Conjugate addition nucleophiles, aldol reactions

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

There is also a frontier orbital effect that assists conjugate addition over the aldol reaction, You will reeall that the carbonyl carbon is a relatively hard centre, whereas the 3 carbon of an enone is soft, As the nucleophilic enolate becomes more stabilized with extra electron-withdrawing groups, it beeomes increasingly soft and hence more likely to attack the [J carbon,... 

The key substrates for conjugate addition are the a, 3-unsaturated carbonyl compounds. When the double bond is inside a chain or ring these compounds are available via a wide variety of routes including the aldol reaction and are generally stable intermediates that can be stored for use at wiU. When the double bond is exo to the ring or chain (exo-methylene compounds), the unhindered nature of the double bond makes them especially susceptible to attack by nucleophiles (and radicals), This reactivity is needed for conjugate additions but the compounds are unstable and polymerize or decompose rather easily,... 

The reaction starts with the (relatively nucleophilic) DABCO undergoing conjugate addition to ethyl acrylate. This will form an enolate that can then attack the acetaldehyde in an aldol reaction. 

Because of the stability of iron tricarbonyl diene complexes, conjugated dienals are protected from polymerization when complexed, while other reactions can be carried out at the aldehyde functionaUty. A number of synthetically attractive nucleophilic transformations of the aldehyde can be performed on these complexes. These include, aldol reactions, Michael additions, reactions with organozinc, -silicon, -boron, and -tin... 

Steps 1, 3 phosphate transfers steps 2, 5, 8 i.somerizations step 4 retro-aldol reaction step 5 oxidation and nucleophilic acyl substitution steps 7, 10 phosphate transfers step 9 E2 dehydration Nucleophilic acyl substitution of acetyl dihydrolipoamide by coenzyme A Cl and C6 of glucose become -CH groups C3 and C4 become CO -Citrate and isocitrate E2 elimination of water, followed by conjugate addition (CH3)2CHCH2COCOr E2 reaction... 

The use of these materials in a range of reactions [isomerization of alkenes and alkynes, C—C bond formation, aldol condensation, Knoevenagel condensation, nitroaldol reactions, Michael addition, conjugate addition of alcohols, nucleophilic addition of phenylacetylene, nucleophilic ring opening of epoxides, oxidation reactions, Si—C bond formation, Pudovik reaction (P—C bond formation) and synthesis ofheterocycles] have been discussed in detail by Ono [248], as well as in the other cited reviews. We will thus discuss here only selected examples. 

The poor yield in this conjugate addition is due primarily to the numerous competing reactions the ketone enolate can self-condense (aldol), can condense with the ketone of MVK (aldol), or can deprotonate the methyl of MVK to generate a new nucleophile. The complex mixture of products makes this n ute practically useless, (continued on next page)... 

A related route to 3-oxoalkylphosphonates involves the conjugate addition of trialkyl phosphites to a,P-unsaturated ketones and hydrolysis of the intermediate oxaphospholenes. The utility of this method is enhanced by the nucleophilic character of the intermediate oxaphosphorane, which facilitates the stereoselective aldol reaction resulting in the formation of p-substituted y-ketophos-phonates. - The pentacovalent oxaphospholene reacts with dialkyl azidocarboxylates to give P-hydrazido-y-ketophosphonates in excellent yields. ... 

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