Process to modify molecules does double work

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

Inspired by your liver and activated by light, a chemical process developed in labs at Rice University and in China holds great 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 of simultaneously adding two different functional groups to single alkenes, organic molecules extracted from petrochemicals containing at least one carbon-carbon double bond in combination with: hydrogen atoms

Better yet, they say, is that these alkenes”not activated– that is, they lack reactive atoms near the double bond – and so far it has proved challenging to improve.

The chemical pathway described in the Journal of the American Chemical Society would establish a library of precursors for the pharmaceutical industry and improve polymer production.

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

“These enzymes are like buzzsaws that grind up molecules before they can 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 behind a carbon-centered radical that contains an unpaired electron.

“That electron really wants to find a partner, so the P450 immediately gives a oxygen atom (the ‘rebound’), oxidizing the molecule,” he said. “In the body, that helps to deactivate these molecules so you can get rid of them.

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

Process to modify molecules does double work

Chemists at Rice University developed a method to add two fragments to an alkene molecule in one process. The 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 common method that uses manganese to catalyze the ‘radical rebound’.

West said while P450 uses the nearby element, iron, to catalyze the biological reaction, previous experiments in the Rice lab and elsewhere, manganese was shown to have potential.

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

That reaction resulted in one functionalization. Why not go for two?

West said Bian also came up with the idea of ​​adding a photocatalyst to the mix. “If you shine a light on it, it gets excited and you can do things that would be impossible in the future.” ground statelike activating fluorocarbon small molecules to make radical fragments with carbon-fluorine bonds, which are important for pharmaceutical and materials science‘, he said. “Now we can attach these to our molecule of interest.”

The end result is a mild and modular process of adding two functional groups to one alkene in one step.

“First we have the 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 up and does this radical ligand transfer to add a chlorine, nitrogen, or sulfur atom .”

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

He said that along with pharmaceutical and materials sciences, chemical biology may also benefit from the process, especially because of its affinity with pClicka method discovered by Rice chemist Han Xiao to attach drugs or other substances to antibodies.

Co-authors are Rice undergraduate David Nemoto Jr. and graduate student Shih-Chieh Kao, and Yan He and Yan Li of Hefei. Wang is a professor at Hefei. West is the Norman Hackerman-Welch Young Investigator and an assistant professor of chemistry.

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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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Rice University

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