Resolution, classical asymmetric

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

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. 

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

In the course of developing the melatonin agonist 1 (Fig. 1), potentially indicated for the treatment of sleep disorders, we evaluated approaches to the chiral cyclopropane intermediates 2 a and 2 b based on both classical resolution and asymmetric induction. Conceptually, these intermediates could be derived from di-hydrobenzofurans 3, 4 and 5 each of these was used at one stage or another during our research and development work. 

Outside the amino acid and carbohydrate pools, derivatives of natural and unnatural tartaric acid (l- and d- respectively) merit attention as chiral syn-thons, in addition to their more familiar applications in classical resolution and asymmetric synthesis. Biologically active compounds prepared from tartrates (Scheme 5.34) include the symmetry-based HIV protease inhibitor (78) [96] and the endotoxin inhibitors (79) [97]. 

As there was an amine handle for the formation of diastereomeric salts, classical resolution of to obtain CP-465,022 was also an option (Scheme 23). With the ability to thermally racemize the wrong antipode, one could envision a dynamic resolution (or, asymmetric transformation). In the presence of the appropriate chiral acid, there would be an equilibrium of the enantiomers of CP-392,110 in solution, with only the desired antipode CP-465,022 crystallizing out as the insoluble diastereomeric salt. Pfizer has developed a number of other atropisomers, and this sort of dynamic resolution has been worked out for one of those candidates. 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

A classical chiral resolution method was established, prior to investigation of the asymmetric addition of lithium acetylide to the ketimine 5. 

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Enzymes as chiral catalysts play a role in all three methods. In nature enzymes catalyse all production of chiral compounds. In the laboratory enzymes can catalyse asymmetric synthesis, as well as resolve racemates. Which of the three methods is chosen in different cases depends on several factors, like price of starting materials, number of synthetic steps, available production technology and know-how etc. There is at present a constant ongoing development of synthetic methods and biotransformation is one field. Utilization of method i) requires knowledge of classical organic synthesis, enzymes have already played their role. Enzymes may play a part both in asymmetric synthesis and resolution. 

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. 

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