Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides
Author(s)Zou, Yekui; Spokoyny, Alexander M.; Zhang, Chi; Yu, Hongtao; Lin, Yu-Shan; Pentelute, Bradley L.; Simon, Mark; ... Show more Show less
MetadataShow full item record
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.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Organic & Biomolecular Chemistry
Royal Society of Chemistry, The
Zou, Yekui, Alexander M. Spokoyny, Chi Zhang, Mark D. Simon, Hongtao Yu, Yu-Shan Lin, and Bradley L. Pentelute. “Convergent Diversity-Oriented Side-Chain Macrocyclization Scan for Unprotected Polypeptides.” Org. Biomol. Chem. 12, no. 4 (2014): 566–573.
Author's final manuscript