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

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $476,288

## Abstract

Project Summary
 The biological activity of organic molecules is strongly impacted by the oxygen, nitrogen and carbon
functional groups on their hydrocarbon scaffolds. Classically, the practice of organic synthesis has focused on
building these scaffolds while concurrently introducing this functionality. We hypothesized that, analogous to
nature, a late stage oxidation strategy, i.e., direct introduction of oxidized functionality into C(sp3)-H bonds of
molecule scaffolds, would provide opportunities to diversify molecular structures and streamline syntheses.
Our preliminary studies using novel transition metal catalysts have validated late stage C-H oxidation as a
powerful approach for streamlining synthetic sequences and directly diversifying natural products and other
complex structures. Building on this strong foundation, we plan to discover new catalysts to expand the scope
of C(sp3)-H functionalizations possible. These reactions will broaden the functionality that can be introduced,
sites that can be accessed, and classes of natural products and medicinal compounds that can be derivatized
and synthesized.
 The key to our approach is to develop transition metal catalysts that mediate C(sp3)-H bond cleavage
and functionalization, enabling tunable control over reactivity, as well as site-, chemo-, and stereoselectivity.
We have discovered and commercialized palladium/sulfoxide catalysts for allylic C-H functionalizations, iron
catalysts for aliphatic C-H hydroxylations, and manganese catalysts for intramolecular C(sp3)-H aminations.
These catalysts proceed with unprecedented levels of reactivity and tunable selectivities in complex molecule
settings, without the need for directing groups. These reactions and the late stage derivatization approach
have already begun to be utilized by pharmaceutical companies in drug discovery and metabolite identification.
The major challenges in the application of this strategy as a comprehensive C(sp3)-H functionalization
approach to enable drug discovery are the development of new intermolecular methods and the expanded
capacity for site-, chemo-, and stereoselectivities. To overcome these challenges, we will develop 1) new
palladium/sulfoxide complexes for catalyst-controlled asymmetric induction and complex fragment couplings;
2) new base metal complexes for aliphatic C-H hydroxylations that proceed with alternate catalyst-controlled,
predictable site selectivities and increased tolerance of π-systems and nitrogen-containing compounds; and 3)
new base metal complexes for intra- and intermolecular C-H amination and alkylations. Analogous to the
impact of cross-coupling methods on C(sp2)-C(sp2) bond formation in drug discovery, these reactions will
ultimately empower scientists to form C(sp3)-O, -N, and -C bonds from ubiquitous C(sp3)-H bonds in complex
molecule scaffolds. This will reinvigorate efforts to explore natural products and other complex molecules as
sources of medicines and biological research too...

## Key facts

- **NIH application ID:** 10140372
- **Project number:** 5R35GM122525-05
- **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:** 2021
- **Award amount:** $476,288
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140372

## Citation

> US National Institutes of Health, RePORTER application 10140372, Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis (5R35GM122525-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140372. Licensed CC0.

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