Molecular Recognition in Cyclodextrin Complexes of Amino Acid Derivatives. 2.¹ A New Perturbation:  The Room-Temperature Crystallographic Structure Determination for the N-Acetyl-p-methoxy-l-phenylalanine Methyl Ester/β-Cyclodextrin Complex

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate various small organic molecules, forming inclusion complexes. Because CD complexes are held together purely by noncovalent interactions, they function as excellent models for the study of chiral and molecular recognition mechanisms. Recently, room-temperature crystallographic studies of both the 2:2 N-acetyl-L-phenylalanine methyl ester/beta-CD and 2:2 N-acetyl-L-phenylalanine amide/beta-CD complexes were reported. The effect of changes in carboxyl backbone functional group on molecular recognition by the host CD molecule was examined for the nearly isomorphous supramolecular complexes. A new perturbation of the system is now examined, specifically perturbation of the aromatic side chain. We report a room-temperature crystal structure determination for the 2:2 N-acetyl-p-methoxy-L-phenylalanine methyl ester/beta-CD inclusion complex. The complex crystallizes isomorphously with the two previously reported examples in space group P1; the asymmetric unit consists of a hydrated head-to-head host dimer with two included guest molecules. The crystal packing provides both a nonconstraining extended hydrophobic pocket and an adjacent hydrophilic region, where hydrogen-bonding interactions can potentially occur with primary hydroxyl groups of neighboring CD molecules and waters of hydration. The rigid host molecules show no sign of conformational disorder, and water of hydration molecules exhibit the same type of disorder observed for the other two complexes, with a few significant differences in locations of water molecules in the hydrophilic region near guest molecules. There is evidence for modest disorder in the guest region of an electron density map. In comparing this system with the two previously reported complexes of phenylalanine derivatives, it is found that the packing of the guest molecules inside the torus of the CD changes upon substitution of a methoxy group at the para position of the aromatic phenyl ring. Backbone hydrogen-bonding interactions for the guest molecules with the CD primary hydroxyls and waters also change. This structure determination is a new and revealing addition to a small but growing database of amino acid and peptidomimetic interactions with carbohydrates.

Chiral discrimination in cyclodextrin complexes of amino acid derivatives: β-cyclodextrin/ N -acetyl- l -phenylalanine and N -acetyl- d -phenylalanine complexes

“…3 and 4) is appropriate. The same four CD primary hydroxyls are involved in intermolecular H-bonding in each of these structures as in those reported earlier [O6(8)⅐⅐⅐O6(12) and O6(2)⅐⅐⅐O6 (6)] (19,20). These hydrogen bonds appear to be an integral component of the Im packing motif.…”

“…These hydrogen bonds appear to be an integral component of the Im packing motif. Comparison of the H-bonding interactions of the D-enantiomer at room temperature and of the L-enantiomer at low temperature with those reported for the structures of the L-enantiomers of the N-acetylphenylalanine methyl ester, the N-acetylphenylalanine amide, and the N-acetylp-methoxyphenylalanine methyl ester (19,20) reveal a generally conserved network, especially in the A pocket. The guest located in monomer A of the ␤-CD͞N-Ac-D-F complex interacts via oxygen OH(47) with water w31, a water commonly observed to interact with amino acid derivative guest molecules that display intermediate packing of the CD dimers.…”

“…A second operation on this moiety involved rotating it 180°about an axis passing through the midpoint of the torus; the guests were shifted slightly to achieve acceptable contact distances within the torus. The atom numbering scheme ‡ used here is closely correlated with those reported earlier for analogous complexes (19,20).…”

“…This CD primary hydroxyl is commonly disordered in the amino acid derivative complexes previously reported, but, in this complex, only the one conformer is observed. With these observations in mind, it appears that the unusually well ordered structure for the Denantiomer complex results from a combination of effects: the presence of a water molecule in the torus (W62), the presence of a bridging water molecule between the A and B binding The numerical labeling scheme is that used in the reports for the crystal structures of the N-acetyl-L-phenylalanine methyl ester complex (19), the N-acetyl-L-phenylalanine amide complex (19), and the N-acetyl-L-p-methoxyphenylalanine methyl ester complex (20). Red numbers refer to either ␤-cyclodextrin primary hydroxyl groups (Upper portion of the figure) or secondary hydroxyl groups (Lower portion of the figure).…”

“…To differing extents, the more hydrophilic backbones of the guest molecules interact with water molecules between the sheets and, in most cases, via bridging water molecules with hydroxyl moieties of cyclodextrins or other guests in the next layer. Examples of N-acetyl-L-phenylalanine complexes with different backbone structures (19), with a modified benzyl side chain (20) and for a single complex at different levels of kinetic energy, have been determined (J.L.C. and J.J.S., unpublished results).…”