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.

Biosynthesis and Chemical Applications of Thioamides

“…Peptide conformational changes can result from the elongated CS bond and the higher rotational barrier for the C–N bond (∼5 kcal/mol), which reduces conformational flexibility. Additional altered physiochemical properties include (i) thioamide N–H groups being more acidic (Δp K a = −6) than the corresponding amide, (ii) thioamide N–H groups being better hydrogen bond donors, and (iii) the sulfur lone pairs of thioamides being weaker hydrogen bond acceptors relative to oxygen lone pairs in amides . Therefore, thioamides are suitable for evaluating the contribution of single hydrogen bonds to protein folding and/or stability.…”

“…Additional altered physiochemical properties include (i) thioamide N−H groups being more acidic (ΔpK a = −6) than the corresponding amide, 18 (ii) thioamide N−H groups being better hydrogen bond donors, 19 and (iii) the sulfur lone pairs of thioamides being weaker hydrogen bond acceptors relative to oxygen lone pairs in amides. 20 Therefore, thioamides are suitable for evaluating the contribution of single hydrogen bonds to protein folding and/or stability. Substitution of an amide with a thioamide also imparts significant spectroscopic and electrochemical changes.…”

Native Chemical Ligation of Thioamide-Containing Peptides: Development and Application to the Synthesis of Labeled α-Synuclein for Misfolding Studies

“…Thioamides are nearly isosteric with the natural oxoamides found in the peptide backbone, but there are some subtle differences. Sulfur has a larger van der Waals radius than oxygen (1.85 vs 1.40 Å), and the thiocarbonyl bond is somewhat longer than the oxocarbonyl bond (∼1.60 vs ∼1.25 Å). − The thioamide NH is a stronger hydrogen bond donor than the oxoamide NH, while the sulfur is a slightly weaker hydrogen bond acceptor than the corresponding oxygen. − The thioamide sulfur is also more reactive as a nucleophile, reactivity commonly observed in cyclization during Edman degradation. , Despite these differences, the thioamide is generally stable at physiological pH and can be incorporated in an α-helix or a β-turn without grossly perturbing secondary structure. − …”

Backbone Modification of β-Hairpin-Forming Tetrapeptides in Asymmetric Acyl Transfer Reactions

“…For tetrapeptide 7 , the band of the Aib NH at 3424 cm −1 is similar to the Aib NH of tetrapeptide 4 . The band of Phe thioamide NH at 3287 cm −1 corresponds to a typical thioamide NH absorption in a 1←4 t C 10 to β-turn of a 10-membered ring hydrogen bond . The absorption of the (π-Me)-His NH at 3356 cm −1 is parallel with that of tetrapeptide 4 , implying that the second interstrand hydrogen bond in tetrapeptide 7 is not affected when a more acidic thioamide NH serves as the hydrogen bond donor in the first interstrand hydrogen bond.…”