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

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.