NMR‐Solution Structures of Fluoro‐Substituted β‐Peptides: A 314‐Helix and a Hairpin Turn. The First Case of a 90° OCCF Dihedral Angle in an α‐Fluoro‐Amide Group

To further study the preference of the antiperiplanar (ap) conformation in α‐fluoro‐amide groups, two β‐peptides, 1 and 2, containing a (2‐F)‐β3hAla and a (2‐F)‐β2hPhe 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 β‐heptapeptide is capable of ‘breaking’ the 314‐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° FCCO dihedral angle, enforced by the 314‐helical folding in a β‐tridecapeptide (cf. 1; Fig. 4). This is interpreted as a consequence of cooperative folding in the longer β‐peptide. A F‐substituent placed in the turn section of a β‐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 β‐tetrapeptides (with helix‐preventing configurations of the two central β2/β3‐amino acid residues) provides unusually tight hairpin structural clusters (cf. 3 and 4a; Figs. 8 and 9). The skeleton of the β‐tetrapeptide H‐(R)β3hVal‐(R)β2hVal‐(R)β3hAla‐(S)β3hPhe‐OH (4a) is proposed as a novel, very simple backbone structure for mimicking α‐peptidic hairpin turns.