Conformational Analysis of Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics

Abstract

In an effort to design structural mimics of protein and peptide reverse-turns, the conformations of 5,5-, 6,5-, and 7,5-fused 1-aza-2-oxobicycloalkane amino acids have been evaluated. The conformational preferences of these proline-derived bicyclic lactams have been studied by Monte Carlo molecular mechanics searches, and the reverse-turn inducing properties of the calculated structures have been quantitatively assessed using various geometrical parameters. All of the four possible diastereoisomers arising from two of the three stereogenic centres [C3 and bridgehead carbon atom; Pro Cα is (S) in all compounds] have been considered for each bicyclic scaffold. These studies have revealed that the (3S)-Pro Cα(S) configuration is an effective turn-inducer, although the torsion angles of the backbone do not always mimic those of classical β-turns. A dependence of the turn-inducing ability on lactam ring size and bridgehead stereochemistry has also been found. Reverse-turn mimetic bicyclic lactams have been shown to exhibit a tendency to form an inverse γ-turn or a type II′ β-turn. Experimental 1H-NMR and FT-IR spectroscopic data of model compounds in chloroform solutions have complemented our computer modelling studies and have confirmed our conclusions.