Pyridine-containing chiral macrocycles for the enantioselective recognition of amino acid derivatives and their molecular dynamics simulations

Abstract

Two novel C 2-symmetric optically active pyridine-15-crown-5 type ligands containing lipophilic chains at the stereogenic centres, macrocycles 5 and 6, were prepared from ( S)-1,2-propanediol and ( S)-3-aryloxy-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These novel macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K values of up to 1363.5 M −1, Δ G o of up to 17.86 kJ mol −1 and a selectivity ratio of 80:20) by 1H NMR titration method. These macrocyclic host exhibited enantioselective binding towards the l-enantiomer of phenylalanine methyl ester hydrochloride with K L/ K D up to 8.57 in CDCl 3 containing 0.25% CD 3OD. Experimental results have been detailed with molecular dynamic calculations at atomic level concerning the molecular recognition and discrimination properties of a chiral pyridino-15-crown-5. The binding free energies were calculated as ∼−25 kJ mol −1. The results indicated that the host binds and discriminates valine salts better than phenylalanine salts. The molecular dynamics, MM/PBSA calculations are consistent with the 1H NMR results.