Synthesis and kinetic investigation of the selective acidolysis of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-α,α-dialkylglycine cyclohexylamides

Abstract

Several derivatives of N-phenylacetyl-N-benzyl-α,α-dimethylglycine cyclohexylamide and their α,α-dibenzylglycine analogues were synthesised by a Ugi-Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl group at the nitrogen atom were synthesised. The compounds in each of these three sets differed from each other at the position 4 of the N-benzyl (and N-phenyl) group. These adducts were submitted to acidolysis with TFA to obtain the corresponding free acids, the reactions being monitored by HPLC and data collected for kinetic purposes. The kinetic data were submitted to Hammett uni-and biparametric relationships and the results analysed in terms of structure-reactivity in connection to the sensitivity of the reaction rates to the electronic contributions of the various substituents in position 4 of the aromatic rings. The results allowed comparison with information obtained in previous investigations and rationalise the contribution of the substituent at the nitrogen atom to the lability of the C-terminal amide bond.

Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction

“…They concluded that the acidolysis of the C-terminal amide bond depends mostly on polar substituent parameters rather than steric. In addition, they achieved the isolation of an oxazolone derivative, thereby confirming Goodman’s proposal and demonstrating that amide cleavage proceeds through a cyclic intermediate [ 15 ]. A similar behavior was also observed for N -acylated peptoids, which trigger the loss of peptoid monomer from the sequence, a phenomenon also explained through an oxazolinium-based mechanism [ 16 ].…”

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

“…In addition, the use of ketones or ketimines as substrates in such reactions, in order to generate structures bearing tetrasubstituted carbons, entails additional obstacles, since the inherent steric factors observed in these systems enhance the difficulty level in these synthetic methodologies [ 23 ]. In addition, the use of acyclic ketones typically requires preformation of the imine intermediate in a separate step, and the yields of the Ugi are often modest [ 24 , 25 , 26 ].…”

Synthesis of N-alkyl-Cα,α-dimethylglycine derivatives

“…This difficulty can only be overcome by taking advantage of synthetic methodologies not usually used in peptide chemistry, such as the methodology based on the Ugi reaction, which we have been developing over the last decade. [17][18][19][20] Several studies on the biological activity of N-methyl, C α,α -dimethylglycine, (Me-Aib) have been reported. Me-Aib has been widely used as a specific model substrate for system A amino acid transport, 21 which is expressed strongly in transformed and malignant cells.…”