NMR and theoretical calculations: a unified view of the cis/trans isomerization of 2-substituted thiazolidines containing peptides

The cis/trans isomerization of peptides containing the pseudoproline (4R)-thiazolidine-4-carboxylic acid Cys(Psi (R1,R2) pro) is investigated from both an experimental and a theoretical point of view by NMR and DFT calculations. A series of Ac-Cys(Psi(R1,R2) pro)-OCH3 and Ac-Cys(Psi(R1,R2) pro)-NHCH3 peptides were prepared to assess the influence of the substitution at the C2 position as well as of the amide following the thiazolidine residue. For each compound, the cis/trans ratio along with free energy, the puckering of the thiazolidine ring and the free rotational energy barrier are reported and discussed. We observe there is a pronounced effect of the C2 substituents and of the chirality upon the cis/trans ratio with the population of the cis content in the order (2R)-Cys(Psi(CH3,H) pro)<(2S)-Cys(Psi(H,CH3) pro)