Stereochemistry of enolate alkylation

The stereochemistry of enolate alkylation follows the general rule governing the stereochemistry of reactions an achiral starting material yields an achiral or racemic product. For example, when cyclohexanone (an achiral starting material) is converted to 2-ethylcyclohexanone by treatment with base and CH3CH2I, a new stereogenic center is introduced, and both enantiomers of the product are formed in equal amounts—that is, a racemic mixture. 

The stereochemistry of enolate alkylations has been studied by determining the stereochemistry of products from alkylation of cyclic ketones. The stereochemistry of alkylation of the enolates 1 and 2 has been determined. While 1 shows no... 

Mechanism of Enolate Alkylation SN2 reaction, inversion of electrophile stereochemistry... 

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

The effect of crown ethers on the rates and stereochemistry of the alkylation of metal acetoacetates has been studied by Cambillau et al. (1976, 1978) and Kurts et al. (1973, 1974). Since the enolate can adopt various conformations ([96]—[99]), O-alkylation may produce either the cis ([100]) or the trans ([101]) isomer, whereas C-alkylation affords [102]. The reaction of the sodium... 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Many functional groups are stable under conditions for the alkylation of pseudoephedrine glycinamide enolates, including aryl benzenesulfonate esters (eq 18), rert-butyl carbamate and rerf-butyl carbonate groups (eq 19), tert-butyldimethylsilyl ethers, benzyl ethers, ferf-butyl ethers, methoxymethyl ethers, and alkyl chlorides. The stereochemistry of the alkylation reactions of pseudoephedrine glycinamide and pseudoephedrine sarcosinamide is the same as that observed in alkylations of simple A(-acyl derivatives of pseudoephedrine. 

In addition, the lithium enolate derived from pseudoephedrine propionamide has been shown to undergo highly diastereoselective Mannich reactions with p-(methoxy)phenyl aldimines to form enantiomerically enriched a,p-disubstituted p-amino acids (Table 10). As observed in alkylation reactions using alkyl halides as electrophiles, lithium chloride is necessary for the reaction of aldimines. With respect to the enolate, the stereochemistry of the alkylation reactions is the same as that observed with... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

In recent years, investigations of the diastereoselectivity and enantioselectivity of alkylations of metal enolates of carboxylic acid derivatives have become one of the most active areas of research in synthetic organic chemistry. Intraannular, extraannular and chelate-enforced intraannular chirality transfer may be involved in determining the stereochemistry of these alkylations. 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Enantioselectivity can also be based on structural features present in the reactants. A silyl substituent has been used to control stereochemistry in both cyclic and acyclic systems. The silyl substituent can then be removed by TBAF.326 As with enolate alkylation (see p. 32), the steric effect of the silyl substituent directs the approach of the acceptor to the opposite face. 

It has been found that when 8,e-enolates bearing (3-siloxy substiments are subject to iodolactonization, the substituent directs the stereochemistry of cyclization in a manner opposite to an alkyl substituent. Suggest a TS structure that would account for this difference. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 12.5.2), so the correct stereochemistry is established for the C—O bond. The final stereocenter for which configuration must be established is the methyl group at C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not very stereoselective. However, since this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate was formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C(6). 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

They have employed the strategy of intramolecular trans alkylation of azetidin-2-ones since C-4 substituted azetidin-2-one enolates, predominantly yield the C-3, 4-frans-diastereomer upon reaction with electrophiles, [45] thus, providing control of stereochemistry of substituents at the cyclohexyl ring (Scheme 25). 

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