Optical resolution continued

Crystallization continues to be the most widely used method of separating or resolving enantiomers (optical resolutions). The manufacture of chemicals and pharmaceuticals as purified optical isomers, or enantiomers, has taken on a pivotal importance in the pharmaceutical, agricultural and fine chemicals industries over the past 15-20 years. Crystallization has been and continues to be the most widely used method of separating or resolving enantiomers (optical resolutions), and is particularly well suited to separations at large scale in manufacturing processes (Jacques etal., 1981 Roth etai, 1988 Wood, 1997 Cains, 1999). 

The continued downscaling of transistor sizes is essential to the continuation of Moore s law. Lithography has always been a limiting factor. Optical lithography is limited by the optical resolution... 

Preferential crystallisation is one option for optical resolution on a manufacmr-ing scale. Online polarimetry and refractometry have been used to d3mamically optimise the process for resolution of DL-threonine in aqueous solution by variation of process parameters such as degree of supersaturation, seed quantity, initial enantiomeric excess and scale [148]. The method is claimed to be suitable for control of quasi-continuous processes. 

Optical resolution of enantiomeric mixtures which have been obtained by short chemical syntheses continues to be the method of choice for a wide variety of compounds. For instance, the industrial synthesis of (-)-menthol starts from thymol which is catalytically hydrogenated to furnish all four diastereomers in racemic form. 

In order to increase the efficiency of biocatalytic transformations conducted under continuous flow conditions, Honda et al. (2006, 2007) reported an integrated microfluidic system, consisting of an immobilized enzymatic microreactor and an in-line liquid-liquid extraction device, capable of achieving the optical resolution of racemic amino acids under continuous flow whilst enabling efficient recycle of the enzyme. As Scheme 42 illustrates, the first step of the optical resolution was an enzyme-catalyzed enantioselective hydrolysis of a racemic mixture of acetyl-D,L-phenylalanine to afford L-phenylalanine 157 (99.2-99.9% ee) and unreacted acetyl-D-phenylalanine 158. Acidification of the reaction products, prior to the addition of EtOAc, enabled efficient continuous extraction of L-phenylalanine 157 into the aqueous stream, whilst acetyl-D-phenylalanine 158 remained in the organic fraction (84—92% efficiency). Employing the optimal reaction conditions of 0.5 gl min 1 for the enzymatic reaction and 2.0 gl min-1 for the liquid-liquid extraction, the authors were able to resolve 240 nmol h-1 of the racemate. 

Scheme 42 Continuous flow optical resolution of acetyl-D,L-phenylalanine using an immobilized aminoacylase enzyme.

To continue the synthesis (Figure 2.52), (-)-ketone E was treated with methylene triphenylphosphorane to give F. Deprotection followed by oxidation of F afforded the naturally occurring (+)-mispyric acid (59), whose absolute configuration was determined as 25,45. Similarly, the other diastereomer G obtained by optical resolution afforded unnatural (2R,4R)-(—)-59. ... 

Scheme 6.38 Illustration of the optical resolution of rac-acetylphenylalanine conducted under continuous flow.

Between 1954 and 1969 this enzymatic resolution method had been employed by Tanabe SeiycUcu Co., Ltd. for the production of several L-amino acids. In the 1960s we extensively studied the immobilization of aminoacylase for continuous optical resolution... 

T. Tosa, T. Mori, N. Fuse and 1. Chibata, Studies on Continuous Enzyme Reactions. IV. Preparation of a DEAE-Sephadex-Aminoacylase Column and Continous Optical Resolution of Acyl-DL-Amino Acids, Biotechnol. Bioeng.,... 

Cram and co-workers have continued their elegant work on host-guest com-plexation and particularly on chiral recognition in solution. The syntheses of a large number of stereoisomeric macrocyclic polyethers that contain chiral units have been described. The general shape is as shown, (10), giving a chiral cavity. They have been used for optical resolution of racemic alkyl ammonium salts and the catalytic reduction of enantiomers. ... 

Active immobilized enzyme for the continuous optical resolution of D,L-lysine methyl ester... 

Tosa, T., Mori, T., Fuse, N., and Chibata, L, "Studies on continuous enzyme reaction. IV. Preparation of a DEAE-sephadex-aminoacylase column and continuous optical resolution of acyl-DL-amino acids." Biotechnol. Bioeng., 9,603-615 (1967). 

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