Of racemic mixtures

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. 

Optically active thiiranes have been obtained by resolution of racemic mixtures by chiral tri-o-thymotide. The dextrorotatory thymotide prefers the (5,5)-enantiomer of 2,3-dimethylthiirane which forms a 2 1 host guest complex. A 30% enantiomeric excess of (5,5)-(—)-2,3-dimethylthiirane is obtained (80JA1157). 

A better solution for preparative columns is the development of separation media with substantially increased selectivities. This approach allows the use of shorter columns with smaller number of theoretical plates. Ultimately, it may even lead to a batch process in which one enantiomer is adsorbed selectively by the sorbent while the other remains in the solution and can be removed by filtration (single plate separation). Higher selectivities also allow overloading of the column. Therefore, much larger quantities of racemic mixtures can be separated in a single run, thus increasing the throughput of the separation unit. Operation under these overload conditions would not be possible on low selectivity columns without total loss of resolution. 

At present moment, no generally feasible method exists for the large-scale production of optically pure products. Although for the separation of virtually every racemic mixture an analytical method is available (gas chromatography, liquid chromatography or capillary electrophoresis), this is not the case for the separation of racemic mixtures on an industrial scale. The most widely applied method for the separation of racemic mixtures is diastereomeric salt crystallization [1]. However, this usually requires many steps, making the process complicated and inducing considerable losses of valuable product. In order to avoid the problems associated with diastereomeric salt crystallization, membrane-based processes may be considered as a viable alternative. 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

Fig. 5-19. Cascaded system for countercurrent 99 %+ separation of racemic mixtures [75].

The cyclic steady state SMB performance is characterized by four parameters purity, recovery, solvent consumption, and adsorbent productivity. Extract (raffinate) purity is the ratio between the concentration of the more retained component (less retained) and the total concentration of the two species in the extract (raffinate). The recovery is the amount of the target species obtained in the desired product stream per total amount of the same species fed into the system. Solvent consumption is the total amount of solvent used (in eluent and feed) per unit of racemic amount treated. Productivity is the amount of racemic mixture treated per volume of adsorbent bed and per unit of time. 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

The steroid ring structure is complex and contains many chiral carbons (for example at positions 5, 8, 9,10,13,14 and 17) thus many optical isomers are possible. (The actual number of optical isomers is given by 2" where n = the number of chiral carbons). From your knowledge of biochemistry you should have realised that only one of these optical isomers is likely to be biologically active. Synthesis of such a complex chemical structure to produce a single isomeric form is extremely difficult, especially when it is realised that many chemical reactions lead to the formation of racemic mixtures. Thus, for complete chemical synthesis, we must anticipate that... 

Before we leave the enzymatic modification of terpenoids, we should point out that enzymes are also employed to resolve racemic mixtures of terpenoids. The principles of Bus are similar to those employed in the resolution of racemic mixtures of amino acids (see Chapter 8). 

With this single example we have in tact described two uses of enzymes in alicyclic chemistry, the reduction of ketone groups and the resolution of racemic mixtures. 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

Conduritols and inositols are cyclic polyalcohols with significant biological activity. The presence of four stereogenic centers in the stmcture of conduritols allows the existence of 10 stereoisomers. Enzymatic methods have been reported for the resolution of racemic mixtures or the desymmetrization of meso-conduritols. For example, Mucor miehei lipase (MML) showed enantiomeric discrimination between all-(R) and all-(S) stereoisomers ofconduritol E tetraacetate (Figure 6.52). Alcoholysis resulted in the removal of the four acetyl groups ofthe all-(R) enantiomer whereas the all-(S) enantiomer was recovered [141]. 

Both the alkyl and the acyl have two asymmetric centers the iron and the )3-carbon. Accordingly, each composition exists as a pair of racemic mixtures. When the two diastereomeric racemic mixtures of the acyl are separately subjected to the decarbonylation in Eq. (54), only partial (<50%) epimerization is observed by NMR spectroscopy. This indicates that in the reactive intermediate, presumably three-coordinate CpFe(PPh3)COCH2-CH(Me)Ph, the iron substantially retains its asymmetry, and is therefore not planar. 

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

We monitored the percent conversion of epichlorohydrin and enantiomeric excess of the recovered S-epichlorohydrin with time by using GC-FID. Approximately 54% conversion and >99% ee were obtained in about 4 h reaction time. After 4 h, the epichlorohydrin was removed under vacuum at room temperature and diol was removed at a temperature of 329 K. The recovered catalyst was further treated in the HKR of racemic mixture of fresh epichlorohydrin. In the second run, we observed a decrease in the conversion and ee compared to the fresh catalyst. The Co-salen was again recovered after the second run by removing all the products under vacuum and recycled two more times. With each subsequent HKR reaction, the conversion and ee were found to decrease with time (22). Table 43.1 summarizes the initial rates and ee s determined from the four runs without intermediate catalyst regeneration. Interestingly, the initial catalyst activity was resumed when the catalyst was regenerated with acetic acid prior to recycle. 

The methods which have been used to determine the configurational stability of organotin compounds and those which have successfully been applied to synthesize such optically active molecules are reviewed, including the chromatographic resolution of racemic mixtures. 

In carrying out kinetic resolution, these in the standard approach are limited to 50% yield regarding the racemate. However, different approaches were developed [28] to overcome this limitation. The classical standard solution is to reracemize the unconverted enantiomer. A more advanced solution is the establishment of a dynamic kinetic resolution that has considerably expanded the synthetic scope of chemical processes. Here, the unconverted enantiomer is, in contrast to the latter method, racemized in situ. A great number of novel enzymatic methods have been developed [29]. Within this chapter, process solutions for enzymatic resolutions of racemic mixtures will be highlighted. 

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. 

A closer similarity exists between the C2-symmetric octahedral isospecific model sites, which have been proposed for the heterogeneous polymerization catalysts,13 15 and some slightly distorted octahedral metal complexes, including bidentate or tetradentate ligands, which have recently been described as active in isospecific olefin polymerization in the presence of MAO.128-130 In fact, all these catalytic systems can be described in terms of racemic mixtures of active species with A or A chiralities. 

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