N-Methylated Peptide Synthesis via Generation of an Acyl N-Methylimidazolium Cation Accelerated by a Brønsted Acid |
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Authors: | Dr Yuma Otake Yusuke Shibata Dr Yoshihiro Hayashi Prof Dr Susumu Kawauchi Prof Dr Hiroyuki Nakamura Prof Dr Shinichiro Fuse |
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Institution: | 1. Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8503 Japan;2. School of Materials and Chemical Technology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8552 Japan;3. Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601 Japan |
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Abstract: | The development of a robust amide-bond formation remains a critical aspect of N-methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N-methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N-methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate-limiting generation of acyl imidazolium cations from mixed carbonic anhydrides. |
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Keywords: | acylation amino acids anhydrides continuous flow peptides |
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