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

Published: 08/19/2026, 12:00 AM

Nature (2026) Cite this article 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. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Prices may be subject to local taxes which are calculated during checkout All data are in the Supplementary Information. NMR data are provided in image and peaklist format; original NMR spectra files are available from the corresponding author (M.D.L.) on reasonable request. Crystallographic data have been deposited to the Cambridge Crystallographic Data Centre (deposition nos. 2534489 and 2534490). Pandhurnekar, C. P., Pandhurnekar, H. C., Mungole, A. J., Butoliya, S. S. & Yadao, B. G. A review of recent synthetic strategies and biological activities of isoxazole. J. Heterocycl. Chem. 60, 537–565 (2023). Article CAS Google Scholar Ganesh, B. H. et al. Pyrrole: a decisive scaffold for the development of therapeutic agents and structure–activity relationship. ChemMedChem. 19, e202300447 (2024).