title: Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides.
abstract: Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr 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 SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.
authors: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. blp@mit.edu.
authors: Yekui
authors: Y
authors: Zou
authors: Alexander M
authors: AM
authors: Spokoyny
authors: Chi
authors: C
authors: Zhang
authors: Mark D
authors: MD
authors: Simon
authors: Hongtao
authors: H
authors: Yu
authors: Yu-Shan
authors: YS
authors: Lin
authors: Bradley L
authors: BL
authors: Pentelute
mesh_terms: D003500:Cyclization; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D047028:Macrocyclic Compounds; D019151:Peptide Library; D010455:Peptides