Alkylation of dienolates

If ethyl acetoacetate is treated with two equivalents of LDA, a dianion is formed. This dienolate is more reactive at the end carbon, since that anion is delocalized over just one EWG the other anion is alpha to two EWGs, making 

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Enolates may be derived from a,/l-unsaturated ketones 16 by base-catalyzed proton abstraction. Under kinetic control the a -proton is abstracted and a cross-conjugated metal dienolate is formed, whereas under thermodynamic conditions the extended dienolate is the major product3,, l. Successful alkylations of dienolates derived from cyclic a,/l-unsaturated ketones have been performed (see Section 1.1.1.3.1.1.2.1.). The related a,/ -unsaturated ester systems have also been investigated22-24. Open-chain structures 16 pose a rather complicated... 

Examples of alkylations of dienolates derived from a,/J-unsaturated ketones by base-catalyzed proton abstraction38 38" are shown for enolate 32. Here it is also evident that the presence of a 1,3-interaction greatly influences the diastereoselectivity. 

Alkylations of Dienolates of a,P-Unsaturated Carboxylic Acid Derivatives... 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Alkylation of the steroidal enone 36 provides information about the importance of the reaction conditions for the diastereoselectivity82. The notable difference between the observed d.r. s is difficult to rationalize but clearly the solvent conditions have a strong influence on the structure and aggregation of the intermediate dienolate anion71,82. 

The regioselectivity of alkylations of silyl dienol ethers has been studied87,88. These reactions favor y-alkylation products. In contrast, alkylations of the corresponding lithium enolates mainly occur in the a-position. Substituents on the silyl diene unit, as well as the substituents at the silicon, strongly influence the regioselectivity of the reaction87 91,... 

Copper dienolate of a p,y-unsaturated acid (cf., 7, 82-83). The site of alkylation of the dienolate of the acid 1 is markedly dependent on the counterion. The lithium... 

One of the simplest methods for preparation of an a,/J-unsaturated acyl silane is by hydrolysis of a 1-alkoxy-l-trimethylsilylbutadiene, the conjugated dienol ether of a,fi-unsaturated acyl silane, prepared by deprotonation and alkylation of the 1-alkoxydiene (Scheme 42)11. This method is generally limited in application to simple substrates, presumably due to the complexity of preparation of more highly functionalized 1-alkoxy dienes. 

Dicarbonyl compounds,2 The alkylation of O-silyl dienolates is y-regioselec-tive and thus provide a useful route to protected 1,5-dicarbonyl compounds. Examples ... 

The acid-catalyzed, amino-Claisen rearrangement of substituted A-vinyliso-quinuclidenes such as 40 and 41 (Scheme 1) served as the foundation of a novel entry to the molecular framework of lycorine (105). Thus, y-alkylation of the thermodynamic dienolate generated from 40, which was readily available from the Diels—Alder adduct 39, provided 41. Subsequent thermolysis of 41 for 24 hr... 

In a synthesis of PGEt reported by Corey 89) for the preparation of the 0,S-acetal-protected dienol thioether aldehyde 122, the ylide generated from phosphonium salt 119 was used as an electrophile in the alkylation of 118. The following Wittig reaction of the resulting phosphonium salt 120 with the thioenolether aldehyde 121 in the presence of phenyllithium as the base gave intermediate 122 in 35% yield. 

The a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

A variety of lithium dialkylamide bases can be used to produce cross-conjugated lithium dienolates, which may then be alkylated with even less reactive alkylating agents, e.g. propyl iodide, in good to excellent yields without equilibration to the corresponding extended dienolates. a -Alkylations of cyclo-hex-2-enones, certain cyclopent-2-enones, l(9)-octalin-2-ones and steroidal 4-en-3-ones have been accomplished by this procedure. ... 

Stork and Danheiser have developed a highly useful procedure for the synthesis of 4-alkylcyclohex-2-enones, which involves a -alkylations of cross-conjugated lithium dienolates of 3-alkoxycyclohex-2-enones, followed by metal hydride reduction of the carbonyl group and hydrolysis (Scheme 30). Numerous applications of this procedure have been reported.Two different alkyl groups may be introduced at the 6-position of a cyclohex-2-enone derivative without difficulty. While dialkylation is generally not a problem in alkylations of cross-conjugated dienolates of cyclohex-2-enones, it was observed when relatively acidic 3-chlorocyclohex-2-enones were employed. ... 

The stereochemistry of alkylations of extended dienolates of enones such as (70) has been extensively investigated (Scheme 33).In general, the results are similar to those found for the related decalone enolates (43a) and (44), i.e. steric factors within the anion play a dominant role. Thus, axial attack is preferred with (70 R = H), but equatorial attack is strongly favored when an angular methyl group is present (70 R = Me). There is a modest preference for axial alkylation when an angular ethoxycarbonyl... 

The reader is referred to two reviews for numerous examples of intramolecular 7-alkyIations of ketone dienolates. Lansbury et al. have achieved some success in synthesizing 7-alkylated a,3-unsaturated ketones via the use of dienolates of 7-benzenesulfonyl enones and trilithiated derivatives of a -ben-zenesulfonyl enones as nucleophiles. 

The position of alkylation of homoannular silyl dienol ethers is apparently dramatically influenced by the nature of the alkylating agent and catalyst. Reetz and cowoikers reported that 1-trimethylsiloxy-... 

Lewis acid catalyzed alkylations of cross-conjugated silyl dienol ethers provide routes to a -alkylated ketones. A short synthesis of the sesquiterpene ( )-ar-turmerone has been accomplished using the cross-conjugated TMS dienol ether of mesityl oxide (equation 9). ... 

Although there are only a few examples of alkylations of carboxylate enolates which are exocyclic to five-membered carbocyclic rings, the usual steric factors seem to control the stereoselectivity of these reactions. Thus, the dienolate (111) underwent reaction with 4-bromo-l-butene anti to the methoxymethyl substituents with high diastereoselectivity " and enolates derived from norbomane-2-carboxylates (112)... 

The total synthesis of ( )-trichostatin A has been carried out by two routes [67] one uses the y-alkylation of a silyl dienol ether with an acetal which gives the ether in a Mukaiyama reaction. A Wittig olefination followed by DDQ oxidation gives a ketoester which reacts with hydroxylamine to give trichostatin A in 22% overall yield (Scheme 20). 

Ley also used the alkylation of a p-dicarbonyl dienolate 248 to assemble the precursor 250 for an electrophile-induced cyclisation (Scheme 34) (63). The enol of the p-ketoester 250 underwent... 

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