Novel method to synthesize valuable fluorinated drug compounds

The research team was led by Associate Professor Koh Ming Joo from the NUS Department of Chemistry, together with Professor Eric Chan from the NUS Department of Pharmacy and Pharmaceutical Sciences and Professor Liu Peng from the University of Pittsburgh, United States of America.

The research breakthrough was published in the scientific journal Nature Chemistry on 20 February 2025.

Four-membered heterocycles such as oxetanes and β-lactones are common motifs in natural products and pharmaceuticals, with numerous examples documented in both synthetic and biological studies. The introduction of fluorine into organic molecules often imparts desirable attributes, which has contributed to successful outcomes in drug discovery. In this vein, isosteric replacement of a CH₂ unit within an oxetane (or C=O group within a β-lactone) with CF₂ results in α,α-difluoro-oxetanes, a prized class of heterocyclic compounds with combined attributes of small-ring heterocycles and fluorine. While these fluorinated oxetanes hold great promise as lead compounds for further development into new medicines, their synthetic preparation has largely eluded chemists.

Assoc Prof Koh said, "Traditional ways of constructing the oxetane ring cannot directly produce α,α-difluoro-oxetanes, owing to a lack of suitable fluorine-containing precursors or reagents, or both. Furthermore, traditional chemistry often leads to complications such as ring rupture, defluorination and other undesired side reactions. A new synthetic approach was clearly needed."

A novel method to synthesise fluorinated oxetanes

The researchers deviated from the standard logic of synthesis by designing a new strategy that inserts a difluorocarbene species selectively into the structure of readily available three-membered epoxides. This process is facilitated by an inexpensive copper catalyst, which stabilises the difluorocarbene generated from a commercially available organofluorine precursor. The resulting copper difluorocarbenoid complex coordinates with the epoxide and triggers site-selective ring cleavage and cyclisation, to yield the desired α,α-difluoro-oxetane product via a metallacycle intermediate. Computational studies by Prof Liu's group provided insight into the new reactivity mode and its underlying mechanism. Additionally, lipophilicity and metabolic stability studies performed by Prof Chan's team supported the potential of these fluorinated oxetanes as valuable drug scaffolds.

To demonstrate the practical utility of their method, the researchers successfully synthesised fluorine-containing analogues of oxetane, β-lactone and carbonyl pharmacophores commonly found in a variety of biologically active compounds. Computed electrostatic potential maps of isosteric oxetane, α,α-difluoro-oxetane and β-lactone further indicated the potential of these compounds to serve as analogues of each other.

"By inventing a reliable route to fluorine-containing oxetanes, we can now incorporate these motifs into the design of novel small-molecule therapeutics. This opens up exciting opportunities to develop new medicines that could potentially treat previously incurable diseases," added Assoc Prof Koh.

Studies are ongoing to investigate the biological properties of these newly synthesised drug analogues and extend the methodology to other classes of heterocyclic drug-like compounds.