Column chromatography enantiomer/diastereomer separation

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Diastereomers of nitro derivative of 45 (R = NO2) were separated on a silica gel column chromatography, and enantiomers of cis-3H,7H derivative of 45 (R = H) were separated by chiral HPLC (06USA2006/0004028). 

Corey has developed a method to resolve the ( )-5-HETE methyl ester enantiomers using the isocyanate of dehydroabietylamine 32 to form diastereomeric carbamates 33a-33b (Scheme 2.13). Separation of the diastereomers was achieved by column chromatography and the free alcohol was regenerated using trichlorosilane. The two examples given above constitute chemical resolution using external agents. 

The enantiomers of trans-2-ACPC were separated by Yamazaki et al. [78]. The Boc-protected racemic amino acid was acylated with / -(+)- -methylbenzylamine by use of a mixed anhydride (Scheme 5). The diastereomers 34 and 35 were separated by silica gel column chromatography after removal of the acid-labile Boc group. The absolute configuration was proved by X-ray diffraction of 35. The amino acid enantiomers 36 and 37 were obtained after strong acid treatment of 34 and 35, and anion-exchange desalting of the product [78]. 

The compound contains two chiral centers (C2, C4) and exists as a mixture of roughly equal proportions of two diastereomers 2RS,4RS 2RS,4SR), each with two enantiomers [61]. As a consequence, the three substituents of the tetrahydrofuran are equally distributed up or down versus the heterocyclic ring. Notably, the two diastereoisomers can be separated by column chromatography. 

One general scheme for separating enantiomers requires chemical conversion of a pair of enantiomers into two diastereomers with the aid of an enantiomerically pure chiral resolving agent. This chemical resolution is successful because the diastereomers thus formed are different compounds, have different physical properties, and often can be separated by physical means (most commonly fractional crystallization or column chromatography) and purified. The final step in this scheme for resolution is chemical conversion of the separated diastereomers back to the individual enantiomers and recovery of the chiral resolving agent. 

Once again, the ratio of diastereomers is the same as that of the original enantiomers. High-pressure liquid chromatography has been used in a similar manner and has wider applicability. The direct separation of enantiomers by gas or liquid chromatography on a chiral column has also been used to determine optical purity. " Other methods... 

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