In a recent paper published in the Journal of Organic Chemistry, researchers under the direction of Associate Professor Shinji Harada from Chiba University's Graduate School of Pharmaceutical Sciences and Institute for Advanced Academic Research have carried out a Diels-Alder reaction for the synthesis of cancer medications.
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A key component of organic chemistry, hydrocarbazole is a building block for many biologically active substances, such as anticancer medications like vinblastine and minovincine and insecticides like strychnine. As such, one of the most important areas of research is the development of synthesis techniques for these molecules.
Their recent breakthrough utilized organic compounds known as indole-incorporated siloxydienes and innovative rare earth catalysts for this purpose. Despite their progress, there remains potential for further enhancement in substrate applicability and catalyst reactivity.
For the synthesis of hydrocarbazole compounds with a tetrasubstituted carbon or a carbon atom bonded to four different substituents at the adjacent position to the nitrogen atom, a specific type of siloxydiene substrate containing a substituent at the second carbon (C2) position of the indole ring is essential.
Kopsinine is a well-known example of one of these substances. It is attracting a lot of interest in pharmaceutical research because of its anti-inflammatory and anticancer qualities. Nevertheless, these siloxydiene substrates are quite low reactive.
To solve this problem, Dr. Harada and his colleagues, including Professor Miki Hasegawa from the Department of Chemistry and Biological Science at Aoyama Gakuin University's College of Science and Engineering, developed a novel method for creating complex hydrocarbazole compounds that contain tetrasubstituted carbon.
Our method uses a new lanthanide-based catalyst and can be used to synthesize complex compounds with high purity. Furthermore, in this method, the lanthanide catalyst can be recycled, thus paving the way for sustainable chemical processes.
Dr. Shinji Harada, Associate Professor, Chiba University
Initially, the researchers tried to use a chiral helical ytterbium catalyst they had previously designed to carry out the Diels-Alder process on a methyl-substituted siloxydiene substrate. No response occurred. This resulted from the substrate's poor reactivity, which was ascribed to the methyl group.
To counteract this, they tried to structurally alter the catalyst to increase its Lewis acidity or its capacity to take in electron pairs and make room around the core metal. By incorporating the triflimide salt, they created a ytterbium triflimide catalyst. Despite the low yield, they managed to use it to get the desired hydrocarbazole molecule.
The primary metal, ytterbium, was swapped out for the lanthanide metal holmium by the researchers in an additional modification to the catalyst. The resultant chiral holmium triflimide catalyst greatly increased the yield to 95% and the product's capacity to generate a single version of the compound rather than its mirror image.
Furthermore, after the process, this catalyst was easily recoverable. The several complicated hydrocarbazole molecules demonstrated this technique's versatility the researchers were able to manufacture. They produced a noteworthy tetracyclic molecule with five chiral centers. They also investigated the response processes using computational and experimental techniques.
These findings will contribute to accelerating the development of new drugs. At first glance, this research may seem technical and esoteric; however, its results have the potential to affect every aspect of our lives, including medicine, environment, and food.
Dr. Shinji Harada, Associate Professor, Chiba University
This research could enhance people's health and quality of life by supporting a sustainable chemical and pharmaceutical sector globally.
Journal Reference:
Harada, S., et al. (2024) Synthesizing Chiral Hydrocarbazoles with a Tetrasubstituted Carbon Using Holmium-Catalyzed Enantioselective [4 + 2] Cycloaddition: Mechanistic Insights from Luminescence and DFT Studies. Journal of Organic Chemistry. doi.org/10.1021/acs.joc.4c00837