Researchers from the National University of Singapore (NUS) have developed a boron-catalysed method to transform oxetanes which are small four-membered ring molecules into larger, medicinally relevant 1,3-oxazinanes by the selective insertion of two building blocks, a carbon unit and a nitrogen unit.
The research team was led by Associate Professor KOH Ming Joo from the NUS Department of Chemistry. The research breakthrough was published in the scientific journal Nature Synthesis on 12 March 2026.
Multi-heteroatom rings such as 1,3-oxazinanes occupy a unique and important position in heterocyclic chemistry, and are frequently leveraged in drug development as local anaesthetics or for treating illnesses such as acquired immune deficiency syndrome (AIDS) and tuberculosis. However, traditional ways of preparing these six-membered heterocycles often require many separate steps, starting from specially prepared materials. This can create more chemical waste, take longer, and limit the range of structures that chemists can easily explore.
Assoc Prof Koh said, “We wanted to design a novel approach for the rapid assembly of 1,3-oxazinanes from cheap and readily accessible starting materials, without relying on specialised functionalities to facilitate the reaction.”
The researchers developed an innovative strategy that harnesses boron-based “frustrated Lewis pair” (FLP) activation to upgrade cheap and readily available oxetanes to 1,3-oxazinanes. The FLP is an approach where two reactive partners work together without permanently neutralising each other. This chemistry enables oxetanes to be deconstructed and rebuilt into a larger ring by reacting them with amines (a common nitrogen-containing compound) and commercially available carbon sources such as formalin, geminal diol or 1,1'-thiocarbonyldiimidazole. Importantly, the reaction can be performed in air, without completely removing moisture, and avoids some conventional atom-inserting reagents that are often sensitive and difficult to handle. This catalytic ring enlargement method also works with many different chemical functional groups, and can be applied to modify the skeletal structure of bioactive compounds, potentially speeding up the creation of potential medicinal compounds.
“We believe that FLP-mediated chemistry would provide a general way to access 1,3-oxazinanes and accelerate the synthesis of target molecules, by enabling chemoselective late-stage editing and minimising protecting group chemistry,” added Assoc Prof Koh.
Studies are ongoing to extend this multicomponent skeletal editing concept to construct other synthetically challenging classes of heterocycles for medicinal chemistry applications.
Nature Synthesis
Experimental study
Not applicable
Heteronuclear dual-atom insertion into oxetanes via frustrated Lewis pair activation