Synthetic methods unlock the pathway to valuable fluorinated drug compounds for new drugs

Researchers at the National University of Singapore (NUS) have pioneered a new catalytic transformation that converts epoxides to fluorinated oxane. By unlocking the path to these valuable drug scaffolds, this discovery could potentially open the door to new drugs for drug discovery applications.

The research team was led by Associate Professor Koh Ming Joo of the NUS Chemistry Office, Professor Eric Chan of the Department of Pharmaceuticals and Pharmaceutical Sciences and Professor Liu Peng of the University of Pittsburgh, USA.

The research breakthrough was published in Nature Chemistry on February 20, 2025.

Four-membered heterocycles such as oxatane and β-lactone are common motifs in natural products and pharmaceuticals, and many examples have been documented in both synthetic and biological studies. The introduction of fluorine into organic molecules often gives desirable attributes, which contributes to successful drug discovery results.

In this vein, replacing the CH2 units within oxatane (or C = O groups within β-lactones) with CF2 and CF2 produces α,α-difluorooxane. Heterocycles and fluorine. These fluorinated oxanes are highly promising as lead compounds for further development into new drugs, but their synthetic formulations have largely escaped chemists.

Association. Professor Koh said, “The traditional methods of constructing oxatan rings cannot directly produce α,α-difluorooxetane due to lack of suitable fluorine-containing pre-wounds or reagents, or both. Furthermore, Traditional chemistry often leads to complications. Rings, elimination and other unwanted side reactions were clearly required.”

A new method for synthesizing fluorinated oxanes.

The researchers deviated from the standard logic of synthesis by designing a new strategy to selectively insert difluorocarbene species into the structures of readily available three-membered epoxides. This process is facilitated by inexpensive copper catalysts that stabilize the difluorocarbenes produced from commercially available organfluorin precursors.

The resulting copper difluorocarbenoid complex prepares with the epoxide, causing site-selective ring cleavage and cyclization, and produces the desired α,α-difluoro-oxetene product via the metallacile intermediate.

Computational studies by Professor Liu’s group provided insight into new modes of reactivity and their underlying mechanisms. Furthermore, lipophilicity and metabolic stability studies conducted by Professor Chang’s team supported the potential of these fluorinated oxatanes as valuable drug scaffolds.

To demonstrate the practical utility of the method, researchers have employed fluorine-containing analogs of pharmacologic oxatane, β-lactone and carbonyl, commonly found in a variety of biologically active compounds. It was successfully synthesized. The calculated electrostatic latent maps of isosteric oxytanes, α, α-difluoro-oxetanes and β-lactones further demonstrate the possibility that these compounds may be similar to each other.

“By inventing a reliable route to fluorine-containing oxanes, these motifs can be incorporated into the design of new small molecule therapeutics, which could potentially treat previously unnatural diseases. It opens up exciting opportunities to develop new drugs,” Assoc added. Professor KOH.

Research is currently underway to investigate the biological properties of these newly synthesized drug analogs and to extend the methodology to other classes of heterologous drug-like compounds.