Ten-membered cyclotripeptides. III. Synthesis and conformation of cyclo(-Me beta Ala-Phe-Pro-) and cyclo(-Me beta Ala-Phe-DPro-).

Abstract

The 10-membered cyclotripeptide cyclo(-Me beta Ala-Phe-Pro) 3 and its diastereoisomer cyclo(-Me beta Ala-Phe-DPro-) 4 have been synthesized under mild cyclization conditions starting from linear precursors containing C-terminal proline. The crystal and molecular structure of the two models has been determined by X-ray crystallography. Analysis of the NMR spectra supported by NOE data clearly indicates that the conformations found in the crystals are retained in solution. Both cyclotripeptides exhibit a cis-cis-trans backbone conformation. The two tertiary peptide bonds, at the proline and Me beta Ala nitrogen atoms, adopt a cis conformation whereas the CO-NH junctions are trans in both the models. The deviations from planarity of the peptide units vary from delta omega values of ca. 18 degrees for the Pro-Me beta Ala and DPro-Me beta Ala bonds to ca. 7 degrees for Phe-Pro and Phe-DPro bonds. Relevant conformational details of 3 and 4, as revealed by X-ray and NMR analysis, are reported. Crystals of 3 are monoclinic: P2(1), a = 5.317(2), b = 17.059(6), c = 9.514(3) A, beta = 99.18(3), Z = 2. The final R and Rw are 0.054 and 0.071 respectively. Crystals of 4 are orthorhombic: P2(1)2(1)2(1), a = 8.797(2), b = 19.440(9), c = 21.605(10) A, Z = 8. The final R and Rw are 0.069 and 0.104 respectively.