-H functionalizations), as well as the
iron-catalyzed radical trapping protocols (for δ C-H functionalizations), will enable the combination of both
strategies for the invention of further biologically useful, synthetic methods. Furthermore, the future extension
of this strategy to catalytic tethers of varying sizes will allow for the functionalization of other unbiased C-H
positions (α, β, γ, δ, ε to alcohols, acids, or amines). Notably, regioselectivity in each of these cases will
depend on the length of the tether, rather than substrate-biased selectivity. Ultimately, the value and
significance of this chaperone-mediated, radical relay strategy for targeted C-H functionalization will be
demonstrated via manipulation of the anti-cancer drug, paclitaxel. The synthetically challenging modification of
the C6 position, which is coincidentally the site most prone to in vivo metabolism, will be accomplished by the
proposed β C-H functionalizations of the C7 alcohol. The targeted introduction of pharmacologically valuable
groups to...

## Key facts

- **NIH application ID:** 9962463
- **Project number:** 5R35GM119812-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** David A Nagib
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,557
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962463

## Citation

> US National Institutes of Health, RePORTER application 9962463, Chaperones for Radical Relays: Enabling Directed C-H Functionalizations (5R35GM119812-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962463. Licensed CC0.

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