The 1,2,3,5-tetrazoline family of chemicals, which has considerable potential for the production of medicines, biological probes, and other chemical products, has been the subject of a first-generation generic technique of synthesis developed by chemists at Scripps Research.
The first chemical in this as-yet-unknown family was created by the researchers in 2019, but the new procedure, which was disclosed on December 3 in the Journal of Organic Chemistry, is now more widespread and effective.
Dale Boger, PhD, the Richard and Alice Cramer Professor of Chemical at Scripps Research and the study’s principal author, adds that “for the first time, the chemistry community may access these potential molecules and examine their unique features.”
Zhi-Chen Wu, PhD, who was a graduate student in the Boger lab at the time of the work and is currently a medicinal chemist at Amgen, is the article’s primary author.
Methods that enable the synthesis of novel chemicals always hold the promise of creating novel pharmaceuticals and other goods with interesting and useful properties. Given the effectiveness of the closely related 1,2,4,5-tetrazines, the 1,2,3,5-tetrazines have been viewed as being particularly promising. The later substances, which were found in 1959, have distinctive reactivity patterns and are frequently employed to create new materials, medicines, and chemical probes that mark biological entities. The 1,24,5-tetrazolines are most famous for their applications in “click chemistry” reactions, so named for their simplicity of usage and effective, targeted reactivity with target molecules. The extensive applications of chemistry were honored with this year’s Nobel Prize in Chemistry.
In the more than 60 years since their discovery, “the 1,2,4,5-tetrazolines have become enormously valuable for chemistry,” claims Boger.
Despite having the same chemical formula as 1,2,4,5-tetrazines but a different atom arrangement, 1,2,3,5-tetrazines have proven to be significantly harder to find. But Wu and Boger discovered plenty of evidence of its promise when they completed the first 1,2,3,5-tetrazole synthesis in 2019. One finding was that the substance can quickly and efficiently react through “ligation reactions” with substances known as amidines (a type of reaction that joins two fragments together). These ligations, according to the scientists, could serve as the foundation for new molecular probes and labeling methods for biology as well as the construction of medications and other chemical goods. Additionally, the researchers discovered proof that the 1,2,3,5-tetrazine’s reactivity varied from that of the 1,2,4,5-tetrazine in a way that would permit the simultaneous employment of the two tetrazine classes in specific situations without causing crossover reactivity.
The original 1,2,3,5-tetrazine synthesis was relatively time-consuming and only produced one product. The new technique, in contrast, provides a broad approach for rapidly producing several variations of these compounds from cheap, commercially available starting chemicals in just five reaction steps.
The scientists will now create more fresh 1,2,3,5-tetrazolines with their coworkers at Scripps Research in order to investigate their capabilities in click chemistry and other applications.
According to Boger, “I believe this represents the beginning of a new chapter that may prove to be as relevant, enduring, and significant as the one for 1,2,4,5-tetrazolines.”
