Geometrical optimisation of 1,1′-binaphthalene receptors for enantioselective molecular recognition of excitatory amino acid derivatives

Abstract

A series of optically active 1,1′-binaphthalene-derived receptors with N-(pyridine-2,6-diyl)acetamide [CONH(py)] H-bonding sites in the 6,6′-positions has been prepared for the enantioselective complexation of the N-carbobenzyloxy (Cbz)-protected excitatory amino acids aspartic (Asp) and glutamic (Glu) acid via two COOH· · ·CONH(py) H-bonding arrays and additional secondary bonding interactions. The conformational homogeneity of the receptors is enhanced by locking the dihedral angle θ about the chirality axis through the C(1)–C(1′) bond of the 1,1′-binaphthalene moiety either by bridging the 2,2′-positions or by attaching bulky substituents to these centres. Computer modelling has shown that bridging is more efficient in locking this dihedral angle than the introduction of bulky substituents, and these predictions have been confirmed by ¹H NMR binding studies in CDCl₃ and in CDCl₃–CD₃OD 99.8∶0.2. Plots of the enantioselectivity Δ(ΔG°) (difference in stability between diastereoisomeric complexes) in the recognition by the bridged receptors as a function of the enforced dihedral angle θ are peak-shaped, and the highest values have been measured in CDCl₃ (300 K) for the complexation of the enantiomers of N-Cbz-Asp [Δ(ΔG°) = 6.9 kJ mol^–1] and N-Cbz-Glu [Δ(ΔG°) = 5.2 kJ mol^–1] by (R)-21 (θ = 86 ± 4°). The more stable diastereoisomeric complexes are highly structured, and tight host–guest bonding has been confirmed by the observation of up to five intermolecular NOEs. Enforcing the conformational homogeneity by bridging represents a new general principle for improving the chiral recognition potential of 1,1′-binaphthalene receptors.