Photocatalytic oxygen-atom transmutation of oxetanes
Article Date: 15 October 2025 | Journal: Nature | Authors: Ying-Qi Zhang, Shuo-Han Li, Xinglong Zhang, Ming Joo Koh et al.
Summary
The authors report a general photocatalytic method that replaces the endocyclic oxygen atom in oxetanes with nitrogen-, sulfur- or carbon-based groups in a single operation. This ‘‘oxygen-atom transmutation’’ converts readily available oxetanes into a wide range of non-aromatic four-membered saturated heterocycles and carbocycles (for example azetidines, thietanes and cyclobutanes) that are valuable in medicinal chemistry. The protocol shows broad functional-group compatibility, is suitable for late-stage functionalisation of complex molecules and simplifies routes that would otherwise require multiple steps.
Mechanistic studies indicate that chemoselectivity arises from preferential reaction at the endocyclic oxygen to form an acyclic dihalide intermediate; subsequent nucleophile-promoted ring reconstruction furnishes the new four-membered framework.
Key Points
- A photocatalytic strategy enables replacement of the oxetane oxygen with N, S or C nucleophiles to give diverse four-membered rings in one step.
- The method tolerates a wide range of functional groups and is applicable to late-stage functionalisation of complex substrates.
- Products accessible include azetidines, thietanes and cyclobutanes—scaffolds of increasing interest in drug discovery for their stability and target-specific properties.
- Mechanism: selective activation of the endocyclic oxygen produces an acyclic dihalide intermediate that undergoes efficient ring reconstruction in the presence of a nucleophile.
- This single-step atom swap can markedly shorten synthetic sequences needed to access cyclic pharmacophores from common oxetane precursors.
- The work provides practical and mechanistic insight that could be adopted broadly in medicinal and synthetic chemistry programmes.
Context and relevance
Four-membered saturated rings are prized in medicinal chemistry for their unique physicochemical profiles—improving potency, metabolic stability and selectivity in many cases. Oxetanes are readily available and commonly used motifs; an operationally simple method to exchange the oxygen atom expands the synthetic toolbox by turning oxetanes into many other valuable cyclic building blocks without lengthy rework. This aligns with ongoing trends in late-stage functionalisation and modular synthesis aimed at accelerating analogue generation in drug discovery.
Why should I read this?
Short version: clever trick, big payoff. If you or your team fiddle with drug-like molecules, this paper shows a one-step way to turn oxetanes into a bunch of other four-membered rings that normally need multiple steps. It saves time, keeps sensitive groups intact and is useful for quickly making analogues — neat for medicinal chemists and synthetic teams who want shortcuts that actually work.
Author note
Punchy take: this isn’t just another reaction paper — it’s a practical tactic for swapping a single atom to unlock new scaffolds from an abundant starting point. For groups focused on rapid analogue synthesis or late-stage edits, the method is highly relevant and worth reading closely.