Two Chiral Centers

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

When a molecule contains two chirality centers as does 2 3 dihydroxybutanoic acid how many stereoisomers are possible ... 

We can use straightforward reasoning to come up with the answer The absolute config uration at C 2 may be R or S Likewise C 3 may have either the R or the S configura tion The four possible combinations of these two chirality centers are... 

To convert a molecule with two chirality centers to its enantiomer the configura tion at both centers must be changed Reversing the configuration at only one chirality center converts it to a diastereomeric structure... 

Erythro and three describe the relative configuration (Section 7 5) of two chirality centers within a single molecule... 

The situation is the same when the two chirality centers are present m a ring There are four stereoisomeric 1 bromo 2 chlorocyclopropanes a pair of enantiomers m which the halogens are trans and a pair m which they are cis The cis compounds are diaste reomers of the trans... 

Now think about a molecule such as 2 3 butanediol which has two chirality centers that are equivalently substituted... 

Many naturally occurring compounds contain several chirality centers By an analysis similar to that described for the case of two chirality centers it can be shown that the maximum number of stereoisomers for a particular constitution is 2" where n is equal to the number of chirality centers... 

Section 7 10 When a molecule has two chirality centers and these two chirality cen ters are not equivalent four stereoisomers are possible... 

Section 7 13 Addition reactions of alkenes may generate one (Section 7 9) or two (Sec tion 7 13) chirality centers When two chirality centers are produced then-relative stereochemistry depends on the configuration (E or Z) of the alkene and whether the addition is syn or anti... 

A novel technique for dating archaeological samples called ammo acid racemiza tion (AAR) IS based on the stereochemistry of ammo acids Over time the configuration at the a carbon atom of a protein s ammo acids is lost m a reaction that follows first order kinetics When the a carbon is the only chirality center this process corresponds to racemization For an ammo acid with two chirality centers changing the configuration of the a carbon from L to D gives a diastereomer In the case of isoleucme for example the diastereomer is an ammo acid not normally present m proteins called alloisoleucme... 

Erythro (Section 7 11) Term applied to the relative configura tion of two chirality centers within a molecule The erythro stereoisomer has like substituents on the same side of a Fischer projection... 

Merrifield method See solid phase peptide synthesis Meso stereoisomer (Section 7 11) An achiral molecule that has chirality centers The most common kind of meso com pound IS a molecule with two chirality centers and a plane of symmetry... 

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. 

Tartaric acid [526-83-0] (2,3-dihydroxybutanedioic acid, 2,3-dihydroxysuccinic acid), C H O, is a dihydroxy dicarboxyhc acid with two chiral centers. It exists as the dextro- and levorotatory acid the meso form (which is inactive owing to internal compensation), and the racemic mixture (which is commonly known as racemic acid). The commercial product in the United States is the natural, dextrorotatory form, (R-R, R )-tartaric acid (L(+)-tartaric acid) [87-69-4]. This enantiomer occurs in grapes as its acid potassium salt (cream of tartar). In the fermentation of wine (qv), this salt forms deposits in the vats free crystallized tartaric acid was first obtained from such fermentation residues by Scheele in 1769. 

As a result of having two chiral centers, four stereoisomers of ascorbic acid are possible (Table 1) (Fig. 2). Besides L-ascorbic acid (Activity = 1), only D-araboascorbic acid (erythorbic acid (9)) shows vitamin C activity (Activity = 0.025-0.05). The L-ascorbic acid stmcture (1) in solution and the soHd state are almost identical. Ascorbic acid crystallizes in the space group P2 with four molecules in the unit cell. The crystal data are summarized in Table 2. 

In writing Eischer projections of molecules with two chirality centers, the molecule is arranged in an eclipsed conformation for projection onto the page, as shown in Eigure 7.9. Again, horizontal lines in the projection represent bonds coming toward you vertical bonds point away. 

Synthesis of the prototype begins with Friedel Crafts acetylation of salicylamide ( ). Bromination of the ketone (25) followed by displacement with amine gives the corresponding ami noketone ( ). Catalytic hydrogenation to the ami noalcohol completes the synthesis of labetolol (24). The presence of two chiral centers at remote positions leads to the two diastereomers being obtained in essentially equal amounts. 

Molecules like lactic acid, alanine, and glyceraldehyde are relatively simple because each has only one chirality center and only two stereoisomers. The situation becomes more complex, however, with molecules that have more than one chirality center. As a general rule, a molecule with n chirality centers can have up to 2n stereoisomers (although it may have fewer, as we ll see shortly). Take the amino acid threonine (2-amino-3-hydroxybutanoic acid), for example. Since threonine has two chirality centers (C2 and C3), there are four possible stereoisomers, as shown in Figure 9.10. Check for yourself that the R,S configurations are correct. 

Assign R or S stereochemistry to the two chirality centers in isocitrate, and tell whether OH and H add to the Si face or the Re face of the double bond. 

Aldotetroses are four-carbon sugars with two chirality centers and an aldehyde carbonyl group. Thus, there are 22 = 4 possible stereoisomeric aldotetroses, or two d,l pairs of enantiomers named erythrose and threose. 

Problem 26.3 The amino acid threonine, (2S,3ft)-2-amino-3-hydroxybutanoic acid, has two chirality centers. 

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