Chemists at the University of Chicago have introduced a new method to build certain molecules more efficiently, using a "placeholder" technique that avoids previous complicated processes. The method could accelerate drug discovery and suggests new approaches for chemical synthesis.
"In creating many of these molecules, called pyrazoles, you often end up with two products when you only want one, and they're hard to separate," explained Alexander Fanourakis, a postdoctoral researcher at the university and the study's lead author. "Our method ensures only the desired molecule is produced, potentially opening new doors."
Mark Levin, associate professor of chemistry at UChicago and senior author, emphasized, "The shape is everything. Correctly connected molecules become effective drugs, while incorrectly connected ones can be harmful."
Pyrazoles, used in drugs and agricultural chemicals, often result in a mixture of end products, requiring purification. Fanourakis noted, "You're sometimes interested in the minor end product, leading to waste."
The team developed a new process involving previously underexplored reactions, where a placeholder atom occupies one challenging site on the molecule, allowing further reactions to replace the placeholder with the desired atoms. They tested this method with difficult-to-make molecules, achieving perfect selectivity.
Ali remarked on the method's efficiency, "Every saved step is not only time saved but also energy, waste, and by-products reduced."
Fanourakis highlighted the method's potential in drug discovery, stressing that it allows chemists to expedite structural testing. "You can have a guarantee that whatever you put on it will go exactly where you want it to," Ali added.
Levin believes this concept could be influential in other areas of chemistry. "The idea that you can use these atom replacements even to control selectivity has been eye-opening," he said.
Other University of Chicago contributors to the study include Liao Chen, Patrick Kelly, and Abigail Bracken, alongside Johnson & Johnson chemist Christopher Kelly. The research, funded by several foundations and grants, was published on April 3, 2025, in Nature.
Citation: “Strategic atom replacement enables regiocontrol in pyrazole alkylation.” Fanourakis et al, Nature, April 3, 2025.
Funding: Packard Foundation, Bristol Myers Squibb, University of Chicago Quad Scholars Grant, National Science Foundation, Seymour Goodman Fund.