Alcohols as Replacements of the Central Amide in β-Turns, Synthesis of Pro-Aib Hydroxyethylene Isostere and Analysis in Model β-Turn Peptides

Abstract

Pro-Aib hydroxyethylene isosteres (S,R)- and (S,S)-7 were synthesized by cascade addition of 2-methyl-1-propenylmagnesium bromide to Boc-Pro-OMe in the presence of CuCN, followed by ketone reduction and olefin oxidation. By protecting the amine and hydroxyl groups in an oxazolidinone ring, hydroxyethylene isosteres 7 were successfully incorporated into Boc-Phe-Pro- ψ -[CH-(OH)-CH2]-Aib-NHBn(α -Me) (S,R)-and (S,S)-11, which were characterized by 1H NMR and IR spectroscopy. Examination of the NOESY spectra and the influence of solvent changes on the chemical shifts of the amide and carbamate proton signals for (S,R)-and (S,S)-11 indicated that both hydroxyethylene isosteres could adopt compact turn structures. The alcohol appears to act as a hydrogen donor in a seven-membered ring intramolecular hydrogen bond. In addition, analysis of the respective peptide (S,S)-16, in which the hydroxyl group was masked as a methyl ether, showed that the turn conformation was disrupted, and indicated the importance of the alcohol as a hydrogen-bond donor for turn stability.