近日，新加坡国立大学Koh, Ming Joo团队研究了氧烷的光催化氧原子嬗变。相关论文于2025年10月15日发表在《自然》杂志上。

非芳香族杂环和碳环构成了无数生物活性和功能分子的骨架。值得注意的是，它们的饱和环分子，如氮啶、硫烷和环丁烷，在药物化学中引起了越来越多的关注。这些分子通常具有与药物发现相关的物理化学性质：效力、稳定性、代谢稳定性和靶标特异性。在现成的氧烷中替换氧原子将为各种环状药物载体提供直接途径，然而这种原子交换在非芳香分子中很少有报道。

研究组报告了一种通用光催化策略，该策略选择性地用氮基、硫基或碳基部分取代氧烷的氧原子，在一次操作中将其转化为多种饱和循环构建块。这种原子交换方法具有高官能团相容性，适用于后期功能化，大大简化了药物和复杂药物类似物的合成，否则需要多步路线。机制研究揭示了化学选择性的起源，化学选择性允许内环氧原子优先反应产生无环二卤化物中间体，然后在亲核物质存在下进行有效的环重建。

附：英文原文

Title: Photocatalytic oxygen-atom transmutation of oxetanes

Author: Zhang, Ying-Qi, Li, Shuo-Han, Zhang, Xinglong, Koh, Ming Joo

Issue&Volume: 2025-10-15

Abstract: Non-aromatic heterocycles and carbocycles form the skeleton of countless bioactive and functional molecules1,2. Of note, four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes have garnered increasing attention in medicinal chemistry3-7. These molecules often possess physicochemical properties relevant to drug discovery: potency, stability, metabolic stability and target specificity3. The replacement of oxygen atoms in readily available oxetanes would offer a direct route to a variety of these cyclic pharmacophores, yet such atom swapping has been rarely reported for non-aromatic molecules. Here we report a general photocatalytic strategy that selectively substitutes the oxygen atom of an oxetane with a nitrogen-, sulfur- or carbon-based moiety, transforming it into a diverse range of saturated cyclic building blocks in a single operation. This atom swapping method exhibits high functional group compatibility and is applicable to late-stage functionalization, substantially simplifying the synthesis of pharmaceuticals and complex drug analogues that would otherwise require multi-step routes. Mechanistic investigations unveil insights on the origin of chemoselectivity that allows the endocyclic oxygen atom to react preferentially to generate an acyclic dihalide intermediate, which then undergoes efficient ring reconstruction in the presence of a nucleophilic species.

DOI: 10.1038/s41586-025-09723-3

Source: https://www.nature.com/articles/s41586-025-09723-3