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.