Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

• Main Authors: Zou, Yekui (Contributor), Spokoyny, Alexander M. (Contributor), Zhang, Chi (Contributor), Yu, Hongtao (Author), Lin, Yu-Shan (Author), Pentelute, Bradley L. (Contributor), Simon, Mark (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: Royal Society of Chemistry, The, 2015-02-25T19:59:34Z.
• Subjects: Article
• Online Access: Get fulltext

 Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the S[subscript N]Ar reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously "scan" two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a S[subscript N]Ar transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.