Molecular recognition by natural macrocycles. Part II. Esterolytic activity and chiral discrimination of amino acid derivatives by the zwitterionic form of (+)-tubocurarine †

Abstract

The esterase and complexation properties of the zwitterionic form of a macrocyclic alkaloid (+)-tubocurarine possessing two phenolic nucleophilic groups are described. Cleavage of 4-nitrophenyl esters of N-protected phenylalanine enantiomers involves reaction paths with one and two alkaloid molecules. Substrate binding enantioselectivity is large and is opposite to the kinetic enantioselectivity, leading to the modest observed enantioselectivity of the reaction, which reaches a maximum (k_L/k_D ≈ 1.5) at ca. 0.002 mol dm^–3 alkaloid concentration and practically disappears on going to 0.01 mol dm^–3 alkaloid solution. Addition of boric acid initially enhances the reaction rate and enantiospecificity, but in more concentrated borate solutions the expected inhibition due to blocking of the phenolate groups is observed. For the first time reported for an alkaloid, the esterolytic activity of (+)-tubocurarine towards 4-nitrophenyl acetate falls on a common Brønsted plot together with cyclodextrins and some synthetic macrocycles. Binding of enantiomers of differently charged derivatives of alanine, phenylalanine and β-phenylethylamine to the zwitterionic form of (+)-tubocurarine in aqueous solution was studied by ¹H NMR and fluorescence titration. The binding constants vary from <5 dm³ mol^–1 for alanine to ca. 50 dm³ mol^–1 for phenylalanine derivatives and the binding enantioselectivity varies from marginal for N-acetylphenylalanine enantiomers to a quite notable, three-fold differentiation between L- and D-phenylalanine. While the enantiospecificity depends primarily on electrostatic interactions, the overall stability is determined by guest hydrophobicity. This conclusion was confirmed by docking calculations for enantiomers of phenylalanine. Addition of amino acid derivatives to solutions containing (+)-tubocurarine and highly fluorescent 8-anilinonaphthalenesulfonate anion leads to enantioselective spectral responses which are indicative of formation of ternary complexes.

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