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ACS Meeting News

Light rearranges rings

Contraction reaction kicks an atom out of saturated heterocycles

by Bethany Halford
August 25, 2021

Scheme shows a blue-light initiated rearrangement that converts a tetrahydropyran into a cyclopentyl alcohol.

Chemists have become adept at changing the groups on the periphery of molecules, sort of like changing decorations on a mantlepiece. But changing a molecule’s core scaffolding is more challenging. Researchers have now discovered a way to rearrange molecular cores by turning certain 6-membered rings into 5-membered rings. The transformation could be used to alter the skeletons of molecules, including pharmaceuticals and agrochemicals, into novel structures.

Visible light powers the ring-contraction reaction, which University of California, Berkeley, graduate student Justin Jurczyk presented on Wednesday at ACS Fall 2021, a meeting of the American Chemical Society. Jurczyk spoke during a session in the Division of Organic Chemistry. The reaction converts saturated heterocycles with 6 atoms, including cyclic amines, ethers (example shown), and thioethers, into 5-carbon rings with pendant amines, alcohols, or thiols, respectively. “We’re not adding any atoms; we’re not deleting any atoms,” Jurczyk told C&EN. “We’re really just rearranging where they are in space.”

UC Berkeley’s Richmond Sarpong, who led the research effort along with Merck & Co.’s Yu-hong Lam and Charles S. Yeung, said that the work was inspired by a report from 2008 where chemists had done the same skeletal rearrangement on a sugar derivative. Sarpong said that his team wanted to make the reaction more general, so that it could be used on different types of heterocycles, not just sugars. “At the core of molecules are pretty strong bonds,” Sarpong said. These bonds, typically C–C, C–N, and C–O, are not easy to break, he added.

The team from UC Berkeley and Merck realized they could use a light-initiated radical reaction to break the carbon-heteroatom bond if the bond was adjacent to an aromatic ketone. “We activate the ketone, it can extract a hydrogen atom, and then it creates a radical on the core of the molecule,” breaking the bond, Sarpong explained. The chemists report numerous variations on the ring contraction reaction, including an enantioselective version that uses chiral phosphoric acids. The research was recently published in Science (2021, DOI: 10.1126/science.abi7183). Next, the chemists are working on a method for efficiently installing the requisite aromatic ketone onto the saturated heterocycle.

Mark Levin, a chemistry professor at the University of Chicago who develops methods for modifying molecular scaffolds, said in an email that the report is “an incredibly creative, tour-de-force study.” The reaction, he said, “stands to be immediately and immensely useful.”



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