(+)-18-crown-6 tetracarboxylic acid (18C6H(4)) has been used as a chiral selector for various amines and amino acids. To further clarify the structural scaffold of 18C6H(4) for chiral separation, single crystal X-ray analysis of its glycine(+) (1), H3O+ (2), H5O2+ (3), NH4+ (4), and 2CH3NH3+ (5) complexes was performed and the guest-dependent conformation of 18C6H(4) was investigated. The crown ether ring of 18C6H4 in 3, 4, and 5 took a symmetrical C2 or C2-like conformation, whereas that in 1 and 2 took an asymmetric C1 conformation, which is commonly observed in complexes with various optically active amino acids. The overall survey of the present and related complexes suggests that the molecular conformation of 18C6H4 is freely changeable within an allowable range, depending on the molecular shape and interaction mode with the cationic guest. On the basis of the present results, we propose the allowable conformational variation of 18C6H4 and a possible transition pathway from its primary conformation to the conformation suitable for chiral separation of racemic amines and amino acids.

To clarify the structural scaffold of (+)-18-crown-6 tetracarboxylic acid ((+)-18C6H4) for the optical resolution of a chiral amino acid, the crystal structures of its equimolar complexes with L- and D-isomers of tyrosine (Tyr), isoleucine (Ile), methionine (Met) and phenylglycine (PheG) were analysed by X-ray diffraction methods. (+)-18C6H4 took very similar conformations for all complexes. Although the chemical structure of (+)-18C6H4 is C2-symmetric, it took a similar asymmetric ring conformation of radius ca. 6.0 A. In all complexes, the amino group of chiral amino acids was located near the center of the ring and formed three hydrogen bonds and five electrostatic interactions with eight oxygen atoms of the ether ring and carboxyl groups. Also, the Calpha atom of chiral amino acids participated in Calpha-H...O interaction with the oxygen atom of (+)-18C6H4. In contrast, the carboxyl group of chiral amino acids did not directly interact with (+)-18C6H4. These results indicate that the structural scaffold of (+)-18C6H4 for the optical resolution of chiral amino acids is mainly based on the mode of interaction of (+)-18C6H4 with the amino and Calpha-H groups of chiral amino acids. The differences in interaction pattern and binding energy between the L- and D-isomers of each amino acid are discussed in relation to the chiral recognition of (+)-18C6H4.

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The separation of enantiomers is a subject of great interest, because the biologically effective chiral drug is either of enantiomers and the antipode is regarded as the impurity showing sometime high toxicity. Recently, the HPLC with chiral stationary phases (CSPs) has been extensively used to achieve the direct enantiomer separation. Crown ether, first introduced by Pedersen in 1967, 1,2) was shown by Cram et al. 3,4) to resolve enantiomers by the host-guest complexation. Since then, the optically active crown ether derivatives have been widely used for the optical syntheses, resolutions and analyses of chiral amino compounds. A novel CSP derived from crown ether, which was prepared by immobilizing (ϩ)-18-crown-6 tetracarboxylic acid ((ϩ)-18C6H 4 ) on 3-aminopropylsilanized silica-gel, was reported by Machida et al. 5) to show the effective enantiomer separation of amino compounds, and has been widely used as a chiral selector for the primary amines in capillary electrophoresis (CE) 6-9) and HPLC. [10][11][12] As for the enantiomer separation of D/L-amino acids by HPLC with (ϩ)-18C6H 4 immobilized CSP, it has been generally accepted that L-isomers are commonly eluted prior to D-amino acids, indicating that D-amino acids form more stable interactions with (ϩ)-18C6H 4 than L-amino acids. Because no systematic investigation was performed on the discrimination mechanism of (ϩ)-18C6H 4 between D-and Lisomers, we recently analyzed the crystal structures of the complexes of (ϩ)-18C6H 4 with D-and L-isomers of tyrosine, isoleucine, methionine and phenylglycine, and clarified the common structural scaffold of (ϩ)-18C6H 4 for D/L-separation of these chiral amino acids. 13)On the other hand, concerning the first elution rule of Lamino acid in CE with (ϩ)-18C6H 4 , an exception was recently observed for the chiral separation of L/D-serine (Ser).14,15) To clarify why D-Ser is eluted prior to L-Ser, we investigated the chiral interactions of (ϩ)-18C6H 4 -L-Ser (L1) and (ϩ)-18C6H 4 -D-Ser (D1) complexes by the X-ray single crystal analyses. In addition, the crystal structures of (ϩ)-18C6H 4 -L-glutamic acid (L-Glu) (L2) and (ϩ)-18C6H 4 -DGlu (D2) complexes were also analyzed, as one of the examples according to the first elution rule of L-isomer. In this paper, we report the common as well as different interaction modes between the L-and D-isomers of these two amino acids. The atomic numberings of (ϩ)-18C6H 4 , Ser and Glu are given in Fig. 1. Results and DiscussionHPLC Analysis The separation data for D-/L-Ser and D-/L-Glu are given in Table 1. L-Glu was eluted prior to D-Glu, according to the first elution rule of L-amino acid in HPLC using (ϩ)-18C6H 4 column. 5) In the case of Ser, however, the elution order of D-and L-isomers was reversed, and D-isomer ; 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Received September 6, 2005

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