A research team led by Professor Andrew Smith at the University of St Andrews has identified a previously unrecognized molecular rearrangement that helps explain how chirality can be controlled in a reaction long thought to be unpredictable. The finding resolves an 80-year-old problem in reaction chemistry and provides new guidance for designing selective processes used in pharmaceuticals and advanced materials.
Kang, T., O’Yang, J., Kasten, K., Allsop, S. S., Lewis-Atwell, T., Farrar, E. H. E., Juhl, M., Cordes, D. B., McKay, A. P., Grayson, M. N., & Smith, A. D. (2026). The catalytic enantioselective [1,2]-Wittig rearrangement cascade of allylic ethers. Nature Chemistry. https://doi.org/10.1038/s41557-025-02022-4
Chirality remains a central concern in chemical engineering and molecular design. Many compounds exist in two mirror-image forms that share the same atomic composition but behave differently in biological and chemical systems. In medicine, one chiral form may deliver therapeutic benefit while its counterpart is inactive or harmful. As a result, developing reactions that reliably produce a single “handed” form is a long-standing goal in synthesis.
Professor Andrew Smith at the University of St Andrews stated,
“Our findings open the door to new asymmetric transformations based on mechanistic pathways that chemists previously dismissed as inaccessible.”
The work, focuses on the [1,2]-Wittig rearrangement, a reaction first reported more than eight decades ago. The reaction enables carbon–carbon bond formation through internal atomic reorganization, but its stereochemical outcome has historically been difficult to control. Because of this unpredictability, the rearrangement has seen limited use in settings where precise chirality is required.
Using a combination of laboratory experiments and quantum chemical calculations, the researchers revisited the mechanism of the reaction under catalytic conditions. Their analysis revealed that the process does not proceed as a single uncontrolled step, as previously assumed. Instead, the catalyst first directs an initial asymmetric rearrangement that establishes molecular handedness. This step is followed by a secondary molecular reshuffle that preserves the established chirality rather than scrambling it.
This second step had not been identified in earlier mechanistic models. By accounting for it, the team was able to explain how chirality can be retained throughout the reaction sequence. According to Smith, the result challenges long-held assumptions about rearrangement reactions and shows that pathways once considered unsuitable for asymmetric synthesis can, in fact, be guided with the right catalytic framework.
The study was carried out in collaboration with researchers at the University of Bath, including Dr. Matthew Grayson, who co-led the work. Their combined experimental and computational approach allowed them to test reaction pathways that are difficult to observe directly, linking theoretical predictions with measured outcomes.
From an engineering perspective, the significance of the work lies in its implications for process design. Understanding how catalysts influence not just the start of a reaction but also subsequent internal rearrangements allows chemists to think differently about reaction cascades. Rather than avoiding complex rearrangements, engineers may now be able to incorporate them into controlled, selective manufacturing routes.
The findings also point to broader opportunities beyond pharmaceuticals. Chiral control is increasingly important in the development of functional materials, including polymers, sensors, and optoelectronic systems. A clearer understanding of how molecular reshuffling can be directed expands the range of reactions available for producing these materials with consistent properties.
While further work will be needed to adapt the approach to industrial conditions and a wider range of substrates, the study provides a mechanistic framework that can be built upon. By revealing how chirality can survive and even be reinforced through internal molecular rearrangements, the research offers a practical route toward cleaner, more selective synthesis strategies.
In resolving a problem that has persisted for decades, the work illustrates how revisiting classical reactions with modern analytical and computational tools can yield insights that are directly relevant to contemporary engineering challenges.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
