Cyclic β-tetra- and pentapeptides: Synthesis through on-resin cyclization and conformational studies by X-ray, NMR and CD spectroscopy and theoretical calculations

Abstract

The solution-phase synthesis of the simplest cyclic β-tetrapeptide, cyclo(β-Ala)4(4), as well as the solid-phase syntheses through side chain anchoring and on-resin cyclization of the cyclic β3- tetrapeptide cyclo(-β3hPheβ33hLeu- β3hLys-β3hGln-) (14) and the first cyclic β3-pentapeptide cyclo(-β3hVal- β3hPhe-β3hLeu-β3hLys- β3hLys-) (19) are reported. Extensive computational as well as spectroscopic studies, including X-ray and NMR spectroscopy, were undertaken to determine the preferred conformations of these unnatural oligomers in solution and in the solid state. cyclo(β-Ala)4(4) with no chiral side chains is shown to exist as a mixture of rapidly interchanging conformers in solution, whereas inclusion of chiral side chains in the cyclo- β3-tetrapeptide causes stabilization of one dominating conformer. The cyclic β3-pentapeptide on the other hand shows larger conformational freedom. The X-ray structure of achiral cyclo(β-Ala)4(4) displays a Ci-symmetrical 16-membered ring with adjacent C=O and N-H atoms pointing pair wise up and down with respect to the ring plane. CD spectroscopic examinations of all cyclic β-peptides were undertaken and revealed results valuable as starting point for further structural investigations of these entities. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.