Enantiomers chemical resolution

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). 

D-Pantolactone and L-pantolactone are used as chiral intermediates in chemical synthesis, whereas pantoic acid is used as a vitamin B2 complex. All can be obtained from racemic mixtures by consecutive enzymatic hydrolysis and extraction. Subsequently, the desired hydrolysed enantiomer is lactonized, extracted and crystallized (Figure 4.6). The nondesired enantiomer is reracemized and recycled into the plug-flow reactor [33,34]. Herewith, a conversion of 90-95% is reached, meaning that the resolution of racemic mixtures is an alternative to a possible chiral synthesis. The applied y-lactonase from Fusarium oxysporum in the form of resting whole cells immobilized in calcium alginate beads retains more than 90% of its initial activity even after 180 days of continuous use. The biotransformation yielding D-pantolactone in a fixed-bed reactor skips several steps here that are necessary in the chemical resolution. Hence, the illustrated process carried out by Fuji Chemical Industries Co., Ltd is an elegant way for resolution of racemic mixtures. 

In an effort to synthesize the chiral alkaloid, optically active 37 was prepared by chemical resolution, but both enantimoers were partially racemized when reacted with potassium amide in ammonia. Efforts to resolve ( )-39 failed to give the desired enantiomer. 

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Cyclodextrins (CDs) are chiral compounds which interact with enantiomers via diastereomeric interactions. The separation is achieved because of the difference in stabilities of the resulting diastereomeric complexes formed between each enantiomer and the CD. In the first CEC experiments incorporating CDs, di-methylpolysiloxane containing chemically bonded permethylated (3- or y-CD (Chirasil-DEX) was chemically bonded to the inner walls of fused silica capillaries [139,140]. Electoosmotic flow is generated in these capillaries in the same manner as in fused silica capillaries. The Chirasil-DEX does not mask all the silanol groups, so while EOF is decreased, it is not entirely diminished by the coating. Since that time, CDs or CD derivatives have been bonded to silica particles which were then packed into capillaries, and the CD has been incorporated into continuous polymer beds known as monoliths. Table 3 shows some different CSPs, enantiomers separated, resolution, and the number of theoretical plates per meter. 

Chemical resolution of tetrahydroharmine (4 in Fig. 8) with camphorsul-fonic acid afforded the optically pure enantiomers (4a,b) (32). Fragmen-... 

An enantioselective synthesis of TIQ-1-carboxylic acids 91a,b has recently been reported (279). Hydrolysis of the optically active methyl ether enantiomer of hydantoin 103 was accomplished by 20% sodium hydroxide in refluxing methyl cellosolve and led to the dimethyl ether analog of 91a, which was used to establish the absolute configuration of the products. Amino acids 91a,b have also been prepared by chemical resolution of the N,0-benzylated acid 108 with optically active 1-phenylethylamines. Catalytic debenzylation of enantiomer 109a gave... 

If an ordinary chemical synthesis yields a racemic modification, and if this cannot be separated by our usual methods of distillation, crystallization, etc., how do we know that the product obtained is a racemic modification It is optically inactive how do we know that it is actually made up of a mixture of two optically active substances The separation of enantiomers (called resolution) can be accomplished by special methods these involve the use of optically active reagents, and will be discussed later (Sec. 7.9). 

Corey has developed a method to resolve the ( )-5-HETE methyl ester enantiomers using the isocyanate of dehydroabietylamine 32 to form diastereomeric carbamates 33a-33b (Scheme 2.13). Separation of the diastereomers was achieved by column chromatography and the free alcohol was regenerated using trichlorosilane. The two examples given above constitute chemical resolution using external agents. 

Okamoto, Y, Ikai, T. (2008) Chiral HPLC for efficient resolution of enantiomers. Chemical Society Reviews, 37, 2593-2608. 

One general scheme for separating enantiomers requires chemical conversion of a pair of enantiomers into two diastereomers with the aid of an enantiomerically pure chiral resolving agent. This chemical resolution is successful because the diastereomers thus formed are different compounds, have different physical properties, and often can be separated by physical means (most commonly fractional crystallization or column chromatography) and purified. The final step in this scheme for resolution is chemical conversion of the separated diastereomers back to the individual enantiomers and recovery of the chiral resolving agent. 

Obtaining enantiomerically pure samples of chiral molecules is extremely important when synthesizing pharmaceuticals. When a synthesis yields a mixture of enantiomers, the enantiomers may be separated from each other using a process called chemical resolution. For a discussion of this method, go to the Focus On feature for Chapter 26, Chemical Resolution of Enantiomers, on the MasteringChemistry site. 

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. 

Most methods for the resolution of enantiomers contained in a reaction mixture consist in the conversion of the compounds into stable or transient diastereoisomers and separation of the latter on the basis of their different physico-chemical properties. 

For most chemical transformations, especially for industrial applications, the yield of 50% cannot be accepted. Since each enantiomer constitutes only 50% of the racemic mixture, the best way to increase the yield of the desired enantiomer is racemization of the unwanted one (Scheme 5.7). This reaction mustproceed simultaneously with the enzymatic kinetic resolution. In order to indicate the dynamic character of such processes, the term dynamic kinetic resolution has been introduced. 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

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