Chiral 1,1′‐Binaphthyl Molecular Clefts for the Complexation of Excitatory Amino‐Acid Derivatives

Abstract

AbstractThe complexation of N‐benzyloxycarbonyl (Cbz) derivatives of the excitatory amino acids L‐aspartic acid (Asp; 1), L‐glutamic acid (Glu; 3), and, for the first time, L‐kainic acid ((2S,3S,3S)‐2‐carboxy‐4‐(1‐methylethenyl)pyrrolidine‐3‐acetic acid; Kai; 5) was studied in CDCl3 with a diversity of chiral receptors consisting of a 1,1′‐binaphthyl spacer with (carboxamido)pyridine (CONH(py)) functionality attached to the 6,6′‐positions in the major groove. Receptors of type A possess two N‐(pyridin‐2‐yl)carboxamide H‐bonding sites (e.g. 7), whereas type B‐receptors have two N‐(pyridine‐6,2‐diyl)acetamide residues attached (e.g. 8 and 9). Complexes of excitatory amino‐acid derivatives and other, achiral α,β‐dicarboxylic acids with these receptors are primarily stabilized by two sets of CO···HN and OH ··· N H‐bonds. Optically active type‐A receptors such as (R)‐ and (S)‐7 showed a preference for the larger Glu derivative, whereas type‐B receptors such as (R)‐ and (S)‐8 and (R)‐ and (S)‐9 formed more stable complexes with the smaller Cbz‐Asp. To improve the poor enantioselectivity shown by 7–9, additional functionality was introduced at the 7,7′‐positions of the 1,1′‐binaphthyl spacer, and the nature of the H‐bonding sites in the 6,6′‐positions was varied. Screening the diversity of new racemic receptors for binding affinity, which had been shown in many examples by Cram to correlate with enantioselectivity, demonstrated that (+)‐10 and (+)‐11 formed the most stable complexes with dicarboxylic acids, and these receptors were synthesized in enantiomerically pure form. Both are type‐B binders and contain additional PhCH2O (10) and MeO (11) groups in the 7,7′‐positions. By 1H‐NMR binding titrations, the complexation of (R)‐ and (S)‐ 10 and (R)‐ and (S)‐11 with the excitatory amino‐acid derivatives was studied in CDCl3, and association constants Ka between 103 and 2 · 105 l mol−1 were measured for the 1:1 host‐guest complexes formed. Whereas both 10 and 11 formed stable complexes, enantioselective binding was limited to the PhCH2O‐substituted receptor 10, with the (R)‐enantiomer complexing Cbz‐Asp by 0.7 kcal mol−1 more tightly than the (S)‐enantiomer. The structures of the diastereoisomeric complexes were analyzed in detail by experimental methods (complexation‐induced changes in 1H‐NMR chemical shifts, 1H{1H} nuclear Overhauser effect (NOE) difference spectroscopy) and computer modeling. These studies established that an unusual variety of interesting aromatic interactions and secondary electrostatic interactions are responsible for both the high binding affinity (ΔG° up to 7.2 kcal mol−1) and the enantioselection observed with (R)‐ and (S)‐10. In an approach to enhance the enantioselectivity by reducing the conformational flexibility of the 1,1′‐binaphthyl spacer, an additional crown‐ether binding site was attached to the 2,2′‐positions in the minor groove of the type‐B receptors (R)‐ and (S)‐48. Both the binding affinity and the enantioselectivity (Δ(ΔG°) up to 0.7 kcal mol−1) in the complexation of the excitatory amino‐acid derivatives by (R)‐ and (S)‐48 were not altered upon complexation of Hg(CN)2 at the crown‐ether binding site, demonstrating lack of cooperativity between the minor‐ and major‐groove recognition sites.