Isomers with chiral centres

The tetrahedral asymmetric carbon atom is known as a chiral or stereogenic are discussed in Section 11.3 centre. These molecules, which are non-identical (not superimposable) with their mirror images, are called enantiomers. 

When R r2 R R, then these two mirror images are not superimposable-they are enantiomers 

Enantiomers rotate plane-polarised light in opposite directions. The (+)-enantiomer (or dextrorotatory enantiomer) rotates the light to the right while the (-)-enantiomer (or laevorotatory enantiomer) rotates the light to the left. The amount of rotation is called the specific rotation, [a], and this is measured using a polarimeter. (By convention, the units of [a], 10 degree 

A 1 1 mixture of two enantiomers is known as a racemate or racemic mixture and this does not rotate plane-polarised light (it is optically inactive). The separation of a racemic mixture into its two enantiomers is called resolution. 

The optical purity of a compound is a measure of the enantiomeric purity and this is described as the enantiomeric excess (ee). 

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Key point. The spatial arrangement of atoms determines the stereochemistry, and hence the shape, of organic molecules. When different shapes of the same molecule are interconvertable on rotating a bond, they are called conformational isomers. In contrast, configurational isomers cannot be interconverted without breaking a bond and examples include alkenes and isomers with chiral centres, which rotate plane-polarised light. 

Isomers with chiral centres (optical isomers) are configurational isomers with the same chemical and physical properties, which are able to rotate plane-polarised light clockwise or anticlockwise. 

We can see why a compound with chiral centres should end up optically inactive by looking again at the eclipsed conformer. The molecule itself has a plane of symmetry, and because of this symmetry the optical activity conferred by one chiral centre is equal and opposite to that conferred by the other and, therefore, is cancelled out. It has the characteristics of a racemic mixture, but as an intramolecular phenomenon. A meso compound is defined as one that has chiral centres but is itself achiral. Note that numbering is a problem in tartaric acid because of the symmetry, and that positions 2 and 3 depend on which carboxyl is numbered as C-1. It can be seen that (2R,3S) could easily have been (3R,2S) if we had numbered from the other end, a warning sign that there is something unusual about this isomer. 

There are two chiral centres In (47) so a mixture of diastereoisomers is produced in 75 and 15% yields. Fortunately the major isomer is the analgesic. In fact only one enantiomer of this diastereo isomer is analgesic and so (48) is resolved with camphor sulphonic acid before esterification. The other enantiomer is a useful cough suppressant. 

Enantiomer A molecule with a chiral centre (asymmetric carbon atom) existing as two isomers designated D and L that may have different physiological or pharmacological activities. 

The geometrical isomers are xxii and xxiii. The cis and trans both will exist in two optically active forms along with their one racemic modification. Therefore, the optically active forms of cis and trans will all be different and we will have two pairs of enantiomers. This is also according to the rule of 2 optically active forms where n represents the number of different chiral centres. 

However, when the two substitutes are same as in cyclopropane 1, 2-dicarboxylic acid (xxiv), we will again have two geometrical isomers cis and trans, but because the molecule contains two similar chiral centres ( ), we will have (+) and (-) forms coming from the trans only along with its racemic variety. The cis form, having a (vertical) plane of symmetry will represent the mesovariety. Therefore, the condition is the same as in tartaric acid. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Thus, the anticholinergic activity of the alkaloid hyoscyamine is almost entirely confined to the (—)-isomer, and the (+)-isomer is almost devoid of activity. The racemic ( )-form, atropine, has approximately half the activity of the laevorotatory enantiomer. An anticholinergic drug blocks the action of the neurotransmitter acetylcholine, and thus occupies the same binding site as acetylcholine. The major interaction with the receptor involves that part of the molecule that mimics acetylcholine, namely the appropriately positioned ester and amine groups. The chiral centre is adjacent to the ester, and also influences binding to the receptor. 

Configurational isomers with several chiral centres... 

Configurational isomerism involving one chiral centre provides two different structures, the two enantiomers. If a structure has more than one chiral centre, then there exist two ways of arranging the groups around each chiral centre. Thus, with n chiral centres in a molecule, there will be a maximum number of 2" configurational isomers. Sometimes, as we shall see in Section 3.4.5, there are less. 

The other two isomers are the (15,25) and (IR,2R) isomers, and these two also share a mirror image relationship, have the opposite configuration at both chiral centres, and are, therefore, a pair of enantiomers. From a structure with two chiral centres, we thus have four stereoisomers that consist of two pairs of enantiomers. Stereoisomers that are not enantiomers we term diastereoisomers, or sometimes diastereomers. Thus, the (15,25) and (1R,2R) isomers are diastereoisomers of the (l/f,25) isomer. Other enantiomeric or diastere-omeric relationships between the various isomers are indicated in the figure. 

