Reactions That Produce Enantiomers

A reaction of an achiral molecule may introduce a chirality center, producing a chiral product. For example, reaction of the following ketone with hydrogen in the presence of a catalyst results in addition of the hydrogen to the carbon-oxygen double bond, producing 2-butanol  

If a drug is used as a racemic mixture, often only one of the enantiomers is responsible for the desired pharmacological effect. The other enantiomer may have a lesser effect, or no effect, or may even be responsible for undesired side effects. One example is perhexiline. a racemic drug that was used to treat abnormal heart rhythms. This drug was responsible for a number of deaths in the 1980s because one enantiomer was metabolized much more slowly than the other and accumulated at toxic levels. If perhexiline had been marketed only as the more rapidly metabolized enantiomer, it might have been a safer drug. 

An example of improved efficacy of an enantiomerically pure version of a drug over the racemic version is provided by citalopram. The racemic version, known as Celexa, is marketed as an antidepressant. Studies on the resolved enantiomers have shown that the S-enantiomer is the active one and that it has a more rapid onset of action and a more favorable benefit-to-risk ratio than the racemate. As a result, (S)-citalo-pram (escitalopram or Lexapro) is now being marketed. Not only is this a better and safer drug, but the pharmaceutical company that developed citalopram was able to extend its markel exclusivity for an additional 3 years. 

Sales of single enantiomer drugs exceeded 159 billion in 2002. Some of these come from biological sources, but the majority are synthetic. For this reason, the development of synthetic methods that produce only a single enantiomer of chiral compounds is a very active research area in both academic and pharmaceutical research labs. Chiral or asymmetric syntheses, which produce only the desired enantiomer, are much preferred over resolution processes, in which at least half of the initial compound is discarded. 

All of the chiral compounds that we have seen so far have had one or more carbons substituted with four different groups. However, there are other situations that also give rise to chiral compounds. Some of the other possibilities are described here. 

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A reaction that produces a predominance of one enantiomer over other is known as enantioselective synthesis. To carry out an enantioselective reaction, a chiral reagent, solvent, or catalyst must assert an influence on the course of the reaction. In nature, most of the organic or bioorganic reactions are enantioselective, and the chiral influence generally comes from various enzymes. Enzymes are chiral molecules, and they possess an active site where the reactant molecules are bound momentarily during the... 

The introduction of branches also makes it possible to have stereoisomers. Compounds with a single methyl branch at any position other than carbon 2 or the exact center of the chain can exist as one of two possible enantiomers, whereas compounds with two or more branches have a number of different stereoisomers (e.g., enantiomers, me so isomers, or diastereomers). Generic reactions that produce racemic mixtures or mixtures of stereoisomers will be discussed first, followed by descriptions of methods used to make individual stereoisomers. 

The Focus On box on page 433 described a hydroboration reaction that produces a single enantiomer of a chiral alcohol as the product. The chirality of one enantiomer of the boron hydride reagent is used to control the formation of a single enantiomer of the product. As discussed in that Focus On box, the drawback to this reaction is that it requires one mole of the chiral borane for each mole of chiral alcohol that is produced. The chiral reagent is rather expensive because it must be resolved or prepared from another enantiomerically pure compound. A more desirable process would use the expensive chiral reagent as a catalyst so that a much smaller amount could be employed to produce a larger amount of the chiral product. 

Imagine a chemical reaction that produces a product the percentage of each enantiomer formed in that reaction is unknown, but the specific rotation of the product is measured to be -10.5°. To determine the percentage of each enantiomer, begin with the knowledge that specific rotation is additive. If the product is 2-butanol, the specific rotation of one pure enantiomer of 2-butanol must be obtained. Someone must prepare or isolate the pure enantiomer, measure its specific rotation, and then report it in the hterature. Should you intuitively know the speeific rotation of each enantiomer No This is not intuitively obvious it is an experimentally determined property, so someone has to do the experiment. 

A reaction that produces one enantiomer in preference to the other. 

Enantioselective reaction A reaction that produces one enantiomer in preference to the other. Catalytic reduction of the following alkene in the presence of an (i )-BINAP-Ru catalyst gives (S)-naproxen in greater than 98% enantiomeric excess (>99% < 1%). 

Certain heterocyclic compounds are also important aromatic substances in wines, such as pyrazines in Cabernet Sauvignon and Sauvignon Blanc wines (see Section 8.2.11.1.7) and both enantiomers of 3-hydroxy-4,5-dimethyl-5if-furan-2-one (sotolon), which occur in white wines, sherries and are a key component of the typical aroma of aged Port wines. The precise chemical reactions leading to the formation of bouquet substances are not yet widely known. There are two types of reactions that produce bouquet constituents oxidation, which is characterised by the presence of aldehydes and acetals (e.g. in Madeira-type wines) and reduction (such as in quality table wines after a period of bottle maturation the flavour of low-quahty wines does not improve under the same conditions, but instead maturation often leads to a loss of freshness). During wine aging, glycosides of terpenic alcohols and... 

