天津大学马军安团队报道了四唑与芳基二氮鎓盐通过银催化的分子间环加成使氨基酸和肽多样化。相关研究成果于2023年5月22日发表于国际一流学术期刊《德国应用化学》。

氨基酸和肽的选择性结构修饰是有机化学、化学生物学以及药理学和材料科学的核心策略。在这种情况下，已知具有显著治疗特性的四唑环的形成将扩大非天然氨基酸的化学空间，但受到的关注较少。

该文中，研究人员发现在相同的实际条件下，α-氨基酸衍生的重氮酮的经典单分子Wolff重排可以被与芳基二氮鎓盐的更快的分子间环加成反应所取代。这种策略提供了一个有效的合成平台，可以将蛋白质生成的α-氨基酸转化为大量前所未有的四唑修饰氨基酸衍生物，同时保留立体中心。密度泛函理论研究揭示了反应机理，并提供了有关化学选择性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拟肽和类药物氨基酸衍生物。

附：英文原文

Title: Tetrazole Diversification of Amino Acids and Peptides via Silver-Catalyzed Intermolecular Cycloaddition with Aryldiazonium Salts

Author: Xuan-Yu Liu, Yi-Lin Yang, Yanfeng Dang, Ilan Marek, Fa-Guang Zhang, Jun-An Ma

Issue&Volume: 2023-05-22

Abstract: 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.

DOI: 10.1002/anie.202304740

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202304740