Nine-membered cyclodepsitripeptides containing the retroisomeric sequence of ergot peptides

In order to examine factors influencing cyclodepsitripeptide formation and stability, three cyclic peptide models containing the alpha-hydroxyacyl-alpha-aminoacylprolyl sequence, corresponding to the peptide lactone cyclo(-Xha-Pro-Xaa-) (Xha = Hiv, Lac; Xaa = Phe, DPhe, DAla), retroisomeric with respect to the ergot oxa-cyclolic peptide moiety, have been considered. Starting from 2,5-dioxomorpholines, aminoacyl incorporation reaction led, through intermediate tetrahedral adducts (aza-cyclols), to the corresponding nine-membered cyclodepsitripeptides cyclo(-Hiv-Pro-DPhe-) 4a, cyclo(-Lac-Pro-DPhe-) 4b, and cyclo (-Hiv-Pro-DAla-) 4c. Compounds 4a-c contain a CONH peptide bond in the nine-membered ring and are stable on standing. Solution conformations of 4a-c, as inferred by NMR spectra and NOE experiments, have been studied. A cis-cis-trans backbone conformation, analogous to that observed in the case of previously studied nine-membered cyclodepsitripeptides containing two proline residues in the ring, is proposed for 4a-c.