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.
Photo Credit: Rodolfo Clix
Scientific Frontline: Extended "At a Glance" Summary: Single-Atom Substitution for Pyrrole Synthesis
The Core Concept: University of Chicago chemists have developed a "skeletal editing" technique to swap a single oxygen atom for a carbon atom within a molecule, directly converting isoxazoles into pyrroles.
Key Distinction/Mechanism: Instead of synthesizing complex pyrrole molecules from scratch, this method uses a substitution reaction to attach a propargyl group (containing three carbons) to an isoxazole ring. The ring is then cut, and the oxygen atom is replaced with one of the new carbon atoms, completing the conversion in a single flask over one to two days.
Major Frameworks/Components:
- Pyrroles: A family of molecules foundational to life, forming the basis of heme in blood and chlorophyll in plants, but traditionally difficult and expensive to synthesize in the laboratory.
- Isoxazoles: Molecules structurally near-identical to pyrroles, differing by a single atom (oxygen instead of carbon), but significantly cheaper and easier to manufacture.
- Skeletal Editing: An approach to chemical synthesis that focuses on making targeted alterations to the core structure of existing molecules rather than building them entirely anew.
- Propargyl Group: A specific three-carbon atom group utilized in the substitution reaction to facilitate the oxygen-to-carbon swap.
Branch of Science: Synthetic Chemistry, Pharmacology, Molecular Biology.
Future Application: The technique will allow pharmaceutical scientists to rapidly and cost-effectively generate diverse pyrrole variants for drug testing. It also enables precise mapping of how specific atoms within a molecule influence drug efficacy and function.
Why It Matters: By drastically reducing the time, complexity, and cost of synthesizing vital biological building blocks (e.g., reducing the cost of one specific molecule variant from $2,000 per gram to its $11 per gram precursor), this method removes significant bottlenecks in pharmacological research and drug discovery.
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 at the University of Chicago has demonstrated 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 synthesize a family of molecules known as pyrroles, which includes many widely used medicines, and it is significantly simpler, faster, and more cost-effective than previous processes.
The inventors hope the method will help accelerate the discovery of 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 August 19 in the journal Nature. “We hope this opens up possibilities for both research and drug discovery.”
Making Useful Molecules
Pyrroles are compounds that most people have not heard of, but they quietly make life on Earth possible. For example, pyrroles form the basis of the heme that allows our blood to carry oxygen and the chlorophyll that enables plants to photosynthesize.
However, they can be very difficult to synthesize in the laboratory, which limits how much experimentation can be conducted with them.
Pyrroles have a set of molecules that are near twins, however: another family of very common molecules called isoxazoles, whose structures are almost identical except for a single atom. Where pyrroles have a carbon atom, isoxazoles have an oxygen atom. Furthermore, isoxazoles are much easier to synthesize 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 of the paper.
Bracken and Lawrie are members of the laboratory of Professor Mark Levin, which specializes in finding ways to make significant changes to molecules more easily—an approach they call “skeletal editing.” Normally, to create a new molecule, scientists must start from scratch; the Levin laboratory designs techniques that allow researchers to quickly swap atoms in and out of existing molecules.
The team set out to determine if they could directly convert isoxazoles into pyrroles by swapping a single atom.
After rigorous trial and error, they discovered a technique that significantly reduces the number of required steps and shortens the process to just one to two days. Unlike previous methods, the new process can be completed in the same flask from start to finish.
The key proved 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 discovery 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 is also helpful for testing to determine which parts of molecules perform specific functions, 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 expanding the chemistry.
“This method doesn’t work on every single variation, so it would be really interesting to expand the scope of the reaction,” said Lawrie.
Funding: National Institutes of Health, National Science Foundation Graduate Research Fellowships Program, UChicago Quad Scholars Program, Beckman Scholars Program.
Published in journal: Nature
Title: Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit
Authors: Abigail J. Bracken, Alexandra P. Lawrie, Isabella F. Romita, and Mark D. Levin
Source/Credit: University of Chicago | Louise Lerner
Edited by: Scientific Frontline
Reference Number: chm090126_01
