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

Abstract

Isoxazoles and pyrroles feature prominently in pharmaceutical and bioactive compounds of interest^1,2. 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 pyrroles^3,4. 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.