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 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.