Copper complexes chiral recognition

Marchelli used the copper(II) complex of histamine-functionalized P-cy-clodextrin for chiral recognition and separation of amino acids [27]. The best results were obtained for aromatic amino acids (Trp). Enantioselective sensing of amino acids by copper(II) complexes of phenylalanine-based fluorescent P-cyclodextrin has been recently published by the same author [28, 29]. The host containing a metal-binding site and a dansyl fluorophore was shown to form copper(II) complexes with fluorescence quenching. Addition of d- or L-amino acids induced a switch on of the fluorescence, which was enantioselective for Pro, Phe, and Trp. This effect was used for the determination of the optical purity of proline. 

There have also been examples of ligand-exchange CSPs. Schmid et al. [159] used a ligand-exchange monomer as a chiral selector. The chiral selector, monomer, cross-linker, and charged monomer were polymerized to produce monolithic capillaries capable of chiral recognition and generation of EOF. The separation is achieved due to the differences in the stability between the ternary mixed copper complexes formed by the enantiomers and the CSP. 

ABSTRACT. The copper(n) complexes of p-cyclodextrins functionalized with aliphatic or pseudoaromatic amines were used for the chiral recognition of unmodified amino acids. Molecular recognition, assisted by non-covalent interactions, was proved by means of thermodynamic and spectroscopic (c.d., e.p.r. and fluorescence) measurements. A cis-disposition of amino groups seems to assist enantiomeric selectivity. The copper(II)-p-cyclodextrin complexes can be used as mobile phase additives in HPLC to separate enantiomeric mixtures of unmodified aromatic amino acids. 

The analysis of the c.d. spectra of copper(II) mixed complexes supports the previously hypothesis put forward for chiral recognition. In fact, whilst the spectra of aliphatic amino acid pairs are all virtually superimposible, for the mixed complexes of aromatic amino acids the c.d. spectra are remarkably different for each diastereomeric pair in both the UV and the visible region, as shown in Figure 8 for the TrpO in the copper(II) ternary complexes with CDhm [35]. 

The D-enantiomer of such bidentate compounds was generally retained more than L-enantiomer. Mixtures of methanol/acetonitrile/water or dichloromethane/methanol were often used as eluents. Chiral recognition based on CLEC was also involved in the enantiomer separation of amino acids and (3-adrenergic blocking agents on silica gel plates coated with the copper(II) complex of enantiomeric amino acids (L-proline, L-arginine, and lR,3R,5R-2-azobicyclo [3.3.0]octan-3-carboxylic acid). 

The chiral molecular recognition manifested in copper(II) simple and mixed complexes with biofunctional ligands (amino acids, dipepti s, etc..) was found to be strongly dependent on the formation of weak bonds between side chain residues [21,22], as shown in Figure 2. 

Bearing this in mind, we designed and synthesized a number of P-CD derivatives [27-34] which could i) bind copper(II) forming a multisite recognition system ii) show thermodynamic stereoselectivity in copper(II) ternary complexes iii) perform chiral separation of unmodified amino acid enantiomers. Among the monofunctionalized P-CD derivatives, only those functionalized in position 6 with diamines show chiral molecular recognition [29,32,35-37]. On the contrary, the P-CDs both functionalized in position 3 and those where a triamine was attached to the narrower rim of the toroid do not act as chiral receptors. 2-(aminomethyl)pyridine, histamine and NH3 molecules were used to obtain the three isomers of P-CDs (Figure 3), but only the A,BCD-NH2 molecule, coordinated to the copper(II) ion, is seen to have enatioselective effects on aromatic amino acids [38]. 

Conversion of amino acids to produce a diaster-eoisomeric peptide by reaction with an N-carboxy-anhydride, e.g., L-Phe-N-carboxy-anhydride, has been used for determination of optical purity using RPC. Alternatively, for analysis of amino acid enantiomers without derivatization, two options are available (1) chiral mobile phases such as the N,N-di- -propyl-L-alanine-copper(n) complex can be used with reversed-phase columns, and (2) stationary phases with a covalently bound ligand capable of stereo recognition can be used. Such ligands include cyclodextrins, albumins, glycoproteins, and copper(II) complexes. 

---