Intramolecular H‐bonds and thioamide rotational isomerism in thiopeptides

Abstract

Mono‐ and dithionated N‐acyl amino acid and dipeptide N′‐methylamides were synthesized using Lawesson's reagent and 5‐thioacetyl thioglycolic acid. The conformation of the thionated models was characterized by IR, 13C, and 1H NMR spectroscopy, including NOE experiments. The formation of —C=S…H—N—C=X (X = O or S) intramolecular H‐bonds of the type 2 → 2. 1 → 3 and 1 → 4 was evidenced by the characteristic shifts of the IR stretching frequencies of the NH group. Act‐Pro‐NHCH3 (4) and Act‐Prot‐NHCH3 (5) were found to be present as mixtures of rotational isomers about the CS—N bond. 13C chemical shifts of the γ‐ and β‐carbons of the proline ring elucidated the conformation (Z or E) of the tertiary thioamide group. Our results suggest that the conformation of thiopeptides is determined by two factors: 1) the H‐bond donating and accepting ability of the thioamide group and 2) the repulsion between the thiocarbonyl sulfur atom and the side chain groups of the neighbouring amino acid residues.