A catalytic technology that enables easy and precise assembly of core structural frameworks — the "backbone" of bioactive substances — has been developed in South Korea. The breakthrough is expected to contribute to new drug development and the high-value-added fine chemical industry.
A research team led by Professor Seo Sang-won of the Department of Physics and Chemistry at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) succeeded in synthesizing beta-methylene carbonyl derivatives, a key scaffold in pharmaceuticals, exclusively as single enantiomers using a nickel (Ni) catalyst, the institute said Thursday.
Enantiomers are molecules composed of the same atoms but possessing three-dimensional structures that are non-superimposable mirror images of each other. Since human proteins are made of amino acids with specific mirror-image configurations, the stereochemistry of molecules plays a critical role in biological reactions.
For drug molecules in particular, one enantiomer may produce a therapeutic effect while its mirror counterpart can be ineffective or even cause side effects. Selectively synthesizing only the effective configuration is therefore considered a core challenge in new drug development.
Beta-methylene carbonyl, the target of this research, is an important molecular scaffold found widely in various drug candidates and natural products. However, existing methods for imparting specific stereochemistry were limited, requiring strong bases or complex auxiliary substances that imposed significant process constraints.
The research team solved this challenge by using nickel, a transition metal abundant on Earth, instead of expensive noble metals. They devised a synthesis pathway that directly reacts alkynes with carbonyl compounds through a newly designed nickel catalyst system.
The catalyst system achieved high levels of both regioselectivity — ensuring molecules bond precisely at the desired position — and enantioselectivity, assembling molecules in only one mirror-image form.
The system also operated stably across complex molecular structures and diverse functional group environments, confirming its applicability to pharmaceutical structural modification and natural product synthesis. The team also elucidated the operating mechanism of the nickel catalyst through density functional theory (DFT)-based calculations.
