Optical resolution production

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. 

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. 

One of the most important characteristics of IL is its wide temperature range for the liquid phase with no vapor pressure, so next we tested the lipase-catalyzed reaction under reduced pressure. It is known that usual methyl esters are not suitable for lipase-catalyzed transesterification as acyl donors because reverse reaction with produced methanol takes place. However, we can avoid such difficulty when the reaction is carried out under reduced pressure even if methyl esters are used as the acyl donor, because the produced methanol is removed immediately from the reaction mixture and thus the reaction equilibrium goes through to produce the desired product. To realize this idea, proper choice of the acyl donor ester was very important. The desired reaction was accomplished using methyl phenylth-ioacetate as acyl donor. Various methyl esters can also be used as acyl donor for these reactions methyl nonanoate was also recommended and efficient optical resolution was accomplished. Using our system, we demonstrated the completely recyclable use of lipase. The transesterification took place smoothly under reduced pressure at 10 Torr at 40°C when 0.5 equivalent of methyl phenylthioacetate was used as acyl donor, and we were able to obtain this compound in optically pure form. Five repetitions of this process showed no drop in the reaction rate (Fig. 4). Recently Kato reported nice additional examples of lipase-catalyzed reaction based on the same idea that CAL-B-catalyzed esterification or amidation of carboxylic acid was accomplished under reduced pressure conditions. ... 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

More recently, Tietze s group adapted the well-known domino Knoevenagel-Hetero-Diels-Alder MCR to the efficient synthesis of the deoxyaminosugar (-l-)-D-Forosamine starting from nitroacetone, aqueous formaline, and ethyl vinyl ether (Scheme 65) [169]. The expected racemic dihydropyran was obtained in 37% yield and further transformed to the optically pure product in eight steps in chiral resolution with chiral HPLC. 

A contemporaneous study on the same subject utilized a chemical correlation method where (—)-A-benzylargemonine chloride, obtained by sequential optical resolution and quatemization of ( )-7V-methylpavine (5), underwent a multistep degradative process to furnish (-)-A,A-dimethyl-di-H-propyl aspartate. Comparison of this final product with L-aspartic acid of known chirality led to the absolute configuration of (—)-5 (115,158). (—)-Eschscholtzine (9) was assigned the same absolute configuration by correlation of its ORD curve and optical rotation with those of (—)-argemonine (775). 

Contrary to the optical resolutions described in Sections 2.1.1.-2.1.3., which depend on the solubility or chromatographic properties ( Thermodynamic resolution ), the kinetic resolution rests on rate differences shown by the enantiomers when reacted with an optically active reagent. In the ideal case, only one enantiomer is converted into the envisaged product and the other enantiomer is unchanged. In this way, optical resolution is reduced to the more simple separation of two different reaction products. In practice, only two methods of kinetic resolution are reasonably general and reliable the Sharpless epoxidation of allylic alcohols and the enzymatic transesterification of racemic alcohols or carboxylic acids. 

Despite its efficiency in numerous cases optical resolution is by no means a trivial operation. In each case the optimum method has to be found by laborious trial and error procedures the optical purity of the material has to be secured and its absolute configuration has to be established before the compound can be used in a synthetic sequence. These drawbacks of optical resolution led chemists to start their syntheses from optically active natural products (the so-called chiral carbon pool ). A variety of suitable ex-chiral-pool compounds including carbohydrates, amino acids, hydroxy acids, and terpenoids are shown. 

Optical resolution of the dithiol The problem of optical resolution of racemic disulfides has been successfully tackled (77JOC925). The bis-thiol (128) was reacted with a chiral bis-sulfenyl chloride, the resultant mixture of diastereomers separated, and the product reconverted to the starting material by NaBH4 reduction. Subsequent iodine oxidation gave the chiral epidisulfides (Scheme 40). 

Problem 5.23 Answer True or False to each of the following statements and explain your choice. ( ) There are two broad classes of stereoisomers, (b) Achiral molecules cannot possess chiral centers, (c) A reaction catalyzed by an enzyme always gives an optically active product, (d) Racemization of an enantiomer must result in the breaking of at least one bond to the chiral center, (e) An attempted resolution can distinguish a racemate from a meso compound. <... 

