Cyclodextrins racemates

The essential oils of the Mentha species are known to be valuable ingredients of pharmaceutical and cosmetic preparations. Menthone, isomenthone, menthol and menthyl acetate, the most important Mentha oil constituents, are defined by their amounts as substantial parameters of mentha oil quality. Even off-line HPTLC/enan-tio-GC coupling has proved to be a valuable method in authenticity control of mint and peppermint oils. After preseparating by HPTLC (silica gel dichloromethane) the menthyl acetate fraction is isolated and directly injected for stereodifferentiation with permethyl p-cyclodextrin. Racemic menthyl acetate was detected by Kreis et al. as a frequently used adulteration of Mentha oils [20]. 

Fig. 1. a-Cyclodextrin—racemic 1-phenylethanol complex. 0(A) and 0(B) denote disordered hydroxyl groups, corresponding to S- and R-isomers, respectively. Water molecules are denoted by Wl, W2, W3, and W4. 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

Table 2. Retention Data for Racemic Compounds Separated on a p-Cyclodextrin Stationary Phase ...

Figure 3.7 shows some early examples of this type of analysis (39), illustrating the GC determination of the stereoisomeric composition of lactones in (a) a fruit drink (where the ratio is racemic, and the lactone is added artificially) and (b) a yoghurt, where the non-racemic ratio indicates no adulteration. Technically, this separation was enabled on a short 10 m slightly polar primary column coupled to a chiral selective cyclodextrin secondary column. Both columns were independently temperature controlled and the transfer cut performed by using a Deans switch, with a backflush of the primary column following the heart-cut. 

Figure 3.7 [continued) (b) Chromatograms of (iii) the dichloromethane extract of strawberry fruit yoghurt analysed with an apolar primary column, with the heart-cut regions indicated, and (iv) a non-racemic mixture of y-deca-(Cio) and 7-dodeca-Cj2 lactones isolated by heart-cut transfer, and separated by using a chiral selective modified cyclodextrin column. Reproduced from A. Mosandl, et al J. High Resol. Chromatogr. 1989, 12, 532 (39f. 

Figure 3.8 Second-dimension chiral cyclodextrin capillary column separation of a non-racemic pair of nonachlorobomane compounds extracted from dolphin blubber, shown with expanded attenuation in the inset. The primary separation (not shown) was performed on an apolar primary capillary column. Reproduced from H.-J. de Geus et al. J. High Resol. Chromatogr. 1998, 21, 39 (59).

Figure 10.1 Analysis of racemic 2,5-dimethyl-4-hydroxy-3[2H]-furanone (1) obtained from a strawbeny tea, flavoured with the synthetic racemate of 1 (natural component), using an MDGC procedure (a) dichloromethane extract of the flavoured strawbeny tea, analysed on a Carbowax 20M pre-column (60 m, 0.32 mm i.d., 0.25 p.m film thickness earner gas H2, 1.95 bar 170 °C isothermal) (b) chirospecific analysis of (1) from the sti awbeny tea exti act, ti ansfened foi stereoanalysis by using a pemiethylated /3-cyclodextrin column (47 m X 0.23 mm i.d. canier gas H2, 1.70 bar 110 °C isothemial). Reprinted from Journal of High Resolution Chromatography, 13, A. Mosandl et al., Stereoisomeric flavor compounds. XLIV enantioselective analysis of some important flavor molecules , pp. 660-662, 1990, with permission from Wiley-VCH.

The type of CSPs used have to fulfil the same requirements (resistance, loadabil-ity) as do classical chiral HPLC separations at preparative level [99], although different particle size silica supports are sometimes needed [10]. Again, to date the polysaccharide-derived CSPs have been the most studied in SMB systems, and a large number of racemic compounds have been successfully resolved in this way [95-98, 100-108]. Nevertheless, some applications can also be found with CSPs derived from polyacrylamides [11], Pirkle-type chiral selectors [10] and cyclodextrin derivatives [109]. A system to evaporate the collected fractions and to recover and recycle solvent is sometimes coupled to the SMB. In this context the application of the technique to gas can be advantageous in some cases because this part of the process can be omitted [109]. 

Macaudiere et al. first reported the enantiomeric separation of racemic phosphine oxides and amides on native cyclodextrin-based CSPs under subcritical conditions [53]. The separations obtained were indicative of inclusion complexation. When the CO,-methanol eluent used in SFC was replaced with hexane-ethanol in LC, reduced selectivity was observed. The authors proposed that the smaller size of the CO, molecule made it less likely than hexane to compete with the analyte for the cyclodextrin cavity. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

Many racemic mixtures can be separated by ordinary reverse phase columns by adding a suitable chiral reagent to the mobile phase. If the material is adsorbed strongly on the stationary phase then selectivity will reside in the stationary phase, if the reagent is predominantly in the mobile phase then the chiral selectivity will remain in the mobile phase. Examples of some suitable additives are camphor sulphonic acid (10) and quinine (11). Chiral selectivity can also be achieved by bonding chirally selective compounds to silica in much the same way as a reverse phase. A example of this type of chiral stationary phase is afforded by the cyclodextrins. 

Reversed Phase with Racemic-hydroxy propyl groups attached to the Cyclodextrin... 

Reaction conditions 0.1 g of the zeolite Y modified catalyst, tested in a conventional glass microreactor with racemic butan-2-ol (7.35 x 10" mol h-1), prevaporized in a nitrogen diluent (6.2 -6.7 x 10" mol h-1). Products were analyzed using on-line GC with a 40m capillary y- cyclodextrin colimm with trifluoroacetyl stationary phase, temperature programmed from 25-70 "C with a split ratio of 120 1. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Capillary electrophoresis employing chiral selectors has been shown to be a useful analytical method to separate enantiomers. Conventionally, instrumental chiral separations have been achieved by gas chromatography and by high performance liquid chromatography.127 In recent years, there has been considerable activity in the separation and characterization of racemic pharmaceuticals by high performance capillary electrophoresis, with particular interest paid to using this technique in modem pharmaceutical analytical laboratories.128 130 The most frequently used chiral selectors in CE are cyclodextrins, crown ethers, chiral surfactants, bile acids, and protein-filled... 

Kang, J. and Ou, Q., Chiral separation of racemic mexilitine hydrochloride using cyclodextrins as chiral additive by capillary electrophoresis,. Chromatogr. A, 795, 394, 1998. 

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodextrin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

While much attention has been paid to the chemistry of cyclodextrin complexes in solution, there have been relatively few studies of their solid-state reactions. One such reaction is the decarboxylation of phenylethylmalonic acid, 155. In solution this is catalyzed by fj-cyclodextrin, and yields racemic 2-phenylbutyric acid, 156 (230). The malonic acid forms a crystalline 1 1 complex with p-cyclodextrin in which decarboxylation occurs at a much lower temperature than in the crystalline diacid. Interestingly, the product formed in the clathrate reaction is nonracemic, the optical yield being 7%. 

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