Design, Synthesis, and Conformational Analysis of a Proposed Type I β-Turn Mimic

Abstract

In an effort to design a dipeptide structural mimic of protein and peptide β-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 1H 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 β-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° of those predicted for an ideal type I β-turn (φ1 = −82°, ψ1 = −20°, φ2 = −107°, ψ2 = −18°) and that this conformation was shown to...