Like modern-day alchemists, medicinal chemists use the ‘magical’ chemical properties of compounds to transform them into safe and effective treatments. Sometimes, a molecule’s mirror image (or its chiral counterpart) can hold the secret to unlocking its full therapeutic potential.
For instance, the two different forms, or enantiomers, of chiral sulfonescan exert very different effects in biological systems. Used as building blocks for bioactive compounds, chiral sulfones hold the potential for treating an extensive array of diseases, from breast cancer to tuberculosis.
Unsurprisingly, chiral sulfone synthesis has garnered extensive research attention especially around innovations that can enhance the efficiency and selectivity of producing specific enantiomers.
“We wanted to develop a new method that overcomes the limitations of current strategies, particularly the challenge of precisely functionalising complex sulfone-based molecules,” said Xinglong Zhang, a Scientist at A*STAR’s Institute of High Performance Computing (IHPC). “The method also broadens the range of substrates we can use, providing chemists with a new tool for synthesising these compounds.”
Together with researchers from Guizhou University, China and Nanyang Technological University, Singapore, Zhang employed a catalyst called N-heterocyclic carbene (NHC) in the hopes of developing a novel, efficient and selective method for attaching sulfone groups to organic molecules located at a distance from the catalyst’s substrate reaction site.
“For long-range spatial control, we need a carbene catalyst that can extend beyond its immediate reactive centre, which requires thought on the desired features of carbene catalysts,” said Zhang.
The team explored NHC-catalysed reactions between two groups of molecules (enone aryl aldehydes and sulfonyl chlorides), identifying the conditions and substrates required for optimal chiral sulfone synthesis.
The team leveraged advanced modelling techniques such as Density Functional Theory (DFT) simulations to pinpoint the reaction’s critical transition states and deduce the most probable mechanistic pathways.
“Our computational tools helped identify the unusual key intermediate from the catalytic cycle, which was eventually captured experimentally by high-resolution mass spectroscopy (HRMS),” said Zhang. “The computational insights we gained were instrumental in determining the rate-limiting steps and unravelling the key molecular underpinnings governing the reaction’s enantioselective outcome.”
Ultimately, this approach led to the successful development of a new highly enantioselective method for chiral sulfone synthesis which produced high yields of a single, specific mirror-image form of the desired chemical. Moving forward, the team aims to delve deeper into the applications of this novel mode of carbene activation.
“From a computational point of view, we want to further investigate and understand the detailed mechanisms behind such sulfonylation reactions, such as how bases affect reaction rate and yield,” said Zhang. ”From an experimental angle, plans are in place to capitalise on the dual reactivity nature of sulfonyl chlorides and explore the additional usage of such reagents in chemical synthesis and catalysis.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of High Performance Computing (IHPC).
