Pasteur resolution procedure

Comparison of the Solid-State Ionic Chiral Auxiliary Method of Asymmetric Synthesis with the Pasteur Resolution Procedure... 

Fig. 4 Comparison of the solid-state ionic chiral auxiliary method of asymmetric synthesis with the Pasteur resolution procedure...

In principle, any of the photoproducts shown in Table 4 could have been prepared in enantiomerically pure form by irradiating their achiral precursors in solution to form a racemate and then separating the enantiomers by means of the classical Pasteur resolution procedure [36]. This sequence is shown in the lower half of Fig. 3. The top half of Fig. 3 depicts the steps involved in the solid-state ionic chiral auxiliary method of asymmetric synthesis. The difference between this approach and the Pasteur method is one of timing. In the ionic chiral auxiliary method, salt formation between the achiral reactant and an optically pure amine precedes the photochemical step, whereas in the Pasteur procedure, the photochemical step comes first and is followed by treatment of the racemate with an optically pure amine to form a pair of diastereomeric salts. The two methods are similar in that the crystalline state is crucial to their success. The Pasteur resolution procedure relies on fractional crystallization for the separation of the diastereomeric salts, and the ionic chiral auxiliary approach only gives good ees when the photochemistry is carried out in the crystalline state. 

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. 

The preceding example demonstrates the general view that the procedure most likely to alter the crystallization thermod)mamics of true race-mate systems will entail the formation of dissociable diastereomer species [50-54]. In most instances, these diastereomers are simple salts formed between proton donors and proton acceptors, or electron-pair donors and electron-pair acceptors. For example, the first resolving agents introduced for acidic enantiomers were alkaloid compounds, and hydroxyl acids were used for the resolution of basic enantiomers. This t) e of resolution procedure has been known since the time of Pasteur, and extensive tables of resolving agents and procedures are available [48,55,66]. 

Mechanical Separation of Crystals. The first instance of resolution was by L. Pasteur who was able to resolve crystals of sodium ammonium tartrate (which recrystallizes in two distinct, nonsuperimposable forms below 2TC). Although this procedure is rarely used, one might be able to seed a racemic solution resulting in only one... 

The crystallization procedure employed by Pasteur for his classical resolution of ( )-tartaric acid (Section 5-1C) has been successful only in a very few cases. This procedure depends on the formation of individual crystals of each enantiomer. Thus if the crystallization of sodium ammonium tartrate is carried out below 27°, the usual racemate salt does not form a mixture of crystals of the (+) and (—) salts forms instead. The two different kinds of crystals, which are related as an object to its mirror image, can be separated manually with the aid of a microscope and subsequently may be converted to the tartaric acid enantiomers by strong acid. A variation on this method of resolution is the seeding of a saturated solution of a racemic mixture with crystals of one pure enantiomer in the hope of causing crystallization of just that one enantiomer, thereby leaving the other in solution. Unfortunately, very few practical resolutions have been achieved in this way. 

The Pasteur method can also be applied to the resolution of neutral racemates, if these can be first converted into an acidic or basic derivative from which eventually a mixture of crystalline diastereoisomeric salts may be prepared by appropriate neutralisation. Thus, a racemic alcohol (e.g. ( )-octan-2-ol, Expt 5.220) may be converted into the corresponding racemic hydrogen phthalate ester by heating with phthalic anhydride, and the ester is then resolved by the Pasteur procedure using an optically active base. The resulting optically active hydrogen phthalate ester is then carefully hydrolysed with aqueous sodium hydroxide to regenerate one of the optically active forms of the alcohol. 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

Following Pasteur s work in the 1860s, which elucidated some roles of microbes in acetification (wine turning to vinegar), interest in microbial transformations slowly developed. By the end of the century several processes were in use. Even resolution of some racemates to obtain (at least one) optically pure enantiomer were viable procedures (e.g., lactic and mandelic acids). An observation that yeast (in fermentations) is capable of reducing 17-ketosteroids to 17(3-hydroxysteroids in the late 1930s ultimately led to a search for other microbially mediated chemical transformations. 

This reaction was first reported by Marckwald in 1904. It is the synthesis of chiral L-valeric acid (a-methyl propanoic acid) from the pyrolysis of brucine salt of racemic o -methyl-o -ethylmalonic acid. Therefore, it is generally known as the Marckwald asymmetric synthesis. Occasionally, it is also referred to as the Marckwald method. In this reaction, the brucine salts of racemic a-methyl-a-ethylmalonic acid essentially exist as a pair of diastereomers that are separated by fractional crystallization the one with lower solubility is isolated. Upon pyrolysis of such crystalline salt at 170°C, the corresponding brucine salt of L-valeric acid forms upon decarboxylation, resulting in a 10% e.e. In addition, Marckwald defined the asymmetric synthesis as reactions that produce optically active molecules from symmetrically constituted compounds with the use of optically active materials and exclusion of any analytical processes, such as resolution. However, this work was challenged as not being a trae asymmetric synthesis because the procedure was similar to that of Pasteur. In fact, the If actional crystallization of the diastereomers is a resolution process. This process is used as base for many other preparations of chiral molecules, such as tartaric acid and under its influence, the kinetic resolution and tme asymmetric synthesis have been developed in modem organic synthesis. The asymmetric synthesis has been redefined by Morrison and Mosher as the reaction by which an achiral unit of the substrate is converted into a chiral unit in such a manner that the two resulting stereoisomers are produced in unequal amounts. ... 

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