Synthesis of Cyclobutane‐Containing Tricyclic β‐Lactams Based on a Saturated Scaffold Enabled by Iron‐catalysed [2 + 2]‐Cycloaddition
Year: 2025
Type: article
Abstract: 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.
Source: Chemistry - A European Journal
Authors: Lea Freitag, Johannes Zeh, Levi A. Ziegenhagen, Felix J. Becker, Dragoș‐Adrian Roșca
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,640
OpenAlex ID: W4414572522