A new path to elusive fluorinated oxetanes

Small, polar rings and electron-withdrawing atoms are both well-loved motifs in medicinal chemistry. So oxetanes and fluorine atoms could be a match made in drug discovery heaven.

Researchers also predict that oxetanes decorated with fluorines would have valuable pharmacological properties. But examples of such compounds in the literature are rare, and “there’s no general method to synthesize these compounds,” says organic chemist Ming Joo Koh at the National University of Singapore.

Koh and his team wanted to rectify that. With help from Peng Liu, a computational chemist at the University of Pittsburgh, the researchers devised a simple, copper-catalyzed method for implanting fluorinated carbenes into epoxides to generate the previously elusive α-α-difluorooxetanes (Nat. Chem. 2025, DOI: 10.1038/s41557-024-01730-7).

It wasn’t easy, Koh says: epoxides are prone to ring-opening reactions, and fluorinated carbenes also tend to bust rings open. The researchers carried out extensive screening to find a metal-and-carbene pairing that would nudge the ring to expand and rearrange rather than simply rupture.

The team's solution is based on a well-known reaction called the Stevens rearrangement. It also takes inspiration from the growing list of skeletal editing reactions for making targeted tweaks to ring structures, Koh says.

The researchers demonstrated their approach by creating difluorinated precursors to several oxetane-containing drugs. They also found that the same method can expand oxetanes into five-membered fluorinated furans.

In an email to C&EN, Oleksandyr Grygorenko, an organic chemist at Taras Shevchenko National University of Kyiv who was not involved in the work, calls it “fascinating chemistry” with “great potential” for making fluorinated oxetanes accessible in drug discovery. He hopes that having an easier way to make these rings will pave the way for researchers to learn more about their biological activity.

Koh says he and his team are collaborating with folks from their university’s pharmacy department to see if the molecules they are making have drug-like properties. Their preliminary results show that α-α-difluorooxetanes have good metabolic stability and lower lipophilicity compared with undecorated oxetanes and ß-lactams.

The team is already working on expanding this method to other ring systems and other carbenes. “I think there's a lot of opportunities to exploit this chemistry towards other types of transformations,” Koh says. “There's really a lot of things that can be done.”