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Propargyl‐Assisted Selective Amidation Applied in C‐terminal Glycine Peptide Conjugation
Author(s) -
Vong Kenward King Ho,
Maeda Satoshi,
Tanaka Katsunori
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201604247
Subject(s) - propargyl , chemistry , reactivity (psychology) , bioconjugation , glycine , alkyl , nucleophile , peptide , intermolecular force , combinatorial chemistry , stereochemistry , organic chemistry , amino acid , catalysis , molecule , biochemistry , medicine , alternative medicine , pathology
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.