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Synthesis of cyclobutane-containing tricyclic β-lactams based on a saturated scaffold enabled by iron-catalysed (2 + 2)-cycloaddition

Highly saturated, three-dimensional β-lactams are valuable motifs in medicinal chemistry, yet general routes to cyclobutane-fused analogues remain scarce. Here we disclose a concise strategy that delivers pyrrolidine-, piperidine-, and azepane-based tricyclic β-lactams. A pyrimidinediimine-iron cata...

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Bibliographic Details
Main Authors: Freitag, Lea (Author) , Zeh, Johannes (Author) , Ziegenhagen, Levi A. (Author) , Becker, Felix J. (Author) , Roşca, Dragoş-Adrian (Author)
Format: Article (Journal)
Language:English
Published: November 17, 2025
In: Chemistry - a European journal
Year: 2025, Volume: 31, Issue: 64, Pages: 1-9
ISSN:1521-3765
DOI:10.1002/chem.202502476
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/chem.202502476
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.202502476
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Author Notes:Lea Freitag, Johannes Zeh, Levi A. Ziegenhagen, Felix J. Becker, and Dragoș-Adrian Roșca
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Summary:Highly saturated, three-dimensional β-lactams are valuable motifs in medicinal chemistry, yet general routes to cyclobutane-fused analogues remain scarce. Here we disclose a concise strategy that delivers pyrrolidine-, piperidine-, and azepane-based tricyclic β-lactams. A pyrimidinediimine-iron catalyst first constructs the cyclobutane ring and the N-heterocycle in one step through an intermolecular [2 + 2]-cycloaddition of allyl amines; a subsequent photochemical intramolecular C─H insertion then forges the β-lactam. The major products adopt rigid, cage-like conformations confirmed for the pyrrolidine series by single-crystal X-ray diffraction. Comprehensive conformer sampling (using CREST), DFT-calculated NMR shifts, and DP4 statistical analysis establish the stereochemistry across the library. Strain-release opening of the β-lactam ring furnishes methylphenidate analogues in a single step, underscoring the scaffolds’ synthetic versatility. Comparative studies on the corresponding bicyclic systems highlight the unique three-dimensionality imparted by the additional cyclobutane ring, further expanding the toolbox for lead-oriented synthesis.
Item Description:Im Titel steht der Ausdruck "2 + 2" in eckiger Klammer
Online veröffentlicht am 26. September 2026
Gesehen am 20.01.2026
Physical Description:Online Resource
ISSN:1521-3765
DOI:10.1002/chem.202502476

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