Enantioselectivity, -cyclodextrin complexation

III. APPLICATION OF CAPILLARY ELECTROPHORESIS FOR DETERMINATION OF ENANTIOSELECTIVE BINDING CONSTANTS OF CHIRAL DRUG/CYCLODEXTRIN COMPLEXES... 

Asymmetric hydrohalogenation of fraws-2-butenoic acid has been achieved in a crystalline a-cyclodextrin complex using gaseous HBr at 20 °C and HC1 at 0 °C. The products were formed with 58% and 64% e.e., respectively, and were of (S )-configuration81. This contrasts with the low enantioselectivity of halogenation attempted in the same paper (vide supra). 

G. Trainor, R. Breslow, High acylation rates and enantioselectivity with cyclodextrin complexes of rigid substrates, J. Am. Chem. Soc., 1981, 103, 154—158. 

Hydrobromination of the same substrate in the a-cyclodextrin complex gave the monobromide with the opposite configuration at 46 % e.e.. This clearly shows that ethyl trans-cinnamate forms complexes with a- and 3-cyclodextrins such that the anti-addition of hydrogen bromide occurs with high but different enantioselectivities in the two cases to yield monobromide derivatives of opposite chiralities. A detailed mechanism, however, could not be described at the present time for the observed asymmetric induction in the hydrobromination and bromination of the a-cyclodextrin complex, because no crystalline or molecular structures were determined for the ester included in a-cyclodextrin. 

Asymmetric Michael addition of benzenethiol to 2-cyclohexenone and maleic acid esters proceeds enantioselectively in their crystalline cyclodextrin complexes. The adducts were obtained in 38 and 30% ee respectively. In both cases, the reaction was carried out in water suspension (Scheme 31). ... 

Addition of a chiral carrier can improve the enantioselective transport through the membrane by preferentially forming a complex with one enantiomer. Typically, chiral selectors such as cyclodextrins (e.g. (4)) and crown ethers (e.g. (5) [21]) are applied. Due to the apolar character of the inner surface and the hydrophilic external surface of cyclodextrins, these molecules are able to transport apolar compounds through an aqueous phase to an organic phase, whereas the opposite mechanism is valid for crown ethers. 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

Rao et al. [100] for the first time report the biomimetic approach for the synthesis of a single enantiomer of p-aminoalcohol. In this approach p-cyclodextrin formed by the inclusion of complex 77 with racemic aryloxyepoxide which reacted enantioselectively with amines imder solid state condition to give the product in 100% ee and 70-79% isolated yield. The yield which was above 50% was explained in terms of continuous racemization of the... 

An example of the above mentioned cascade complexation of carboxylates by macrocyclic receptors containing metal ionic centers is the inclusion of oxalate by the dien dicobalt complex 9 (Martell, Mitsokaitis) [12]. Similarly, the -cyclodextrin (jS-CD) 10, modified with a zinc cation bound by a triamine side chain, encapsulates anions like 1-adamantylcarboxylate in its cavity, fixing them by combined electrostatic and hydrophobic interactions [13], Zinc s group achieved the enantioselective transport of the potassium salts of N-protected amino acids and dipeptides by making use of the cation affinity of... 

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

The main components of the membrane of the enantioselective, potentiometric electrode are chiral selector and matrix. Selection of the chiral selector may be done accordingly with the stability of the complex formed between the enantiomer and chiral selector on certain medium conditions, e.g., when a certain matrix is used or at a certain pH. Accordingly, a combined multivariate regression and neural networks are proposed for the selection of the best chiral selector for the determination of an enantiomer [17]. The most utilized chiral selectors for EPME construction include crown ethers [18-21], cyclodextrins [22-35], maltodextrins 136-421, antibiotics [43-50] and fullerenes [51,52], The response characteristics of these sensors as well as their enantioselectivity are correlated with the type of matrix used for sensors construction. 

The same author has reported chiral recognition of a-amino acids by native, anionic, and cationic a- and (3-cyclodextrins [17]. Both carboxylates and amines (monosubstituted as well as hexa- and heptasubstituted) were included in this study. The best results obtained were those from a combination of (S)- and (P)-AcTrp complexed by per-NH -[3-cyclodextrin with K=2,310 and 1,420 (1/mol). In the detailed study of chiral recognition of substituted phenyl-acetic acid derivatives by aminated cyclodextrins, these were found to be again only modest with respect to the enantioselection attained [18]. 

Using the native cyclodextrin, the enantiomers of amino acid derivatives were enantioselectively complexed [21]. Further, for a more detailed analysis, zwitterionic tryptophan was employed [22]. For the complexation studies performed on this molecule the a-cyclodextrin was used, as its inner cavity is the smallest. The H NMR measurements showed that (R)-tryptophan formed a stronger complex with a-cyclodextrin compared with the (S) enantiomer. This is due to the number of hydrogen bonds which can be formed between each enantiomer and the host molecule. The NMR studies showed another very interesting fact the amino acid is very likely forming no intracavity complex. It has been suggested that it is coordinated near the rim of the cyclodextrin. 

Zwitterionic cyclodextrins were designed and synthesized by Tabushi a long time ago as artificial receptors for amino acids in water [25]. Only a very low enantioselectivity was detected for Trp. Inoue also studied the complexation of two new P-cyclodextrin derivatives bearing m-toluidinyl and [(9-fluorenyl)-amino]alkylamino groups with various D/L-amino acids by fluorescence spectroscopy in buffered (pH=7.2) aqueous solution. An enantioselectivity as high as 33 was found for D/L-leucine and the former host [26]. 

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. 

The chiral selectors most commonly used as additives in the buffer can be divided into three main categories inclusion systems [e.g., cyclodextrins (CDs) or crown ethers], enantioselective metal-ion complexes [e.g. cop-per(II)-L-histidine or copper(II)-aspartame], and optically active surfactants (e.g., chiral mixed micelles or bile acids). Cyclodextrins are the most widely reported, and they are used in low-pH buffers for the resolution of... 

Cyclodextrins have been covalently modified for catalytic oxidation, such as compounds 57, 62-65 (Schemes 3.14 to 3.16) [44, 45]. Enantioselective epoxidation of styrene derivatives, and carene using 20-100 mol% of the CD-ketoester 57 has been achieved. The inclusion-complex formation was confirmed by aH NMR titration experiments, confirming the 1 1 substrate catalyst stoichiometry under the reaction conditions. In the oxidation of carene, NOE and ROESY experiments showed different behavior according to the size of the R group (Scheme 13.14). Evidence was found for the formation of inclusion complexes with compounds 58 and 59. On the other hand, compounds 60 and 61 proved to interact with the catalyst via a tail inclusion vide infra). The increased diastereoselectivity observed with compounds 58 and 59 might be explained by a closer proximity to the covalently linked dioxirane. 

Recently, an attempt was made to induce chirality in a meta cycloaddition via complexation with cyclodextrins (Sch. 13) [48]. 1/1 inclusion complexes of 72 and P-cyclodextrin can be synthesized and irradiated at 2 = 300nm. Two regioisomers 73a and 73b are isolated with different enantiomeric excesses. The results can be explained by interactions of different intensity with the chiral environment at the transition state U. In the case of pathway (a) leading to 73a the interaction with the cyclodextrin is more expressed then for pathway (b) leading to 73b. Thus, the formation of 73a occurs with higher enantioselectivity. 

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