A Korean research team has successfully chemically synthesized herpotrichone, a rare natural substance evaluated for its potential in treating dementia and Parkinson's disease, for the first time worldwide.

Herpotrichone is found in extremely small quantities only in fungi that live in symbiosis with bean weevils.

The Korea Advanced Institute of Science and Technology (KAIST) announced on Thursday that a research team led by Professor Han Sun-kyu from the Department of Chemistry has successfully synthesized the natural anti-neuroinflammatory substances herpotrichone A, B, and C, discovered in fungi that live in symbiosis with bean beetles.

Herpotrichone has a complex structure consisting of five rings and was considered impossible to synthesize in a laboratory. Even after Chinese researchers first discovered herpotrichone A and B in nature in 2020, research had relied solely on the extremely small amounts extracted from the fungus.

The KAIST research team estimated how herpotrichone is produced inside fungi and devised a method to synthesize it in the laboratory. The key was to utilize the “Diels–Alder reaction,” a chemical reaction in which molecules combine like puzzle pieces to form ring structures.

The research team also focused on the weak attractive force between molecules, known as “hydrogen bonding.” By carefully designing the reaction to ensure that hydrogen bonding occurs in the correct direction, the team could avoid unwanted byproducts and induce the formation of herpotrichone.

As a result, they successfully synthesized herpotrichone A, B, and C, which were previously difficult to obtain, with high precision. In particular, they analyzed the structures of the key components of herpotrichone to determine the conditions under which hydrogen bonding occurs most effectively, and used this knowledge to design the reaction to occur accurately.

In the process, new substances not yet discovered in nature were also created, and some show promising pharmacological effects, making them candidates for new drugs. Notably, by-products obtained during previous syntheses were confirmed to be identical to naturally occurring herpotrichone C, demonstrating the potential to predict natural compounds through artificial synthesis.

“This achievement represents the first synthesis of a rare natural product with pharmacological activity related to degenerative neurological diseases and systematically presents the principles of biomimetic synthesis of complex natural products,” Professor Han said. “It will likely be widely utilized in the development of natural product-based anti-neuroinflammatory therapeutics and further studies on the biosynthesis of this natural product group.”

The paper titled “Total Synthesis of (+)-Herpotrichones A–C” was published on July 16 in the Journal of the American Chemical Society (JACS). Lee Yoo-jin, a Ph.D. candidate in the Department of Life Science at KAIST, participated in the study as the first author.