Microflow Synthesis of Peptides
Shinichiro Fuse
Graduate School of Pharmaceutical Sciences, Nagoya University
Professor
Peptides have become increasingly important as drugs and their candidates. However, the most conventional chemical peptide synthesis usually requires the use of an excess amount of expensive coupling agents and additives, therefore, peptide synthesis is high cost and wasteful. We have demonstrated micro-flow peptide synthesis using less wasteful, inexpensive, and highly active reagents[1]-[6]. Undesired reactions caused by the highly active reagents were suppressed by using microflow technologies.
Our synthetic approach is based on the rapid and strong activation of carboxylic acid 1 with the highly active reagent. Undesired reactions of highly active 2 were suppressed by precise control of residence time of 2 and reaction temperature enabled by the microflow technologies. The active species 2 was reacted with nucleophile 3 affording desired peptide 4. This approach was also useful for macrolactamization for the synthesis of cyclic peptides (Figure 1).
Microflow technologies not only enabled the development of less wasteful and low-cost synthetic processes for peptides but also gave us valuable insights into rapid reactions that can not be easily analyzed by conventional batch techniques.
Figure 1. Micro-flow peptide synthesis using less wasteful, inexpensive, and highly active reagents.
References
[1] S. Fuse, Y. Mifune, T. Takahashi, Angew. Chem. Int. Ed. 2014, 53, 851.
[2] S. Fuse, Y. Mifune, H. Nakamura, H. Tanaka, Nat. Commun. 2016, 7, 13491.
[3] Y. Otake, H. Nakamura, S. Fuse, Angew. Chem. Int. Ed. 2018, 57, 11389.
[4] Y. Otake, Y. Shibata, Y. Hayashi, S. Kawauchi, H. Nakamura, S. Fuse,
Angew. Chem. Int. Ed. 2020, 59, 12925.
[5] O. Shamoto, K. Komuro, N. Sugisawa, T-H. Chen, H. Nakamura, S. Fuse,
Angew. Chem. Int. Ed. 2023, e202300647.
[6] N. Sugisawa, A. Ando, S. Fuse, Chem. Sci., 2023, 14, 6986.
Keywords: microflow synthesis, peptide, amidation,
