The Role of the Amino Acid-Derived Side Chain in the Preorganization of C2-Symmetric Pseudopeptides: Effect on SN2 Macrocyclization Reactions

Abstract

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br(-) has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds.