Stereoselective reactions examples

Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

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. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

If R and R are different, the two faces of the double bond become nonequivalent, permitting stereoselective reactions at the double bond. These effects have been explored, for example, using 4-silyl-2-pentenes. Reactions such as epoxidation and hydroboration proceed by preferential addition fiom the face opposite the bulky silyl substituents. 

The hydrogenation of 2-methyl(methylene)cyclohexane is an example of a stereoselective reaction, meaning one in which stereoisomeric products are formed in unequal fflnounts from a single starting material (Section 5.11). 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Some examples of stereoselective reactions, involving bond formation at the least hindered side, opposite to an alkyl substituent, are shown below. 

However, if both maleic and fumaric acid gave the dl pair or a mixture in which the dl pair predominated, the reaction would be stereoselective but not stereospecific. If more or less equal amounts of dl and meso forms were produced in each case, the reaction would be nonstereoselective. A consequence of these definitions is that if a reaction is carried out on a compound that has no stereoisomers, it cannot be stereospecific, but at most stereoselective. For example, addition of bromine to methylacetylene could (and does) result in preferential formation of trans-1,2-dibromopropene, but this can be only a stereoselective, not a stereospecific reaction. 

The catalytic enantioselective addition of vinylmetals to activated alkenes is a potentially versatile but undeveloped class of transformations. Compared to processes with arylmetals and, particularly alkylmetals, processes with the corresponding vinylic reagents are of higher synthetic utility but remain scarce, and the relatively few reported examples are Rh-catalysed conjugate additions. In this context, Hoveyda et al. reported very recently an efficient method for catalytic asymmetric allylic alkylations with vinylaluminum reagents that were prepared and used in Thus, stereoselective reactions... 

Intramolecular reactions can also occur between carbonyl groups and allylic silanes. These reactions frequently show good stereoselectivity. For example, 7 cyclizes primarily to 8 with 4% of 9 as a by-product. The two other possible stereoisomers are not observed.98 The stereoselectivity is attributed to a preference for TS 7A over TS 7B. These are both synclinal structures but differ stereoelectronically. In 7A, the electron flow is approximately anti parallel, whereas in 7B it is skewed. It was suggested that this difference may be the origin of the stereoselectivity. 

Notably, not only electron-rich dienes, but also electron-deficient dienes nicely participate in the reaction and react benzaldehyde with similar ease and in a similar sense of stereoselectivity. For example, methyl sorbate provides the 1,2-anti isomer exclusively in good yield with excellent regio- and stereoselectivity (run 7). The regioselectivity reacting at Cl of the diene skeleton might stem from electronic factors rather than from other factors such as coordination the coordination of the ester oxygen to nickel metal center, since ( , )-l-(methoxymethyl)-4-methyl-l,3-butadiene and (E,E)-1-(hydroxymethyl)-4-methyl-l,3-butadiene furnish the C4 adducts selectively together with the Cl adducts as minor products (not shown). Notably,... 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

It is interesting to note that Diels-Alder-type reactions (example 23, Table I) occur in a different and stereoselective way in the presence of a nickel catalyst (55). This fact strongly supports the hypothesis of metallacycle intermediates. 

Other examples from Wilke s group are given in (examples 11-13), leading to highly stereoselective reactions, which have been exploited for asymmetric syntheses in the presence of appropriate asymmetric ligands. This subject requires separate review, however, and will not be treated further here. The reader is referred to the review by Bogdanovic (7).4... 

Also, the 1,4-dialkoxylation of acyclic 1,3-dienes was stereoselective. For example, the reaction of ( , )-2,4-hexadiene gave the d,l products 38 by a 1,4-syn addition. The double bond was exclusively of E configuration (equation 18). 

Ionic Diels-Alder reactions (12, 531-532). The allyl cations derived from allyl alcohols or ethers are reactive dienophiles that undergo Diels-Alder reactions at low temperature with high stereoselectivity.1 Example ... 

