Enantiomeric purity advantages

As already mentioned, chiral cations are involved in many areas of chemistry and, unfortunately, only few simple methods are available to determine their optical purity with precision. In the last decades, NMR has evolved as one of the methods of choice for the measurement of the enantiomeric purity of chiral species [ 110,111 ]. Anionic substances have an advantage over neutral reagents to behave as NMR chiral shift agents for chiral cations. They can form dia-stereomeric contact pairs directly and the short-range interactions that result can lead to clear differences in the NMR spectra of the diastereomeric salts. 

Chiral acetals/ketals derived from either (R,R)- or (5,5 )-pentanediol have been shown to offer considerable advantages in the synthesis of secondary alcohols with high enantiomeric purity. The reaction of these acetals with a wide variety of carbon nucleophiles in the presence of a Lewis acid results in a highly diastereoselective cleavage of the acetal C-0 bond to give a /1-hydroxy ether, and the desired alcohols can then be obtained by subsequent degradation through simple oxidation elimination. Scheme 2-39 is an example in which H is used as a nucleophile.97... 

A major advantage that nonenzymic chiral catalysts might have over enzymes, then, is their potential ability to accept substrates of different structures by contrast, an enzyme will select only its substrate from a mixture. Striking examples are the chiral phosphine-rhodium catalysts, which catalyze die hydrogenation of double bonds to produce chiral amino acids (10-12), and the titanium isopropoxide-tartrate complex of Sharpless (11,13,14), which catalyzes the epoxidation of numerous allylic alcohols. Since the enantiomeric purities of the products from these reactions are exceedingly high (>90%), we might conclude... 

As was already mentioned, the phenomenon of nonequivalence of NMR spectra of enantiomers in chiral solvents is a basis for the determination of enantiomeric purity of a variety of chiral sulfur compounds. This method, developed by Pirkle, has the advantage over other methods of being absolute that is, the chemical shift difference between enantiotopic nuclei induced by the chiral solvent increases with increasing optical purity of the solvent, whereas the relative intensities of the signals that are used to measure the enantiomeric composition of the solute are not affected. 

Finally, one should note that the determination of enantiomeric purity by means of chiral shift reagents appears to be more advantageous than the method of Pirkle because the magnitude of nonequivalence A5 is generally greater, thus leading to a more accurate... 

In addition to ELS, charged aerosol (CA) or corona detector has more recently been introduced as a very promising HPLC detection system [105] while the sensitivity of the two systems is quite close, CA detector offers the advantage of a nearly linear response factor, particularly crucial for the assessment of enantiomeric purities, whereas ELS provides a nonlinear response at very low or high levels of analytes, resulting from several light scattering mechanisms and particle size distribution. 

In what appears to be a particularly irmovative development in the area of UV/ Vis-based ee screening systems, the determination of the enantiomeric purity of chiral alcohols 9 is based on a new concept of using two enantioselective enzymes to modify the product (84). The method allows the determination of ee values independent of the concentration, which may be of significant advantage in directed evolution projects. It can be used in three different biocatalytic processes, namely biohydroxylation of alkanes, reductase-catalyzed reduction of ketones, and lipase-or esterase-catalyzed ester hydrolysis. 

The precision of enantiomeric purity determinations by gas chromatography is high123 124-1 >s. This statement holds not only for small enantiomeric purities ( 0% ee), e.g., in the differentiation of a true racemate from enantiomerically slightly enriched mixtures (in reactions devoted to the amplification of optical activity under prebiotic conditions), but also for very high enantiomeric purities (— 100% ee), with detection of 1.0 to 0.1% (and less) of enantiomeric impurities (see Section 3.1.5.8). It is always advantageous if the enantiomer present as an impurity is eluted as the first peak from the gas chromatographic column (Section 3.1.5.3.). This is achieved by the proper selection of the chirality of the nonracemic stationary phase147-188 which, unfortunately, is not possible for the cyclodextrin phases. 

Few methods are available to determine enantiomeric purity of aldehydes by NMR spectroscopy of diastereomeric derivatives. The formation of imines. oxazolidines and more recently the advantageously C2-symmetrical imidazolidines with optically pure reagents can be utilized. 

