Chirality center reactions

In the preceding section, we saw that Sj 2 reactions at chiral centers occur with inversion of configuration. In contrast, an S l reaction at a chiral center reaction usually gives a mixture of enantiomers. For example, (5)-3-bromo-3-methylhexane reacts with water, a poor nucleophile, to give a racemic mixture of 3-methyl-3-hexanol. The reaction occurs by way of an achiral carbocation intermediate with a plane of symmetry (Figure 10.4). Because the carbocation intermediate has a plane of symmetry, the nucleophile can attack equally well from either side of the plane to give a racemic mixture. 

The transformation of ethylene to the carbene requires the re-pairing of three electron pairs. It is a phase-preserving reaction, so that the loop is an ip one. The sp -hybridized carbon atom formed upon H transfer is a chiral center consequently, there are two equivalent loops, and thus conical intersections, leading to two enantiomers. 

Figure 10.3-40. The rating for the disconnection strategy carbon-heteroatom bonds is illustrated, Please focus on the nitrogen atom of the tertiary amino group. It is surrounded by three strategic bonds with different values. The low value of 9 for one ofthese bonds arises because this bond leads to a chiral center. Since its formation requires a stereospecific reaction the strategic weight of this bond has been devalued. In contrast to that, the value of the bond connecting the exocyclic rest has been increased to 85, which may be compared with its basic value as an amine bond.

Ketene formation is a common side reaction- scambling of chiral centers... 

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

This target molecule again contains a chiral center and we inspect Table 18 for help. Table 18. Some enantioselective reactions that produce difunctional products... 

Benzyl bromide can be converted into ethylbenzene (731) by the reaction of Me4Sn. The use of HMPA as a solvent is important. Overall inversion of configuration takes place at the chiral center of deuterated benzyl bro-mide[598]. The cyanomethyiation[599] and methoxymethyiation[600] of aromatic rings are carried out by the reaction of cyanomethyltributyltin (732) and methoxymethyltributyltin. 

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

Many of the reactions we ve already encountered can yield a chiral product from an achi ral starting material Epoxidation of propene for example creates a chirality center by adding oxygen to the double bond... 

We 11 continue with the three dimensional details of chemical reactions later m this chapter First though we need to develop some additional stereochemical principles con cernmg structures with more than one chirality center... 

A reaction that introduces a second chirality center into a starting material that already has one need not produce equal quantities of two possible diastereomers Con sider catalytic hydrogenation of 2 methyl(methylene)cyclohexane As you might expect both CIS and trans 1 2 dimethylcyclohexane are formed... 

Section 7 9 A chemical reaction can convert an achiral substance to a chiral one If the product contains a single chirality center it is formed as a racemic mixture Optically active products can be formed from optically inactive... 

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... 

Wnte the organic products of each of the following reactions If two stereoisomers are formed show both Label all chirality centers / or 5 as appropriate... 

The same cannot be said about reactions with alkyl halides as substrates The conver Sion of optically active 2 octanol to the corresponding halide does involve a bond to the chirality center and so the optical purity and absolute configuration of the alkyl halide need to be independently established... 

None of the bonds to the chirality center is broken when hydroxide attacks the carbonyl group Had an 8 2 reaction occurred instead inversion of configuration at the chirality center would have taken place to give (8) (—) 1 phenylethyl alcohol... 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

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... 

Absolute configuration (Section 7 5) The three dimensional arrangement of atoms or groups at a chirality center Acetal (Section 17 8) Product of the reaction of an aldehyde or a ketone with two moles of an alcohol according to the equation... 

The stereochemical outcome of these reactions can be explained by considering the transition-state geometry. For example, applying the Houk model (495) to akyhc alcohols and their derivatives, the smallest substituent at the preexisting chiral center is oriented "inside" over the face of the transition-state ring and the oxygen atom "outside" (483). 

High levels of asymmetric induction have been achieved in the hydroboration of 1,3-, 1,4-, and 1,5-dienes with thexylborane (482,483,489,490). The first chiral center is formed by an intermolecular reaction. In the second step, the organoborane intermediate undergoes an intramolecular hydroboration, creating the second chiral center with high diastereoselectivity. 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

Other mechanisms must also operate, however, to account tor the fact that 5-10% of the product is formed with retained configuration at the chiral center. Isotopic labeling studies have also demonstrated that the 3-bromo-2-butyl radical undergoes reversible loss of bromine atom to give 2-butene at a rate which is competitive with that of the bromination reaction ... 

The reaction of diethyl tartrate with sulfur tetrafluonde at 25 °C results in replacement of one hydroxyl group, whereas at 100 °C, both hydroxyl groups are replaced by fluonne to form a,a -difluorosuccinate [762] The stereochemical outcome of the fluonnation of tartrate esters is retention of configuration at one of the chiral carbon atoms and inversion of configuration at the second chiral center [163,164, 165] Thus, treatment ofdimethyl(+)-L-tartrate with sulfur tetrafluonde gives dimethyl meso-a,a difluorosuccinate as the final product [163, 164], whereas dimethyl meso tartrate is converted into a racemic mixture of D- and L-a,a -difluorosuccmates [765] (equation 80)... 

This reaction does not involve any of the bonds to the chirality center, and so both the starting alcohol (—) and the product bromide (3-) have the same relative configuration. 

Once we grasp the idea of stereoisomerism in molecules with two or more chirality centers, we can explore further details of addition reactions of alkenes. 

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