Enantiomer separation optical resolution

Pasteur s success in 1848 of the first enantiomer separation (optical resolution) of racemic acid as ammonium sodium ( )-tartrate tetrahydrate together with McKenzie s success in 1904 of the first asymmetric synthesis prompted many chemists to synthesize optically active compounds without recourse to the vital force of organisms, although by employing the capacity of a special species of organism, Homo sapiens, to discriminate left from right. Pasteur remarked in 1883 that The universe is dissymmetric. Since then chemists efforts have been focused on the control of asymmetry in this world of chiral and nonracemic materials. 

There are three methods available for the enantioselective synthesis of pheromones (1) derivation from enantiopure natural products, (2) enantiomer separation (optical resolution), and (3) chemical or biochemical asymmetric synthesis. Practitioners of enantioselective synthesis must be familiar with the analytical methods for the determination of enantiomeric purity of an optically active compound. These basic methods will be explained briefly in this section, and discussed in depth through examples in the later sections of this chapter. 

There are two drawbacks in employing the chiral pool approach. First, a natural product usually exists as a single enantiomer, and therefore only a single enantiomer of a pheromone can be prepared easily. Secondly, a natural product possesses a definite structure, which is often quite different from that of a pheromone. Accordingly, the synthesis may become lengthy to remove the undesired structural features in the starting natural product. 

Numerous racemates have been separated into their enantiomers since the first success in 1848 by Pasteur. The traditional method is to derivatize a racemate into a mixture of two diastereoisomers by means of so-called resolving agents, and then to separate the diastereoisomers by recrystallization or chromatography. Recent development of chiral stationary phases for chromatographic separation of the enantiomers made it possible to separate them even without derivatization. Another method of choice is to use enzymes for enantiomer separation. Examples in this chapter will illustrate the use of these methods. After enantiomer separation, the absolute configuration and the enantiomeric purity of the resulting enantiomers must be determined. 

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Subsequently, the absolute configuration of the natural lineatin was determined as (lR,4S,5R,7R)-77 by our second synthesis, as shown in Figure 4.16.35 The first step was the cycloaddition of dichloroketene to isoprene to construct a cyclobutane ring. The symmetrical cyclobutanone A was then converted to ( )-bicyclic lactone B. Enantiomer separation (optical resolution) of ( )-B was executed as follows. Reaction of ( )-B with the resolving agent C (derived from chrysanthemic acid) yielded a diastereomeric mixture... 

We then synthesized the two enantiomers 90 and 90 of lardolure as shown in Figure 4.41.74 The first task was the enantiomer separation (optical resolution) of ( )-lactone A, which was an intermediate in the synthesis of l,3,5-yy -( )-lardolure. Treatment of ( )-A with (3 )-prolinol furnished B, whose 3,5-dinitrobenzoates C and D could be separated by silica-gel chromatography. The absolute configuration of D could be determined as depicted by its conversion to the known lactone (-)-F via (—)-E. The... 

The sandfly Lutzomyia longipalpis is the vector of the protozoan parasite Leishmania chagasi, the causative agent of visceral leishmaniasis in South and Central America. Population control of L. longipalpis is therefore of urgent importance to prevent the disease. In 1994, Hamilton and coworkers isolated the male-produced pheromone of L. longipalpis from Jacobina, Brazil, and proposed its structure as 3-methyl-a-himachalene (96, Figure 4.47) with unknown stereochemistry. We first synthesized ( R, 3R, 1 S )-( )-96.81 Enantiomer separation (optical resolution) of a synthetic intermediate enabled us to prepare both the enantiomers of 96, and their bioassay and GC comparisons with the natural pheromone showed the latter to be (lS,3S,lR)-96. 

Frontalin (98, Figure 4.49) is the active component of the aggregation pheromone of the southern pine beetle (Dendroctonus frontalis), the western pine beetle (Dendroctonus brevicomis) and the Douglas-fir beetle (Dendroctonuspseudotsugae). Mori s 1975 synthesis of the enantiomers of frontalin via enantiomer separation (optical resolution) of an intermediate87 enabled their bioassay, and only (lS,5/ )-98 was bioactive as the pheromone component of D. brevicomis.32 A recent study on female D. frontalis revealed its (15, 5/C)-98 to be of about 91% ee.88... 

In 1981, I synthesized (—)-A-factor (127) as shown in Figure 5.I.1 The starting material was (—)-paraconic acid (A) obtained by enantiomer separation (optical resolution) of ( )-A. In the next year in cooperation with Mr. K. Yamane both (—)-127 and (+)-127 were synthesized from the enantiomers of paraconic acid. The identity of (—)-127 with the natural A-factor was established by their identical spectral properties including the circular dichroism (CD) spectra.2... 

We became interested in synthesizing both the enantiomers of differolide to clarify whether one or both of them are bioactive. Our synthesis is summarized in Figure 5.14 and 5.15.23 Because both the enantiomers 135 and 135 were necessary for bioassay, we adopted enantiomer separation (optical resolution) of an intermediate as our key step (Figure 5.14). A crystalline acetal (-)-B was obtained from ( )-A and (—)-menthol, and analysed by X-ray to reveal its structure as (—)-B, basing on the known absolute configuration of (-)-menthol. When (+)-menthol was used for acetal formation, crystalline (+)-B was obtained in a similar manner. We thus secured both (-)-B and (-t-)-B as pure crystals. 

