title: Synthesis of Peptides by Silver-Promoted Coupling of Carboxylates and Thioamides: Mechanistic Insight from Computational Studies.
abstract: The mechanism of the recently described N→C direction peptide synthesis through silver-promoted coupling of N-protected amino acids with thioacetylated amino esters was explored by using density functional theory. Calculation of the potential energy surfaces for various pathways revealed that the reaction proceeds through silver-assisted addition of the carboxylate to the thioamide, which is followed by deprotonation and silver-mediated extrusion of sulfur as Ag2 S. The resulting isoimide is the key intermediate, which subsequently rearranges to an imide through a concerted pericyclic [1,3]-acyl shift (O-sp(2) N 1,3-acyl migration). The proposed mechanism clearly emphasises the requirement of two equivalents of Ag(I) and basic reaction conditions, which is in full agreement with the experimental findings. Alternative rearrangement pathways involving only one equivalent of Ag(I) or through O-sp(3) N 1,3-acyl migration can be excluded. The computations further revealed that peptide couplings involving thioformamides require significant conformational changes in the intermediate isoformimide, which slow down the rearrangement process.
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC, 3010, Australia. chutton@unimelb.edu.au.
authors.forename: Craig A
authors.identifier: http://orcid.org/0000-0002-2353-9258
authors.initials: CA
authors.lastname: Hutton
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC, 3010, Australia.
authors.forename: Jing
authors.initials: J
authors.lastname: Shang
authors.affiliation: School of Chemistry and Bio21 Institute, The University of Melbourne, 30 Flemington Road, Parkville, VIC, 3010, Australia. uwille@unimelb.edu.au.
authors.forename: Uta
authors.identifier: http://orcid.org/0000-0003-1756-5449
authors.initials: U
authors.lastname: Wille
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D005559:Formamides / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011789:Quantum Theory; D012834:Silver / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013854:Thioamides / Q000737:chemistry*
chemical_list: D002264:Carboxylic Acids; D005559:Formamides; D010455:Peptides; D013438:Sulfhydryl Compounds; D013854:Thioamides; D012834:Silver; C009463:thioformamide
keywords: density functional calculations; peptides; reaction mechanisms; rearrangement; synthetic methods