KAIST develops new catalyst technology for complex pharmaceutical synthesis

- Balancing radical generation and catalyst regeneration unlocks previously difficult reactions

- Room-temperature synthesis of complex ring molecules expected to cut energy and catalyst use

A schematic diagram of the research findings (AI-generated image). [Provided by KAIST]

A new catalyst technology has been developed that can efficiently synthesize chemical compounds that were previously difficult to react, even at room temperature. The advance is expected to improve the efficiency of chemical processes used to produce complex molecules such as pharmaceuticals and bioactive substances.

KAIST announced Sunday that a research team led by Professor Lee Yun-mi of the Department of Chemistry had developed a new catalyst design technology that regulates the reactivity of copper catalysts to simultaneously facilitate radical generation and catalyst regeneration.

Radicals are highly reactive chemical species that readily form new chemical bonds with other substances. While useful for synthesizing structurally complex compounds such as pharmaceuticals, their utility has been limited by a key problem: once a catalyst generates a radical, it often cannot return to its original state, causing the reaction to stall.

The research team focused on "ligands" — molecules that bind to a catalyst and modify its properties. They used an organic molecule called cyclopropeneimine (CPI) as a ligand to regulate the oxidation and reduction characteristics of the copper catalyst.

The key insight was that effective catalysis requires not just generating large numbers of radicals, but also balancing that process with regeneration of the catalyst to its original state after each reaction.

In tests comparing multiple ligands, some that excelled at generating radicals produced almost none of the desired final product. The CPI ligand, by contrast, enabled both radical generation and catalyst regeneration to proceed smoothly, raising overall reaction efficiency.

Using this approach, the team successfully synthesized 3,3-disubstituted oxindoles — ring-shaped molecules used in the synthesis of pharmaceuticals and bioactive substances — in high yields.

Bromine-containing compounds reacted efficiently even at room temperature. The team also succeeded in reacting compounds with strong carbon-chlorine bonds that had previously been difficult to break, broadening the range of materials available for synthesis.

From left: KAIST Professor Lee Yun-mi, KAIST integrated master's-doctoral student Jang Se-ra, Yonsei University master's student Jung Sung-ryul, and KAIST integrated master's-doctoral student Kim Su-min. [Provided by KAIST]

The team confirmed that synthesis proceeded smoothly even when the reaction was scaled up to gram quantities and the amount of catalyst was reduced. With further process optimization, the technology is expected to lower the energy and catalyst requirements for pharmaceutical manufacturing and similar applications.

The research is significant for proposing a new design strategy that moves beyond the conventional approach of simply maximizing radical generation, focusing instead on balancing the entire catalytic cycle.

"We confirmed that generating radicals well is not enough on its own — what matters is that the multiple steps making up a single catalytic cycle proceed in a balanced way," Professor Lee said. "We expect this can develop into a synthesis process that efficiently produces complex organic molecules while reducing production costs and energy consumption."

The findings were published online in the Journal of the American Chemical Society on Aug. 3.

nbgkoo@heraldcorp.com