Turn Stabilization in Short Peptides by C-alpha-Methylated alpha-Amino Acids.

The crystal-state conformations of three protected tripeptides, four tetrapeptides, and one pentapeptide, heavily based on the chiral C-alpha-methylated alpha-amino acids Iva, (alpha Me)Nva, and (Me) Val, were assessed by X-ray diffraction analyses. The eight peptide sequences are as follows: Z-((D)-Iva)(2)-(D)-Val-OMe, Z-(D)-Iva-(L)-Iva-Gly-OtBu, Z-(L)-Pro-(D)-Iva-(L)-Iva-Gly-OtBu, Z-(L)-Pro-(L)-Iva-(D)-Iva-Gly-OtBu, Z-Aib-[(L)-(alpha Me)Nva](2)-OtBu, Ac-[(L)-(alpha Me)Val](3)-D-(alpha Me)Val-OtBu, Z-[L-(alpha Me)Val](4)-OH, and Z-(L)-Ala-[(L)-(alpha Me)Nva](4)-OtBu. Two independent molecules were observed in the asymmetric units of Z-(D)-Iva-(L)-Iva-Gly-OtBu and Z-Aib-[(L)-(alpha Me)Nva](2)-OtBu, while three independent molecules were seen in Z-(L)-Ala-[(L)-(alpha Me)Nva](4)-OtBu. All peptides are folded in a single or multiple beta-turn conformations. Interestingly: (i) a water bridge within the N-terminal beta-turn is seen in Z-(L)-Pro-(L)-Iva-(D)-Iva-Gly-OtBu (dihydrate), and (ii) the hydroxyl group of the C-terminal carboxyl functionality of Z-[(L)-(alpha Me)Val](4)-OH generates an oxy-analogue of a beta-turn. The N-terminal beta-turn is missing in molecules A and B, but it does occur, although poorly stabilized, in molecule C, of Z-(L)-Ala-[(L)-(alpha Me)Nva](4)-OtBu.