| Institution: | 1. 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
These authors contributed equally to this work.;2. 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;3. Schulich Faculty of Chemistry and the Resnick Sustainability Center for Catalysis, Technion-Israel Institute of Technology, Haifa, 3200009 Israel |
| 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. |
