title: Unexpected hydrolytic instability of N-acylated amino acid amides and peptides.
abstract: Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R(2)CO, four bonds away from the site of hydrolysis. Electron-rich acyl R(2) groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent's Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.
authors.affiliation: Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis , Indianapolis, Indiana 46202, United States.
authors.forename: J Geno
authors.initials: JG
authors.lastname: Samaritoni
authors.forename: Alexus T
authors.initials: AT
authors.lastname: Copes
authors.forename: DeMarcus K
authors.initials: DK
authors.lastname: Crews
authors.forename: Courtney
authors.initials: C
authors.lastname: Glos
authors.forename: Andre L
authors.initials: AL
authors.lastname: Thompson
authors.forename: Corydon
authors.initials: C
authors.lastname: Wilson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: O'Donnell
authors.forename: William L
authors.initials: WL
authors.lastname: Scott
mesh_terms: D000215:Acylation; D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D006868:Hydrolysis; D010455:Peptides / Q000737:chemistry*; D014269:Trifluoroacetic Acid / Q000737:chemistry
chemical_list: D000577:Amides; D000596:Amino Acids; D002264:Carboxylic Acids; D004151:Dipeptides; D010455:Peptides; D014269:Trifluoroacetic Acid