Crystallization enantioenrichment

These add to aldehydes providing the homoaldol products 351 with high stereoselectivity following the expected stereochemical course, as could be elucidated by several X-ray crystal structure analyses under anomalous dispersion (equation 93). It is currently unknown why the yields are relatively low (21-35%), since we could not detect side products besides traces of starting material. The corresponding lithium-TMEDA complexes, after titanation, deliver good yields (71-79%). The homoaldol products are easily converted to enantioenriched bicyclic y-lactones of type 352 °. 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

In an effort to synthesize enantioenriched diamine complexes, prochiral diamines were mixed with K2 [( )-Me2-BINOLate] and palladium acetate resulting in the formation of the two diastereomers (Figure 9). These diastereomers were both C2-symmetric and assigned as the (R,R)/(R) and (S,S)/(R) configurations based on NMR and X-ray crystallographic studies. The major diastereomer was separated from the minor by crystallization. 

Many of the ligands that have been advocated for analogous reductions provide high enantioselectivity and some can provide good turnover numbers and frequencies [4, 5], Knowles catalyst often results in an ee of about 94-95% if the reaction mixture is monitored. However, crystallization of the N-acylamino acid product often results in enantioenrichment [10, 11]. In addition, hydrolysis of the amide to provide the amino acid itself also provides an opportunity for enantioenrichment (Fig. 3) [10]. 

Cytosine is an essentially flat molecule. The three-dimensional structure of cytosine crystals revealed helices. It is involved in the Genetic Code of 17 amino acids and controls essential features of living systems. Cytosine can form under prebiotic conditions. Nonchiral cytosine spontaneously forms highly enantioenriched crystals upon stirring during crystallization. Furthermore, chiral crystals of cytosine act as chiral initiator for asymmetric autocatalysis with amplification of chirality to provide for a virtually enantiopure compound (Fig. 3.5). 

The TBHP oxidation of trani-2-aroyl-3-arylacrylonitriles in m-xylene was catalysed by bis(3,5-dimethylphenyl)-pyrrolidin-2-yl-methanol. The resulting epoxide was obtained in yields up to 99% with complete control of diastereoselectivity and up to 84% ee. Highly enantioenriched epoxides (> 90% ee) were obtained after a single crystallization. (g)... 

This diagram indicates that 25 at greater than 10% ee should show enantioenrichment upon recrystallization. Using doped sanq>les we showed that while this is true, at least 40% ee is needed to get practical yields of 25 with high enantiopurity. Since CBS reduction of 22 gave 50% ee 24 and Mitsunobu conversion of 24 to 25 maintained this purity level, we would not need a lipase process to produce enantiopure 25. We could achieve this siinply by recrystallization. This was reduced to practice by carrying crude product from the CBS reduction into the Mitsunobu reaction, wWch after a reslurry (to remove triphenyl phosphine oxide and reduced diisopropylazodicarboxylate) and two crystallizations afforded 25 in 40% yield and >96% ee. 

The derivative 39 has also been reported to catalyze the aldol reaction between underivatized hydroxyacetone and activated benzaldehydes, affording the products with low diastereoselectivity and in moderate to high ee [109]. The best results were obtained with (R,R)-tartaric acid as co-catalyst and the absence of a solvent. In addition, a scalable procedure for the reaction with 4-nitrobenzaldehyde was developed involving a single crystallization step in order to obtain the enantiopure branched product of the aldol reaction. j n example of an intramolecular aldol reaction is provided by work of List and coworkers, who found that the formation of enantioenriched 5-substituted-3-methyl-2-cyclohexene-l-ones could be obtained from 4-substituted-2,6-hexadiones with 36 as the catalyst (Scheme 6.51) [llOj. 

Following asymmetric synthesis or chiral separation, further chiral purification is often needed to increase the enantiomeric excess (ee). This occurs often in the pharmaceutical industry because of the requirement for high purity of active pharmaceutical ingredients (APIs). Enantioenrichment by crystallization is therefore an integral part of chiral separation. 

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