Enantiopure chiral substance

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

Preparative chromatography has been used for chiral separations for years, but examples of multi-kg separations (and hence larger ones) were rare until recently. The development of SMB techniques (both hardware and simulation software) has made major breakthroughs in this field. The ability of SMB as a development tool has allowed the pharmaceutical manufacturer to obtain kilo grams quantities of enantiopure drug substances as well benefit from the economics of large-scale production. 

The second alternative is first to make the racemate, and then to resolve the desired enantiomer. However, such resolution is often time-consuming, laborious, and (for industry) very expensive. Conversely, asymmetric homogeneous catalysis gives access to a wide range of enantiopure organic substances from achiral precursors. The chiral catalyst complex directs the orientation of the substrate, giving preference... 

For all analytical methods the quality of the results ultimately relates back to the chemical purity of the very best available SRM and to the linearity of the correlation curve for the experimentally measured property vs. the SRM concentration. For substances that are naturally chiral there is the additional very serious concern about enantiomeric purity. The determination of an enantiomer whether for an enantiomeric purity test, or for an enantiomeric ratio or excess test in the study of a partial racemic mixture, is one of the more difficult analytical problems. To actually report the enantiomeric purity of an enantiomer as better than 99% is truly beyond the capability of current analytical methodology [31], for after all few substances ever have a chemical purity that is guaranteed to be greater than 99%. So, as mentioned earlier, one has to accept the fact that the results are measured relative to an enantiopurity of an SRM that is defined to be 100%. This limitation of course impacts on the true meaning of a calculated enantioexcess, and to a much lesser degree perhaps, in assays of chiral substances extracted from plant materials using calibration data that were obtained for synthetic SRM s. 

A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. If the desired product is an enantiomer, the reaction needs to be sufficiently stereoselective even when atom economy is 100%. For the biological usage we almost need one enantiomer and in high purity. This is because when biologically active chiral compounds interact with its receptor site which is chiral, the two enantiomers of the chiral molecule interact differently and can lead to different chemistry. For example, one enantiomer of asparagines (1.37) is bitter while the other is sweet. As far as medicinal applications are concerned, a given enantiomer of a drug may be effective while the other is inactive or potentially harmful. For example, one enantiomer of ethanbutol (1.38) is used as antibiotic and the other causes blindness. 

For all types of chemical analysis, the quality of the results ultimately relates to the chemical purity of the best available SRM. For naturally chiral substances, there is the additional more serious concern over what constitutes absolute enantiomeric purity. Not even mass spectroscopy, which provides assurance that a substance is chemically pure, can be used to report absolute enantiomeric purities. To actually report an enantiomeric purity higher than 99% is truly beyond the capability of current analytical methodology. ° As noted previously, the fact is that results are measured relative to an enantiopurity defined to be 100%. Chemical purities aside, the measurement of enantiomeric purity and enantiomeric excess is technically the same, the difference being the extent of race-mization. There are only two experimental options, either enantiomeric separations or multivariate spectroscopic analyses, that involve either two distinct detectors or multiple-wavelength detection for a single detector, as noted above. The newly described derivati-zation reactions fulfill the second option. 

A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. 

Diastereo- and enantiopure 1,2-amino alcohols and differentially protected 1,2-diols are motifs that occur widely in bioactive natural products and pharmaceutical substances [132]. Their preparation by KR of the corresponding racemates has been explored widely [133], particularly by asymmetric acyl transfer because these substrates provide a convenient scaffold for probing the influence of H-bonding and n-n-stacking effects on the efficiency of chirality transfer by various catalyst systems. 

The obvious approach for chiral synthesis would be to find a chiral starting material, such as a natural amino acid, carbohydrates, carboxylic acids or terpene. The major source of these chiral starting materials sometimes called chirons is nature itself. The synthesis of a complex enantiopure chemical compound from a readily available enantiopure substance such as natural amino acids is known as chiral pool synthesis. For example, chiral lithium amides 1.39 that are used for several types of enantioselective asymmetric syntheses can be prepared in both enantiomeric forms starting from the corresponding optically active amino acids, and these are often available commercially. 

