Boldly going where no C–H activation has gone before

C –H activation is the art of snipping specific bonds between carbon and hydrogen atoms on an organic molecule to graft a new functional group in place of the relatively unreactive H atom. Over the years, chemists have devised increasingly effective and selective ways to do C-H activation. But some bonds remain tantalizingly out of reach.

Jin-Quan Yu and his team at Scripps Research in California have been working for over 20 years to push the boundaries of which C–H bonds are possible to alter. In a new Science paper, they describe how they stereoselectively snipped a C–H bond and added aryl groups to the position three or four atoms away from the carbonyl carbon of cyclic carboxylic acids (2024, DOI: 10.1126/science.ado1246).

Chemists have gotten pretty good at stereoselectively adding atoms one or two spaces away from carbonyl groups, which coordinate to metal catalysts to direct them to the correct place to carry out the reaction. Proximity to a carbonyl group also makes a C–H bond easier to break. The ability to also add a stereocenter three carbons away, in the γ position, is “very enabling” for synthesis, Yu says. He and his team published a nonstereoselective γ-arylation reaction last year; introducing chirality was the natural next step (Nature 2023, DOI: 10.1038/s41586-023-06000-z).

The pursuit of reactions that can access remote C–H bonds with perfect control over the product’s 3D structure has a somewhat fraught history. In 2019, Frances Arnold’s group at the California Institute of Technology published a Science paper detailing engineered enzymes that produced chiral four-, five-, and six-membered lactam rings through C–H amidation. In 2020, a team from Hokkaido University reported, also in Science, a method using an iridium catalyst to install boron groups at the γ position of amide and ester compounds. Both papers were retracted because the results couldn’t be replicated.

The reaction Yu and his team developed relies on a palladium catalyst with a chiral oxazoline-pyridone ligand that reaches across the ring from the carboxylic acid to the γ position. It can attach a range of aryl halides to acids with five-, six-, and seven-membered rings, creating two new stereocenters in the process. The team also devised a slightly modified catalyst that can access C–H bonds four carbons away from the acid.

“I think it is really spectacular,” Huw Davies, an organic chemist at Emory University, says in an email. The Yu group has a long track record of making big advances in C–H activation methods, he adds, and this work clearly builds on those past insights. He’s interested to see what other functionality will become possible to install stereoselectively to the γ position.

Yu says he has filed a patent for the reaction and has established a start-up, Architect Therapeutics, that is based on using C–H activation catalysts to build novel scaffolds for drug discovery. Identifying how to expand the list of atoms and functional groups that can be attached to the γ position is also on his to-do list, he says. Ideally, he says, an effective C–H activation method means “you could replace the C–H bond with anything you want.”