Conformation of cyclo-(D-phenylalanyl-trans-4-fluoro-D-prolyl)

cyclo(D-Phenylalanyl-trans-4-fluoro-D-prolyl), c(D-Phe-D-FPro), was synthesized and its conformation determined both in solution and in the solid state by ¹H NMR and X-ray analysis, respectively. In the crystals the 2,5-diketopiperazine (DKP) ring assumes the uncommon conformation, for cyclodipeptides containing Pro residue, of a flattened chair, which seemingly results from a compromise between, on the one hand, the DKP-aromatic intramolecular ring-ring attraction (folding), requiring the C^α-C^β bond of the Phe to be axial, and, on the other hand, the intrinsic tendency of the Pro residue to have its C^α-C^β bond equatorial. Unlike the solid state, the ¹H NMR data in CDCl₃ and C₆D₆ demonstrate that in both solutions the DKP ring assumes a boat-like shape, typical for the Pro-containing cyclodipeptides, with the equatorial C^α-C^β bonds in both amino acid residues, which preclude ring-ring folding. A similar conformation was encountered in the closest analog of c(D-Phe-D-FPro), viz. in c(Phe-Pro), both in solution (21, 22, 26) and in the solid state (12). A subtle interplay of intramolecular interactions introduced into a cyclodipeptide by a Pro-type and a Phe-type residue is emphasized.