Professor Andrew Smith of the University of St Andrews is the lead researcher behind a new study that revisits one of organic chemistry’s most difficult rearrangement reactions. The team reports a method for controlling molecular chirality in the [1,2]-Wittig rearrangement, a transformation first described more than 80 years ago and long regarded as too unpredictable for practical asymmetric synthesis.
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 pharmaceutical science because mirror image molecules can behave very differently in biological systems. One chiral form may deliver the intended therapeutic effect, while the other can be inactive or introduce unwanted side effects. As a result, modern synthesis places strong emphasis on reactions that reliably produce a single handed form. Rearrangement reactions, however, have traditionally been excluded from this category due to their tendency to scramble stereochemical information.
Professor Andrew Smith of the University of St Andrews stated,
“This discovery represents a fundamental shift in how we understand and control stereochemistry in rearrangement reactions.”
The [1,2]-Wittig rearrangement exemplifies this challenge. Although the reaction offers an efficient way to reorganize atoms within a molecule, its stereochemical outcome has historically been difficult to predict or influence. For decades, it has been viewed as chemically interesting but unsuitable for applications that require precise control, such as drug synthesis or advanced materials development.
The St Andrews team, working in collaboration with researchers at the University of Bath, approached the problem by combining laboratory experiments with quantum chemical calculations. Their analysis revealed that the reaction does not proceed as a single uncontrolled step. Instead, a chiral catalyst first directs the molecule through an asymmetric rearrangement that establishes its handedness. This is followed by a previously unrecognized molecular reshuffle that preserves, rather than disrupts, the established chirality.
This second step helps explain why stereochemical control is possible in a reaction once thought to resist it. Earlier studies lacked the experimental and computational resolution needed to observe this intermediate behavior, which allowed the rearrangement to be mischaracterized as inherently random. By identifying and describing this hidden stage, the researchers were able to show that chirality can be guided and maintained throughout the process.
According to Professor Smith, the findings represent a change in how chemists understand stereochemical control in rearrangement reactions. Rather than avoiding such transformations, researchers can now consider designing catalysts and reaction conditions that exploit their underlying order. Co lead researcher Dr. Matthew Grayson of the University of Bath has also noted that the work suggests other long standing reactions may be reconsidered using similar mechanistic approaches.
From an engineering standpoint, the implications are practical. Improved control over chirality reduces the need for additional purification steps, which in turn lowers material waste and production costs. The ability to generate single handed molecules more directly is particularly relevant for pharmaceutical manufacturing, where regulatory and safety requirements demand high stereochemical purity.
Beyond medicines, chiral molecules play an increasing role in functional materials, including polymers and organic electronic components. A controlled rearrangement reaction expands the range of synthetic strategies available to materials engineers, offering new ways to build complex structures with defined three dimensional properties.
While further work is needed to test the scalability and robustness of the method across a broader range of substrates, the study demonstrates that even well known reactions can yield new possibilities when examined with modern tools. In this case, uncovering a subtle molecular reshuffle has turned a long avoided transformation into a viable option for selective chemical synthesis.
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).
