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

摘要

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 evaluted. The conformational preferences of these proline-deived 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 C#alpha# is (S) in all compounds have been considered for each bicyclic scaffole. The studies have revealed that the (3S)-Pro C#alpha# (S)configuration is an effective turn-inducer, although the torsion angles of the backbone do not always mimic thsoe of classical #beta#-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 #gamma#-turn or a type II' #beta#-turn. Experimental ~1H-NMR and FT-IR spectroscopic data of model compounds in chloroform soltions have complemented our computer modelling studies and have confirmed our conclusions.