Steric Effects on the Amide Isomer Equilibrium of Prolyl Peptides. Synthesis and Conformational Analysis of N-Acetyl-5-tert-butylproline N‘-Methylamides

Abstract

The influence of a bulky 5-position substituent on the amide isomer equilibrium N-terminal to proline has been explored via the synthesis and analysis of N-(acetyl)proline N‘-methylamide (1) and its respective cis- and trans-5-tert-butylproline amide diastereomers 2 and 3. The relative populations of the amide cis- and trans-isomers as well as the energy barriers for amide isomerization of 1−3 in D2O were ascertained using NMR with coalescence and magnetization transfer experiments. The relative populations of free C-terminal amide and hydrogen-bonded amide in the γ-turn conformation were also estimated by integrating the N−H stretch absorbances in the FT-IR spectra of 1−3 in CHCl3 and CCl4. In the prolyl peptides, the 5-tert-butyl substituent was found to exhibit profound effects on the amide isomer equilibrium, on the energy barrier for amide isomerization, and on the stability of the γ-turn conformation. Steric interactions between the 5-position substituent and the N-acetyl group disfavor the amide tr...