Crystallization, diastereomer method

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

Zirconocene dichloride 121 derived from (l-phenylethyl)cyclopentadienyl ligand is formed as a mixture of diastereomers from which the racemic form can be isolated by fractional crystallization. This complex was studied by X-ray diffraction methods and revealed a virtually chiral C2-symmetrical conformation in which the chiral ring-substituents are arranged in a synclinal position relative to the five-membered ring. It was proposed that this conformation is preserved in solution. Using 121 as catalyst the influence of double stereodifferentiation during isospecific polymerization of propylene (Eq. 32) was demonstrated for the first time [142],... 

A pair of enantiomers can be separated in several ways, of which conversion to diastereomers and separation of these by fractional crystallization is the most often used. In this method and in some of the others, both isomers can be recovered, but in some methods it is necessary to destroy one. 

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. 

Besides discovering this method of resolution, Pasteur also discovered the method of conversion to diastereomers and separation by fractional crystallization and the method of biochemical separation (and, by extension, kinetic resolution). 

Crystal structures are available for many (N)4Co-amino acid complexes (Table I). Many of the diastereomers (AS, AS) in the bis-en series have been resolved using classic crystallization (usually via bromocamphor sulfonate, arsenyl-, or antimonyl-tartrate salts) or ion exchange methods (Table II). Reversed-phase ion-pair HPLC, using aryl phosphate or aryl/alkyl sulfonate ion pairing reagents in MeOH/ H20 eluent, has allowed diastereomer separations to be carried out on analytical amounts (28) (Table II). 

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

Unfortunately, in the case of the ter /-butyl derivative, the diastereomers cannot be separated, however, after reduction to the allenic /3-alcohol, the (7 ,A/)-diastereomer of the triphenyl-methyl derivative was selectively crystallized from hexane. Although not enantiomerically pure, highly enriched chiral methyl-1,3-propanedial equivalents may be prepared on a preparative scale by this method. 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

Quite recently, new methods for stereocontrol in cyclizations of /V-acylami nomethyl ethers have been developed. N,0-acetals of type (19 Scheme 13) were prepared from the corresponding secondary allyl alcohol and the diastereomers were separated by chromatography and/or crystallization. Cyclization with mercury(II) salts and reduction of the organomercury intermediate proceeded with high stereocontrol exerted by the amidal stereogenic center, not the stereogenic center on the original alcohol.237 ... 

A combination of ( ) -/V- ben zy loxycarbon y I am i no acid (Z-amino acid) and ( )-ephedrine is a good example of one method of affording four diastereomers efficiently if seed crystals of less-soluble salt are obtained in advance (Figure 13). 

Distinction should be made at this time between diastereoisomers and enantiomers. The former are characterized by the presence of at least two closely associated asymmetric centers in the molecular structure, either of which can epimerize. Altogether then there are two pairs of enantiomers for a total of four stereochemically unique individuals. Diastereoisomers have different physical properties and as a result discriminations, and even separations, can be done relatively easily. Enantiomers on the other hand differ in only one physical property, i.e. the direction of rotation of polarized light. Reaction of an enantiomeric racemic mixture with a third chiral species will produce a mixture of diastereomers therefore facilitating their identification or their separation. Early examples of this were the separations done by fractional crystallization of salts produced by a derivatization reaction with, for example, the alkaloid (-)-brucine. Fractional crystallization would never seem to be an effective analytical method yet it was used with some success in a forensic sciences context to confirm the presence of (L)-cocaine by a carefully contrived microcrystalline test. The physical properties... 

Meso- and D,L-2,3-dimethoxy-2,3-diphenylsuccinonitrile 39 were obtained in a 1 1 ratio by a preparative dimerization procedure. Their configurations were assigned by crystal structure analysis 74). According to nmr both diastereomers have a configuration with the phenyl groups in the anti position. From a conformational analysis by the force field method it was concluded that these conformations remain the preferred ones also for the isolated molecules meso-39 was calculated to be 1.2 kcal mol-1... 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

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