SKKU researchers develop dual-function catalysts for complex molecular synthesis

In the chemistry labs at Sungkyunkwan University, a team led by Professor Do Hyun Ryu has solved a problem that has long frustrated organic chemists: how to build complex molecules with precision when multiple things need to happen at once in the same reaction vessel.

The challenge is straightforward to state but devilishly hard to execute. When you want to synthesize a pharmaceutical or a natural product, you're often starting with relatively simple molecules and trying to coax them into intricate three-dimensional structures with multiple stereocenters—points in the molecule where atoms are arranged in a specific spatial orientation. Get the geometry wrong and the compound won't work. Get it right and you have something valuable. The problem is that most reactions don't care about precision. They'll happily form bonds in the wrong places or create the wrong three-dimensional arrangement. Controlling where a reaction happens and how atoms end up oriented in space, simultaneously, has remained one of organic synthesis's central difficulties.

Ryu's team, working in collaboration with Professor Hyunwoo Kim's group at the Korea Advanced Institute of Science and Technology, developed a chiral organic catalyst—a molecule engineered to be handed, like a left or right glove—that can do something unusual: it can promote two entirely different types of carbon-carbon bond-forming reactions with high selectivity. In their first study, published in Angewandte Chemie International Edition, they showed that the same catalyst could execute both an asymmetric allylation reaction, which had previously been difficult to control, and an aldol reaction. The catalyst doesn't just speed up these reactions; it actively steers them toward the desired outcome, controlling both which reaction site gets activated and how the resulting molecules arrange themselves in three dimensions. The team successfully synthesized various chiral compounds and demonstrated the method's utility by preparing (+)-dimethyl citramalate, a biologically active natural product. Computational modeling using density functional theory revealed the mechanism—how the catalyst's structure guides both selectivity and stereochemistry.

In a second study, Ryu's team tackled a different but related problem: building tetrahydrofuran ring structures—five-membered rings containing one oxygen atom that appear frequently in natural products and drugs—with multiple stereocenters already in place. Traditionally, chemists had to start with materials that already possessed the desired stereochemical features, which limited their options and often required more synthetic steps. Ryu's approach inverted this constraint. Using a chiral organic catalyst, the team could construct multiple stereocenters from simple starting materials that had no pre-existing stereochemical structure. The resulting compounds could then be further modified into more complex molecules. They demonstrated the method's potential by synthesizing an intermediate for (+)-altholactone, a natural product with anticancer activity.

What unites both studies is their shared philosophy: use a chiral catalyst to wrest control over reaction sites and molecular geometry simultaneously. Neither study is incremental tinkering. Both represent expansions of what asymmetric synthesis can accomplish. Ryu noted that these approaches open new possibilities for building complex structures more precisely and efficiently, and that the team expects the methods to extend to a wider range of asymmetric reactions, potentially offering useful strategies for synthesizing pharmaceuticals and natural products more efficiently than current methods allow.

The work was supported by grants from South Korea's National Research Foundation and the Korea Basic Science Institute. The research team included Terim Seo, Rameshwar Prasad Pandit, and Dong Gyu Kim from SKKU, along with Donghun Kim from KAIST, in the first study, and Hosung Lee and Dong Kyu Kim from SKKU in the second. The implications are practical: if these catalytic methods can be extended and refined, they could accelerate the development of new drugs and natural product-based compounds by making their synthesis faster and more reliable.