Swapping out one letter in a word can entirely change its meaning. Similarly, swapping one atom in a molecule can completely change its identity.
A group of chemists with the University of Chicago has shown a new way to make a single-atom edit to a molecule, without changing any of its other components. The innovative method can be used to make a family of molecules known as pyrroles that includes many widely used medicines—and is significantly simpler, faster and more cost-effective than previous processes.
The inventors hope the method could help speed up the process of discovering new drugs.
“There are a lot of pyrroles that have never been made before, or have been made but are very expensive,” said chemist and graduate student Abigail Bracken, co-first author of the paper published Aug. 19 in Nature. “We hope this opens up possibilities for both research and drug discovery.”
Making useful molecules
Pyrroles are one of those things that most people haven’t heard about, but that quietly make life on Earth possible. For example, pyrroles form the basis of the heme that lets our blood carry oxygen and the chlorophyll that lets plants photosynthesize.
But they can be very difficult to synthesize in the laboratory, which limits how much experimentation can be done with them.
However, pyrroles have a set of molecules that are near-twins: another family of very common molecules called isoxazoles, whose makeups are almost identical except for a single atom. Where pyrroles have a carbon atom, isoxazoles have an oxygen atom. And they are much, much easier to make in the laboratory.
“For example, for one of the molecules we made, the isoxazole version costs $11 per gram, but the pyrrole version of that molecule is $2,000 per gram,” said chemist and graduate student Alexa Lawrie, also a co-first author on the paper.
Bracken and Lawrie are members of the laboratory of Prof. Mark Levin, which specializes in finding ways to make big changes to molecules more easily—an approach they call “skeletal editing.” Normally, if you’d like to make a new molecule, you have to start from scratch; the Levin lab designs techniques that allow scientists to quickly swap atoms in and out of existing molecules.
The team set out to see if they could find a way to directly turn isoxazoles directly into pyrroles, by swapping just a single atom.
After rigorous trial and error, they discovered a technique that significantly cuts the number of required steps and shortens the process to just one to two days. Unlike previous methods, the new process can also be completed in the same flask from start to finish.
The key turned out to be using a substitution reaction to attach a specific group of atoms containing three carbons—known as a propargyl group—to the ring, and then cutting the ring and replacing the oxygen atom with one of the new carbon atoms.
Expanding the scope
The find could be extremely useful for pharmaceutical scientists looking to develop new drugs, the team said.
“This means you can very quickly make a number of different pyrroles to test, which previously would have been time-consuming and expensive,” said Lawrie.
It’s also helpful for tests to determine which parts of molecules perform different actions, which is key knowledge for designing better drugs.
“If you can keep the ring the same and only change out one atom at a time, that could be very helpful for exploring how a drug works and which parts carry out which actions,” explained Bracken.
Members of the team plan to continue to expand the chemistry, they said.
“This method doesn’t work on every single variation, so it would be really interesting to expand the scope of the reaction,” said Lawrie.
Citation: “Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit.” Bracken, Lawrie, Romita and Levin, Nature, Aug. 19, 2026.
Funding: National Institutes of Health, National Science Foundation Graduate Research Fellowships Program, UChicago Quad Scholars Program, Beckman Scholars Program.
