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

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.