A reaction which leads to the exclusive or predominant formation of one of the several possible stereoisomeric compounds is called stereoselective reaction. A reaction where a given isomer leads to one product while another stereoisoimer leads to opposite product is called a stereospecific reaction. Let us illustrate this by examples. 

It is an example of stereoselective reaction as it leads predominantly one form. 

Hydrogen-bond donors have the ability to enhance the selectivities and rates of organic reactions. Examples of catalytic active hydrogen-bond donor additives are urea derivatives, thiourea derivatives (Scheme 10, Tables 12 and 13) as well as diols (Table 14). The urea derivative 7 (Scheme 9) increases the stereoselectivity in radical allylation reactions of several sulphoxides (Scheme 10)171. The modest increase in selectivity was comparable to the effects exerted by protic solvents (such as CF3CH2OH) or traditional Lewis acids like ZnBr2172. It was mentioned that the major component of the catalytic effect may be the steric shielding of one face of the intermediate radical by the complex-bound urea derivative. 

To the best of our knowle( e, there is no example of a Sn2 reaction with retention of configuration if the reaction center is a saturated carbon atom However, if the reaction center is a silicon atom, it is possible, by changing the substrate or the nucleophilic reagent, to obtain highly stereoselective reactions with either predominant retention or inversion of configuration. For example, when la and 1 b are... 

An example pertinent lo stereoselective reactions and medicinal chemistry, is a change in the chirality sense in a series of closely related compounds ... 

The description of a stereoselective reaction primarily requires characterization of enantiomeric and/or diastereomeric products by their configuration (not their stereochemistry , see Introduction). Problems have not arisen with enantiomers but difficulties (see enumerations in refs 1 and 2) are. or perhaps were, apparent for diastereomers, a focal point having been acyclic compounds, in particular aldol addition products. These are pertinent examples to illustrate the problems and their various solutions very well ... 

The description of stereoselective reactions in which one new stereogenic unit is created, i.e., where a pair of enantio- or diastereomers can result, is straightforward. However, there are now numerous examples known of stereoselective reactions in which two or more stereogenic units are generated in the bond-forming step. Accordingly, more than two stereoisomers are formed. In principle, stating the ratio of the stereoisomeric products would suffice for the description of the outcome of such a reaction. However, mechanistic rationalization and prediction of the results are vastly simplified when subsets of the stereoisomers and their relative ratios are considered. Here the terms simple and induced diastereoselectivity play an important practical role. 

In the course of some stereoselective reactions the inducing chiral unit is destroyed. A classical example is the enantioselective Meerwein Ponndorf reduction of a ketone with a chiral Grig-nard compound33 ... 

Simple empirical rules for assigning diastereomeric compounds can be found frequently in literature on stereoselective reactions. In a typical example, the vinyl methyl protons of 13a have a smaller chemical shift (3 = 1.68) than those of isomer 13b (3 = 1.74), apparently due to the proximity of the phenyl group. Accordingly, the sequence of the acetyl methyl protons is reversed394. 

In the case of electrophilic addition, the reactions of tricyclic dienes 1 with several electrophilic reagents have been investigated.1 7 Interestingly, some of these compounds undergo addition reactions with remarkable syn stereoselectivity. For example, the reaction of dimethyl tricy-clo[4.2.2.02,5]deca-3,9-diene-7,8-dicarboxylate with iodine azide solution, prepared in situ from an excess of sodium azide and iodine monochloride, in acetonitrile at — 5 C provided the. yyn-4-azido-3-iodo derivative 2 (Table 1) in 90% yield.1,2,4,6 The formation of the 5,>,n-4-azido-3-iodo derivative 2 is thought to be the first example of a syn addition of iodine azide to an alkene.1,2 The formation of the syn-product is best explained by the twist strain theory,8 according to which the syn transition structure A is favored over the an/7-coplanar transition structure B.1... 

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