# Atom-swapping reaction sequences enabled by decarbonylation and decarboxylation

> **NIH NIH R35** · IOWA STATE UNIVERSITY · 2022 · $313,600

## Abstract

The constant search for new chemical entities to address unmet medical needs compels the continued invention
of new molecular editing approaches to derivatize complex small molecules. Single atom changes in a molecule
alter the electronic properties of the molecule without extensive accompanying structural changes and are known
to dramatically alter its biological activity. However, methods that enable substitutions of atoms embedded in the
carbon framework of a molecule remain sparse. Substitution of a single atom – “atom swapping” – in the core
structure of a molecule, rather than on the periphery, is challenging to execute because it involves multiple bond-
breaking and bond-forming events. The conventional approach for introducing single atom changes in a molecule
is thus to re-design synthesis routes to access atom-swapped derivatives. We challenge this long-standing
practice by presenting a general strategy for atom swapping that proceeds in two stages – oxidation and
transition metal-catalyzed carbon-extrusion reactions. The proposed research encompasses carbon-to-oxygen
and carbon-to-nitrogen substitutions, and the conversion of lactones to lactams or cycloalkenes. The key step in
all the proposed transformations is a transition metal-catalyzed decarbonylation or decarboxylation reaction. We
will focus our efforts on the discovery and development of catalysts that promote decarbonylation and
decarboxylation reactions on core motifs native to natural products and pharmaceuticals. These proposed
reactions require that the catalyst be able to: 1) activate inert amide or ester bonds yet promote challenging
carbon-heteroatom reductive eliminations; and 2) undergo site-selective oxidative addition. To identify catalysts
that fulfil both criteria, we will examine ligand effects in each step of the catalytic cycle to enable rational ligand
design and optimization. We will then interface the newly developed catalytic systems with well-documented C-
H oxidation and rearrangement reactions to directly modify the carbon framework of cyclic natural products and
pharmaceuticals. Realization of the goals of this proposal will circumvent tedious de novo synthesis for a single
atom change and bring to fruition a highly desired transformation in the pharmaceutical industry.

## Key facts

- **NIH application ID:** 10500155
- **Project number:** 1R35GM146854-01
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Junqi Li
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $313,600
- **Award type:** 1
- **Project period:** 2022-07-05 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500155

## Citation

> US National Institutes of Health, RePORTER application 10500155, Atom-swapping reaction sequences enabled by decarbonylation and decarboxylation (1R35GM146854-01). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10500155. Licensed CC0.

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