Many living species give off light, but the one that we are probably most familiar with is the firefly. The chemical reaction that produces light from the firefly, so-called bioluminescence, is fairly well understood. It is known from many experiments that the molecule that is involved in the bioluminescence of fireflies is o-luciferin, which is drawn in Figure 4.13 along with its enantiomer L-luciferin. This is an old but very descriptive name for this compound. "Lucifer" is a reference to fire (and the... 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Most of the biochemical reactions that take place in the body, as well as many organic reactions in the laboratory, yield products with chirality centers. Fo example, acid-catalyzed addition of H2O to 1-butene in the laboratory yield 2-butanol, a chiral alcohol. What is the stereochemistry of this chiral product If a single enantiomer is formed, is it R or 5 If a mixture of enantiomers i formed, how much of each In fact, the 2-butanol produced is a racemic mix ture of R and S enantiomers. Let s see why. 

Oxidation of racemic sulphoxides with an optically active W-chloro caprolactam derivative produces a good yield of the corresponding sulphone. The utility of this reaction, however, is that one enantiomer of the sulphoxide is left unreacted and so can be isolated in pure form106. 

How are the smafl-to-microscale excesses of one enantiomer over the other, produced by any of the scenarios outlined above, capable of generating a final state of enantiomeric purity In 1953 Frank [16] developed a mathematical model for the autocatalytic random symmetry breaking of a racemic system. He proposed that the reaction of one enantiomer yielded a product that acted as a catalyst for the further production of more of itself and as an inhibitor for the production of its antipode. He showed that such a system is kinetically unstable, which implies that any random fluctuation producing a transient e.e. in the 50 50 population of the racemic... 

Scheme 7 Diels-Alder reaction of a single precursor proceeds via different transition states that produce two isomeric intermediates, each of which can be converted to one of the enantiomers of the novel Tynacantha marginata sesquiterpenoid [64]...

Enzymes may be used either directly for chiral synthesis of the desired enantiomer of the amino acid itself or of a derivative from which it can readily be prepared, or for kinetic resolution. Resolution of a racemate may remove the unwanted enantiomer, leaving the intended product untouched, or else the reaction may release the desired enantiomer from a racemic precursor. In either case the apparent disadvantage is that the process on its own can only yield up to 50% of the target compound. However, in a number of processes the enzyme-catalyzed kinetic resolution is combined with a second process that re-racemizes the unwanted enantiomer. This may be chemical or enzymatic, and in the latter case, the combination of two simultaneous enzymatic reactions can produce a smooth dynamic kinetic resolution leading to 100% yield. 

Once this process is explored with the model system to assess the level of enantioselectivity, we will then prepare alkyl zinc reagent 48 from 44 using standard methods - - and cross couple 48 to aryl bromide 18 using the appropriate chiral catalysts (Scheme 7). Although the acetonide stereocenter in 48 is somewhat remote from the coupling site, the stereocenter may serve to enhance the stereoselectivity of the cross-coupling process because the two possible products are diastereomers, not simply enantiomers. This reaction will produce 49 from (S)-48 and 30 from (R)-48 that can then be converted to epoxides 31 and 32 using standard methods. Epoxide 31 leads to heliannuol D 4 after base-promoted epoxide cyclization and deprotonation. Similarly, epoxide 32 leads to heliannuol A 1 after acid-promoted cyclization. 

When in carbenium ions of this type R1 R2 R3, these carbenium ions react with achiral nucleophiles to form chiral substitution products R1 R2R3C—Nu. These must be produced as a 1 1 mixture of both enantiomers (i.e., as a racemic mixture). Achiral reaction partners alone can never form an optically active product. But in apparent contradiction to what has just been explained, not all SN1 reactions that start from enantiomerically pure alkylating agents and take place via achiral carbenium ions produce a racemic substitution product. Let us consider, for example, Figure 2.13. 

The stereostructure of the alkoxide intermediate of a Flomer-Wadsworth-Emmons reaction that affords the trans-alkene was shown in Figure 11.13 (as formula A). The Still-Gen-nari variant of this reaction (Figure 11.14) must proceed via an alkoxide with the inverse stereostructure because an alkene with the opposite configuration is produced. According to Figure 11.15, this alkoxide is a 50 50 mixture of the enantiomers C and ent-C. Each of these enantiomers contributes equally to the formation of the finally obtained civ-con figured acrylic ester D. 

As we saw in Chapter 7, one of the goals of synthetic organic chemistry is to develop methods that produce only a single enantiomer of a desired chiral compound rather than the usual racemic mixture that is the result of most reactions. Recently, a method has been developed that employs one enantiomer of a chiral borane to prepare a single enantiomer of a chiral alcohol from an achiral alkene. The chiral borane that is used is /rans-2,5-dimethylborolane. 

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