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2024.06.24
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[College of Science and Engineering] A joint research group led by Professor Miki Hasegawa and Associate Professor Masashi Harada of the Chiba University International Advanced Research Center and Graduate School of Pharmaceutical Sciences has succeeded in one-step synthesis of a complex compound that will be useful in new drug development. ~Lanthanides pave the way for the future of drug discovery and the environment~
A joint research group led by Associate Professor Masashi Harada of the Institute for Advanced Study and Graduate School of Pharmaceutical Sciences, Chiba University, and Professor Miki Hasegawa of the Faculty of College of Science and Engineering, Aoyama Gakuin University, has succeeded in synthesizing compounds with complex structures crucial for drug development with high precision in just one step using a catalyst based on "lanthanides" (Note 1). This research is expected to enable the efficient synthesis of active ingredients in pharmaceuticals. The results of this research were published on May 22, 2024 (Wednesday) in the American Chemical Society's academic journal, "the Journal of Organic Chemistry."
Research background
The development of new drugs requires compounds with complex structures. In particular, the group of compounds known as "carbazoles" (Note 2) are attracting attention due to their numerous biological activities. For example, vinblastine, a naturally derived anticancer drug, has a carbazole as a substructure and exhibits potent pharmacological activity. However, synthesizing these compounds artificially and sustainably is currently extremely difficult. This is because carbazoles have complex structures with many substituents (other atomic groups attached to the compound). In particular, the structure known as a "tetrasubstituted carbon," in which four different substituents are bonded to one carbon atom, poses a major obstacle to chemical synthesis. Therefore, there has been a need to develop efficient methods for synthesizing carbazoles, as well as to establish technologies that allow for the reuse of the resources used.
Figure 1: Plan for high-purity carbazole synthesis using the Diels-Alder reaction Research results
In this study, we successfully synthesized complex carbazole compounds containing tetrasubstituted carbons by developing catalysts using lanthanide elements such as holmium (element symbol: Ho) Note 3). Among the various lanthanide catalysts, the holmium catalyst showed the best results in terms of both efficiency and purity.
The key to this success lies in the ingenious use of a chemical reaction called the "Diels-Alder reaction" (Note 4). This reaction is excellent because it not only allows for the creation of complex carbazoles in a single step by combining two simple structural starting materials, but also allows for the simultaneous creation of tetrasubstituted carbons (Figure 1).
Figure 1: Plan for high-purity carbazole synthesis using the Diels-Alder reaction 
Figure 2: Holmium-catalyzed Diels-Alder reaction (Si: silicon-containing substituent) However, the Diels-Alder reaction, which creates tetrasubstituted carbons, did not proceed with the existing lanthanide catalysts possessed by the research group. This was because one of the starting materials used in the reaction had a steric hindrance that prevented the reaction from proceeding. To solve this dilemma, the research group devised a new catalyst structure. Specifically, they overcame the steric hindrance by creating space around the holmium. This innovation had the dual effect of enhancing the catalytic function of holmium and successfully enabled the efficient bonding of starting materials that had previously not reacted together (Figure 2).
Figure 2: Holmium-catalyzed Diels-Alder reaction (Si: silicon-containing substituent) 
A 3D model capturing the moment when two raw materials combine. What is noteworthy is the extremely high purity of the carbazole produced using this method. Compounds exist in two symmetrical forms, like mirror images, and are usually obtained as a mixture of these two forms. However, in this study, we succeeded in selectively producing only one form with 99% purity. This high purity is extremely important in drug development because the two forms of a compound can exhibit completely different effects in the body.
Furthermore, the holmium used as a catalyst can be recovered after the reaction. Lanthanides are valuable natural resources essential for electronic devices and electric vehicles. This recovery and reuse technology makes a significant contribution to the efficient use of resources and environmental protection.
The research group not only developed this innovative synthesis method, but also utilized three different cutting-edge technologies to "visualize" the function of the catalyst (Figure 3).
1. [Utilizing the "luminescence" of lanthanides]: Similar to holmium, which was used as a catalyst, europium (element symbol: Eu) Note 5) also functioned as an excellent catalyst for carbazole synthesis. The research group succeeded in capturing the state change of the catalyst during the reaction as a change in light by utilizing the property that the way europium luminescent changes depending on the surrounding environment. This is a very groundbreaking attempt that allows us to indirectly "see" the site of a chemical reaction.
2. [Investigating the catalyst's "fingerprint"]: Just as humans have unique fingerprints, molecules also have their own unique fingerprints. The research group used a technique called mass spectrometry to investigate the catalyst's "molecular fingerprint." As a result, they were able to confirm that the catalyst had the structure exactly as designed. In other words, this confirmed that the ideal catalyst was functioning correctly.
3. [Reproducing the reaction with a computer]: Finally, we reproduced the chemical reaction on a computer using the latest computational science method called density functional theory. As a result, we were able to explain at the atomic level why only specific types of compounds are selectively formed.
These efforts have made visible the "this happens, then this happens, then this happens" processes in the invisible world of molecules. As a result, we were able to scientifically support the reasons why this innovative synthesis method is successful.
A 3D model capturing the moment when two raw materials combine. Future prospects
This research is expected to significantly contribute to accelerating new drug development. In particular, it will enable the efficient artificial synthesis of drugs with a carbazole structure, such as vinblastine, which is known as a cancer treatment. Furthermore, the lanthanide recycling technology will contribute to the realization of a sustainable chemical and pharmaceutical industry. In addition, the visualization of catalysts is expected to be useful for designing better catalysts and synthesizing more difficult compounds. By applying this technology to other fields in the future, it is expected that environmentally friendly chemical reactions will become more widespread.
■ Glossary
Note 1) Lanthanides: A collective term for 15 elements included in rare earth elements. They possess unique properties such as magnetism and luminescence, and have the potential to bring about innovation in various fields. In recent years, they have been found to be buried on the seabed within Japan's exclusive economic zone, and are expected to play an important role in Japan's resource strategy.
Note 2) Carbazole: A compound consisting of three linked rings, each composed of 12 carbon atoms and 1 nitrogen atom. It is also known as a substructure of complex compounds that exhibit biological activity, including pharmaceuticals.
Note 3) Holmium: One of the lanthanide elements. It is used in magnets and medical lasers. On the other hand, it is rarely used as a catalyst in chemical synthesis. It is found in relatively large quantities in the Earth's crust, but it is considered a rare element because it is difficult to purify, and its recovery and reuse are essential.
Note 4) Diels-Alder reaction: A reaction in which a molecule with four carbon atoms and a molecule with two carbon atoms bond, forming a hexagon with six carbon atoms arranged in a ring.
Note 5) Europium: One of the lanthanide elements. It is an element that emits red light when exposed to certain types of light. It was formerly used as a red phosphor in cathode ray tube televisions.
■ About the research project
This research was primarily supported by the Grants-in-Aid for Scientific Research (C) "Synthesis of Polysubstituted Cyclic Skeletons Achieved with Multiple Reaction-Promoting Lanthanide Catalysts" (22K06496).
■ Paper Information
Paper title: Synthesizing Chiral Hydrocarbazoles with a Tetrasubstituted Carbon Using Holmium-Catalyzed Enantioselective [4 + 2] Cycloaddition: Mechanistic Insights from Luminescence and DFT Studies
Authors: Shinji Harada*, Shihori Sekino, Marisa Inaba, Ayumi Okita, Tetsuhiro Nemoto, Shigeru Arai, Hitomi Ohmagari, Miki Hasegawa, and Atsushi Nishida
Journal name: The Journal of Organic Chemistry
DOI: https://doi.org/10.1021/acs.joc.4c00837
