Novel Catalysis Yields Elusive Fluorinated Oxetanes for Drug Discovery

Researchers at the National University of Singapore (NUS) have developed a novel catalytic process that converts epoxides into fluorinated oxetanes—highly sought-after drug molecules previously considered synthetically inaccessible. This new approach makes these valuable drug scaffolds more readily available, potentially facilitating the development of innovative pharmaceuticals.

This collaborative research was spearheaded by Associate Professor Koh Ming Joo from NUS’s Department of Chemistry, in partnership with Professor Eric Chan from the NUS Department of Pharmacy and Pharmaceutical Sciences, and Professor Liu Peng from the University of Pittsburgh, USA. Their findings have been published in the prestigious journal Nature Chemistry.

Four-membered heterocycles, such as oxetanes and β-lactones, are crucial structures frequently found in natural products and pharmaceuticals. Their biological and synthetic importance has long been recognized. Introducing fluorine into these organic molecules significantly enhances their properties, a process known as fluorination, widely used in drug discovery. Specifically, replacing a CH2 group in oxetanes (or a C=O in β-lactones) with a CF2 unit produces α,α-difluoro-oxetanes.

These α,α-difluoro-oxetanes uniquely combine the advantages of small-ring heterocycles and fluorinated groups, making them highly attractive as lead compounds for pharmaceuticals. However, their synthesis has historically been challenging. Traditional synthetic methods lacked suitable fluorinated precursors or reagents and often resulted in problematic side reactions, such as ring opening or defluorination.

Associate Professor Koh Ming Joo emphasized the necessity of their new method, stating, "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. Traditional chemistry often leads to complications such as ring rupture, defluorination, and other undesired side reactions. A new synthetic approach was clearly needed."

To address this challenge, the researchers developed an innovative method involving the selective insertion of a difluorocarbene species into readily available epoxides. This reaction is catalyzed by an affordable copper catalyst, stabilizing difluorocarbene derived from commercially accessible organofluorine precursors. This copper-difluorocarbenoid intermediate interacts precisely with epoxides, initiating a ring-opening process followed by cyclization to form the desired α,α-difluoro-oxetanes.

Professor Liu’s team's computational analyses clarified the reaction mechanism and unique reactivity, while Professor Chan's group's studies on lipophilicity and metabolic stability highlighted the pharmaceutical potential of these fluorinated oxetanes.

To demonstrate practical applications, the team successfully synthesized fluorinated analogs of several important pharmacophores, including oxetanes, β-lactones, and carbonyl-based structures commonly found in biologically active molecules. Additionally, computational studies comparing electrostatic potentials confirmed the potential of these new fluorinated compounds as analogs of established drug molecules.

Associate Professor Koh Ming Joo remarked, "By inventing a reliable route to fluorine-containing oxetanes, we can now incorporate these motifs into novel small-molecule therapeutics. This opens exciting opportunities to develop medicines that could potentially treat previously incurable diseases."

Further investigations are ongoing to explore the biological activities of these newly developed drug analogs and to expand the catalytic methodology to additional heterocyclic compounds with therapeutic potential.