β‐Alanine containing cyclic peptides with predetermined turned structure. V

In the present paper we describe the synthesis, purification, single crystal x‐ray analysis, and solution structural characterization by nmr spectroscopy, combined with restrained molecular dynamic simulations, of the cyclic hexapeptide cyclo ‐(Pro‐Phe‐β‐Ala‐Phe‐Phe‐β‐Ala). The peptide was synthesized by classical solution methods and the cyclization of the free hexapeptide was accomplished in good yields in diluted methylenechloride solution using N , N ‐dicyclohexyl‐carbodiimide. The compound crystallizes in the monoclinic space group P2 1 from methanol/ethyl acetate. The molecule adopts in the solid state a conformation characterized by cis β‐Ala 6 ‐Pro 1 peptide bond. The α‐amino acid residues are at the corner positions of turned structures. The Pro 1 ‐Phe 2 segment is incorporated in a pseudo type I β‐turn, while Phe 4 ‐Phe 5 is in a typical type I β‐turn. Assignment of all 1 H and 13 C resonances was achieved by homo‐ and heteronuclear two‐dimensional techniques in dimethylsulfoxide (DMSO) solutions. The conformational analysis was based on inter‐proton distances derived from rotating frame nuclear Overhauser effect spectroscopy spectra and homonuclear coupling constants. Restrained molecular dynamic simulation in vacuo was also performed to built refined molecular models. The molecule is present in DMSO solution as two slowly interconverting conformers, characterized by a cis ‐ tran isomerism around the β‐Ala 6 ‐Pro 1 peptide bond. This work confirms our expectations on the low propensity of β‐alanyl residues to be positioned at the corners of turned structure. © 1994 John Wiley & Sons, Inc.