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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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
November 17, 2025
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| In: |
Chemistry - a European journal
Year: 2025, Jahrgang: 31, Heft: 64, Pages: 1-9 |
| ISSN: | 1521-3765 |
| DOI: | 10.1002/chem.202502476 |
| Online-Zugang: | 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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| Verfasserangaben: | Lea Freitag, Johannes Zeh, Levi A. Ziegenhagen, Felix J. Becker, and Dragoș-Adrian Roșca |
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| 520 | |a 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. | ||
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