Enantiomers enantiomeric excess

The mixtures of racemic acids and chiral bases were extracted with supercritical carbon dioxide. The extracts were collected as separate samples successively in time. Each of them was examined separately. The results of ibuprofen extraction are presented in Figure 3a. The extracts contained the (+)-enantiomer in 20-40 % optical purity while the raffinate was rich in (-)-enantiomer (enantiomeric excess= 44 7 %). Further purification of the extracts can be carried out by multiple extraction (Figure 3b). We have succeed to separate the cis-chrysanthemic acid mixture in a single extraction step with excellent enantiomeric excess for the (-)-enantiomer (greater than 95 %). The enantiomeric excess of the (+)-enantiomer was 90 % after three subsequent extraction. The resolution of ibuprofen was less efficient The... 

Compounds Enriched Enantiomer Enantiomeric Excess [%] Manzanilla Oloroso ... 

The enantiomeric excess of 3.10c has been determined by HPLC analysis using a Daicel Chiracel OD column and eluting with a 60 / 1 (v/v) hexane(HPLC-grade) / 2-propanol(p.a.) mixture. At a flow of 1 ml per minute the rentention times for the different isomers of 3.10c were 6.3 min. (exo, major enantiomer) 7.1 min. (exo, minor enantiomer) 7.7 min. (endo, major enantiomer) 10.7 min. (endo, minor enantiomer). 

The enantiomeric excess (ee) is defined as %(major enantiomer) - %(minor enantiomer). 

Mixtures containing equal quantities of enantiomers are called racemic mixtures Racemic mixtures are optically inactive Conversely when one enantiomer is present m excess a net rotation of the plane of polarization is observed At the limit where all the molecules are of the same handedness we say the substance is optically pure Optical purity or percent enantiomeric excess is defined as... 

Enantiomeric excess (Section 7 4) Difference between the per centage of the major enantiomer present in a mixture and the percentage of its mirror image An optically pure material has an enantiomenc excess of 100% A racemic mixture has an enantiomeric excess of zero... 

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

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). 

Figure 2.24, Determination of the enantiomeric excess of 1-phenylethanol [30, 0.1 mmol in 0.3 ml CDCI3, 25 °C] by addition of the chiral praseodymium chelate 29b (0.1 mmol), (a, b) H NMR spectra (400 MHz), (a) without and (b) with the shift reagent 29b. (c, d) C NMR spectra (100 MHz), (c) without and (d) with the shift reagent 29b. In the C NMR spectrum (d) only the C-a atoms of enantiomers 30R and 30S are resolved. The H and C signals of the phenyl residues are not shifted these are not shown for reasons of space. The evaluation of the integrals gives 73 % R and 27 % S, i.e. an enantiomeric excess (ee) of 46 %...

Asymmetric epoxidation of racemic unsaturated fluoro alcohols by the chiral Sharpless reagent can be exploited for kmetic resolution of enantiomers The recovered stereoisomer has 14-98% enantiomeric excess [55] (equation 50)... 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Wide variations in stereoselectivity are possible between the and Z isomers (79). In hydrogenation of several ( )- and (Z)-a-acylaminocinnamic acid derivatives, the Z isomers gave greater enantiomeric excesses at 15-100 times the rate of reduction of the isomer, but in all cases the 5 enantiomer was formed in greater excess (//7). The greater effectiveness of Z-olefins is general If8). 

Since the first separation of enantiomers by SMB chromatography, described in 1992 [95], the technique has been shown to be a perfect alternative for preparative chiral resolutions [10, 21, 96, 97]. Although the initial investment in the instrumentation is quite high - and often prohibitive for small companies - the savings in solvent consumption and human power, as well as the increase in productivity, result in reduced production costs [21, 94, 98]. Therefore, the technique would be specially suitable when large-scale productions (>100 g) of pure enantiomers are needed. Despite the fact that SMB can produce enantiomers at very high enantiomeric excesses, it is sometimes convenient to couple it with another separation... 

