Optical resolution of enantiomers

A similar effect has been reported in the crystallization of non-chiral molecules, where the presence of small amounts of chiral additive forces the entire system to crystallize in an enantiomorphous crystal, which upon further solid-state reaction can be converted into polymers of a single handedness [184,185]. Chiral auxiliaries, which affect crystal nucleation enantios-electively, have been successfully used for the large-scale optical resolution of enantiomers [186-188]. 

The asymmetric synthesis approach for obtaining optically active thiahelicenes is still in its infancy and so far this approach has led to unsatisfactory optical purity. Therefore, while waiting for innovative approaches related to asymmetric synthesis, researchers involved in this field make extensive use of optical resolution of enantiomers, which, up to the present time, represents the most practical way to obtain optically pure thiahehcenes. 

Okamoto Y, Nagamura Y, Fukumoto T, Hatada K (1991) Chromatographic optical resolution of enantiomers on polyamides ctmtaining 1,2-disubstituted cyclohexane moiety as a chiral residue. Polym J 23 1197-1207... 

The question that emerges at the climax of this survey relates to the possibility of using crystalline inclusion phenomena for optical resolutions of molecular species. Can this be done effectively with suitably designed host compounds The definitely positive answer to this question has elegantly been demonstrated by Toda 20) as well as by other investigators (see Ch. 2 of Vol. 140). An optically active host compound will always form a chiral lattice. Therefore, when an inclusion type structure is induced, one enantiomer of the guest moiety should be included selectively within the asymmetric environment. 

K. Naemura, K. Kittaka, M. Murata, H. Ida, K. Hirose, Y. Tobe, Lipase-Catalyzed Enantioselective Alcoholysis of Enol Acetates Optical Resolution of Ketones and Aldehydes Using Lipases in Organic Solvents , Enantiomer 1996, 1, 219-222. 

From the synthetic viewpoint the optical resolution of sulfonium salt 110 is of great interest because its enantiomers served as starting material for the synthesis of chiral a-dehydrobiotin 111(156). 

An extremely important aspect in pharmaceutical research is the determination of drug optical purity. The most frequently applied technique for chiral separations in CZE remains the so-called dynamic mode where resolution of enantiomers is carried out by adding a chiral selector directly into the BGE for in situ formation of diastereomeric derivatives. Various additives, such as cyclodextrins (CD), chiral crown ethers, proteins, antibiotics, bile salts, chiral micelles, and ergot alkaloids, are reported as chiral selectors in the literature, but CDs are by far the selectors most widely used in chiral CE. 

Since many useful organic compounds, such as pharmaceuticals and food additives, have asymmetric carbon atoms, there are enantiomers of them. In most cases, only one enantiomer is useful as a biologically active substance, the others not showing such activity and sometimes having a harmful effect. Therefore, a racemic mixture of such compounds which have been chemically synthesized cannot be used, especially for pharmaceuticals, and thus the troublesome optical resolution of the racemic mixture by means of a conventional organic synthetic process for such optically active substances is unavoidable. 

Among the possible uses of optically active polymers, the preparation of stationary chiral phases for chromatographic resolution of enantiomers is the... 

Racemic modifications may be resolved. There are very few examples of this approach having been employed successfully. The racemic cylic ether (RS)-36, which contains two CH2OCH2CO2H arms attached to the 3 and 3 positions on the axially chiral binaphthyl units, has been resolved (48-50, 93, 94) to optical purity in both its enantiomers by liquid-liquid chromatography using a chiral stationary phase of either (R)- or (S)-valine adsorbed on diatomaceous eaitii. Very recently, the optical resolution of crown ethers (/ S)-37 and (/ 5)-38, incorporating the elements of planar chirality in the form of a rron -doubly bridged ethylene unit, has been achieved (95) by HPLC on (+)-poly(triphenyl-methyl methacrylate). 

In the optical resolution of DL-threonine mixtures by batch preferential crystallization, changes of solution concentration and crystal purity were measured. The mechanism of nucleation of the un-seeded enantiomer was discussed to explain the purity decrease of the resolved crystals. From the observation of crystallization behavior of the seed crystals of L-threonine, it was concluded that the existence of the D-enantiomer on the surface of the seed caused the sudden nucleation when they grew to attain sufficient amounts. 

