Molecule customization process does double duty

Rice University graduate student Kang-Jie (Harry) Bian sets up photosensitive molecules for an experiment in chemist Julian West’s lab. Bian is lead author on a study inspired by natural processes to enable modular difunctionalization of alkene molecules for drug and material design. Credit: Rice University

Inspired by your liver and activated by light, a chemical process being developed in labs at Rice University and in China holds promise for drug design and the development of unique materials.

Researchers led by rice chemist Julian West and Xi-Sheng Wang of the University of Science and Technology of China, Hefei, report their successful catalytic process to simultaneously add two distinct functional groups to single alkenes, organic molecules derived from petrochemical products containing at least one carbon-carbon double bond associated with hydrogen atoms.

Better yet, they say, is that these alkenes are “disabled“- that is, they lack reactive atoms near the double bond – and so far they have proven difficult to improve.

The chemical pathway detailed in the Journal of the American Chemical Society could simplify the creation of a library of precursors for the pharmaceutical industry and improve polymer manufacturing.

West, whose lab designs synthetic chemistry processes, said the initial inspiration came from an enzyme, cytochrome P450, which the liver uses to remove potentially harmful substances. molecules.

“These enzymes are like circular saws that grind molecules before they get you in trouble,” he said. “They do this through an interesting mechanism called radical rebound.”

West said P450 finds carbon-hydrogen bonds and removes the hydrogen, leaving a carbon-centered radical that includes an unpaired electron.

“This electron really wants to find a mate, so the P450 will immediately return a oxygen atom (the ‘bounce’), oxidizing the molecule,” he said. “In the body, it helps deactivate those molecules so you can get rid of them.

“That kind of rebound is powerful,” West said. “And Harry (lead author Kang-Jie Bian, a graduate student at Rice) wondered if we could do something like that to transfer different fragments onto this radical.”

Molecule customization process does double duty

Rice University chemists have developed a method to add two fragments to an alkene molecule in a single process. This discovery could simplify the design of drugs and materials. Credit: West Research Group/Rice University

Their solution was to enable what they call radical ligand transfer, a general method that uses manganese to catalyze “radical rebound”.

West said P450 uses the neighboring element iron to catalyze the biological reaction, previous experiences at the Rice lab and elsewhere have shown that manganese has potential.

“Manganese helped the process be more selective and a bit more active, as well as being much cheaper and easier,” he explained. “It can transfer a bunch of different atoms, like chlorine, nitrogen, and sulfur, just by changing the commercial ingredient you add to the reaction.”

This reaction represented a functionalization. Why not go together?

West said Bian also came up with the idea of ​​adding a photocatalyst to the mix. “When you light him up, he gets excited and you can do things that would be impossible in the ground statehow to activate fluorocarbon small molecules to make radical moieties that have carbon-fluorine bonds, which are important for pharmaceuticals and material science“, he said. “Now we can attach them to our molecule of interest.”

The end result is a smooth, modular process for adding two functional groups to a single alkene in a single step.

“First we have carbon-carbon double bond of a molecule of interest, the alkene,” West said, summarizing. “Then we add this valuable fluorocarbon, and then the manganese catalyst swims in and does this radical ligand transfer to add a chlorine atom, nitrogen or sulfur.”

He noted that the collaboration between Rice and Wang’s lab was a natural result of Bian moving to Rice from Hefei, where he earned his master’s degree. “We really focused on the manganese aspect of this work, and Wang’s group not only brought their expertise in photocatalysis, but also developed and tested carbon-fluorine fragments, and showed that they would work very well. well in this system,” West said.

He said that with pharmaceutical and materials sciences, chemical biology could also benefit from the process, in particular for its affinity with pClicka method discovered by Rice chemist Han Xiao to attach drugs or other substances to antibodies.

The co-authors are Rice’s undergraduate David Nemoto Jr. and graduate student Shih-Chieh Kao, along with Yan He and Yan Li from Hefei. Wang is a teacher in Hefei. West is the Norman Hackerman-Welch Young Investigator and Assistant Professor of Chemistry.

In a hurry to develop drugs? Here is your CAT

More information:
Kang-Jie Bian et al, Modular difunctionalization of unactivated alkenes by bio-inspired radical ligand transfer catalysis, Journal of the American Chemical Society (2022). DOI: 10.1021/jacs.2c04188

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