Examples of Stereospecific Reactions

In stereospecific reactions the configuration of the product is directly related to the configuration of the reactant and is determined by the reaction mechanism. Stereoisomeric reactants give different, usually stereoisomeric, products. The reaction mechanism determines the stereochemical relationship between the reactants and products. For any given reaction, stereospecificity may be lost or altered if there is a change in the mechanism. For example, the S 2 reaction occurs with stereospecific inversion. However, when the mechanism shifts to because of a change in reactants or reaction conditions, stereospecificity is lost. 

Bromination of Alkenes The bromination of substimted alkenes provides a number of examples of stereospecific reactions. These can be illustrated by considering the Z- and -stereoisomers of disubstituted alkenes. The addition of bromine is usually stereospecifically anti for unconjugated disubstituted alkenes and therefore the Z- and E -alkenes lead to diastereomeric products. When both substituents on the alkene are identical, as in 2-butene, the product from the Z-alkene is chiral, whereas the product from the E-alkene is the achiral meso form (see p. 132). 

The preference for anti addition is also evident from the formation of the trans product from cyclic alkenes. 

Bromination of simple alkenes normally proceeds via a bromonium ion and is stereospecifically anti. Exceptions occur when the bromonium ion is in equilibrium with a corresponding carbocation. 

Dihydroxyiation and Epoxidation-Hydroiysis of Aikenes (see Secfion 2A.2.2 for additionai discussion) 

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This means that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific but at most stereoselective. The concerted reactions, including SN2 displacements, E2 elimination of alkyl halides, anti and Syn addition to alkenes are all stereoselective. In the case of chiral or geometric substrates the nature of the product depends on the unique stereoelectronic requirement of the reaction. These are examples of stereospecific reactions. 

Electrophilic addition of the halogens and related X—Y reagents to alkenes and alkynes has been a standard procedure since the beginning of modem organic chemistry.1 Anti electrophilic bromination of such simple compounds as cyclohexene and ( )- and (Z)-2-butene, and variants of this reaction when water or methanol are solvents (formation of halohydrin or their methyl ethers, respectively), are frequently employed as prototype examples of stereospecific reactions in elementary courses in organic chemistry. A simple test for unsaturation involves addition of a dilute solution of bromine in CCU to the... 

Numerous examples of stereospecific reactions in the gas phase are reported in the mass spectrometric literature [1,2]. Many if not most of them, however, deal with relatively rigid systems, e.g., 1, or polyfunctional molecules such as derivatives of tartaric acid [6] the latter gave rise to the first chirality effect observed in mass spectrometry [7]. For stereogenic centers linked by flexible alkyl chains, however, diastereoisomeric differentiation in ion fragmentation is often poor. Two epimers of the aminoalkanol 2, for example, show quite small differences in their mass spectra whereas these differences increase if the two centers are linked by cyclization upon formation of 3 as indicated in Scheme 2 with the epimeric center being marked by an asterisk [8]. 

The property that the stereochemical result of an electrocyclic reaction is absolutely predictable is called stereospecificity. A stereospecific reaction will give you one stereochemical result when a cis starting material is used, and the opposite result when a trans starting material is used. Other examples of stereospecific reactions include Sn2 substitutions, catalytic hydrogenation of alkynes or alkenes, and dihydroxylation and bromination of alkenes. 

Another familiar and important example is syn and anti addition to double bonds. There are many examples of stereospecific reactions involving additions to carbon-carbon double bonds. Addition can be anti or syn, depending on the mechanism. If the mechanism specifies syn or anti addition, different products will be obtained from the E- and Z-isomers. 

Eliel (1962) proposed the following definition Stereospecific as applied to a reaction means that stereoisomerically different starting materials give rise to stereoisomerically different products. The reactions of bromine with traws-butene-2 and cis butene-2 are examples of stereospecific reactions. The trans isomer yields the meso-dibromide (V) whereas the cis isomer affords the di-dibromide VI). 

Many examples of stereospecific allylation consistent with the above mechanism have been reported. As one example, the regioselective and highly diastereoselective allylation of the lactone 17 with the optically active allylic phosphate 16 proceeded with no appreciable racemization of the allylic part to give the lactones l8 and 19, and the reaction has been used for the synthesis of a polypropionate chain[26]. 

Some stereospecific reactions are listed in Scheme 2.9. Examples of stereoselective reactions are presented in Scheme 2.10. As can be seen in Scheme 2.9, the starting materials in these stereospecific processes are stereoisomeric pairs, and the products are stereoisomeric with respect to each other. Each reaction proceeds to give a single stereoisomer without contamination by the alternative stereoisomer. The stereochemical relationships between reactants and products are determined by the reaction mechanism. Detailed discussion of the mechanisms of these reactions will be deferred until later chapters, but some comments can be made here to illustrate the concept of stereospecificity. 

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

Although a few other acyclic examples of stereospecific isomerisation of hexatrienes are known, specially in the field of natural product like steroid chemistry, the commonest reactions of this type are in cyclic hexatrienes. Cyclooctatriene and cyclooctatetraene are systems in which the electrocyclic reaction goes very readily and they show an interesting trend. 

