Resolution 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. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

New Industrial-scale Resolution by Diastereomeric Salt Formation Utilizing Molecular Recognition Mechanism... 

Success or failure in resolution by the diastereomeric salt formation method is not determined only by the molecular structures of compounds used and physical properties of the salt crystals but also by the resolution environment such as solvent. Therefore, the proposed working hypothesis may not always be effective in all combinations of the resolution system. However, this idea will be helpful in minimizing tedious trial error experimental efforts in the laboratory. 

PROSPECT OF INDUSTRIAL RESOLUTION BY DIASTEREOMERIC SALT FORMATION... 

Kozma, D. Ed., (2002) CRC handbook of Optical Resolution via Diastereomeric salt Formation, CRC Press, Boca Raton Florida. 

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. 

Sakai, K., Sakurai, R., Yuzawa, A. and Hirayama, N. (2003) Practical continuous resolution of a-amino-E-caprolactam by diastereomeric salt formation using a single resolving agent with a solvent switch method, Tetrahedron Asymmetry 14, 3713-3718. 

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. 

CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, Kozma, D., Ed., CRC Press Boca Raton, 2002. 

H. Hiramatsu, K. Okamura, 1. Tsujioka, S.-l. Yamada, R. Yoshioka, Crystal structure-solubility relationships in optical resolution by diastereomeric salt formation of DL-phenylglycine with (lS)-(+)-camphor-10-sulfonic acid, J. Chem. Soc. Perkin Trans. 2 (2000) 2121-2128. 

If the decision is made to use a resolution rather than a synthetic route, the question then arises of whether this should be a classical crystallization, a kinetic resolution, or a chromatographic separation. If the compound either contains ionic groups (and a suitable reagent for diastereomeric salt formation is inexpensive and available) or even better, if it crystallizes as a conglomerate, then crystallization may seem the most suitable technique. 

A short three-step synthesis has been developed for the -N(Et)2 derivative 291. (—)-N-Boc-0-benzyl (S) tyrosine among 63 optically pure resolving agents was found suitable for a large-scale resolution via diastereomeric salt formation. The (S) configuration was assigned to the (—) form by X-ray of the diastereomeric complex (03JOC7379). 

If alkaloids are mentioned in connection with racemate resolution, one is usually inclined to think at first of the classical methods of resolution using diastereomeric salt formation by combination of the alkaloid base and an organic acid. 

Kaboudin B, Alaie S, Yokomatsu T (2011) Resolution of enantiomers of [a-hydroxy-(o-chlorophenyl)methyl]phosphinic acid via diastereomeric salt formation with enantiopure 1-phenylethylamines. Tetrahedron Asymmetry 22 1813-1816... 

Diastereomeric relationships provide the basis on which a number of important processes depend. Resolution is the separation of a mixture containing equal quantities of enantiomers (termed a racemate or racemic mixture) into its components. Separation is ordinarily effected by converting the mixture of enantiomers into a mixture of diastereomers by treatment with an optically active reagent (the resolving agent). Since the diastereomers will have different physical and chemical properties, they can be separated by conventional methods and the enantiomers regenerated in a subsequent step. An example of this method is shown in Scheme 2.2 for the resolution of a racemic carboxylic acid by way of diastereomeric salt formation using an optically active amine. The / -acid-/ -amine and S-acid-/ -amine salts are separated by fractional recrystallization, and the resolved carboxylic acid is freed from its amine salt by acidification. 

The method relies on the p and the n salts having different solubilities and they must not form solid solutions or double salts. The more insoluble salt is allowed to precipitate, is filtered, and the purified acid is recovered by adding mineral acid. Enantiomeric resolution via diastereomeric salt formation is well established and many systems have been studied and cataloged. ... 

Racemate resolution methods via diastereomeric salt formation may be classified into the following categories 1) resolution by formation of noncovalent diastereomers (diastereomeric salt formation, diastereomeric complex formation, etc.) and 2) resolution by formation of covalent diastereomers. 

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... 

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