Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300072, P. R. China.
Schulich Faculty of Chemistry and the Resnick Sustainability Center for Catalysis, Technion-Israel Institute of Technology, Haifa, 3200009, Israel.
Angew Chem Int Ed Engl. 2023 Sep 11;62(37):e202304740. doi: 10.1002/anie.202304740. Epub 2023 Jun 12.
Selective structural modification of amino acids and peptides is a central strategy in organic chemistry, chemical biology but also in pharmacology and material science. In this context, the formation of tetrazole rings, known to possess significant therapeutic properties, would expand the chemical space of unnatural amino acids but has received less attention. In this study, we demonstrated that the classic unimolecular Wolff rearrangement of α-amino acid-derived diazoketones could be replaced by a faster intermolecular cycloaddition reaction with aryldiazonium salts under identical practical conditions. This strategy provides an efficient synthetic platform that could transform proteinogenic α-amino acids into a plethora of unprecedented tetrazole-decorated amino acid derivatives with preservation of the stereocenters. Density functional theory studies shed some light on the reaction mechanism and provided information regarding the origins of the chemo- and regioselectivity. Furthermore, this diazo-cycloaddition protocol was applied to construct tetrazole-modified peptidomimetics and drug-like amino acid derivatives.
选择性的氨基酸和肽的结构修饰是有机化学、化学生物学，也是药理学和材料科学的核心策略。在这方面，形成具有显著治疗特性的四唑环可以扩展非天然氨基酸的化学空间，但受到的关注较少。在这项研究中，我们证明了经典的α-氨基酸衍生的重氮酮的单分子沃尔夫重排反应可以在相同的实际条件下被更快的芳基重氮盐的分子间环加成反应所取代。该策略提供了一个有效的合成平台，可以将蛋白质氨基酸转化为大量前所未有的四唑修饰的氨基酸衍生物，同时保留立体中心。密度泛函理论研究揭示了反应机制，并提供了关于化学和区域选择性起源的信息。此外，该重氮环加成方案被应用于构建四唑修饰的肽类似物和类似药物的氨基酸衍生物。
