Optical resolutions

Tartaric acid is noteworthy for a) the excellent way in which the majority of its salts Crystallise, and h) the frequent occurrence of salts having mixed cations. Examples of the latter are sodium potassium tartrate (or Rochelle salt), C4H40 NaK, used for the preparation of Fehling s solution (p. 525), sodium ammonium tartrate, C4H OaNaNH4, used by Pasteur for his early optical resolution experiments, and potassium antimonyl tartrate (or Tartar Emetic), C4H404K(Sb0). The latter is prepared by boiling a solution of potassium hydrogen tartrate (or cream of tartar ) with antimony trioxide,... 

Infrared instruments using a monochromator for wavelength selection are constructed using double-beam optics similar to that shown in Figure 10.26. Doublebeam optics are preferred over single-beam optics because the sources and detectors for infrared radiation are less stable than that for UV/Vis radiation. In addition, it is easier to correct for the absorption of infrared radiation by atmospheric CO2 and 1420 vapor when using double-beam optics. Resolutions of 1-3 cm are typical for most instruments. 

A particular point of interest included in these hehcal complexes concerns the chirality. The heUcates obtained from the achiral strands are a racemic mixture of left- and right-handed double heUces (Fig. 34) (202). This special mode of recognition where homochiral supramolecular entities, as a consequence of homochiral self-recognition, result from racemic components is known as optical self-resolution (203). It appears in certain cases from racemic solutions or melts (spontaneous resolution) and is often quoted as one of the possible sources of optical resolution in the biological world. On the other hand, the more commonly found process of heterochiral self-recognition gives rise to a racemic supramolecular assembly of enantio pairs (204). 

Microorganisms and their enzymes have been used to functionalize nonactivated carbon atoms, to introduce centers of chirahty into optically inactive substrates, and to carry out optical resolutions of racemic mixtures (1,2,37—42). Their utifity results from the abiUty of the microbes to elaborate both constitutive and inducible enzymes that possess broad substrate specificities and also remarkable regio- and stereospecificities. 

In many cases only the racemic mixtures of a-amino acids can be obtained through chemical synthesis. Therefore, optical resolution (42) is indispensable to get the optically active L- or D-forms in the production of expensive or uncommon amino acids. The optical resolution of amino acids can be done in two general ways physical or chemical methods which apply the stereospecific properties of amino acids, and biological or enzymatic methods which are based on the characteristic behavior of amino acids in living cells in the presence of enzymes. 

J. Jaques, A. CoUet, and S. WiUen, Enantiomers, Racemate, and Resolutions,]o m Wiley Sons, Inc., New York, 1981 The Chemical Society of Japan, eds., Kikan Kagaku Sosetsu (No. 6, Resolution of Optical Isomers), Gakkai Shuppan Senta, Tokyo, Japan, 1989 G. C. Barrett ia Ref. 1, Chapt. 10, pp. 338—353 S. Otsuka and T. Mukaiyama, Progress of ylsymmetric Synthesis and Optical Resolution (ia Japanese), Kagaku Dojia, Kyoto, Japan, 1982. 

Optical resolution is another method of producing (—)-mentho1 from racemic materials. (A)-Menthol is treated with optically active resolving agents to separate the (—)-mentho1 from the (+)-menthol, which is further processed by racemization over a nickel catalyst and recycled (156). 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Retention and stereoselectivity on the BSA columns can be changed by the use of additives to the aqueous mobile phase (30). Hydrophobic compounds generally are highly retained on the BSA, and a mobile-phase modifier such as 1-propanol can be added to obtain reasonable retention times. The retention and optical resolution of charged solutes such as carboxyUc acids or amines can be controlled by pH and ionic strength of the mobile phase. 

If very pure amine is desired the product described above is dissolved with 1.04 parts of crystalline oxalic acid in eight parts of hot water. After clarification with Norite, the filtered solution on cooling deposits crystals of the acid oxalate. About 5 g. of the salt remains in each 100 cc. of the mother liquor most of this can be obtained by evaporation and further crystallization. The amine is liberated from the pure oxalate with potassium hydroxide, distilled with steam, and purified as described above. When a known amount of amine is desired in water solution (as for optical resolution) a weighed amount of the (anhydrous) oxalate is decomposed and the amine is distilled quantitatively with steam. 

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). 

Optical resolution of the dithiirane 1-oxides 2 and 3 was accomplished by HPLC equipped with a chiral column (97T12203). Absolute configurations of 2a and 2b were determined by X-ray crystallography. Tire stereospecific isomerization (epimerrzation) of 2a to 3b and 2b to 3a was observed during the resolution study. 

Two pieces of chemical evidence support the three-membered ring formulation. The bifunctional oxazirane prepared from glyoxal, tert-butylamine, and peracetic acid (6) can be obtained in two crystalline isomeric forms. According to the three-membered ring formula there should be two asymmetric carbon atoms which should allow the existence of meso and racemic forms. A partial optical resolution was carried out with 2-7i-propyl-3-methyl-3-isobutyloxazirane. Brucine was oxidized to the N-oxide with excess of the oxazirane. It was found that the unused oxazirane was optically active. 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

Negawa M., Shoji F. (1992) Optical Resolution by Simulated Moving-Bed Adsorption Technology, J. Chromatogr. 590 113-117. 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

The optical resolution of the chemically synthesised N-acetyl-DL-phenylalanine by an acylase enzyme is given in reaction 4 (Figure 8.6). A selective hydrolysis of N-acetyl-L-phenylalanine is performed. 

The Japanese firm Tanabe Inc Ltd has been operating, since 1969, the optical resolution of DL-amino acids using aminoacylase. The prindple is based on the asymmetrical hydrolysis of N-acyl-DL-amino add by amino acylase which gives the L-amino add and the unhydrolysed acyl-D-amino add. 

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