Copper catalyzed deprotection of selenazolidine for one-pot synthesis of proteins and cyclic peptides

Own to their diverse of natural functions, 1 proteins have been one of the most important biomolecules to study in life science. The chemical synthesis of large protein depends on solid phase peptide synthesis (SPPS) and peptide ligation, most notably the native chemical ligation (NCL). 2 NCL requires cysteine (Cys) residue at the N-terminus of one peptide and thioester in the C-terminus of a second. 3 The Cys-residue at N-terminus of middle peptide segments is usually protected to avoid the intramolecular cyclization, in which the most common protecting group is thiazolidine (Thz). In addition, selenocysteine mediated NCL (Sec-NCL) was developed as alternative method, and selenazolidine (Sez) was also developed as a protecting group of Sec for protein synthesis. 4 The NCL/desulfurization and Sec-NCL/desalinization were reported earlier to overcome the limitation of the requirement of Cys in the NCL reactions. However, multiple HPLC purification during the protein synthesis lead to low yield of final target protein. To increase the efficiency of chemical protein synthesis, here we described a one-pot synthesis of protein and cyclic peptide by copper mediated deprotection of Sez. 5, 6

Figure 1. The synthesis of protein and cyclic peptide in one-pot, based on Sec-NCL, and copper-mediated Sez deprotection, and chemoselective deselenization.

References
1. von Döhren, H.; Keller, U.; Vater, J.; Zocher, R. Chem. Rev. 1997, 97, 2675-2706.
2. Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed. 2008, 47, 10030-10074.
3. Dawson, P. E.; Muir, T. W.; Clarklewis, I.; Kent, S. B. H. Science 1994, 266, 776-779.
4. Reddy, P. S.; Dery, S.; Metanis, N. Angew. Chem. Int. Ed. 2016, 55, 992-995.
5. Zhao, Z.; Metanis, N. Angew. Chem. Int. Ed. 2019, 58, 14610-14614.
6. Zhao, Z.; Metanis, N. J. Org. Chem. 2019, accepted.