NMR-Solution structures of fluoro-substituted beta-peptides: A 3(14)-helix and a hairpin turn. The first case of a 90 degrees O=C-C-F dihedral angle in an alpha-fluoro-amide group

To further study the preference of the antiperiplanar (ap) conformation in a-fluoro-amide groups, two beta-peptides, 1 and 2, containing a (2-F)-beta(3)hAla and a (2-F)-beta(2)hPhe residue; have been synthesized. Their NMR-solution structures in CD3OH were determined and compared with those of non-F-substituted analogs, 3 and 4a. While we have found in a previous investigation (Helv. Chim. Acta 2005,88, 266) that a stereospecifically introduced F-substituent in the central position of a P-heptapeptide is capable of 'breaking' the 3(14)-helical structure by enforcing the F-C-C=O ap-conformation, we could now demonstrate that the same procedure leads to a structure with the unfavorable ca. 90 degrees F-C-C=O dihedral angle, enforced by the 3(14)-helical folding in a beta-tridecapeptide (cf. 1; Fig. 4). This is interpreted as a consequence of cooperative folding in the longer beta-peptide. A F-substituent placed in the turn section of a beta-peptidic hairpin turn was shown to be in an ap-arrangement with respect to the neighboring C=O bond (cf. 2; Fig. 7). Analysis of the non-F-substituted beta-tetrapeptides (with helix-preventing configurations of the two central beta(2)/beta(3)-amino acid residues) provides unusually tight hairpin structural clusters (cf. 3 and 4a; Figs. 8 and 9). The skeleton of the beta-tetrapeptide H-(R)beta(3)hVal-(R)beta(2)hVal-(R)beta(3)hAla-(S)beta(3)hPhe-OH (4a) is proposed as a novel, very simple backbone structure for mimicking apeptidic hairpin turns.