Enantiomers, asymmetric synthesis resolution

There are two different approaches for the production of enantiomers asymmetric synthesis and racemate resolution. The first, in special cases, allows a favourable production as costs are concerned, e.g. in case of the asymmetric hydrogenation of double bonds by use of optimized chiral transition metal complexes. In most cases, however, asymmetric syntheses, especially multi-step ones, are restricted to the laboratory scale. 

Enzyme-Catalyzed Asymmetric Synthesis. The extent of kinetic resolution of racemates is determined by differences in the reaction rates for the two enantiomers. At the end of the reaction the faster reacting enantiomer is transformed, leaving the slower reacting enantiomer unchanged. It is apparent that the maximum product yield of any kinetic resolution caimot exceed 50%. 

Kinetic Resolutions. From a practical standpoint the principal difference between formation of a chiral molecule by kinetic resolution of a racemate and formation by asymmetric synthesis is that in the former case the maximum theoretical yield of the chiral product is 50% based on a racemic starting material. In the latter case a maximum yield of 100% is possible. If the reactivity of two enantiomers is substantially different the reaction virtually stops at 50% conversion, and enantiomericaHy pure substrate and product may be obtained ia close to 50% yield. Convenientiy, the enantiomeric purity of the substrate and the product depends strongly on the degree of conversion so that even ia those instances where reactivity of enantiomers is not substantially different, a high purity material may be obtained by sacrificing the overall yield. 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

The novel phenomenon of converting racemic substrates into a single enantiomer of the product hy dynamic kinetic resolution (DKR) via racemization of the substrates has been a formidable challenge in asymmetric synthesis. Recently, DKR has been receiving increasing attention since it can overcome the limitations... 

The modes of addition shown in Figure 6.3 are similar to those shown in Figure 6.2 and are consistent with extant mechanistic work [6,9] they accurately predict the identity of the slower reacting enantiomer. It should be noted, however, that variations in the observed levels of selectivity as a function of the steric and electronic nature of substituents and the ring size cannot be predicted based on these models alone more subtle factors are clearly at work. In spite of such mechanistic questions, the metal-catalyzed resolution protocol provides an attractive option in asymmetric synthesis. This is because, although the maximum possible yield is 40 %, catalytic resolution requires easily accessible racemic starting materials and conversion levels can be manipulated so that truly pure samples of substrate enantiomers are obtained. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

For a nonracemic mixture of enantiomers prepared by resolution or asymmetric synthesis, the composition of the mixture was given earlier as percent optical purity (equation 1), an operational term, which is determined by dividing the observed specific rotation (Mobs) of a particular sample of enantiomer with that of the pure enantiomer ( max), both of which were measured under identical conditions. Since at the present, the amount of enantiomers in a mixture is often measured by nonpolarimetric methods, use of the term percent optical purity is obsolete, and in general has been replaced by the term percent enantiomeric excess (ee) (equation 2) introduced in 197163, usually equal to the percent optical purity, [/ ] and [5] representing the relative amounts of the respective enantiomers in the sample. 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

Before an asymmetric synthesis appeared of levofloxacin (1, (—)-ofloxacin), (—)- ofloxacin was isolated via optical, enzymatic, and crystallization resolution of the racemic ofloxacin (17) Drugs Future, 1992 Hayakawa et al., 1986, 1991). For instance, tricyclic core 52 was converted to ( + )-3,5-dinitrobenzoyl derivative 54 in 75% yield (Scheme 4.5). The enantiomers were then separated via high-performance liquid chromatography (HPLC) with a SUMIPAX OA-4200 column to deliver optically pure benzoyl esters 55a and 55b (Drugs Future, 1992 Hayakawa et al., 1986, 1991). 

Figure 2.7 Energy profile of resolution or asymmetric synthesis. In both cases the diasteromeric transition states leading to different enantiomers have different energy and this difference A A G1- governs the enantiomeric excess of products.

The E-value is related to the difference in free energy of activation for reaction with the two enantiomers by A A G =-RT InE. A reaction between the enzyme and one enantiomer passes through a transition state of different energy from the transition state resulting from reaction with the other (Figure 2.7) and E is constant throughout the reaction. As mentioned above there are two products in a resolution process the enantiomeric excesses of which depend on the degree of conversion. This feature is a major difference from asymmetric synthesis. In asymmetric synthesis there is only one product and the ee is independent of conversion. 

As discussed in part 2.2.3 biocatalysis may be used both in asymmetric synthesis and resolution in order to obtain enantiopure compounds. A major difference between asymmetric synthesis and resolution is that the former in theory may give 100% yield of the wanted enantiomer. Resolution on the other hand can only give 50% yield since the starting point is a mixture of 50% of each enantiomer. This is the classical disadvantage of 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. 

Martin wrote at the end of his review in 1974 6) It is our intimate conviction that further work on these unique molecules. .. should be highly rewarding in many fields of chemistry. To our opinion this conviction is verified now because the knowledge obtained from these molecules in the field of NMR an UV-spectroscopy, resolution of enantiomers and asymmetric synthesis appears to become more generally useful in several areas of organic chemistry. 

The biotransformation of organofluorine materials into optically active functionalized fluo-rinated materials along with a discussion on the effect of fluorine atom(s) during enantio-selective and/or diastereoselective transformations is described. The ability of microorganisms to discriminate between enantiomers is particularly important regarding resolution and asymmetric synthesis. Furthermore, the use of chiral fluorinated materials in the design and preparation of new types of biologically active materials is discussed. 

The ability of the microorganism to discriminate between enantiomers is very important regarding resolution and asymmetric synthesis. The ability of microorganisms to exert prochirality stereospecific control in their catalyses overcomes this problem because it permits direct asymmetric synthesis of chiral products from symmetric starting materials. Norcadia corallina -276 is a... 

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

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. 

The fundamentals of structure and stereochemistry have been considered in previous chapters in some detail. There are, however, practical aspects of stereochemistry that have not yet been mentioned, particularly with regard to chiral compounds. How, for instance, can a racemic mixture be separated into its component enantiomers (resolution) what methods can be used to establish the configuration of enantiomers how can we tell if they are pure and how do we synthesize one of a pair of enantiomers preferentially (asymmetric synthesis) In this chapter, some answers to these questions will be described briefly. 

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