We (J. Org. Chem. 2004,69, 7234) used the power of the Sharpless oxidations to convert the prochiral 10 into the epoxy diol 11. Base-catalyzed cascade cyclization then converted 11 into crystalline 12, again with high diastereomeric and enantiomeric purity. An advantage of this approach is that by changing the absolute sense of the epoxidation and/or the dihydroxylation, it should be possible to selectively prepare each of the four enantiomerically-pure diastereomers of 12. 

These compounds were expected to possess useful antimalarial activity because the crucial peroxy moiety is held in, what we believe to be, the requisite relative orientation for maximal activity, and the carbonyl group is capable of rotation into novel orientations unavailable to the natural product. A further advantage of this class is that the carbonyl substituent is readily introduced by simple acylation reactions. Other virtues of this class of compounds are (1) their synthetic accessibility (2) the wide variety of analogues available and (3) enantiomeric purity of the products is assured. 

It is important to remember that the advantage of increased enantiomeric purity gained during an asymmetric amplification is always accompanied by the disadvantage of reduced reaction rates when compared with the enantiopure chiral auxiliary.35 Although this reduction in reaction rate may not present a problem for fast reactions, it may be necessary to increase the amount of catalyst or chiral reagent in slower reactions in order to have reasonable reaction times. 

Another recent example by Peukert and Jacobsen (199) took advantage of the first polymer supported Jacobsen s catalyst 8.53 (Fig. 8.31) comparable with the soluble catalyst in asymmetric epoxidation and its full characterization (200, 201). The supported catalyst, prepared from the activated carbonate of hydroxymethyl PS and from a soluble phenolic catalyst (201), was used to catalyze the opening of racemic alkyl epoxides (Mi, Fig. 8.31) with substituted phenols and yielded the 50-member aryloxy alcohol library L15 with good enantiomeric purity (average >90%, never below 80% e.e.). 8.53 was also used to produce the chiral intermediate monomer set M3 (Fig. 8.31) which was used to make two 50-member chiral libraries L16 (1,4-diary-loxy 2-propanols) and L17 (3-aryloxy-2-hydroxy propanamines) with excellent enantiomeric excess following the straightforward synthetic schemes reported in Fig. 8.31. 

Enantiomeric purity is also accessible by chemical correlations. Taking advantage of the various stereospecific substitutions that occur at silicon, one can correlate an enantiomer of unknown absolute rotation with a known one. Such chemical correlations are similar to those used to establish relative configuration (cf. Sect. II-F-3). 

A new n.m.r. shift reagent, tris-[3-(t-butylhydroxymethylene)-d-camphorato]-europium(m), should prove to be useful for the determination of enantiomeric purity of chiral / -phen ethyl amines.2 For example, it was found that the CHNH2 resonances of (R)- and (S)-amphetamines were separated by 0.7 p.p.m. in a carbon tetrachloride solution of the europium reagent ( 0.15 mol 1 l. In comparison to the use of optically active solvents for the same purpose, this technique has the advantage of showing very large shifts between resonances of enantiomers. Mass spectrometry has been used in the detection of mescaline and tetrahydro-isoquinoline precursors as biochemical intermediates.3 Spectral differences of 4-chloro-2-nitrobenzenesulphonyl derivatives of ephedrine and related compounds have been used for identification purposes.4... 

Two successive reactions independently setting up stereogenic centres has an arithmetical advantage, at some expense in overall yield, with respect to the enantiomeric purity of the major product, as Horeau (48) and Eliel (49) have pointed out. Although the selectivity in the steps leading to 191 and 198 are only 85 15 and 67 33, respectively, the methyl (+)-nonactate 202 and its enantiomer were obtained at the end of the sequence in a ratio of 92 8. This is because the proportion of the major enantiomer 202 is obtained by multiplying 0.85 by 0.67, whereas the proportion of the minor enantiomer is obtained by multiplying 0.15 by 0.33. The enantiomeric purity of the... 

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