Although some applications for preparative-scale separations have already been reported [132] and the first commercial systems are being developed [137, 138], examples in the field of the resolution of enantiomers are still rare. The first preparative chiral separation published was performed with a CSP derived from (S -N-(3,5-dinitrobenzoyl)tyrosine covalently bonded to y-mercaptopropyl silica gel [21]. A productivity of 510 mg/h with an enantiomeric excess higher than 95% was achieved for 6 (Fig. 1-3). 

Several chiral selectors have been used in the separation of enantiomers by distillation [198]. Among them, the bisalcohol 8 (Fig. 1-6) has permitted obtainment of the ketone (+)-9 with an enantiomeric excess of 95 %. This example shows the feasibility of the process even though, in this particular case, the price of the chiral selector might prohibit scale-up of the separation. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

The enantiomeric excess which is achieved for a given ally carbamate is independent of the carbonyl compound used it reflects the skill of the operator in the crystallization procedure. The high degree of reagent-controlled chirality transfer is also obvious from the reaction with either enantiomer of 2-benzyloxypropanal103a 107a. 

For the determination of the enantiomeric excess. 23 mg of the mi-hydroxy ester (containing 2 5% //-product) and 9 mg of tris[3-(heptafluoropropylhydroxymethylene)-a-camphorato]europium are dissolved in 0.5 mL of CDC13. The ec is calculated from the peak heights and areas of the resolved doublets, due to the methyl groups attached to C-2. of the minor (f) 1.74) and major (<5 1.98) enantiomers. 

The submitters report obtaining the product in 99% yield. The enantiomeric excess of the Mosher ester of 3 was measured to be 98% using a Chiralcel OD column (40% 2-propanol/hexane). This optical purity measurement substantiated the optical purity assessment made by 111 NMR studies of 3 and racemic 3 prepared using a different method3. Addition of the chiral shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III) resulted in clear resolution of the respective aromatic proton signals for the two enantiomers, which was demonstrated with the racemate. Under similar conditions, NMR analysis of 3 showed that within the detectable limits of the experiment (ca. <3%), there was none of the disfavored enantiomer. 

The enantioselectivity of biocatalytic reactions is normally expressed as the enantiomeric ratio or the E value [la], a biochemical constant intrinsic to each enzyme that, contrary to enantiomeric excess, is independent of the extent of conversion. In an enzymatic resolution of a racemic substrate, the E value can be considered equal to the ratio of the rates of reaction for the two enantiomers, when the conversion is close to zero. More precisely, the value is defined as the ratio between the specificity constants (k st/Ku) for tho two enantiomers and can be obtained by determination of the k<-at and Km of a given enzyme for the two individual enantiomers. 

However, considering practical limitations, that is, the availability of optically pure enantiomers, E values are more commonly determined on racemates by evaluating the enantiomeric excess values as a function of the extent of conversion in batch reactions. For irreversible reactions, the E value can be calculated from Equation 1 (when the enantiomeric excess ofthe product is known) or from Equation 2 (when the enantiomeric excess ofthe substrate is knovm) [la]. For reversible reactions, which may be the case in enzymatic resolution carried out in organic solvents (especially at extents of conversion higher than 40%), Equations 3 or 4, in which the reaction equilibrium constant has been introduced, should be used [lb]. 

Assuming that the enzymatic reaction is highly enantioselective, then even after only four cycles the enantiomeric excess will have reached 93.4% whereas after seven catalytic cycles the enantiomeric excess is >99% (Figure 5.3). This type of deracemization is really a stereoinversion process in that the reactive enantiomer undergoes stereoinversion during the process. One of the challenges of developing this type of process is to find conditions under which the enzyme catalyst and chemical reactant can coexist, particularly in the case of redox chemistry in which the coexistence of an oxidant and reductant in the same reaction vessel is difficult to achieve. For this... 

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