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

Abstract

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.alpha..sbd.C.beta. bond of the Phe to be axial, and, on the other hand, the intrinsic tendency of the Pro residue to have its C.alpha..sbd.C.beta. 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.alpha..sbd.C.beta. 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.