DESIGN, SYNTHESIS, AND CONFORMATIONAL-ANALYSIS OF A PROPOSED TYPE-I BETA-TURN MIMIC

In an effort to design a dipeptide structural mimic of protein and pep tide p-turns, we have prepared and evaluated the conformation of deriv atives of the novel, highly constrained ten-membered lactam, (3S,-10S) -(6E)-2-azacyclodec-6-enone (1). A synthetic route utilizing ring-clos ing olefin metathesis (RCM) has been used to prepare this novel ten-me mbered ring in high yield. X-ray crystallography and H-1 NMR analysis have established that ring closure proceeds to give the trans-olefin a nd that 1 exists in two conformations, that of a chair-chair and chair -boat. Monte Carlo-molecular mechanics conformational searching has in dicated that this ring system would be a good mimic of a type I beta-t urn. The synthesis of model tri-and tetrapeptide analogues based on 1 is reported. NMR studies indicate that the tetrapeptide derivatives co nstrain the i + 1 and i + 2 torsion angles to within 30 degrees of tho se predicted for an ideal type I beta-turn (phi(1) = -82 degrees, psi( 1) = -20 degrees, phi(2) = -107 degrees, psi(2) = -18 degrees) and tha t this conformation was shown to be stable in both hydrogen-bonding so lvents as well as non-hydrogen bonding solvents at various temperature s.