Organocatalytic and Scalable Syntheses of Unsymmetrical 1,2,4,5‐Tetrazines by Thiol‐Containing Promotors

• Published in: Angewandte Chemie International Edition Vol. 58; no. 4; pp. 1106 - 1109
• Main Authors: Mao, Wuyu, Shi, Wei, Li, Jie, Su, Dunyan, Wang, Xiaomeng, Zhang, Lyuye, Pan, Lili, Wu, Xiaoai, Wu, Haoxing
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 21.01.2019; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: annulations; Catalysts; Chemistry; Chemistry, Multidisciplinary; Functional groups; heterocycles; Hydrazine; Hydrazines; Nitriles; Organic chemistry; organocatalysis; Peptides; Physical Sciences; Science & Technology; synthetic methods; DRUG; ARYLTETRAZINES; ONE-POT SYNTHESIS; RELEASE; MOLECULES; PROBES; organocatalysis; TETRAZINE DERIVATIVES; nitriles; annulations; heterocycles; CHEMISTRY; CLICK; synthetic methods
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201812550

Despite the growing application of tetrazine bioorthogonal chemistry, it is still challenging to access tetrazines conveniently from easily available materials. Described here is the de novo formation of tetrazine from nitriles and hydrazine hydrate using a broad array of thiol‐containing catalysts, including peptides. Using this facile methodology, the syntheses of 14 unsymmetric tetrazines, containing a range of reactive functional groups, on the gram scale were achieved with satisfactory yields. Using tetrazine methylphosphonate as a building block, a highly efficient Horner–Wadsworth–Emmons reaction was developed for further derivatization under mild reaction conditions. Tetrazine probes with diverse functions can be scalably produced in yields of 87–93 %. This methodology may facilitate the widespread application of tetrazine bioorthogonal chemistry. Thiols such as glutathione serve as novel catalysts for the tetrazine formation. This simple, mild, scalable approach has broad substrate tolerance and allows access to unsymmetric tetrazines, including robust building blocks for further derivatizations. This methodology could enable most chemical laboratories to prepare tetrazine bioorthogonal probes and other reagents to address challenges in biomedicine, organometallic chemistry, and materials research.