近日，美国芝加哥大学Mark D. Levin团队报道了由异噁唑经氧到碳骨架编辑合成吡咯。相关论文发表在2026年8月19日出版的《自然》杂志上。

异噁唑和吡咯在药物及生物活性化合物中占有重要地位。尽管它们的核心结构仅相差一个原子（氧与碳），但各自的从头环组装却需要截然不同的合成方法，因为电子相容的异噁唑环可适用多种逆合成切断，而这些切断对于相应的吡咯而言却难以实现。鉴于这两类杂环在结构上的相似性，骨架编辑为满足这一需求提供了契机，因为它使得非传统的逆合成切断成为可能。

研究组实现了异噁唑的氧到碳原子替换，以一锅法序列获得吡咯。他们确定N-丙炔基烯胺酮是连接这两类杂环的关键中间体，为那些传统合成难以构建的吡咯骨架提供了一种正交的逆合成切断思路。在研究过程中，研究组意外发现了烯胺酮反应性，并开发了一个预测性计算模型，用以捕捉控制反应结果的构象特征。通过将该氧到碳替换反应作为桥梁连接两个杂环，可以实现难以获得吡咯的区域选择性合成。

附：英文原文

Title: Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit

Author: Bracken, Abigail J., Lawrie, Alexandra P., Romita, Isabella F., Levin, Mark D.

Issue&Volume: 2026-08-19

Abstract: Isoxazoles and pyrroles feature prominently in pharmaceutical and bioactive compounds of interest1,2. Although their core structures differ by only a single atom (O versus C), their respective de novo ring assemblies require vastly different syntheses, as the electronically consonant isoxazole core is amenable to a range of disconnections that are inaccessible for the corresponding pyrroles3,4. Given the structural similarity between these two heterocyclic classes, skeletal editing offers an opportunity to meet this need, as it empowers non-traditional retrosynthetic disconnections5. Here we achieve an O-to-C atom replacement of isoxazoles, affording pyrroles in a one-pot sequence. We identify the N-propargylic enaminone as a key intermediate connecting the two heterocycle classes, providing a retrosynthetic disconnection orthogonal to traditional syntheses for otherwise challenging pyrrole scaffolds6. During our investigations, we encountered unexpected enaminone reactivity and developed a predictive computational model capturing the conformational features controlling reaction outcomes7. Regioselective syntheses of elusive pyrroles can be achieved by linking these two heterocycles with an O-to-C replacement reaction.

DOI: 10.1038/s41586-026-10933-6

Source: https://www.nature.com/articles/s41586-026-10933-6