The reaction of cis- and another example of stereospecificity of the dehydration reaction. This reaction, which was first reported by Olberg et al. in 1944 (67) and studied in more detail by Manassen and Pines (68), can be presented schematically as follows ... 

Treatment of the alcohol ( ) with trifluoromethylsulfonic anhydride (triflic anhydride) at -78 C afforded the ester (1 ) which could be isolated and characterized. We knew from previous experience (2J that sulfonyl esters vicinal to an isopropylidene acetal are relatively stable. The triflate T,) reacted cleanly with potassium azide and 18-crown-6 in dichloromethane at room temperature. The crystalline product [68% overall from (1 )] was not the azide ( ) but the isomeric A -triazoline ( )- Clearly the initially formed azide (18) had undergone intramolecular 1,3-cyclo-addition to the double bond of the unsaturated ester (21- ). The stereochemistry of the triazoline (1 ), determined by proton nmr spectroscopy, showed that the reaction was stereospecific. There are several known examples of this reaction ( ), including one in the carbohydrate series ( ). When the triazoline was treated with sodium ethoxide ( ) the diazoester ( ) was rapidly formed by ring-opening and was isolated in 85% yield, Hydrogenolysis of the diazo group of (M) gave the required pyrrolidine ester ( ) (90%). 

A synthesis of the monomeric unit 128 of a peptide nucleic acid analog (PNA) offers an example of stereospecific cross-coupling of a Reformatsky reagent with (Z)-vinylic iodide 126. The coupling reaction of the preformed Reformatsky reagent prepared in dimethoxymethane (methylal) with 126 is carried out using 8% of Pd(PPh3)4 in DMPU as the solvent at 65 °C to afford 127 (equation 70)161. 

Addition of sulfur chlorides and sulfenyl halides to hydrocarbon olefins is a classic example of electrophilic reaction which usually proceeds under mild conditions and results in stereospecific trans-addition via intermediate formation of cyclic episulfonium cation [134]. Ring-opening reactions of episul-fonium cation with nucleophile is responsible for formation of regioisomers when nonsymmetrical olefins are used as substrates. 

Most of the bimolecular absolute asymmetric syntheses are limited to 2+2 cyclobutane formation or polymerization of olefins. Koshima et al. reported a unique example of bimolecular reaction whereby acridine 20 and diphenylacetic acid are assembled in a 1 1 molar ratio by hydrogen bonding, and crystallized in a chiral space group, P2i2i2i.[18] Irradiation of the crystals caused stereospecific decarboxylating condensation to give chiral 21 in 33-39% ee. 

Many pericyclic reactions are stereospecific and, because they have to be run at temperatures higher than ambient, are very robust. It is somewhat surprising that there are very few examples of pericyclic reactions being run at scale, especially in light of our understanding of the factors that control the stereochemical course of the reaction either through the use of a chiral auxiliary or catalyst (Chapter 26). 

One of the earliest industrial applications of monoterpenes is in the steroid synthesis. Robinson annelation is used frequently in these transformations as a key step. The first example of this reaction was by Robinson himself to synthesize a-cyperone from dihydrocarvone.56 This synthesis has been shown to follow a stereospecific course to give (+)-a-cyperone (37) from (+)-dihydrocar-vone (38) (Scheme 5.14).57-59 Since then, numerous modifications and improvements have been made to apply this type of reaction for syntheses of a variety of natural and unnatural products.60... 

Fig. 3.8. A pair of stereospecific reactions (using the type of reaction in Figure 2.28 as an example).

The alkene reduction reactions most frequently observed are of a,3-unsaturated aldehydes, ketones, acids and esters. Examples of stereospecific reductions of acyclic substrates are given in Scheme 50.148.157-159 (j, (, e formation of (123), the double bond of (122) is reduced prior to the aldehyde function. The conversion of (124) to (125) involves oxidation of the intermediate alcohol to the carboxylic acid by bubbling air into the fermentation medium. Stereospecific reductions of a, 3-unsaturated ketones may be similarly effected (Scheme 61). The reduction of the chloro ketone (126) gives (127) initially. This epimerizes under the reaction conditions, and each enantiomer is then reduced further to (128) and (129), with the predominance of the (128) stereoisomer increasing with the size of the R-group. Reduction of ( )-(130) leads to (131) and (132). ... 

Other chemists would argue that this is a load of rubbish and that both are examples of stereospecificity. We should be concerned with the mechanistic element of the reaction. We want to know how the zirconium complex reacts, and this is what the stereospecificity refers to delivery of hydrogen and zirconium to the same side of a multiple bond. The first group of chemists would probably come back with the argument that in order to probe the mechanism in the first place you need two diastereomers of starting material and how can we be sure that the reaction with the triple bond goes by the same mechanism - and so on. Perhaps we should mention that Schwartz himself describes the addition across a triple bond as stereospecific.14... 

Proposed mechanism for reaction of a particular amine group (an example of regiospecificity) with a pendant aldehyde of a coordinated aminoaldehyde, leading to only one optical isomer of an aminol (an example of stereospecificity). The core reaction appears in the inside box. 

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