Researchers at the University of Chicago have developed a new skeletal editing technique that lets chemists create challenging pyrrole compounds from easier-to-assemble isoxazole molecules through an oxygen to-carbon swap.
Abigail Bracken, a fourth-year graduate student in Mark Levin’s laboratory, presented the work in a talk at the ACS Fall 2026 meeting on Tuesday morning in the Division of Organic Chemistry; her coauthors, Alexandra Lawrie and Isabella Romita, reported on the study in poster presentations on Tuesday afternoon. The work was published in Nature last week (DOI: 10.1038/s41586-026-10933-6).
Pyrrole synthesis is “constantly an issue that people are trying to solve,” Bracken told C&EN. Traditional syntheses involve multiple steps and expensive precursors, and the range of substitution patterns is very limited. Though they differ from pyrroles by only one atom, isoxazoles can be made modularly with a greater variety of attachments.
Bringing isoxazoles’ diversity into the pyrrole world via atom swapping would hugely expand the range of building blocks that chemists can access, Levin said. In fact, a 2025 paper in the Journal of Medicinal Chemistry rated isoxazole-to-pyrrole conversion as one of the most potentially valuable skeletal edits to develop.
“It was a long winding road” to figure out how to do it, Levin said. “There were probably three other strategies that we tried, to connect those dots, that didn’t work,” including using titanium to open the isoxazole ring.
Inspired by a pyrrole synthesis from researchers in China, Bracken and Lawrie landed on a three-step approach for the atom swap. The protocol, which can be carried out in a single reaction vessel, starts with attaching a three-carbon group containing a triple bond to the isoxazole’s nitrogen atom. Next comes reduction with zinc dust to open the ring and form a key pyrrole precursor. Finally, a base prompts the molecule to curl into a pyrrole ring, spitting out acetic acid as a by-product.
“Even though the things that are happening in the flask are pretty complicated, the procedure is operationally very simple,” Bracken said.
The team used the reaction to synthesize several pyrrole-containing molecules whose substitution patterns would make them especially difficult or expensive to make via traditional methods. “The pyrroles were either never reported before, or if they were reported, they were really expensive,” Lawrie said.
“It’s a fantastic way of making pyrroles,” said Yoonsu Park, an organic chemist at the Korea Advanced Institute of Science and Technology who developed an oxygen-to-nitrogen swap for making pyrroles in 2024 but was not involved in this work. “They kind of cleverly detour the difficult synthesis with the more straightforward one” in a way that could meaningfully expand the library of pyrrole compounds that chemists can create, he added.
As the University of Chicago researchers explored the reaction scope, they found that some starting materials led to mixtures of products where the substituents on the central ring had shifted positions. Rather than dismiss these as failed reactions, they figured out that the side products were coming from an alternate ring-forming mechanism. Eventually, the team developed a quantitative model for when rearrangement was likely to happen based on the size and shape of the groups on the starting material. The model gives future chemists tools to figure out whether the reaction is likely to work cleanly for the molecules they’re interested in.
“There’s a lot of craft and experimentation gone into this . . . a real lot of mechanistic depth,” said Michael Greaney of the University of Manchester, who also works on skeletal editing for aromatic molecules and was also not involved in the work.
Levin said there are two things he hopes for when his lab develops new chemistry: that people use it, and that it inspires more chemists to come up with creative approaches to synthesis. And he believes this reaction has enormous potential on both fronts. “It’s a different way of thinking about the retrosynthesis that I’m also hopeful is going to get people thinking.”
Lawrie said a friend in another lab working with pyrroles has already contacted her and said she might try the reaction. “That’s actually a really nice example of what we would like to see,” she said.
