Chiral compounds diastereomers

Multiple Chiral Centers. The number of stereoisomers increases rapidly with an increase in the number of chiral centers in a molecule. A molecule possessing two chiral atoms should have four optical isomers, that is, four structures consisting of two pairs of enantiomers. However, if a compound has two chiral centers but both centers have the same four substituents attached, the total number of isomers is three rather than four. One isomer of such a compound is not chiral because it is identical with its mirror image it has an internal mirror plane. This is an example of a diaster-eomer. The achiral structure is denoted as a meso compound. Diastereomers have different physical and chemical properties from the optically active enantiomers. Recognition of a plane of symmetry is usually the easiest way to detect a meso compound. The stereoisomers of tartaric acid are examples of compounds with multiple chiral centers (see Fig. 1.14), and one of its isomers is a meso compound. 

Coordination to the central P atom of two different types of symmetrical bidentate ligands leads to structures of type P(aa)2(bb), which are this time C2-symmetric as detailed in Fig. 16. The same chiral descriptors A and A apply to these compounds. Derivatives like 3,4,14-17 and 19-22 fit this description and have only been reported in racemic form so far. If the ligand bb is itself chiral, then diastereomers are generated. This will be described in the next section. 

Other examples are those of polysubstituted chiral compounds 146 (formed together with a minor diastereomer) (04JOC7114) and 147... 

It is quite common in EPC synthesis either by asymmetric synthesis or by optical resolution via diastereomers (vide infra) that chiral compounds arc obtained in an enantiomerically enriched, yet optically impure, form. In these cases the optical purity may be increased by crystallization if the compound forms either a conglomerate or a racemic mixture. In the case of conglomerates. one simply adds the amount of solvent necessary for dissolving the racemate. The excess enantiomer remains in crystalline form. 

NMR spectroscopy the enantiomers are converted into a pair of diastereomers by chemical reaction with an auxiliary (enantiomerically pure, chiral compound) and the ratio of the peak areas of nonequivalent externally diastereotopic nuclei is measured by NMR. 

A second chiral center generated in a chiral compound may not have an equal chance for R and S configurations a 50 50 mixture of diastereomers is not usually obtained. 

Kinetic resolution.l33 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on p. 102. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,134 since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as 45 with one enantiomer of a chiral epoxidizing agent (see 5-36).135 In the case of 45 the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor)... 

The Evans Cu(II)- and Sn(II)-catalyzed processes are unique in their ability to mediate aldol additions to pyruvate. Thus, the process provides convenient access to tertiary a-hydroxy esters, a class of chiral compounds not otherwise readily accessed with known methods in asymmetric catalysis. The process has been extended further to include a-dike-tone 101 (Eqs. 8B2.22 and 8B2.23). It is remarkable that the Cu(II) and Sn(II) complexes display enzyme-like group selectivity, as the complexes can differentiate between ethyl and methyl groups in the addition of thiopropionate-derived Z-silyl ketene acetal to 101. As discussed above, either syn or anti diastereomers may be prepared by selection of the Cu(II) or Sn(II) catalyst, respectively. 

Chiral compounds are very important substances. Many natural products, medicinal compounds, and biomolecules exist as a single, optically active stereoisomer. Furthermore the opposite enantiomer or diastereomer may not have any physiological activity or may, in fact, have a detrimental physiological effect. There is therefore great interest in reactions in which only one stereoisomeric form of a compound is produced by a particular synthetic sequence. 

The classical method to resolve a racemate is to react the mixture of enantiomers with one enantiomer of some other chiral compound. The products are diastereomers and can be separated by using the usual methods, such as recrystallization or chromatography. Then the separated diastereomers are individually converted back to the enantiomers of the original compound. Figure 7.5 shows how a racemic carboxylic acid can be resolved. 

The separation of chiral compounds will be discussed in Chapter 22. However, the separation of diastereomers can be accomplished using achiral stationary phases. Another alternative is the use of chiral columns for the separation of diastereomers in either the reversed-phase or normal-phase mode. The use of achiral bonded phases without chiral additives, such as phenyl and alkyl bonded phases for the separation of diastereomeric pharmaceutical compounds, is acceptable. Different selectivities can be obtained by employing stationary phases containing varying functionalities (phenyl, polar embedded moieties). The effect of aqueous mobile-phase pH, temperature, and type of organic eluent (acetonitrile versus methanol) can also play a dramatic role on the separation selectivity of diastereomeric compounds. 

M] or [rh] Molecular rotation, defined as [a] x MW/100. Specific rotation corrected for differences in MW. The symbol [M] and the term molecular rotation are now deemed incorrect, and the term molar rotation denoted by [d ] is preferred. meso- Denotes an internally compensated diastereoisomer of a chiral compound having an even number of chiral centres, e.g., me o-tartaric acid. Formally defined as an achiral member of a set of diastereomers that also contains chiral members, mutarotation Phenomenon shown by some substances, especially sugars, in which the optical activity changes with time. A correct presentation is, e.g., [a]n ° + 20.3 -101.2 (2h)(c, 1.2 in HjO). 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

We also consider that a highly efficient method for preparing an appropriate amount of various chiral compounds with 100% enantiopurity on the laboratory scale is the enantioresolution method, as illustrated in Fig. 9.1. In this method, a chiral auxiliary is covalently bonded to racemates, and the obtained diastereomeric mixture can be separated by conventional HPLC on sihca gel. If the chromatogram shows a base-line separation, the diastereomers obtained are enantiopure. 

A molecule that is asymmetric or dissymmetric (and therefore not superimposable on its mirror image) is called a chiral compound this means that all enantiomers are chiral. Such a compound will display optical activity as an individual enantiomer, which is the ability to rotate the plane of plane-polarized light (measured using a polarimeter), which is one way that we can detect the presence of an enantiomer and define its optical purity. Whereas diastereomers usually differ appreciably in their chemical and physical properties, enantiomers differ only in their ability to rotate polarized light and related optical properties. Normally, when a diastereomer that has an enantiomer is synthesized, a 50 50 mixture of the two enantiomeric forms of the compound is produced, and thus no optical activity is observed. However, if the compound is separated into its two enantiomers (or resolved), each enantiomer will show optical activity in a polarimeter the responses of the two enantiomers will differ only in the sign of rotation of plane-polarized light. 

Meso-compound Diastereomer with two or more chiral centres where the four groups on each of... 

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