Design, synthesis, and conformational analysis of a proposed type I β-turn mimic

In an effort to design a dipeptide structural mimic of protein and peptide p-turns, we have prepared and evaluated the conformation of derivatives of the novel, highly constrained ten-membered lactam, (3S,-10S)-(6E)-2-azacyclodec-6-enone (1). A synthetic route utilizing ring-closing olefin metathesis (RCM) has been used to prepare this novel ten-membered ring in high yield. X-ray crystallography and H-1 NMR analysis have established that ring closure proceeds to give the trans-olefin and that 1 exists in two conformations, that of a chair-chair and chair-boat. Monte Carlo-molecular mechanics conformational searching has indicated that this ring system would be a good mimic of a type I beta-turn. The synthesis of model tri-and tetrapeptide analogues based on 1 is reported. NMR studies indicate that the tetrapeptide derivatives constrain the i + 1 and i + 2 torsion angles to within 30 degrees of those 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 that this conformation was shown to be stable in both hydrogen-bonding solvents as well as non-hydrogen bonding solvents at various temperatures.