Shortly after the first announcement of optical resolution of ( )-cyclooctene, Moscowitz and Mislow 13) published a communication in which, on the basis of their MO calculation/they assigned the (S)-configuration to the (—)-enantiomer. Eventually, this conclusion was proved wrong 14,15) and the opposite configuration was assigned when the absolute configuration of (—)-( )-cyclooctene was shown to be directly correlated with that of (+)-tartaric acid 16a,b). 

From other approaches to optically active [2.2]metacyclophanes the following are noteworthy as just mentioned for 64 (medium pressure) liquid chromatography on microcrystalline triacetylcellulose (cf. Ref. 82 ) in ethanol or ether (practicable also at lower temperatures) is a very efficient and successful method for the optical resolution of many axial and planar chiral (aromatic) compounds 83). In many cases baseline-separations can be achieved and thereby both enantiomers obtained with known enantiomeric purity and in amounts sufficient for further investigations, especially for studying their chiroptical properties (see also 3.2 and 3.3). The disub-stituted [2.2]metacyclophanes 57 and 59 (which had been previously correlated to many other derivatives) 78- 79) were first resolved by this method83). 

N Nimura, T. Kinoshita. o-Phthalaldehyde-A -acetyl-t.-cystcine as a chiral derivatization reagent for liquid chromatographic optical resolution of amino acid enantiomers and its application to conventional amino acid analysis. J Chromatogr 352 169-177, 1986. 

Cr(CO)3 coordinates from either the top or bottom side of aromatic rings, bearing two different substituents in ortho or meta position, so that the enantiomers 285 and 286 are obtained. Optical resolution of the enantiomers is carried out by recrystallization, or column chromatography. The racemic complex of benzyl alcohol derivative 287 was separated to 288 and 289 by lipase-catalysed acetylation [68]. Enzymes recognize Cr(CO)3 as a bulky group. Chiral Cr(CO)3-arene complexes are used for asymmetric synthesis [68a]. 

The principle of the optical resolution of racemic pantolactone is shown in Fig. 13. If racemic pantolactone is used as a substrate for the hydrolysis reaction by the stereospecific lactonase, only the d- or L-pantolactone might be converted to d- or L-pantoic acid and the l- or D-enantiomer might remain intact, respectively. Consequently, the racemic mixture could be resolved into D-pan-toic acid and L-pantolactone, or D-pantolactone and L-pantoic acid. In the case of L-pantolactone-specific lactonase, the optical purity of the remaining d-pantolactone might be low, except when the hydrolysis of L-pantolactone is complete. On the other hand, using the D-pantolactone-specific lactonase, d-pantoic acid with high optical purity could be constantly obtained independently of the hydrolysis yield. Therefore, the enzymatic resolution of racemic pantolactone with D-pantolactone-specific lactonase was investigated [138 140]. 

Optical resolution of ( )-deacetamidocolchicine was accomplished on a cellulose triacetate column at low temperature (32). Only (-)-(aS)-deacetamidocolchicine (18) was found to bind to tubulin the (+)-(a/ ) enantiomer was inactive. This firmly established, as already shown earlier (2a), that the aromatic rings A/C in colchicinoids and related alio congeners must be arranged in a counterclockwise fashion to allow a binding to tubulin. This corresponds to a P helicity of the biaryl system (32). 

When a chiral host compound includes one enantiomer of racemic guest compound selectively, optical resolution of the guest can be accomplished. In this chapter, efficient resolutions of racemic compounds by the complexation with various artificial chiral hosts are described. All the data described in this chapter are those obtained in the author s research group. 

In the optical resolution of cyanohydrins, it was first found that brucine (4) is a suitable host for the cyanohydrins which substituted with one aromatic group and one bulky alkyl group. In this case, not only a simple enantiomer separation of rac-cyanohydrin but also its transformation to one enantiomer occurred and one pure enantiomer was obtained in a yield of more than 100%. For example, when a solution of rac-l-cyano-2,2-dimethyl-l-phenylpropanol (61a) (1.0 g, 5.3 mmol) and 4 (2.1 g, 5.3 mmol) in MeOH (2 ml) was kept in a capped flask for 12 h, a 1 1 brucine complex of (+)-61a (2.08 g, 134%, mp 112-114 °C) separated out as colorless prisms. Decomposition of the complex with dil HC1 gave (+)-61a of 97% ee (0.67 g, 134%). From the filtrate, rac-61a (0.33 g, 33%) was obtained.273 The... 

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