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Scanning nitrogen in sp3-rich scaffolds enabled by carbonyl-to-nitrogen atom swap.

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Title: Scanning nitrogen in sp3-rich scaffolds enabled by carbonyl-to-nitrogen atom swap.
Authors: Zhang, Zining (AUTHOR), Liang, Zhehan (AUTHOR), Ye, Rong (AUTHOR), Dong, Guangbin (AUTHOR)
Source: Science. 4/30/2026, Vol. 392 Issue 6797, p536-542. 7p.
Subjects: Amines, Structure-activity relationships, Pharmaceutical chemistry
Abstract: Medicinal chemistry campaigns routinely require access to series of saturated nitrogen heterocycle (SNH)–based analogs that place nitrogen at different positions to probe structure-activity relationships. However, systematic preparation of N-positional variants remains synthetically burdensome. In this work, we report a strategy for nitrogen scanning in sp3-rich scaffolds enabled by the exchange of a carbonyl group with an amine moiety, formally achieving a carbonyl-to-nitrogen (CO-to-N) atom swap. Because ketone positional isomers can be readily obtained through carbonyl transposition or carbon-hydrogen oxidation from a common carbocyclic precursor, the CO-to-N atom swap greatly streamlines the preparation of SNH positional analogs and obviates the need for multiple de novo syntheses. The CO-to-N reaction exhibits exceptional functional group compatibility and generality, which makes it well suited for late-stage modification of complex bioactive molecules and for isotopic labeling. Editor's summary: Cyclic fragments incorporating nitrogen are ubiquitous components of pharmaceuticals. Recently, chemists have introduced a variety of editing techniques to modify these frameworks one atom at a time, mostly focusing on unsaturated rings. Two groups now report complementary methods to diversify saturated cyclic amines (see the Perspective by Wu). Li et al. used mild oxidation to pull an exocyclic nitrogen into a carbon ring. Zhang et al. replaced carbonyl groups embedded in rings with nitrogen, taking advantage of a companion reaction that can readily migrate the carbonyl around the framework beforehand. —Jake S. Yeston [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Scanning nitrogen in sp<superscript>3</superscript>-rich scaffolds enabled by carbonyl-to-nitrogen atom swap.
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  Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 4/30/2026, Vol. 392 Issue 6797, p536-542. 7p.
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  Data: Medicinal chemistry campaigns routinely require access to series of saturated nitrogen heterocycle (SNH)–based analogs that place nitrogen at different positions to probe structure-activity relationships. However, systematic preparation of N-positional variants remains synthetically burdensome. In this work, we report a strategy for nitrogen scanning in sp3-rich scaffolds enabled by the exchange of a carbonyl group with an amine moiety, formally achieving a carbonyl-to-nitrogen (CO-to-N) atom swap. Because ketone positional isomers can be readily obtained through carbonyl transposition or carbon-hydrogen oxidation from a common carbocyclic precursor, the CO-to-N atom swap greatly streamlines the preparation of SNH positional analogs and obviates the need for multiple de novo syntheses. The CO-to-N reaction exhibits exceptional functional group compatibility and generality, which makes it well suited for late-stage modification of complex bioactive molecules and for isotopic labeling. Editor's summary: Cyclic fragments incorporating nitrogen are ubiquitous components of pharmaceuticals. Recently, chemists have introduced a variety of editing techniques to modify these frameworks one atom at a time, mostly focusing on unsaturated rings. Two groups now report complementary methods to diversify saturated cyclic amines (see the Perspective by Wu). Li et al. used mild oxidation to pull an exocyclic nitrogen into a carbon ring. Zhang et al. replaced carbonyl groups embedded in rings with nitrogen, taking advantage of a companion reaction that can readily migrate the carbonyl around the framework beforehand. —Jake S. Yeston [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.aef0610
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        Text: English
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              Text: 4/30/2026
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