Diastereomeric salts 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. 

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

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. 

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. 

Such racemic lactones as substituted -butyrolactones and -valerolactones are resolved by means of the diastereomeric salt formation or the diastereomeric amide formation method.24,25 For example, -decalactone is successfully resolved in the form of its diastereomeric amides derived from a-methylbenzylamine (Figure ll).24... 

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

It is widely known that 1-phenylethylamine (PEA) can be resolved with enantiopure mandelic acid (MA) via diastereomeric salt formation in industrial-scale production. However, the optical purity of PEA obtained was not stable (97-99% ee) whereas more than 99% ee has been steadily obtained in a laboratory. 

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. 

A similar approach was used in the synthesis of 3,4-diazphospholanes. In this case, the addition of a bisphosphine to a diazine gave predominantly the rac-form, which was further elaborated and resolved via diastereomeric salt formation (Scheme 13.3).12... 

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. 

Leusen et al. studied the crystal packing of ephedrine with several phosphoric acid stereoisomers to verify whether a relationship between enthalpy of formation and separation of enantiomers via diastereomeric salt formation exists.They considered four different force fields and determined that the CHARMM program, as implemented in QUANTA, was the best for their application. Their decision was based mainly on the knowledge that non-bonded cutoff distances are larger in CHARMM. A larger cutoff distance is necessary to account for the interaction between different hydrophobic layers in the crystal (interlayer distances of 14—16 A). These authors were unable to quantitatively determine the validity of their hypothesis, although qualitative explanations were derived for their observations. 

The first chemical enantioseparation has been also performed by Pasteur in 1853 [10]. Thereafter, the enantioseparation by the diastereomeric salt formation is most frequently applied to the separation of various racemates in laboratorial and industrial scales. 

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