We can also nse the term epimer to describe the relationship between isomers, where the difference is in the confignration at jnst one centre (see Section 3.4.4). This is shown for the four epimers of o-(- -)-glucose. An interesting observation with the 16 stereoisomers is that optical activity of a particular isomer does not appear to relate to the confignration at any particnlar chiral centre. 

We should compare this system with a 1,4-disubstituted cyclohexane such as 4-methylcyclo-hexanecarboxylic acid (see Section 3.4.4). There is a plane of symmetry in this molecule, so there are no chiral centres but geometric isomers exist, allowing cis and trans stereoisomers. The restrictions imposed by bridging have now destroyed any possibility of geometric isomerism. 

A large proportion of NCEs will have one or more chiral centres. Only single enantiomers can be used nowadays, whereas previously a racemic mixture would have been tested. Different enantiomers produce different pharmacological responses, with one enantiomer usually being more active by at least an order of magnitude. There has been considerable debate on the administration of racemates versus the single active enantiomer or eutomer however, the current trend is to develop only the active optical isomer. The synthetic route employed will, if required, have to utilise chiral-specific reagents and catalysts or the compound will have to be purified after synthesis. With this type of compound, an additional specification or limit is required for the presence of the inactive enantiomer. ... 

Figure 14.11 shows the separation of R and S isomers of a series of structurally related local anaesthetics. Wide separations were achieved for the compounds in this series where it was proposed that the fit of the hydrophobic portion of the analyte into the cyclodextrin was optimal when one of the substituents at the chiral centre was able to interact with the chiral hydroxyl groups on the rim of the cyclodextrin cavity. Table 14.3 shows the association constants calculated for the interaction of the enantiomeric pairs with the dimethylcyclodextrin. The larger the value of K, the... 

Stereoisomerism in compounds with two stereo centres diastereomers and meso structure In compounds whose stereoisomerism is due to tetrahedral stereocentres, the total number of stereoisomers will not exceed 2", where n is the number of tetrahedral stereocentres. For example, in 2,3,4-trihydroxybutanal, there are two chiral carbons. The chiral centres are at C-2 and C-3. Therefore, the maximum number of possible isomers will be 2 = 4. All four stereoisomers of 2,3,4-trihydroxybutanal (A-D) are optically active, and among them there are two enantiomeric pairs, A and B, and C and D, as shown in the structures below. 

The achiral triene chain of (c//-frans-)-3-demethyl-famesic ester as well as its (6-cir-)-isomer cyclize in the presence of acids to give the decalol derivative with four chiral centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Eschenmoser, 1959 W.S. Johnson, 1968,1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric add catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such adds activate oxygen functions selectively (K.B. Sharpless, 1970). 

This internal nucleophilic addition introduces a new chiral centre into the molecule. The carbon of the new centre is known as the anomeric carbon and the two new stereoisomers formed are referred to as anomers. The isomer where the new hydroxy group and the CH2OH are on opposite sides of the plane of the ring is known as the alpha (a) anomer. Conversely, the isomer with the new hydroxy group and terminal CH2OH on the same side of the plane of the ring is known as the beta (P) anomer (Figure 1.12). 

Fig. 32. Schematic representation of the isomers of cyclen-based complexes, with chirality and potential exchange mechanisms between them. From (Dickins et al., 1998), reproduced with permission of the Royal Chemical Society (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS).

Adrafinil has a chirality centre since the sulfur atom of the sulfinyl group still possesses an unshared electron pair and consequently can exist with either an R or S configuration. From the sequence rules, the unshared electron pair, which in the S enantiomer shown below is pointing towards the observer, has the lowest priority. The priority order of the groups attached to the sulfur atom is O > C(C,C,H) > C(C,H,H) > e . The mirror image of this formula represents the R isomer. Note that sulfoxides with two different groups attached always have a chirality centre, since the sulfur atom cannot oscillate through the plane (i.e. there is no pyramidal inversion). 

Lumefantrine contains two stereogenic units, i.e., a Z-configured double bond and a chirality centre whose configuration in the formula given is unspecified. As a result the formula represents two compounds (enantiomers) with R,Z and S,Z configuration, respectively. Both are present in the racemic pharmaceutical. There are formally 22 = 4 isomers possible with this constitution in addition to the isomers of lumefantrine there are also two others with an E-configured double bond. 

A new type of asymmetric induction in this area has been achieved in our group. The need for absolute stereocontrol with the aid of a removable chiral centre, and the observation that the sulfinyl group, recently introduced for Diels-Alder reactions, has not yet been introduced in substrates prone to [3.3] sigmatropic processes, were our motivations. The requisite racemic ketene dithioacetals bearing a sulfinyl group have been prepared and their rearrangement was shown [202] to proceed at ambient temperature. The asymmetric induction was extremely effective, with diastereoselectivi-ties ranging from 93 7 to 99 1, in favour of the (2S,SS) isomer. 

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