Scientists with the National University of Singapore (NUS) have developed a novel approach. If successful, this cutting-edge approach would dramatically reduce the time and costs associated with synthesizing vitally important pharmaceutical precursors. Led by Associate Professor Koh Ming Joo, the team published their findings on “Photocatalytic oxygen-atom transmutation of oxetanes” in the esteemed journal Nature. This exciting new strategy holds the potential to turn readily available oxetane feedstocks into high-value saturated cyclic compounds, where many bioactive molecules found in medicinal chemistry are found.
We herein disclose a synthetic diversification platform for the rapid syntheses of four-membered saturated cyclic motifs. Azetidines, thietanes and cyclobutanes exhibit attractive physicochemical characteristics. As a consequence, they are proving themselves more and more powerful in the pursuit of new drugs. The DOI for the research is 10.1038/s41586-025-09723-3.
The Innovation Behind the Research
This recently developed photocatalytic atom-swapping transformation provides a new strategy for oxetane conversion. This facile new transformation quickly and inexpensively converts them into more highly strained four-membered saturated cyclic molecules. Historically, making these compounds required arduous stepwise syntheses utilizing cycloaddition or nucleophilic substitution chemistries. This is because these traditional methods often restrict the scope of accessible molecular frameworks, slowing progress in the design of diverse pharmacophores.
This new pioneering approach makes the synthesis more efficient and less complex. It opens up exciting new avenues for chemical discovery, focusing on a critical need for new approaches in the field.
“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,” – Assoc Prof Koh.
One particularly interesting thing about this research is how focused it is on improving efficiency and sustainability. The team successfully reduced the number of synthetic steps required to produce advanced drug intermediates from 8 to 12 down to just four. This drastic cut makes the process much harder. It leads to significant economic savings and less waste, a key consideration in today’s greener chemistry.
Efficiency and Environmental Impact
The impact of this efficiency cannot be overstated, especially in a field where time and funding are frequently limited. This approach allows rapid access to sulfur analogues. In doing so, we can increase the strength of prospective drugs, thus making them more appealing for pharma development.
Four-membered saturated cyclic molecules have represented important scaffolds in medicinal chemistry due to their distinctive properties. These molecules come with some really nice features including potency and stability. Their metabolic stability and target specificity are important properties that ensure developing new therapeutic agents. As drug discovery moves faster and faster, the need for compounds like these is ever-increasing.
The Importance of Four-Membered Cyclic Molecules
Recognizing this urgent need, the research team’s findings provide an exciting solution. With their photocatalytic oxygen-atom transmutation strategy, they open up new possibilities for chemists to discover small-molecule therapeutics.
This study expands the frontier of therapeutics fabrication. It’s a step forward for continuing to make a greener industry the new normal in all pharmaceutical practices.
“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,” – Assoc Prof Koh.
This research not only pushes the boundaries of what is possible in drug synthesis but also aligns with ongoing efforts to create more sustainable practices within the pharmaceutical industry.