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

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $549,475

## Abstract

PI, White, M.C.    R35 GM 122525 
  
 1  Project Summary
 2 
 3  The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and
 4  physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group
 5  transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new
 6  functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of
 7  biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and
 8  C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug
 9  discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates.
10  Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their
11  electronic, steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that
12  prior to 2007 viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and
13  commercialized iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts
14  for allylic C–H functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)–
15  H aminations. These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings,
16  without the need for directing groups. The late-stage functionalization approach that has emerged from this work has
17  been utilized in both industrial and academic settings. Building on this considerable foundation, we will undertake
18  major challenges required to broaden the application of late-stage functionalization in chemical synthesis and drug
19  discovery. We will innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity
20  for tolerance of π-functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non-
21  bonding interactions. These advances will make possible new reactions such as oxidative alkylations and catalyst-
22  controlled asymmetric induction and site-divergence. We will develop new base-metal complexes for intermolecular
23  C–H aminations and alkylations with unprecedented selectivities, and discover new ligand types amenable to
24  asymmetric induction. New palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing
25  functionality in complex settings. Cross-coupling reactions will be developed where O and N are introduced as part of
26  complex fragments. Additionally, asymmetric C–H functionalizations that feature catalyst-controlled
27  diastereoselectivities in substrates with pre-existing stereogenic centers will be advanced. Collectively, thi...

## Key facts

- **NIH application ID:** 10330708
- **Project number:** 2R35GM122525-06
- **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:** 2022
- **Award amount:** $549,475
- **Award type:** 2
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330708

## Citation

> US National Institutes of Health, RePORTER application 10330708, Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis (2R35GM122525-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10330708. Licensed CC0.

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