title: Propargyl-Assisted Selective Amidation Applied in C-terminal Glycine Peptide Conjugation.
abstract: Alkyl esters, such as propargyl esters, typically lack the electron-withdrawing inductive effects needed to participate in nucleophilic acyl substitution reactions. Herein, we report an unusual observation in which glycine propargyl ester derivatives displayed selective, base-independent reactivity towards linear alkylamines under mild, metal-free conditions. Through global reaction route mapping (GRRM) modeling calculations, it is predicted that these observations may be governed by factors related to hydrogen-bonding and intermolecular interactions, rather than electron-withdrawing inductive effects. Based on this concept of propargyl-assisted selective amidation, a direct application was made to develop a novel site-specific C-terminal glycine peptide bioconjugation technique as a proof-of-concept, which relies upon the selective reactivity of glycine propargyl esters over that of aspartate and glutamate side-chain-linked propargyl esters.
authors.affiliation: Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
authors.forename: Kenward King Ho
authors.initials: KK
authors.lastname: Vong
authors.affiliation: Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.|Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya Street, Kazan, 420008, Russia.|JST, PRESTO, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000577:Amides / Q000737:chemistry*; D004583:Electrons; D004952:Esters; D005971:Glutamates; D005998:Glycine / Q000737:chemistry*; D006860:Hydrogen Bonding; D010293:Pargyline / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*
chemical_list: D000577:Amides; D004952:Esters; D005971:Glutamates; D010455:Peptides; D010293:Pargyline; D005998:Glycine
keywords: amides; hydrogen bonds; peptides; propargyl esters; selective amidation