# Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $67,583

## Abstract

Project Summary
 The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and
physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group
transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new
functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of
biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and
C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug
discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates.
 Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their electronic,
steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that prior to 2007
viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and commercialized
iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts for allylic C–H
functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)–H aminations.
These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings, without the
need for directing groups. The late-stage functionalization approach that has emerged from this work has been utilized
in both industrial and academic settings. Building on this considerable foundation, we will undertake major challenges
required to broaden the application of late-stage functionalization in chemical synthesis and drug discovery. We will
innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity for tolerance of -
functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non-bonding interactions.
These advances will make possible new reactions such as oxidative alkylations and catalyst-controlled asymmetric
induction and site-divergence. We will develop new base-metal complexes for intermolecular C–H aminations and
alkylations with unprecedented selectivities, and discover new ligand types amenable to asymmetric induction. New
palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing functionality in complex settings.
Cross-coupling reactions will be developed where O and N are introduced as part of complex fragments. Additionally,
asymmetric C–H functionalizations that feature catalyst-controlled diastereoselectivities in substrates with pre-existing
stereogenic centers will be advanced. Collectively, this program will change the way synthetic chemists make and
diversify complex molecules in pursuit of therapeutics, metabolites, and biological pro...

## Key facts

- **NIH application ID:** 11099191
- **Project number:** 3R35GM122525-08S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Maria Christina White
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $67,583
- **Award type:** 3
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099191

## Citation

> US National Institutes of Health, RePORTER application 11099191, Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis (3R35GM122525-08S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11099191. Licensed CC0.

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