Preferential heterochiral cyclic trimerization of 5-(aminoethyl)-2-furancarboxylic acid (AEFC) driven by non-covalent...

Theoretical justification for preferential heterochiral cyclic trimerization of 5-(aminoethyl)-2-furancarboxylic acid (AEFC) is attempted using density functional theory (DFT) calculations. Results from explicit solvent assisted reaction pathways indicate greater stability of heterochiral cyclic tripeptides over their homochiral counterparts, contrary to findings from gas phase and implicit solvent phase results. Pathways explored at M06/6-31G(d,p) and MP2/6-31G(d,p) levels of theory show kinetic preference for heterochiral cyclization. Analysis of optimized geometries reveals existence of strong hydrogen bonding interactions in the solvated heterochiral tripeptides. Thus, the ability of the cyclic tripeptides to form strong noncovalent interactions increases with conversion of stereochemistry at one of its chiral centers from homo to heterochiral conformation. The resulting change in molecular symmetry facilitates the interacting sites to reorient such that the peptide can interact with a nucleophile from both the faces. This is further substantiated by computed IR spectra, NBO and AIM data. Additionally, justification for the stability of heterochiral cyclic tripeptides comes from molecular electrostatic potential and electron density surfaces. These studies show clearly that for the kind of systems presented here, gas phase or implicit solvent phase studies are inadequate in explaining realistic situations. Calculations with solvent molecules, even if a few only, are necessary to substantiate experimental observations.