Synthesis of (-)-ascofuranone was achieved by enantiomer separation (optical resolution) of an intermediate as shown in Figure 5.20 and 5.21.26 Geraniol was adopted as our starting material. 

Crystallization continues to be the most widely used method of separating or resolving enantiomers (optical resolutions). The manufacture of chemicals and pharmaceuticals as purified optical isomers, or enantiomers, has taken on a pivotal importance in the pharmaceutical, agricultural and fine chemicals industries over the past 15-20 years. Crystallization has been and continues to be the most widely used method of separating or resolving enantiomers (optical resolutions), and is particularly well suited to separations at large scale in manufacturing processes (Jacques etal., 1981 Roth etai, 1988 Wood, 1997 Cains, 1999). 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

Lin et al. [95] used capillary electrophoresis with dual cyclodextrin systems for the enantiomer separation of miconazole. A cyclodextrin-modified micellar capillary electrophoretic method was developed using mixture of /i-cyclodextrins and mono-3-0-phenylcarbamoyl-/j-cyclodextrin as chiral additives for the chiral separation of miconazole with the dual cyclodextrins systems. The enantiomers were resolved using a running buffer of 50 mmol/L borate pH 9.5 containing 15 mmol/L jS-cyclodextrin and 15 mmol/L mono-3-<9-phcnylcarbamoyl-/j-cyclodextrin containing 50 mmol/L sodium dodecyl sulfate and 1 mol/L urea. A study of the respective influence of the /i-cyclodcxtrin and the mono-3-(9-phenylcarbamoyl-/i-cyclodextrin concentration was performed to determine the optical conditions with respect to the resolution. Good repeatability of the method was obtained. 

Many optically active hypervalent chalcogen compounds, particularly sulfur compounds, have been synthesized and proposed as important key intermediates in various reactions of the chalcogen compounds.46 Since the synthesis of spirosulfurane by Kapovits and Kalman,47 many optically active spir-osulfuranes were isolated in the last decade. Spirosulfurane 28 was separated into enantiomers by kinetic resolution using a chiral host molecule and found to be optically stable by Drabowicz and Martin.48 Spirosulfurane 29 was separated into enantiomers by chromatographic method by Allenmark and Claeson, and characterized by chiroptical methods.49 Optically active... 

The concentration of the chiral selector, for instance, has considerable influence on the mobility and separation of the enantiomers. Optical resolution varies with the chiral selector concentration and reaches a maximum value at a given optimum concentration. Wren and Rowe proposed a model that describes the influence of the selector concentration on selectivity, and which was extended by Vigh s group ° by including the pH as a separation parameter for weak acidic enantiomers. The latter model shows that the chiral selectivity is determined by the complex s relative mobility, the CD concentration, the degree of dissociation... 

Optical. - This adjective exclusively refers to measurements of optical rotation. It must not be used other than in the combinations optical rotation and optical purity. In particular, the terms optical resolution (better separation of enantiomers) and optical yield must be avoided. 

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. 

Contrary to the optical resolutions described in Sections 2.1.1.-2.1.3., which depend on the solubility or chromatographic properties ( Thermodynamic resolution ), the kinetic resolution rests on rate differences shown by the enantiomers when reacted with an optically active reagent. In the ideal case, only one enantiomer is converted into the envisaged product and the other enantiomer is unchanged. In this way, optical resolution is reduced to the more simple separation of two different reaction products. In practice, only two methods of kinetic resolution are reasonably general and reliable the Sharpless epoxidation of allylic alcohols and the enzymatic transesterification of racemic alcohols or carboxylic acids. 

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). 

Introduction of nitrogen into the anulene ring (e.g. of 95) leads to a methano-azaanulene 107 121) with Q-symmetry which is therefore chiral (like its mono- or disubstituted derivatives)118). The low basicity of 107 (pKa 3.20) prevented its optical resolution by conventional methods (e.g. through salts with optically active acids). Excellent results were obtained, however, (as also in the case of the two isomeric carbocyclic methylesters 97 and 101 and of several derivatives of azaanulene) by chromatography on microcrystalline triacetyl cellulose in ethanol at 7 bar 1221 (see also Section 2.7.1). In many cases base line separations were accomplished to give both (optically pure) enantiomers. Enantiomeric relations were confirmed in all cases by recording the CD-spectra of both fractions. Some results of these separations are shown in Fig. 4 together with the optical rotations ([a]D in ethanol) of the enantiomers. 

The use of sulfoximines in the syntheses of optically active compounds has been reported [429]. A remarkable ketone methylcnation with optical resolution was realized. A highly selective diastereofacial addition of an enantiopure sulfoximine to a racemic ketone, chromatographic separation of the two diastereoisomers and reductive cleavage yielded both enantiomers of p-panasinsene [430], isolated from the root of ginseng, a herb used in Chinese folk medicine. 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

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. 

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]. 

An equimolar mixture of two enantiomers is called a racemate. The separation of two enantiomers that constitute a racemate is called optical resolution or resolution. Their crystalline forms best characterize types of racemates. A racemic mixture is a crystal where two enantiomers are present in equal amounts. A conglomerate is a case where each enantiomer has its own crystalline form. Sometimes their crystals have so-called hemihedral faces, which differentiate left and right crystals. For over a hundred years, crystallization processes have been used for the separation and purification of isomers and optical resolution, both in the laboratory and on an industrial scale. 

Some other optical resolution procedures of rac-BNO (14a) by complexation with various chiral ammonium salts are summarized in the section 6 of this chapter as an example of the progress on novel enantiomer separation technique. 

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