Enzyme-based processes for the resolution of chiral amines have been widely reported [2, 3] and are used in the manufacture of pharmaceuticals, for example, BASF s process for chiral benzylic amine intermediates. Scheme 13.1 [4]. The methods used are enantioselective hydrolysis of an amide and enantioselective synthesis of an amide, both of which are kinetic resolutions. For high optical purity products the processes depend upon a large difference in the catalyzed reaction rates of each enantiomer. 

Fu and co-workers have also applied their planar chiral catalyst 9 to dynamic kinetic resolution of racemic azalactones [50], Azalactones 54 racemize under the reaction conditions, allowing all material to be funneled to optically pure product. Protected (S)-amino acids 55 are formed in excellent yields with moderate enantioselectivities (83-98% yield, 44-61% ee, see Scheme 11). Use of more sterically encumbered alcohols as nucleophiles increases enantioselectivities but reaction rates become slower. 

V-hexadecyltrimethylammonium bromide as a surfactant helped to prevent coagulation of the two substrates in aqueous suspension. It is interesting that, although bulky but small molecules of epoxides (8) easily penetrated the void space in crystals of 3b-c and underwent optical resolution, compounds 5a-b (with long aliphatic chains) and 7b did not form inclusion compounds. The application of suspension conditions resulted in a very efficient optical resolution, sometimes better than that achieved by the classic formation of complexes by recrystallization of host and guest from a common solvent. For comparison, optical resolution of 4c by co-crystallization with the host 6 after two recrystallizations gave the crude product at 100 % ee but only 35 % yield [21], in comparison with 57 % and 85 %, respectively, in hexane and water suspension [20],... 

The design of host compounds for optical resolution has received much attention. Toda [23,24] has reviewed the subject, and has used a number of novel techniques to effect efficient optical separation. He has demonstrated the possibility of resolving a racemic oil by stirring in a water suspension of a chiral host [25], and has applied fractional distillation techniques at different temperatures to separate a variety of racemic guests in the presence of chiral hosts [26]. An overview of the industrial applications and production of optically active materials is given in the book Chirality in Industry [27],... 

Optical resolution of some hydrocarbonds and halogeno compounds by inclusion complexation with the chiral host (9a) has been accomplished.11,12 Preparation of optically active hydrocarbons is not easy and only a few example of the preparation of optically active hydrocarbons have been reported. For example, optically active 3-phenylcyclohexene has been derived from tartaric acid through eight synthetic steps.11 Although one-step synthesis of optically active 3-methylcyclohexene from 2-cyclo- hexanol by the Grignard reaction using chiral nickel complex as a catalyst has been reported, the enantiomeric purity of the product is low, 15.9%.11 In this section, much more fruitful results by our inclusion method are shown. 

Although some kinds of optically active compounds can be prepared by an asymmetric synthesis using a chiral catalyst, this method is not applicable for preparation of all kinds of compounds. Furthermore, optical yields of the product are not always very high. On the contrary, optical resolution method by inclusion complexation with a chiral host is applicable to various kinds of guest compounds as described in this chapter. When optically pure product cannot be obtained by one resolution procedure, perfect resolution can be accomplished by repeating the process, although asymmetric synthetic process cannot be repeated. Especially, optical resolutions by inclusion complexation with a chiral host in a water suspension medium and by fractional distillation in the presence of a chiral host are valuable as green and sustainable processes. 

Optical resolutions of two a-alkoxycarboxylic acids (3a and 3b, Scheme 3) were accomplished with the neutral calcium salt of DBTA (DBTACa) in aqueous ethanol solution. [24] Preparation of the diastereoisomers is quite simple a stoichiometric mixture of DBTA monohydrate and calcium oxide had to solve in hot aqueous ethanol to form DBTACa salt and then racemic acid (3a or 3b) had to add into it. On cooling [Ca(H20)(f -3a)]DBTA.H20 or [Ca(H20)(S-3b)]DBTA.H20 cystallised. Free (S)-3a or (R)-3b was obtained from the corresponding filtrate. In the schemes and the formulas (6) or (R) stands for showing the configuration of the of the major enantiomer in the product. For example, (.S )-3a means that the isolated material contained the 6-isomer in excess, ee values are given in the Tables. 

Figure 9. Optical resolution of 3-phenylglycidic acid methyl ester (MPGM) by lipase and separation of the optically active product, (-)-MPGM, from unnecessary acid using Hollow-Fiber membrane reactor...

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