“Synthesizing only the desired mirror-image form”: DGIST develops precision assembly technology for key drug scaffolds

□ A research team led by Prof. Sangwon Seo of the Department of Physics and Chemistry at DGIST (President Kunwoo Lee) has developed a catalytic technology that can easily and elaboratively assemble key structural frameworks that serve as the “scaffold” of bioactive compounds. Using an abundantly available and inexpensive nickel (Ni) catalyst, the team successfully synthesized “β-methylene carbonyl” derivatives, which form the core framework of many pharmaceuticals, exclusively in a single “mirror-image isomer” form. This technology is expected to play a pivotal role in various fields of precision chemistry including the pharmaceutical industry.

□ Even though the left and right hands appear identical in a mirror, they can never perfectly overlap when superimposed in the same orientation. Similarly, there exist molecules in chemistry that share the same atomic composition yet differ in three-dimensional structure as non-superimposable mirror images, which are called “mirror-image isomers.” Proteins in the human body are likewise composed of amino acids that exist in only one specific mirror-image form.

□ Just as there exists only one key that fits a given lock, one mirror-image form of a drug molecule can serve as an effective therapeutic, while its counterpart may be inactive or even toxic, inducing severe side effects. Therefore, the ability to precisely select and synthesize only one enantiomer that is effective for treating disease is essential in new drug development.

□ The “β-methylene carbonyl,” the key target of this study, is an extremely useful molecular framework widely found in numerous new drug candidates and natural products. However, methods for imparting specific stereochemistry (mirror-image configuration) to this scaffold have been extremely limited, typically requiring application of strong bases or prior installation of complex auxiliary groups onto the substrates.

□ To address this long-standing challenge, Prof. Sangwon Seo’s research team focused on “nickel,” an earth-abundant transition metal, instead of expensive noble metals. Using a newly designed nickel catalytic system, the team developed a novel synthetic route that directly couples readily available chemical feedstocks (alkynes and carbonyl compounds). This catalytic system realized near-perfect “regioselectivity,” ensuring that molecules attach precisely at the desired position when they combine, as well as “enantioselectivity,” whereby assembly occurs exclusively in a single mirror-image form.

□ This reaction proceeds reliably to deliver only the desired transformation, even in complex structures or in the presence of diverse functional groups, without interference. In fact, the team successfully applied this technology to precisely modify complex pharmaceutical structures and efficiently construct key scaffolds required for natural product synthesis, demonstrating practical applicability at a level suitable for commercialization. Additionally, through density functional theory (DFT)-based computational analysis, they elucidated the underlying mechanism by which the nickel catalyst controls bond formation and three-dimensional structure.

□ “This study is significant in that it enables the synthesis of β-methylene carbonyl compounds, which had been considered challenging, through a straightforward approach using an inexpensive nickel catalyst,” stated Prof. Sangwon Seo of the DGIST Department of Physics and Chemistry. “It is expected that this synthetic technology will pave the way for research on stereoselective reactions and substantially contribute to the precision chemical industry and new drug development.”

□ This study was supported by the Outstanding Young Scientist Grants Program of the National Research Foundation of Korea, and the results were published in the top-tier international chemistry journal Angewandte Chemie – International Edition.