The term chiral is also used to describe a sample of a substance. When used in this sense, it is not necessary that every molecule in the sample has the same handedness see the definitions below for optical purity, enantiopurity, etc. A racemic sample is one containing (statistically) equal numbers of right-handed and left-handed enantiomers, and therefore showing zero optical activity at all wavelengths. A sample can also be chiral, nonracemic i.e., it contains an excess of one enantiomer. 

The specifications for both enantiopure and racemic chiral drug substances should be sufficient to establish both chemical and stereochemical aspects of identity, strength, quality and purity. This implies both that the identity test use a stereochemically specific method and that the assay method be stereochemically selective. 

As with the bulk drug substance, spedfications for both enantiopure and racemic chiral drug products should include both a stereochemically spedfic identity test and stereochemically selective assay method. The analytical method to be used should not be arbitrarily chosen to be the same as for the bulk drug but should be chosen on the basis of the composition, method of manufacture, and stability characteristics of the formulation. 

A classical method for the preparation of enantiopure compounds is the resolution of racemate. However, it is much more effective to use the selective synthesis of the desired enantiopure substance via enantioselective approach. Stereoselective methods of synthesis have been widely developed in organic chemistry. The method of asymmetric synthesis has been known since the nineteenth century and asymmetric catalysis has witnessed an enormous amount of development in recent decades as shown in Chapter 3. In contrast, the asymmetric synthesis of coordination compounds has only recently become a subject of systematic investigation. This is no doubt related to the fact that the chirality of coordination compounds is a much more complex phenomenon than that of organic compounds, because of higher coordination and the multitude of possible central atoms. Furthermore, while in organic chemistry the chiral tetrahedral carbon centres can be prepared without racemization, in contrast T-4 metal centres are very often labile. In fact it is even difficult to prepare compounds with a metal centre coordinated to four different monodentate ligands, and thus the possibility of obtaining one enantiomer is excluded in most cases. 

Many chiral organic molecules used as pharmaceuticals have the desired effect in only one molecular form. The mirror image of this form may even be toxic. It is obviously very important to have a chemical process which produces the active form of e.g. a drug with extremely high purity. However, thermodynamic information about such separations is scarce. Nevertheless, several commercially successful production processes for enantiopure pharmaceuticals have been developed on the basis of enzymatic process steps. Extensive research in this area will be driven mainly by the demand for chiral intermediates for pharmaceutical substances or aromatic chemicals. Thermodynamics research on down-stream separations in enzymatic production processes for pharmaceutical molecules (molar mass range 200 - 1000) should be focused much more on the specific conditions of these processes (very dilute concentrations, water-based systems, very small solid particles). 

Therefore, the chiral nature of the drug substance must be known and controlled. This must be done throughout the synthesis of the drug substance, so that the exact chiral species is consistently generated. Also, once an enantiopure compound has been generated, it must be shown that the chirality does not change on stability. Clearly, a chiral metric is required. 

Nature is the world-leading chemist in synthesizing chiral enantiopure substances, and a vast variety of structures isolated from plant or animal sources are available for the synthetic chemist to use as starting materials. Examples of chiral synthons from nature are amino acids, carbohydrates, hydroxy acids, terpenes, alkaloids, and so on (Figure 1.44). The most representative among them are commercially available compounds, such as ascorbic acid, (+)-calcium panthotenate, (—)-carvone, dextrose, ephedrine hydrochloride, (+)-limonene, L-lysine, mannitol, monosodium glutamate, norephedrine hydrochloride, quinidine, quinine, sorbitol, and L-treonine. The chiral pool strategy uses chiral compounds from nature or products derived thereof (e.g., from fermentation processes). Examples of industrial... 

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