Promising “building blocks” for new functional materials

In nature, some animals make strong and elastic fibers. For example, the thread that spiders produce to make webs. These fibers have a polypeptide structure and serve as inspiration for research on the development of functional materials. Alpha (α)-amino acid NOT-Carboxyanhydrides (NCA) are precursors of artificial polypeptides. However, this compound breaks down easily, making it difficult to obtain commercially. Therefore, it is necessary to synthesize the right amount of α-amino acid NCAs where and when they are needed. NCAs are usually synthesized from amino acids of plant origin and phosgene. However, phosgene is extremely toxic and dangerous to use, leading to a growing demand for new chemical compounds and reactions that can substitute for them. Using the photo-on-demand phosgenation method they previously developed, the research group of Associate Professor TSUDA Akihiko at the Graduate School of Science, Kobe University succeeded in synthesizing NCA in a safe, inexpensive way. and simple from chloroform (a common organic solvent) and amino acids. acid.

Patents were filed in connection with this study in November 2018 and November 2019. The academic paper was published online in ACS Omega on October 19, 2022.

main points

• Safe, on-site, on-demand synthesis of polypeptide precursors (NCAs) using light.
• The research group successfully synthesized 11 types of NCA from chloroform (a common organic solvent) and commercial amino acids.
• In the lab, they managed to synthesize these substances at a scale of up to ten grams (and this can be scaled up for production on a kilogram scale)
• Compared to the conventional synthesis method (using phosgene) and phosgene substitution methods, the raw materials are cheaper, the labor involved is easier, and less waste is generated. This could reduce costs as well as the burden on the environment.
• The reaction is favored by visible light, and it is theoretically possible to perform this synthetic reaction using sunlight
• These research results will accelerate the development by industry and academia of functional biologically-derived polypeptides.
• It is hoped that these methods will become established techniques that will greatly contribute to the SDGs and efforts to become carbon neutral.

Research fund

Phosgene (COCl₂) is used as a precursor to polymers and as a pharmaceutical intermediate. The global phosgene market continues to grow by several percent each year, with approximately 8 to 9 million tonnes produced annually. However, phosgene is extremely toxic. For safety reasons, research and development is carried out to find alternatives. In a world-first discovery, Associate Professor Tsuda’s research group irradiated chloroform with ultraviolet light, causing it to react with oxygen and generate high yields of phosgene (Patent No. 5900920) . In order to do this in an even safer and easier way, the research group has found a way to perform the phosgene-generating reactions instantly. They first dissolved the reagents and catalysts in chloroform and generated phosgene by irradiating the solution with light (Patent No. 6057449). In this way, phosgene-based organic synthesis can be performed as if phosgene was not used.

The research group named their discovery “photo-on-demand organic synthesis method” and successfully used it to synthesize many useful organic chemicals and polymers (patent list (in Japanese): Tsuda Lab patents). For example, they were able to synthesize large amounts of chloroformate and carbonate in a safe, inexpensive, and simple way simply by irradiating a mixed solution of chloroform and alcohol (with a base added as needed) with light.

These highly original reactions developed at Kobe University have been improved through cooperation with domestic chemical enterprises, and the final goal of this research is practical implementation. With the addition of funding from JST A-STEP, further applied research is underway, as well as the development of functional polyurethane using this synthetic method.

The photo-on-demand organic synthesis method is highly safe and economical, in addition to having a low impact on the environment. Therefore, it has attracted the attention of industry and academia as a sustainable chemical synthesis method (Highlights of Tsuda Laboratory (in Japanese)).

Research Methodology

In this research, the α-amino acid NOT-Carboxyanhydrides (NCA) have been successfully synthesized from the raw materials chloroform and α-amino acid using the photo-on-demand method. NCA is a polypeptide precursor. Although the α-amino acid dissolves easily in water, it does not in chloroform. This meant that the research group had not been able to synthesize the NCA using the previous photo-on-demand method. However, they discovered that by adding acetonitrile (CH₃CN), which can be mixed with water and chloroform as a solvent, a high yield (about 91%) of NCA could be produced. The reaction was not expected to proceed normally because acetonitrile absorbs light, preventing photo-oxidation of chloroform.

Surprisingly, the researchers found that the reaction occurred despite this obstacle, which led to the positive results of this study. Besides the raw material (amino acid) degraded by light, this photoreaction can also be used to produce NCAs which are normally synthesized by the phosgene method. So far, the research group has successfully synthesized 11 types of NCA using this photoreaction.

A detailed breakdown of the synthesis method is as follows. First, the α-amino acid is suspended in a mixed solution of chloroform and acetonitrile. This is then photo-irradiated for two to three hours at 70°C. After the lamp is turned off, NCA is generated by heating and stirring the solution for about an hour. This product can be extracted and refined to obtain very pure NCA. Photo-oxidation of chloroform is promoted by a light-initiated radical chain reaction cleaving C-Cl bonds. Therefore, synthesis can be performed at a scale of up to 10 grams simply by increasing the size of the reaction vessel and keeping the same light source. It is hoped that by further developing this method, it can be used in a wide range of fields ranging from academia to chemical industries.

Further developments

The new Photo-on-Demand NCA synthesis method developed through this research makes it possible to synthesize large quantities of NCA (which are precursors of polypeptides) in a safe, inexpensive and easy way. This easy obtaining of NCA will stimulate the research and development of artificial polypeptides, which will hopefully lead to the creation of new materials, such as new functional polypeptide fibers that will outperform natural fibers produced by animals. Moreover, it is expected that the synthesis of these new polypeptide fibers using amino acids of plant origin as a starter will allow the development of next-generation biomaterials that meet the needs of the times. The objective of the Tsuda group is the industrial implementation of the photo-on-demand NCA synthesis method. To this end, they offer patent licenses and advice on how to use these techniques to interested companies, in addition to continuing their research and development efforts. They hope to develop this research even further by collaborating with industrialists.