康 · 学术 | Reaction of the Day No. 1755

Oxetane-to-azetidine Skeletal Editing

Dayu Tian1,2, Like Luo1,2, Xian Xiao1, Guang Chen1, Liqiang Zhang1, Jiaxin Wang1, Xiaocheng Wang 1 & Hai-Jun Zhang 1

1State Key Laboratory of Precision and Intelligent Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei, China

—Nature Chemistry, 2026, 18,1800, DOI: 10.1038/s41557-026-02213-7

Recommended by Xiaoxu Wang_ MC3 & Haiping Lv _ MC2

KEY WORDS: Skeletal editing, Mitsunobu reaction (反应类型), oxetanes, amines (原料), azetidines (产物), Csp3-N, Csp2-N (成键类型), B(C6F5)3, BEHT triflate (其他)

ABSTRACT: The identity of heteroatoms within bioactive molecules can profoundly influence their physicochemical and biological properties. Evaluating heterocycle analogues featuring distinct heteroatoms for new therapeutic opportunities, however, often requires laborious de novo syntheses. Here we report a straightforward, two-step, one-pot strategy for the direct skeletal editing of readily available oxetanes into azetidines using a broad range of aromatic and aliphatic amines. This transformation proceeds under simple conditions through Lewis acid-mediated intermolecular aminolysis of oxetanes, followed by an intramolecular Mitsunobu-type dehydrative cyclization to forge the azetidine ring. The resulting non-redox skeletal editing platform features broad substrate scope, excellent functional group tolerance and compatibility with complex, drug-like molecules, enabling rapid access to azetidine analogues from oxetane precursors for heterocycle editing in drug discovery.

Optimization of ring-opening and optimization of ring-closing step

Oxetane substrate scope (selected examples)

Amine substrate scope (selected examples)

Late-stage skeletal editing of drug-like oxetanes (selected examples)

Summary and Comments

In summary, Prof. Hai-Jun Zhang et al. have established a broadly applicable, non-redox skeletal editing strategy that achieves the medicinally important transformation of oxetanes into azetidines under simple conditions. This approach proceeds via Lewis acid-mediated intermolecular aminolysis followed by intramolecular cyclization, providing access to a wide range of azetidine analogues from both simple and complex bioactive molecules. It is precisely through the strategic integration of these two simple transformations that our protocol delivers exceptional functional group tolerance, accommodates structurally diverse amines and enables late-stage skeletal editing of druglike compounds. Compared with the existing oxetane-to-azetidine skeletal editing strategy, our protocol avoids redox activation and specialized photochemical equipment while offering operational simplicity and broad substrate scope. We anticipate that this nonredox skeletal editing platform will accelerate exploration of previously unexplored azetidine chemical space, facilitating rapid analogue synthesis and late-stage diversification in medicinal chemistry and related fields.

张海军教授等人开发了一种广泛应用的非氧化还原骨架编辑策略，能够在简单条件下实现氧杂环化合物向氮杂环化合物的药物重要转化。该方法通过路易斯酸介导的分子间氨基裂解，继而发生分子内环化反应，从而可从简单和复杂的生物活性分子中获得多种氮杂环类似物。正是通过这两种简单反应的巧妙结合，该方法具有优异的官能团耐受性，能够兼容结构多样的胺类化合物，并支持药物候选化合物后期的骨架编辑。与现有的氧杂环至氮杂环骨架编辑策略相比，此方法无需依赖氧化还原活化或专用光化学设备，同时操作简便、底物范围广。