A Breakthrough in the Synthesis of Potent Bioactive Molecules

Many chemical compounds with amazing medical capabilities are found in the natural world. One famous example is penicillin, which was unintentionally found in the Penicillium mold. This discovery demonstrated the potential of natural substances in medicine and transformed the treatment of bacterial illnesses.

Since then, the process of developing new drugs has relied heavily on the identification, isolation, and synthesis of novel bioactive chemicals from bacteria, fungi, and plants.

Eutyscoparols A–G from the fungus Eutypella scoparia and violaceoids A–F from the fungus Aspergillus violaceofuscus are two families of naturally occurring bioactive compounds that have attracted a lot of attention recently.

These substances, which have a hydroxymethyl group and a 2,3-alkylated quinol moiety in common, are thought to have antibacterial and antimalarial properties. To do additional research, scientists have been attempting to synthesize these chemicals in greater amounts since their first discovery in 2020 and 2014.

In a recent study, scientists from Tokyo University of Science (TUS), under the direction of Associate Professor Takatsugu Murata and Professor Isamu Shiina from the Faculty of Science's Department of Applied Chemistry, made significant advancements by creating a productive way to synthesize violaceoid C and eutyscoparol A. Their research was published in the Asian Journal of Organic Chemistry.

Eutyscoparol is a group of compounds whose pharmacological activity had not been thoroughly explored. Our goal was to make this possible through artificial synthesis and support the development of new drugs.”

Dr. Takatsugu Murata, Associate Professor, Department of Applied Chemistry, Tokyo University of Science

The researchers employed a retrosynthetic analysis to simplify the production process. This method simplifies complicated compounds into more manageable components. Using commercially available dinitriles as violaceous A intermediates, they synthesized eutyscoparol A and violaceous C using this approach.

The selection of dinitriles was based on their availability and ability to be transformed into aldehydes, the building blocks of violaceoid A intermediates. Diester was initially created from dinitrile to create an aldehyde. Then, to create protected ether, a tert-butyldiphenylsilyl (TBDPS) group was added to the diester's hydroxy groups for protection. Asymmetric diol was created by reducing this ether.

Following selective protection of one hydroxy group in diol, desymmetrized tetrahydropyranyl (THP)-ether was created. This was subsequently oxidized to yield the aldehyde. After preparing the aldehyde, the scientists carried out a sequence of reactions to create the intermediates violaceoid A and rac-violaceoid B. To create violaceoid A, the aldehyde was first alkylated to form an intermediate, which was then used with the Julia-Kocienski reagent or mesylation to convert to an olefin.

Alcohol was created by using isopropyl alcohol to remove the THP-protecting group from olefin. Two TBDPS groups were then removed from the alcohol to obtain violaceous A. Comparable techniques were used to synthesize Violaceous B.

These upgrades made the procedure significantly more efficient. In contrast to the earlier 10-step procedure that yielded only 11 %, the researchers were able to manufacture violaceous A in 8 steps with a 33 % yield. In a similar vein, they improved upon the previous 9-step procedure with a 15 % yield by preparing violaceous B (rac-2) in 8 steps with a 35% yield.

Following the successful synthesis of the intermediates, the scientists produced eutyscoparol A and violaceoid C. The process of synthesizing violaceoid C was quite simple and involved efficiently hydrogenating the double bond in violaceoid A to produce violaceoid C.

By refluxing the reaction mixture with potassium carbonate and iodomethane, the researchers were able to selectively methylate two of the three hydroxy groups in violaceoid A, leading to the formation of eutyscoparol A. Eutyscoparol A was synthesized in nine steps with a yield of 28%, and violaceoid C in nine steps with a yield of 30%.

The suggested method makes it easier to synthesize these chemicals on a bigger scale and may inspire further investigation into their possible therapeutic uses because of their higher yields and less complicated synthesis stages.

The synthesis of violaceoid A and eutyscoparol C on a subgram scale will help us study their pharmacological effects, which we expect to include cytotoxic, antibacterial, and antimalarial activities.”

Isamu Shiina, Professor, Department of Applied Chemistry, Faculty of Science, Tokyo University of Science