Instability of Amide Bond with Trifluoroacetic Acid (20%): Synthesis, Conformational Analysis, and Mechanistic Insights into Cleavable Amide Bond Comprising β-Troponylhydrazino Acid

Abstract

The instability of an amide bond with dilute trifluoroacetic acid (TFA) is a rare chemical event. The native amide bonds are stable even in the neat TFA, which is one of the reagents that releases the peptides from the solid support in the solid-supported peptide synthesis method. In the repertoire of unnatural peptidomics, α-/β-hydrazino acids and their peptides are explored for the synthesis of N -amino peptide derivatives, and their amide bonds are stable in TFA (∼100%) as natural amide bonds. This report describes the synthesis of a β-hydrazino acid analogue as β-troponylhydrazino acid, containing a nonbenzenoid natural troponyl scaffold. The structural and conformational studies of their hybrid di-/tripeptides with the natural amino acid show that the 2-aminotroponyl residue is involved in hydrogen bonding. Surprisingly, the amide bond of β-troponylhydrazino peptides is cleavable with TFA (∼20%) through the formation of a new heterocyclic molecule N -troponylpyrazolidinone or troponylpyrazolidinone. Tropolone and related compounds are excellent biocompatible chromophores. Hence, β-troponylhydrazino acid could be employed for tuning the peptide structure and considered a promising chromophoric acid-sensitive protecting group of a free amine of amino acids/peptides. It could be applied for the estimation of the free amine group functionality by a UV–vis spectrophotometer.

A new amino acid, hybrid peptides and BODIPY analogs: synthesis and evaluation of 2-aminotroponyl-l-alanine (ATA) derivatives

“…1b). 22 Previously, we have also noticed that the incorporation of the troponyl scaffold at the N-terminal of native di-/tri-peptides significantly alters the peptides' folding behavior (Fig. 1a).…”

Unusual Pseudopeptides: Syntheses and Structural Analyses of Ethylenediprolyl Peptides and Their Metal Complexes with Cu(II) Ion

“…Further, we investigated the hydrogen bonding between amide N– H and C O by 1 H NMR techniques. In literature, the DMSO- d 6 titration 1 H NMR experiment is a well-known method to distinguish the intramolecular/intermolecular hydrogen-bonded amide N–H in the solution . Thus, we performed the DMSO- d 6 titration 1 H NMR experiment with peptides 4a – 4d in solvent CDCl 3 and then compared it with control peptides 3a – 3d .…”

“…In literature, the DMSO-d 6 titration 1 H NMR experiment is a well-known method to distinguish the intramolecular/intermolecular hydrogen-bonded amide N−H in the solution. 36 Thus, we performed the DMSO-d 6 titration 1 H NMR experiment with peptides 4a−4d in solvent CDCl 3 and then compared it with control peptides 3a−3d. Their NMR titration spectra are provided in the Supporting Information (Figures S60−S67).…”

N-Salicyl-AAn-picolamide Foldameric Peptides Exhibit Quorum Sensing Inhibition of Pseudomonas aeruginosa (PA14)

“…In peptide 3a, we noticed marginal downfield shifts (in ppm) of picolylamide N−H (∼0.5 in 3a, ∼0.5 in 3b, and ∼0.2 in 3c/ 3d) and amino acid amide N−H (∼1.0 in 3a, ∼0.5 3b, ∼0.3 in 3c, and ∼0.2 in 3d). In the literature, 25,26 the lower value of chemical shift change indicates the stronger intramolecular hydrogen bonding in CDCl 3 . Our result supports that amino acid residues have significant roles in the intramolecular hydrogen bonding ability of their amide N−H.…”