Chiral compounds optical resolution

P. Newman, Optical Resolution Procedures for Chiral Compounds , Optical Resolution Information Center, Manhattan College, Riverdale, NY, 1978, Vol. 1. 

With few exceptions, enantiomers cannot be separated through physical means. When in racemic mixtures, they have the same physical properties. Enantiomers have similar cliemi cal properties as well. The only chemical difference between a pair of enantiomers occurs in reactions with other chiral compounds. Thus resolution of a racemic mixture typically takes place through a reaction with another optically active reagent. Since living organisms usually produce only one of two possible enantiomers, many optically active reagents can be obtained from natural sources. For instance muscle tissue and (S)-<-)-2-methyl-l-butanol, from yeast fermentation. 

Nitrogen atoms of organic compounds form relatively strong hydrogen bond with OH group of a host compound and amines, amine X-oxides, oximes, and esters of amino acids can be resolved efficiently by complexation with a chiral host. Optical resolutions of these compounds are described. 

Chiral sulphoxides are the most important group of compounds among a vast number of various types of chiral organosulphur compounds. In the first period of the development of sulphur stereochemistry, optically active sulphoxides were mainly used as model compounds in stereochemical studies2 5 6. At present, chiral sulphoxides play an important role in asymmetric synthesis, especially in an asymmetric C—C bond formation257. Therefore, much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, optically active sulphoxides have been obtained in the following ways optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. These methods are briefly discussed below. 

The chiral centre first appears in cyanide (11) but the acid (10) is the ideal compound for resolution as it can form a salt with a naturally-occurring optically active base. 

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. 

Okamoto et al [85] performed the optical resolution of primaquine and other racemic drugs by high performance liquid chromatography using cellulose and amylose tris-(phenylcarbamate) derivatives as chiral stationary phases. Primaquine and other compounds were effectively resolved by cellulose and/or amylose derivatives having substituents such as methyl, tertiary butyl, or halogen, on the phenyl groups. 

Although the first optical resolutions of chiral organosulfur compounds, sulfonium salts 1 and 2, were reported in 1900 by Pope and Peachey (1) and by Smiles (2), the stereochemistry of organosulfur compounds is a relatively new field, which has developed mostly... 

The classical method of EPC synthesis is the preparation of the chiral compound in racemic form and subsequent separation of the enantiomers ( optical resolution ). If the compound contains more than one stereogenic center, it is first prepared as a diastereomerically pure racemate and then submitted to optical resolution. 

It is quite common in EPC synthesis either by asymmetric synthesis or by optical resolution via diastereomers (vide infra) that chiral compounds arc obtained in an enantiomerically enriched, yet optically impure, form. In these cases the optical purity may be increased by crystallization if the compound forms either a conglomerate or a racemic mixture. In the case of conglomerates. one simply adds the amount of solvent necessary for dissolving the racemate. The excess enantiomer remains in crystalline form. 

In the process of optical resolution normally one enantiomer, and hence 50% of the total material, is discarded. When valuable compounds are resolved, this is an intolerable loss. Therefore, methods have been devised which allow recycling of the undesired enantiomer back to the racemate, so that after a few cycles most of the material has been converted into the desired enantiomer. This process has been called optical resolution with chiral economy 46. It can be performed in several variations. 

Despite its efficiency in numerous cases optical resolution is by no means a trivial operation. In each case the optimum method has to be found by laborious trial and error procedures the optical purity of the material has to be secured and its absolute configuration has to be established before the compound can be used in a synthetic sequence. These drawbacks of optical resolution led chemists to start their syntheses from optically active natural products (the so-called chiral carbon pool ). A variety of suitable ex-chiral-pool compounds including carbohydrates, amino acids, hydroxy acids, and terpenoids are shown. 

The hydrocarbon 25 has been partially resolved by asymmetric complexation with Newman s reagent [TAPA ( )-a(2,4,5,7-tetranitro-9-fluorenylideneaminooxy)prop-ionic acid] thereby establishing its chiral Z)2-structure 53). Similarity, the naphthaleno-phane 27b could be resolved by chromatography on silicagel coated with (—)-TAPA 49) and recently also by HPLC on optically active poly(triphenylmethyl methacrylate)49a) which also proved to be very useful for the optical resolution of many other axial and planarchiral aromatic compounds 49b>. 

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). 

As usual in stereochemical research, four main approaches have been applied to the problem of assigning chiralities to optically active cyclophanes. They are listed in order of their reliabilities i) anomalous X-ray diffraction (Bijvoet method), ii) chemical correlations with compounds of known chiralities (preferably established by the Bijvoet method), iii) kinetic resolutions and/or asymmetric syntheses, iv) interpretation of chiroptical properties (mainly circular dichroism) on the basis of (sector) rules including theoretical methods. 

The first experimental verification of these concepts in 1963 by the resolution of 124 through chiral platinum complexes 1371 was soon followed by the assignment of the chirality (—)(R) by an ingenious chemical correlation to a centrochiral compound, namely ( + )-tartaric acid138 . This was confirmed in 1970 by application of the Ryvoet-method to the platinum complex used for optical resolution 139), but is in contrast to an earlier prediction based on an optical model140). 

Kinetic resolution.l33 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on p. 102. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,134 since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as 45 with one enantiomer of a chiral epoxidizing agent (see 5-36).135 In the case of 45 the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor)... 

Chromatography. Under certain conditions, even homochiral and het-erochiral self-assemblies can be separated by achiral methods. Thus, chromatography of partially resolved enantiomers can cause depletion or enrichment of enantiomers on achiral stationary phases with an achiral mobile phase. 14C-Labeled nicotine was first resolved into its enantiomers by high-performance liquid chromatography (HPLC) on an achiral stationary phase (Partisil-ODS or -SCX) through coinjection with optically active nicotine (59). This observation was followed by resolution of a number of chiral compounds by chromatography (<50-62) (Scheme 34). When a chiral diamide in 74% ee was separated on a Kieselgel 60... 

This unit describes those methods that can differentiate between enantiomers found in foods that contribute to their taste and aroma. These compounds are volatile odorants that are most easily analyzed using enantioselective high resolution-gas chromatography (HRGC). Other methods exist for the separation and analysis of chiral compounds, which include optical methods, liquid and planar chromatography, and electrophoresis, but for food volatiles, gas chromatography has evolved to the point where it is now the cornerstone for the most comprehensive analysis of volatile compounds. 

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