Racemic compounds, Splitting

Splitting Racemic Compounds.—The methods by which racemic compounds may be split into their optically active components are several. The three methods used were all originated by Pasteur. The first method has been referred to and consists of the mechanical separation of the two oppositely hemi-hedral forms in which the salts of a racemic compound crystallize. This method is especially applicable in the case of tartaric acid when the sodium-ammonium salt is used. The crystallization and separation must be carried out under definite conditions. If the racemic acid salt is crystallized below 28° the two forms of crystals are produced and a separation can be accomplished. If, however, the crystallization takes place above 28° the two forms of crystals are not produced but the sodium-ammonium racemate crystallizes in unseparable crystals of one form. That is, above 28° the sodium-ammonium racemate crystallizes as such, while, below 28° the racemate splits into its two isomeric components and equal amouts of the sodium-ammonium dextro tartrate and the sodium-ammonium levo tartrate are formed. The second method for the splitting of a racemic compound into its optically active components consists of the formation of the cinchonine, strychnine, or other similar alkaloid salts. When the cinchonine salt of racemic acid is formed it splits into the... 

The classical method, which was followed to prepare the first example of an optically pure chiral organotin compound, is characterized by the use of a auxiliary chiral group necessary to convert the racemic mixture of enantiomers into a mixture of diastereomers which are then separated by a suitable physical method and converted back into the separated enantiomers by splitting off the chiral auxiliary group. This last step is sometimes difficult to achieve 34 ). 

Figure 2.10 Example of a separation with a chiral phase which contains cyclodextrins. The use of a chiral column to separate a racemic mixture of compounds leads to a splitting of the chromatogram signals as can be seen clearly for alcohols, 2 and 4. This chromatogram in isothermal mode, allows the calculation of retention indexes for the separated compounds (adapted from a Supelco illustration).

The template 7a can be split off by water or methanol to an extent of up to 95% (Scheme 2-5). The accuracy of the steric arrangement of the binding sites in the cavity can be tested by the ability of the polymer to resolve the racemate of the template, namely of phenyl-a-D,L-mannopyranoside. Therefore the polymer is equilibrated in a batch procedure with a solution of the racemate under conditions under which rebinding in equilibrium is possible. The enrichment of the antipodes on the polymer and in solution is determined by measuring the specific optical rotation and the separation factor a, i.e., the ratio of the distribution coefficients of the D and L compounds between polymer and solution, is calculated. After extensive optimization of the procedure, a values between 3.5 and 6.0 were obtained [10]. This is an extremely high selectivity for racemic resolution that cannot be reached by most other methods. 

This method was introduced by Polonski and Chimiak 192,193) in 1974 (Scheme 47). It is based on the oxidation of Schiff bases (239) to appropriate oxaziridines (240) in ether using monoperphtalic acid (MPP). Bases (239) are obtained from esters of amino acids and anisyl aldehyde (238) and are oxidised without isolation. Oxaziridines (240) are next hydrolyzed with hydrochloric acid to N-hydroxyamino acids (1) or give p-toluenesulfonates of (76, 213), which crystallize readily, by splitting with hydroxylamine j7-toluenesulfonates in alcohol. Use of benzaldehyde is unfavourable and leads to nitrones. Use of mono-perphthalic acid permits one to follow the progress of the reaction due to precipitation of phthalic acid. This method is general. Because bases (239) racemize only very slowly it is possible to obtain 193) optically active compounds (1,76, 213). 

In racemic resolution processes a racemic mixture of the desired product is produced first. There are several techniques by which this mixture can be separated into its two enantiomers. A favorable option is to react the racemic mixture with another chiral compound to form diastereomers. The latter have different physicochemical properties and thus they can be separated, for example, by chromatographic or crystallization processes. After separation of the diasteromers the chiral auxiliary compound is split-off and separated to re-obtain the desired compound as pure enantiomer. In an alternative concept, called kinetic racemic resolution, the initial racemic mixture is reacted with a chiral reactant or in the presence of a chiral catalyst (e.g., an enzyme) and only one of the two enantiomers of the desired product is transformed into a new compound. The reacted and non-reacted enantiomers are usually easily separated. All processes of racemic resolution have the common disadvantage that both enantiomers, the desired and the undesired one, have to be synthesized initially. Consequently, half of the initial racemic mixture is the undesired enantiomer, which usually has no or very little commercial value. This problem is partialy solved by applying racemization processes in which after separation the pure wrong enantiomer is re-converted into the racemic mixture. The latter is then applied in another round of racemic resolution again to increase the final yield of the desired enantiomer. 

---