How plesiosaurs swam underwater

The process of tailoring molecules has a double duty: Lab uses nature to create flexible precursors for drug and material design

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

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

Even better, they say, is that these alkenes are “inactivated” – that is, they lack reactive atoms near the double bond – and so far they have proven difficult to improve.

The chemical route described in Journal of the American Chemical Society could simplify the creation of a library of precursors for the pharmaceutical industry and improve the production of polymers.

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 molecules.

“These enzymes are the kind of 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 the P450 finds hydrocarbon bonds and removes the hydrogen, leaving a carbon-centered radical that includes an unpaired electron.

“That electron really wants to find a partner, so the P450 will immediately return an oxygen atom (” rebound “), which oxidizes the molecule,” he said. “In the body, it helps to deactivate these molecules so that you can get rid of them.

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

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

West said that while P450 uses the nearby element, iron, to catalyze the biological reaction, previous experiments on the rice lab and elsewhere showed that manganese had potential.

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

That reaction stood for a functionalization. Why not go for two?

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

The end result is a gentle and modular process for adding two functional groups to a single alkene in one step.

“First, we have the carbon-carbon double bond of a molecule of interest, the alkene,” West said, summing it up. “Then we add this valuable fluorocarbon, and then the manganese catalyst swims up and transfers this radical ligand to add a chlorine or 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 with them expertise in photocatalysis but also developed and tested carbon-fluorine fragments, and showed that they would work really well in this system,” said West.

He said that along with drug and materials science, chemical biology can also benefit from the process, especially for its affinity for pClick, a method discovered by risk taker Han Xiao to attach drugs or other substances to antibodies.

Co-author is Rice undergraduate David Nemoto Jr. and PhD student Shih-Chieh Kao, and Yan He and Yan Li from Hefei. Wang is a professor at Hefei. West is Norman Hackerman-Welch Young Investigator and Assistant Professor of Chemistry.

The Cancer Prevention and Research Institute of Texas (RR190025), the Robert A. Welch Foundation (C-2085), the National Key R&D Program of China (2021YFF0701700) and the National Science Foundation of China (21971228, 21772187) supported the research.

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