Month: August 2024

In a recent breakthrough, researchers at Tokyo University of Science have successfully developed an efficient method to synthesize eutyscoparol A and violaceoid C, two naturally occurring compounds with promising antimalarial and antibacterial properties. The new approach involves the synthesis of these compounds using readily available dinitriles. This method requires fewer steps and produces the bioactive compounds in higher yields compared to previous approaches, opening up new avenues for drug development.

The natural world is rich in chemical compounds with remarkable medicinal properties. A notable example is penicillin, discovered by chance from the Penicillium mold. This discovery revolutionized the treatment of bacterial infections and highlighted the potential of natural compounds in medicine. Since then, the identification, isolation, and synthesis of novel bioactive compounds from plants, fungi, and bacteria have become fundamental to drug development.

Recently, two groups of naturally occurring bioactive compounds have garnered significant attention: violaceoids A–F from the fungus Aspergillus violaceofuscus and eutyscoparols A-G from the fungus Eutypella scoparia. These compounds share similar structures, featuring a 2,3-alkylated quinol moiety and a hydroxymethyl group, and are believed to possess antimalarial and antibacterial properties. Following their initial discovery in 2014 and 2020, scientists have been working to produce these compounds in larger quantities for further study.

In a recent study, researchers from Tokyo University of Science (TUS), led by Associate Professor Takatsugu Murata and Professor Isamu Shiina from the Department of Applied Chemistry, Faculty of Science, have made significant progress by developing an efficient method to synthesize eutyscoparol A and violaceoid C. Their work, featured on the cover of Volume 13, Issue 7 of the Asian Journal of Organic Chemistry, and published on 25 April 2024, could lead to new treatments or drugs.

“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,” says Dr. Murata.

The researchers used a retrosynthetic analysis to simplify the production process. This approach breaks down complex molecules into simpler, more accessible materials. They used this method to synthesize eutyscoparol A (4) and violaceoid C (3) starting from commercially available dinitriles (6) through violaceoid A (1) intermediates. Dinitriles were chosen because they are easy to obtain and can be converted into aldehydes (5), which are precursors to violaceoid A intermediates. To make the aldehyde (5), dinitrile (6) was first converted into diester. Then, the hydroxy groups in diester were protected with a tert-butyldiphenylsilyl (TBDPS) group to form protected ether. This ether was reduced to form a symmetric diol. One hydroxy group in diol was then selectively protected to create desymmetrized tetrahydropyranyl (THP)-ether, which was oxidized to produce the aldehyde.

With the aldehyde prepared, the researchers proceeded to synthesize violaceoid A (1) and rac-violaceoid B (2) intermediates through a series of reactions. To prepare violaceoid A (1), the aldehyde was first alkylated to form an intermediate, which was then converted to olefin using mesylation or the Julia–Kocienski reagent. The THP-protecting group in olefin was removed with isopropyl alcohol to produce alcohol. Finally, two TBDPS groups were removed from the alcohol to get violaceoid A (1). Rac-violaceoid B (2) was synthesized using similar methods.

These improvements made the process much more efficient. The researchers synthesized violaceoid A (1) in 8 steps with a 33% yield, compared to the previous 10-step process that had only an 11% yield. Similarly, they prepared rac-violaceoid B (rac-2) in 8 steps with a 35% yield, improving on the earlier 9-step process with a 15% yield.

After successfully synthesizing the intermediates, the researchers moved on to produce violaceoid C (3) and eutyscoparol A (4). The synthesis of violaceoid C (3) was relatively straightforward, involving the hydrogenation of the double bond in violaceoid A (1) to yield violaceoid C (3) with high efficiency. For eutyscoparol A (4), the researchers selectively methylated two of the three hydroxy groups in violaceoid A (1) by refluxing the reaction mixture with potassium carbonate and iodomethane. Overall, violaceoid C (3) was synthesized in nine steps with a 30% yield, and eutyscoparol A (4) in nine steps with a 28% yield.

