Available Chiral Compounds

In sourcing enantiomerically pure starting materials, one thing is certain the scientific efforts of biochemists and chemists and collaborations between academia and industry, with growing interest in the business, are all leading to an increase in the availability of chiral compounds. The job is becoming progressively easier. 

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Compounds isolated from natural sources are frequently optically pure. Thus camphor (11), cholesterol (14), morphine (16), for example, are isolated in the optically pure state. The parent molecule of (13) is D-glucose, and like camphor and cholesterol is readily available in very large quantities. These, and comparable compounds, form what is now described as a chiral pool, i.e. low-cost, readily available, chiral compounds which provide starting materials for conversion into other compounds, of simplified skeletal and functional structure, in which some or all of the chiral features have been retained. 

Although carbohydrates are cheap and readily available chiral compounds, their application in stereoselective synthesis was for a long time limited to ex-chiral-pool syntheses [3]. They have been considered too complex compared to other chiral auxiliaries, for example a-pinene in borane-chemistry [4] or BINAP-derivatives in reduction chemistry [5]. However, it has been shown during the past few years that carbohydrates can be successfully applied as stereodifferentiating tools in many different reaction types such as aldol- [6], hydrogenation- [7], carbonyl addition- [8], Michael- [9], Diels-Alder- [10], hetero-Diels-Alder [11], and rearrangement reactions [12]. 

To accelerate aUylation with aUylstaimanes, addition of a Lewis acid is often required, because coordination of the Lewis acid to the carbonyl can enhance the electrophilicity of the substrate and facilitate the couphng reaction. Since Yamamoto showed that a nonracemic Lewis acid, chiral (acyloxy)borane (CAB), catalyzed enantioselective allylation [73], chiral Lewis acid catalysts have been extensively developed. Above all, easily available chiral compounds such as BINOL and BINAP have been most frequently used as chiral auxiliaries [74], and enantioselective allylations of C-N double bonds and of carbonyl groups have been achieved [48a, 75]. 

Cinchona alkaloids such as quinine and quinidine are readily available chiral compounds. Prelog and Wilhelm reported in 1954 cinchona alkaloid-catalyzed... 

HPLC separations are one of the most important fields in the preparative resolution of enantiomers. The instrumentation improvements and the increasing choice of commercially available chiral stationary phases (CSPs) are some of the main reasons for the present significance of chromatographic resolutions at large-scale by HPLC. Proof of this interest can be seen in several reviews, and many chapters have in the past few years dealt with preparative applications of HPLC in the resolution of chiral compounds [19-23]. However, liquid chromatography has the attribute of being a batch technique and therefore is not totally convenient for production-scale, where continuous techniques are preferred by far. 

The above results are valuable in that an optically active compound is produced in bulk from achiral material. Only a few successful examples of photochemical conversion of achiral into chiral material in the absence of a chiral source have been reported hitherto 49, and in these cases the conversion was carried out on a fragment of a chiral crystal. In our case, chiral crystals are available in bulk, and mass production of the chiral compound is possible. 

A number of specialised stationary phases have been developed for the separation of chiral compounds. They are known as chiral stationary phases (CSPs) and consist of chiral molecules, usually bonded to microparticulate silica. The mechanism by which such CSPs discriminate between enantiomers (their chiral recognition, or enantioselectivity) is a matter of some debate, but it is known that a number of competing interactions can be involved. Columns packed with CSPs have recently become available commercially. They are some three to five times more expensive than conventional hplc columns, and some types can be used only with a restricted range of mobile phases. Some examples of CSPs are given below ... 

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials. To be useful in asymmetric synthesis, they should be readily available in high enantiomeric purity. For many applications, the availability of both enantiomers is desirable. Many chiral molecules can be synthesized from natural carbohydrates or amino acids. The syntheses of (+)-exo-brevicomin (66) and negamycin (67) illustrate the application of such naturally occurring materials. 

For acrylates, or type I reagents, applied in asymmetric Diels-Alder reactions, several chiral auxiliaries such as menthol derivatives, camphor derivatives,16,3 and oxazolidinones4 are available. Carbohydrate compounds have also been reported as chiral auxiliaries in a recent publication, although the stereoselectivity was not good.5 Here are examples in which asymmetric Diels-... 

Chiral 1,1 -binaphthol derivatives are well established as readily available chiral catalysts and auxiliaries for the production of various useful optically active compounds. Tanabe et al. investigated [11] a crystalline-liquid resolution of (1R) -// . v - c h rysanthemic acid utilizing l,l -binaphthyl monoethyl ether (25) (Scheme 3). 

Enzyme reductions of carbonyl groups have important applications in the synthesis of chiral compounds (as described in Chapter 10). Dehydrogenases are enzymes that catalyse, for example, the reduction of carbonyl groups they require co-factors as their co-substrates. Dehydrogenase-catalysed transformations on a practical scale can be performed with purified enzymes or with whole cells, which avoid the use of added expensive co-factors. Bakers yeast is the whole cell system most often used for the reduction of aldehydes and ketones. Biocatalytic activity can also be used to reduce carbon carbon double bonds. Since the enzymes for this reduction are not commercially available, the majority of these experiments were performed with bakers yeast1 41. 

Of great importance was the discovery by Johnson et al. (185) of the stereospecific synthesis of optically active sulfonimidoyl chlorides, which are key substrates for making new types of sulfonimidoyl compounds. The method involves chlorination of readily available chiral sulfinamides with chlorine or A/-chlorobenzotriazole. Scheme 12 summarizes the synthesis of (-)-(/ )-A/-methylphenylsulfonimidoyl chloride 163 from (+HS>N-methyl benzenesulfinamide 164 and its reactions with sodium phenoxide and dimethylamine. 

In the last two decades optically active sulfur compounds have found wide application in asymmetric synthesis. This is mainly because organic sulfur compounds are quite readily available in optically active form. Moreover, the chiral sulfur groupings that induce optical activity can be removed from the molecule easily, under fairly mild conditions, thus presenting an additional advantage in the asymmetric synthesis of chiral compounds. This section deals with reactions in which asymmetric induction in transfer of chirality from sulfur to other centers was observed. This subject has been treated only in a cursory manner in recent reviews on asymmetric synthesis (290-292). 

The chiral compounds (/ )- and (5)-bis(trifluoromethyl)phenylethanol are particularly useful synthetic intermediates for the pharmaceutical industry, as the alcohol functionality can be easily transformed without a loss of stereospecificity and biological activity, and the trifluoromethyl functionalities slow the degradation of the compound by human metabolism. A very efficient process was recently demonstrated for the production of the (5)-enantiomer at >99% ee through ketone reduction catalyzed by the commercially available isolated alcohol dehydrogenase enzyme from Rhodococcus erythropolis (Figure 9.1). The (7 )-enantiomer could be generated at >99% ee as well using the isolated ketone reductase enzyme KRED-101. 

Non steroidal antiinflammatory drugs were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], ristocetin A [33] CSPs under RPmode systems, and on avoparcin CSP under NP mode systems [37]. The enantioresolution of a variety of pro fens was later reported on commercially available vancomycin CSPs [128, 168], and recently on a ME-TAG CSP [58]. Ibuprofen enantiomers were also separated on a CDP-1-containing CSP [55]. Glycopeptide A-40,926 CSP was successfully employed in the analytical and semipreparative separation of 2-arylpropionic acids [63]. 

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