Chirality diastereomeric salt formation

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Our efforts to concretely determine the relative stereochemistry of this dimer have been met by failure. We have made attempts to resolve several of the monomeric tetracyclic aminoaldehydes of type 100 by HPLC using chiral stationary phase, in order to know for sure the structure of the homodimer. The poor solubility of these compounds in typical HPLC solvents hampered these efforts to access enantiopure monomer. A few attempts at diastereomeric salt formation from compounds of type 101 using chiral carboxylic acids were also unsuccessful. Computational analysis corroborates the assumption that the homodimer should be formed preferentially. 

Sakai, K., Saigo, K., Murakami, H., Nohira, H. (1993) Relation between molecular structure and resolvability on optical resolution via diastereomeric salt formation, Symposium on Chiral Compounds (Tokyo), Oct 22. 

Another classic resolution process developed by Ethyl Corp. for (S)-ibuprofen production uses (S)-(-)-a-methylbenzylamine (MAB) as the chiral base for diastereomeric salt formation 49 The difference in solubility between (S)- and (ft)-ibuprofen MAB salts is so substantial that only half an equivalent of MAB is used for each mole of racemic ibuprofen, and no seeding is needed. The process can also be performed in a wide range of solvents, and the unwanted (ft)-ibuprofen can be recycled conveniently by heating the mother liquor in sodium hydroxide or hydrochloric acid. Other designer amines have been developed for resolution of ibuprofen with good stereoselectivities,50 but these chiral amines were prepared specifically for ibuprofen resolution and are thus unlikely to be economical for industrial production. 

The important advantage of a direct crystallization is that a chiral compound does not necessarily possess functional groups which are required for diastereomeric salt formation. The disadvantages include its limited applicability because less than 10% of all crystalline race-mates occur as a conglomerates, poor predictability and very sensitive dependence from the experimental conditions. Thus, as mentioned by some authors, even Louis Pasteur would not have succeeded with his very first enantioseparation had he performed the experiment with the mixed cesium-rubidium salt of tartaric acid at temperatures higher than 27 °C [4]. 

Juvancz, Z. Seres, G. Chiral selective chromatographic analysis. In CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, Kozma, D., Ed. CRC Press Boca Raton, Florida, USA. 

The mechanism of enantiomeric enrichment, by both chiral inclusion and diastereomeric salt formation, is a phenomenon that is not clearly understood. We believe that the analysis of selectivity profiles, together with detailed studies of the structural results, is a rich field which will... 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

Classic chiral resolution through diastereomeric salts formation plays a key role in the pharmaceutical industry... 

Among aU the possible areas discussed previously, the focus of this chapter will be on the two mainstream crystallization processes chiral separation through diastereomeric salts formation and chiral purification by crystallization. To complete the topic, chiral resolution by preference crystallization will also be reviewed and recent development in this area will be highlighted. 

FIGURE 56.5. Schematic diagram of workflow for chiral resolution screening hy diastereomeric salt formation. 

Industrial Application of Chiral Separation Through Diastereomeric Salt Formation... 

Abrecht et al. also reported on an efficient process for the manufacture of carmegliptin by employing a combined approach of diastereomeric salt formation and racemization (Scheme 56.4). In their work, diastereomeric salt screening was first performed on several intermediates and the most promising results were found with enamine rac-ll. Further screening of chiral acids showed that dibenzoyltartaric acid... 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

CE has been applied extensively for the separation of chiral compounds in chemical and pharmaceutical analysis.First chiral separations were reported by Gozel et al. who separated the enantiomers of some dansylated amino acids by using diastereomeric complex formation with Cu " -aspartame. Later, Tran et al. demonstrated that such a separation was also possible by derivatization of amino acids with L-Marfey s reagent. Nishi et al. were able to separate some chiral pharmaceutical compounds by using bile salts as chiral selectors and as micellar surfactants. However, it was not until Fanali first showed the utilization of cyclodextrins as chiral selectors that a boom in the number of applications was noted. Cyclodextrins are added to the buffer electrolyte and a chiral recognition may... 

Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases. Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring chiral bases. Simpler amines of synthetic origin, such as 2-amino-1-butanol, amphetamine, and 1-phenylethanamine, also can be used, but first they must be resolved themselves. 

Amines react with strong acids to form amine salts. The pKas of amine salts are related to the base strength of the corresponding amines. Alkylammonium salts have pKas of 9-10 while arylammonium salts have pKas of 4-5. The fact that these salts are usually water-soluble can be exploited in separating amines from neutral or acidic contaminants. Chiral amines can be used to resolve enantiomeric acids, through the formation of diastereomeric salts. 

An overwhelming majority of classic resolutions still involve the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 6.1). These chiral-resolving agents are relatively inexpensive and readily available in large quantities (Table 6.2). They also tend to form salts with good crystalline properties.8... 

Chiral acids or bases are tested for salt formation with the target racemate in a variety of solvents. The selected diastereomeric salt must crystallize well, and there must be an appreciable difference in solubility between the two diastereoisomers in an appropriate solvent. This type of selection process is still a matter of trial and error, although knowledge about the target racemate and the available chiral-resolving agents and experience with the art of crystallization does provide significant help.9-11... 

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