With improved yields and simpler synthesis steps, the proposed approach makes it easier to produce these compounds on a larger scale and could lead to further research into their potential therapeutic properties. “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,” concludes Prof. Shiina.

The photoisomerization of E-to-Z alkenes has many applications in diverse fields, including organic chemistry, polymer chemistry, and medicinal chemistry. In a new study, researchers from Japan developed a new closed-loop method for photoisomerization of E-to-Z alkenes using a recycling photoreactor. This innovative method utilizes the high-performance liquid chromatography method to recycle the samples, thereby improving efficiency. This eco-friendly method can lead to the sustainable development of various chemicals, including pharmaceuticals.

Z-alkenes are organic compounds with a double bond between two carbon atoms and two substituents attached to the carbon atoms on the same side of the double bond. They are ubiquitous structural components of organic compounds in chemistry and biology. It is well known that many of the Z-alkenes cannot be prepared through conventional methods involving thermodynamic methods while photoisomerization can offer good yields. Photoisomerization is a process in which the structural arrangement of an isomer of a molecule is changed to another isomer by absorption of light. The photoisomerization of E-alkenes to produce Z-alkenes has many applications in the fields of organic chemistry, polymer chemistry, and medicinal chemistry.

Many studies have explored different methods for photoisomerization of E-to-Z alkenes. A notable approach involved a continuous-flow system, in which the photosensitizer was immobilized in an ionic liquid and continuously recycled via a simple phase separation process. Photosensitizers are materials that enhance the rate of photoisomerization reactions by absorbing light energy and transferring it to the reactant molecule. However, current methods based on the use of ionic liquids are time-consuming and difficult to apply to recycling high-performance liquid chromatography (HPLC) technology, which enables the recycling of samples and therefore can enhance the efficiency of photoisomerization.

Inspired by these findings, in a new study, a team of researchers from Japan, led by Professor Hideyo Takahashi from the Faculty of Pharmaceutical Sciences at Tokyo University of Science, explored the photoisomerization of E-cinnamamides to Z-cinnamamides using a recycling photoreactor coupled with an HPLC system. The study, published online in The Journal of Organic Chemistry on June 05, 2024, included contributions from Ms. Mayuko Suga, Ms. Saki Fukushima, and Assistant Professor Dr. Kayo Nakamura, also from Tokyo University of Science.

The team had previously developed a recycling photoreactor based on the deracemization concept. Prof. Takahashi explains, “Our closed-loop recycling photoreactor was initially used to convert a racemate, a mixture of left and right-handed enantiomers of a chiral molecule, into the pure desired enantiomer. It consists of a photocatalyst immobilized on a resin, which converts an undesired enantiomer into a racemate, and an HPLC column which separates the desired enantiomer. In this study, we adapted this method to convert E-cinnamamides to their Z-isomers.”
To employ this method for E-to-Z photoisomerization of alkenes, a photosensitizer that promotes rapid photoisomerization is required. To this end, the researchers screened several commercially available photosensitizers and identified thioxanthone as the best candidate. Next, they investigated its immobilization. Thioxanthone, with functional amide groups as linkages, was immobilized on a modified silica gel. This immobilization not only prevented the leakage of photosensitizer in the solid phase but also enhanced the catalytic activity compared to the parent soluble thioxanthone. This enhancement was particularly interesting, as solid-phase reactions are typically slower than liquid-phase reactions.

This superior catalytic activity was attributed to the introduction of suitable functional groups. The researchers, therefore, evaluated the catalytic activity of various photosensitizers with different functional groups by comparing the total amount of light required for promoting photoisomerization. With the optimal photosensitizer identified, they conducted the photoisomerization reactions in the recycling photoreactor, yielding the desired Z-alkenes in good yields after 4–10 cycles.

“This recycling photoreactor shows promise as an efficient alternative system to produce Z-alkenes,” remarks Prof. Takahashi. “Due to the continuous closed-loop recycling of the samples, it represents an environmentally friendly and sustainable method.”

This innovative method can lead to more eco-friendly development of Z-alkenes, and therefore pharmaceuticals, paving the way towards a sustainable future.