Diastereomeric crystallization, production reactions

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],... 

The alkylation of enolates from some recently developed 2-oxazolidinone auxiliaries will be briefly discussed. The Diels-Alder reaction of the enantiomerically pure 3-(apocamphane-carbonyl)-2(3//)-oxazolone 13 with anthracene gives, diastereoselectively, a 97 3 ratio of diastereomeric adducts63. Recrystallization followed by removal of the apocamphanecarbonyl auxiliary and acylation gives the diastereomerically pure enantiomer 14 in good yield. Subsequent enolate formation and alkylation gives highly diastereoselective reactions and easily purified products due to the fact that the major product is readily crystallized. Thus alkylation... 

The use of tt trahydrofuryl derivatives for synthesis of racemic sugar derivatives has also been reported. It was found that iodine tris(tri-fluoroacetate) oxidizes tetrahydrofuryl trifluoroacetate, to yield a mixture of four diastereomeric 3-deoxypentofuranoses (413-416) in the ratios of 25 15 4 6. The main product, 3-deoxy-f/ireo-pentofuranose tris(trifluoroacetate) (413), readily crystallized out of the reaction mixture.269... 

Synthesis (Pohland, 1953 1955 1963 janssen and Karel (Janssen)1956 Sullivan et al., 1963) In the Grignard reaction of 3-dimethylamino-2-methyl-1-phenyl-propan-lone with benzylmagnesium chloride 4-dimethylamino-3-methyl-1,2-diphenyl-butan-2-ol is formed. The preferred product is the a-diastereomer(75 % a-form, 15 % p-form). The a-form crystallizes and the diastereomeric p-form remains in solution, because of its better solubility. Racemic resolution to obtain the analgetically (+) enantiomer can be achieved on the pure a-Grignard product via fractional crystallization of the salts with D-camphorsulfonic acid. Alternatively the resolution can be achieved by treating the racemic mannich product 3-dimethylamino-2-methyl-1-phenyl-propan-1-one with (-)-dibenzoyltartaric acid in acetone as solvent. 

There are two main routes for the production of D-amino acids chemical synthesis and enzymatic catalysis. As regards conventional chemical synthesis, unless asymmetrical starting compounds or catalysts are used, a mixture of the D- and L-stereoisomers is obtained in equal proportions. The racemic mixture is therefore optically inactive and the stereoisomers must be separated. The separation of the enantiomers by classical crystallization of diastereomeric salts is the most costly production step and in any case this method can only yield 50% of the desired enantiomer [3]. Enzymatic synthesis can solve the above problems, providing optical purity of the D-amino acid and a 100% yield, as well as mild, environment-friendly reaction conditions. 

The crystal structures of the 1,3-oxathiolane derivatives 50 and 51 have been reported <2005EJ01613>. The stereoselectivity of the reaction of benzo-l,3-dithiole A-oxide with various electrophiles has been examined, and the X-ray structures of a number of different diastereomeric products including 52-55 have been determined <2001T10365>. Finally, X-ray diffraction studies have been reported for substituted benzoxathiole 1,1-dioxides 56 and 57 <1996AP361>. 

Stereoselective catalysis in zeolites is still one of the ultimate goals in zeolite science. Earlier work in this field was summarized recently [4]. More recently, Mahrwald et al. [95] reported that the addition of aluminophosphate molecular sieves in the liquid phase alkylation of a-chiral benzaldehydes by butyllithium results in an increased proportion of the so-called Cram product in the diastereomeric mixture. It is argued that in this Grignard type reaction the adsorption of the reactants on the molecular sieves favors the attack at the sterically less hindered position of the molecule. This shape selectivity effect is even observed when the reactant is adsorbed at the outer crystal surface, as demonstrated for the case of the small-pore AIPO4-I7. 

A. Schwartz et al. synthesized several calcium channel blockers of the diltiazem group enantioselectively by using an auxiliary-induced asymmetric Darzens gtycidic ester condensation. The condensation of p-anisaldehyde with an enantiopure a-chloro ester afforded a pair of diastereomeric glycidic esters that possessed significantly different solubility. The major product was crystallized directly from the reaction mixture in 54% yield and in essentially enantiopure form. This major glycidic ester was then converted to diltiazem in a few more steps. 

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