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A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
Published on: September 25, 2017
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Aromatic nitrogen scanning by ipso-selective nitrene internalization.
Tyler J Pearson1, Ryoma Shimazumi1, Julia L Driscoll1
1Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
Science (New York, N.Y.)
|September 28, 2023
Summary
Researchers developed a new method for direct carbon-to-nitrogen replacement in aryl compounds, enabling efficient synthesis of pyridine isomers for drug discovery. This streamlined process simplifies the creation of diverse molecular structures.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Synthetic Methodology
Background:
- Nitrogen scanning in aryl fragments is crucial for drug discovery.
- Current methods necessitate lengthy, parallel synthesis of pyridyl isomers.
- A lack of direct carbon-to-nitrogen (C-to-N) replacement reactions limits efficiency.
Purpose of the Study:
- To develop a site-directable aryl C-to-N replacement reaction.
- To enable unified access to various pyridine isomers.
- To streamline the drug discovery process by simplifying synthesis.
Main Methods:
- A two-step, one-pot procedure involving aryl azides.
- Photochemical conversion of aryl azides to 3H-azepines.
- Oxidatively triggered C2-selective cheletropic carbon extrusion via a spirocyclic azanorcaradiene intermediate.
Main Results:
- Successful regioselective synthesis of pyridine products.
- The reaction proceeds without perturbing the substrate due to ipso-carbon excision.
- Demonstrated application in the synthesis of a pyridyl estrone derivative and a nitrogen scan.
Conclusions:
- The reported nitrene-internalization process provides a novel C-to-N replacement strategy.
- This method offers a more efficient and unified approach to synthesizing diverse pyridine isomers.
- The reaction's site-directability and regioselectivity are advantageous for medicinal chemistry applications.
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