Enantiomers diastereomer comparisons

In determination of the absolute configuration of a-chiral primary amines, BINOL derivatives were used as chiral derivatizing agent.10 In this procedure, the chiral substrate was derivatized with R and S enantiomers of the 2,-methoxy-l,l -binaphthalene-8-carbaldehyde and the XH spectra of both diastereomers were compared. Comparison of the chemical shift differences of the diastereomers has allowed determination of the absolute configuration of the chiral substrate [5]. 

An unusually extensive battery of experimental techniques was brought to bear on these comparisons of enantiomers with their racemic mixtures and of diastereomers with each other. A very sensitive Langmuir trough was constructed for the project, with temperature control from 15 to 40°C. In addition to the familiar force/area isotherms, which were used to compare all systems, measurements of surface potentials, surface shear viscosities, and dynamic suface tensions (for hysteresis only) were made on several systems with specially designed apparatus. Several microscopic techniques, epi-fluorescence optical microscopy, scanning tunneling microscopy, and electron microscopy, were applied to films of stearoylserine methyl ester, the most extensively investigated surfactant. 

A similar analysis reveals that 2 and 3 are also enantiomers. Comparison of any other pairs of stereoisomers, 1 and 2, for example, shows that they are not mirror images The C-2 of 1 is R and C-2 of 2 is S but C-3 of both 1 and 2 is S. Isomers 1 and 2 are also not superimposable. So 1 and 2 are a second type of stereoisomer and are nonsuperimposable, non-mirror images called diastereomers. Diastereomers have the same molecular formula and sequence of bonded elements but different spatial arrangements and are nonsuperimposable, non-mirror images. 

FIGURE 14.3. Comparison of (a) enantiomers that are mirror images of each other, and (b) diastereomers, which are not. 

Catalysis of D-A reactions by Lewis acids makes it possible to conduct the cycloadditions under mild conditions, which promotes higher levels of diastereoselection and enantioselection in comparison to the thermally induced reactions. Control over the formation of single diastereomers or enantiomers in D-A reactions may be achieved using chiral promoters functioning either as chiral auxilliaries substrate control) or chiral catalysts reagent control). 

It is favourable for the functional group to be derivatized to be situated close to the chiral centre of the molecule. Too large a distance from the centre of asymmetry can lead to the impossibility to resolve the diastereomers. If possible one should try to form amides, carbamates or ureas. All these classes of compounds have a relatively rigid structure (in comparison with, for example, esters) which seems to facilitate the separation. If a choice is possible, one of the reagent s isomers should be taken that allows the minor compound of the pair of enantiomers to be eluted first then the small peak will not be lost in the tailing of the leading large one. 

The choice of R (Table 2) is subject to the least number of restrictions. It can be extremely large, i. e. enoate No. 22 in Table 4. From this substrate almost 100 g have been reduced in a strictly enantiomeric fashion. If R and R are interchanged (i. e. if the ( )-and (Z)-isomers of substrates of the type R R=CXCOOH are used) different enantiomers or diastereomers are produced. Therefore, ElZ mixtures of substrates in which the B-carbon becomes chiral by reduction cannot be employed if enantiomerically pure products are expected. As can be seen by comparison of substrates 12 and 13 or 30 and 32 in Table 3, branching in the B-position diminishes the rates without much influence on the Km value. In the case of mono-methyl esters of 2- or 3-methylfumarate, substrate 9 and 10, the Fmax is diminished, too, if the methyl group stands in the B- instead of the a-position. In this case the Xn, value for the B-branched substrate increases about tenfold. 

The atropisomers of 336 were resolved by diastereomer crystallization with (S)-a-phenethylamine. The ee of the process can be monitored by chiral HPLC after methylation of the acids. X-ray structure analysis allowed the assignment the R configuration to the (+) enantiomer. The absolute configuration was also confirmed by comparison of the experimental CD spectra using ethanol with the ZINDO calculated one. 

Disubstituted cyclohexane derivatives present a more complex system because there are two chair conformations as well as other conformations. For all comparisons of enantiomers and diastereomers of cyclohexane derivatives, assume that the chair conformation is the only one of interest (see Chapter 8, Section 8.5.4). Even with this simplifying assumption, both chair conformations must be examined for each diastereomer. An example is 1,2-dimethyl-cyclohexane, which has a cis-diastereomer (G3) and a trans-diastereomer (G4A-G4E). It appears that G3 has a plane of symmetry by simply looking at the planar structure, and this is correct. In other words, G3 is a meso compound. However, G4A is labeled as having no symmetry, which indicates it should be a mixture of enantiomers. Is this correct One enantiomer of trans-diastereomer G4A [(li ,2 S)-dimethyIcycIohexane] has two chair conformations G4B and G4C. There is one axial and one equatorial methyl group in each chair conformation, and in the flat representation (G4A) a line is drawn between the methyl groups that suggests that the structure should be examined for the presence of a plane of symmetry. 

The knots based on neutral, purely organic molecules are obviously not prone to classical diastereomer resolution, and, while chromatographic methods were not suitable for the separation of the two enantiomers of the metal-templated trefoil knot, they have been proved successful in the amide-containing knots. As far as these knotted molecules are concerned, it must be noted that they incorporate classical stereogenic centers (carbon atoms), which makes them very different from the copper-based systems in terms of chirality. In the first instance, the separation of the two enantiomers of six different knots was achieved with a colunm that was not conunercially available (chiral-AD type). Trichloromethane was needed to obtain an optimal separation. The silica gel and the chiral stationary phase were covalently bound so that the material did not bleed out when the lipophilic eluent was used. Moreover, comparison of the experimental CD of the pure enantiomers of a knot with a theoretically calculated CD (based on X-ray structure and a fiiUy optimized AMI geometry) permitted assignment of the absolute configuration of this knot. The latter preparation of soluble knots based on substitution of the 5-position of the pyridine moieties in 13 afforded molecules that were soluble in solvents which could be used in commercially available chiral columns." On the other hand, the substitution of a racemic mixture of knots with chiral auxiliaries allows the separation of the diastereomeric product." ... 

The stereochemical assignment of chiral pharmaceutical compounds has received great interest in the last years. As mentioned, the NMR methodology is based on substrate derivatization with two enantiomers of a suitable chiral reagent and the comparison of the NMR spectra of the resulting pair of diastereomers. The preference of the latter for a specific conformation leads to a variation of the chemical shift of the substituents of the stereogenic carbon of the substrate, which can be directly related to its absolute configuration. Theoretical methods (molecular mechanics, semiempirical, or density functional theory [DFT]) may be used to support the conformational differentiation. 

Thus, in comparison to the situation in most conventional, ground state asymmetric induction reactions, where the chiral auxiliary is intimately involved in the enantiodifferentiating step through its stereoelectronic effects or coordinating ability, the role of the ionic chiral auxiliary in solid state cyclobutanol formation is a relatively passive one. For example, the ionic chiral auxiliary does not need to be located close to the site of reaction and all that is required is that its attachment to the reactant via salt formation does not give rise to diastereomers. In addition, there is no direct correlation between the size and structure of the ionic chiral auxiliary and the extent of ee, nor is it possible to predict which enantiomer of the photoproduct will be favored. This would be akin to making an a priori prediction of crystal and molecular structure, a feat that is currently beyond the scope of modem crj tal engineering. 

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