Isomerism chiral centre

Although the tin hydride reductions of alkyl halides seem simple, one must be careful because these reactions occur by a free radical mechanism. This is important, because the carbon radical produced in the reaction can isomerize68,78 and one often obtains two different stereoisomers from the synthesis. Another problem is that chiral centres can be lost in tin hydride reductions when an optically active halide is reduced. One example of this is the reduction of benzyl-6-isocyanopenicillanate with tributyltin deuteride78 (Scheme 14). The amount of isomerization depends on the temperature, the concentration of the tin hydride and the presence of and /-substituents78-82. However, some authors have reported tin hydride reductions where no racemization was observed78. 

Compounds containing more than one chiral centre or which are subject to geometric isomerism and, therefore, have more than just two mirror image forms. 

Caryophyllenes, as an example of two naturally occurring isomeric sesquiterpenes containing a medium-sized ring, in which the success of the total syntheses lies in the stereoselective control of a chiral centre, in a common synthetic key intermediate, which governs the configuration (JE or Z) of the double bonds present in each one of the two isomers. In this context, a brief reference to Cecropia Juvenile Hormone synthesis by the Syntex group, as well as to Johnson s cationic cyclisation of unsaturated polyolefins to fused polycyclic compounds, is made. 

Having established the origin of the rotamers Gl, G2 and G3, the splitting within each of these groups into further components due to the chiral centres in the amide side-chains was to be examined. These polyhydroxylated side-chains contain solely the threo (RS) form of 3-amino-butane-1,2,4-triol as a racemate (Fig. 19). Accordingly, from the possible 8 chiral centres only 4 have to be taken into consideration. These would lead - without considering other types of isomerism - to 16 isomers (8 pairs of isomers). Including (E)I(Z) isomerism, 48 isomers can be expected. 

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. 

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. 

Optical isomerism of drug molecules is widespread. Many drug molecules only contain one or two chiral centres. A simple example is the naturally occurring neurotransmitter adrenaline. When a compound has no symmetry about a particular carbon atom the carbon atom is said to be a chiral centre. When a compound contains one or more chiral centres it is able to rotate plane-polarised light to the right (+) or the left (-). A chiral centre arises when a carbon atom has four structurally different groups attached to it. 

Before 1940 optically active compounds could only be obtained in stereo-isomerically pure form by isolation from natural sources, by resolution of racemic mixtures, or by a few laboratory controlled enzymic reactions. Many of the chemical reactions described in this book lead to products which contain chiral centres, axes, or planes, but in which the isolated material is the optically inactive (racemic) form. This is a direct consequence of the fact that the reactants, reagents, or solvents are achiral or are themselves racemic. The following selection of reactions drawn from the text illustrate this statement they may be cross-referenced to the relevant discussion sections, namely (a) Section 5.4.1, p. 519, (b) Section 5.4.3, p.542, (c) Section 5.11.7, p.687, (d) Section 8.1.3, p. 1133, e) Section 5.2.4, p. 504 and (/) Section 5.4.2, p. 531. 

Configurational centres impose a rigid shape on sections of the molecule in which they occur. However, their presence gives rise to geometric and optical isomerism. Since these stereoisomers have different shapes, biologically active stereoisomers will often exhibit differences in their potencies and/or activities (Table 2.1). These pharmacological variations are particularly likely when a chiral centre is located in a critical position in the structure of the molecule. The consequence of these differences is that it is now necessary to make and test separately all the individual stereoisomers of a drug. 

The reaction of the tetrabutylammonium salt of cAMP with 4-(bromo-methyl)-2Jf-chromen-2-one yields two products which result from axial and equatorial attack of the phosphate group. What is the isomeric relationship between the two products Determine the configuration of all the chirality centres in both products. 

There are four stereoisomers of 4-sec-butylcyclohexanol. A chirality centre is present in the molecule and, in addition, cis/trans isomerism is possible in the ring. The four isomers are hence (R)-trans-, (S)-trans-y (R)-cis- and (S)-ds-4-sec-butylcyclohexanol. 

In connection with this, an unusual isomerization of the propargyl chiral centre in 89 was observed during a PKR in which 90 was obtained as an only isomer. This result shows the transition formation of positive charges at the propargylic position during the cycloaddition (Scheme 26) [123]. 

A final example of the kind of specificity exhibited by enzymes is provided by squalene oxidocyclase. As shown in Fig. 4.65, this enz)nne catalyzes the conversion of the 30-carbon isoprene derivative squalene 2,3-epoxide, which contains only one asymmetric carbon atom, to the steroid lanosterol in a single step that forms four new carbon-carbon bonds and seven new chiral centres in 100% yield and with no isomeric impurities. 

Stereoisomerism arises from the occurrence within drug molecules of chiral centres. The number of possible stereoisomers is 2", where n is the number (usually unity) of chiral centres. A substantial proportion of the commonly used synthetic drugs contain one or more chiral centres and are commercially available as preparations (dosage forms) containing racemates. Drug preparations containing racemic mixtures have been described as combinations of active drug plus isomeric ballast when one enantiomer produces little or no therapeutic effect (Ariens, 1986). The eudismic or potency ratio is defined as the ratio of the doses (in vivo studies) or the concentrations (in vitro studies)... 

The diltiazem molecule ((3), R3 = OCOMe, R7 = H) has two chiral centres and it is also capable of cis-trans isomerism at these two carbon atoms. In general, the trans compounds do not cause vasodilation. Diltiazem is the dextrorotatory cis enantiomer. The laevorotatory cis enantiomer has a 10-fold longer duration of activity than diltiazem in increasing blood flow in the coronary sinus [75]. 

One usually admits that the discriminative effect between the two enantiomers increases with the proximity of the chiral centre to the site of interaction with the receptor. An empirical rule published by Pfeiffer in 1956 states that the isomeric activity ratio (eudismic ratio) of a highly active... 

When the major gymnochrome B (275) was heated in pyridine at 160°C, it was partially converted into a diastereomer which exhibited a CD curve opposite in sign to that of 275. This implies that the two compounds are both configurational helixes (the configurations of the side-chain chiral centres cannot be modified by the thermal isomerization). The inversion of helicity is accompanied by a... 

I) Draw, or make models of the two isomeric forms of lactic acid, the substance that gives milk its sour taste. Mark the chiral centre with an asterisk. 

Various methods for the generation of carbon-centred radicals have been described earlier in this chapter and these are generally applicable for subsequent intramolecular reaction. Commonly, tributyltin hydride is used to initiate carbon radical formation. For example, treatment of the bromide 56 with tributyltin hydride and AIBN gave the cyclopentanes 57 and 58 (4.53). In such cyclizations, the 4-substituent plays a dominant role in the stereoselection (to favour the trans arrangement between the substituent at this position and the new chiral centre), although the cyclization of the isomeric -alkene occurs with no diastereosele-ctivity. ... 

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