Â鶹ÒùÔº

Researchers from NUS have pioneered a photocatalytic atom-swapping transformation that converts oxetanes into a variety of four-membered saturated cyclic molecules, which are key scaffolds in medicinal chemistry. By introducing a new synthetic blueprint for these prized drug motifs, this discovery could potentially streamline the synthesis of pharmaceuticals and complex drug analogs that would otherwise require multi-step routes.

The research team was led by Associate Professor Koh Ming Joo from the NUS Department of Chemistry, together with Assistant Professor Zhang Xinglong from The Chinese University of Hong Kong, Hong Kong, China.

The research was published in the journal on 15 October 2025.

Non-aromatic (saturated) heterocycles and carbocycles form the skeleton of countless bioactive and functional molecules. Four-membered saturated cyclic molecules such as azetidines, thietanes and cyclobutanes are increasingly valued in drug discovery for their desirable physicochemical properties, such as potency, stability, metabolic stability and target specificity. However, the traditional retrosynthetic approaches typically deconstruct the ring into simpler starting materials that have to be prepared separately through numerous steps. This approach is often energy- and time-consuming and generates excessive waste, particularly in the assembly of complex drug molecules.

Assoc Prof Koh said, "The conventional way of constructing four-membered rings employs cycloaddition or nucleophilic substitution chemistries that limit the range of obtainable molecular scaffolds. There is an urgent need to design a new approach that not only simplifies the synthesis of small-ring pharmacophores but also unlocks uncharted regions of the chemical space."

New atom-swapping logic accelerates synthesis of non-aromatic drug scaffolds

The researchers developed a skeletal editing strategy that selectively exchanges the oxygen atom of an oxetane building block for another functional group (nitrogen, sulfur, or carbon), through reaction with appropriate reagents. This transformation process is achieved by using a photocatalyst to break the oxetane ring into a reactive dibromide compound under visible light.

The ring is then rebuilt using different nucleophiles to give a range of four-membered heterocycles and carbocycles in one pot. Computational studies by Asst Prof Zhang's group provided insights into the underlying mechanism and the origins of the high chemoselectivity.

To demonstrate the value of their method, the researchers successfully simplified the preparation of advanced drug intermediates, reducing the number of synthetic steps from 8 to 12 steps down to four steps, delivering substantial cost savings and waste reduction. The researchers also applied their method to the late-stage editing of complex bioactive oxetanes to obtain heterocyclic drug candidates with enhanced properties, bypassing the need to make them from scratch.

"Our atom-swapping manifold offers a convenient diversification platform to transform readily accessible oxetane feedstocks into different classes of high-value saturated cyclic compounds in one operation. This would empower chemists in their synthetic endeavors by providing new opportunities in making cyclic functional molecules for important applications such as drug discovery," added Assoc Prof Koh.

Studies are ongoing to extend the methodology to heterocyclic drug compounds of various ring sizes relevant to therapeutics.