Carboxylic Acids Lithium enolate formation

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such as N-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to a-hydroxy acids, which are isolated after esterification, e.g., to 1973, or to a-hydroxyamides such as 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962). 

You might think that the presence of the acidic proton in a carboxylic acid would present an insuperable barrier to the formation and use of any enol derivatives. In fact, this is not a problem with either the lithium enolates or the silyl enol ethers. Addition of BuLi or LDA to a carboxylic acid... 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

You might think that the presence of the acidic proton in a carboxylic acid would present an insuperable barrier to the formation and use of any enol derivatives. In fact, this is not a problem with either the lithium enolates or the sUyl enol ethers. Addition of BuLi or LDA to a carboxylic acid immediately results in the removal of the acidic proton and the formation of the lithium salt of the carboxylic add. If BuLi is used, the next step is addition of BuLi to the carbonyl group and the eventual formation of a ketone (see Chapter 10, p. 218). But, if LDA is used, it is possible to form the lithium enolate of the lithium derivative of the carboxylic acid. 

Mixed condensations in which the nucleophilic enolate is derived from an ester have also been developed. Very strong bases have usually been used for enolate formation. For example, the lithium enolate of ethyl acetate is generated using lithium bis(trimethylsilyl)amide as the base. Condensation with carbonyl compounds proceeds readily (entry 13, Scheme 2.1) without apparent complications from proton-transfer reactions between the ester enolate and carbonyl compound. The dilithium salts of carboxylic acids can also add to carbonyl compounds (entry 14, Scheme 2.1). 

The unambiguous synthesis of 3, 4, 4-trihydroxypulvinone (115) has more recently been reported by Ramage and coworkers (Scheme 17) 536). By cleavage of the dioxolanone (117) with the lithium enolate of methyl (4-benzyloxyphenyl)acetate at —78° C the bright yellow carboxylic acid (118) was obtained in hydrated form after work up. Attempts to purify (118) brought about efficient lactone formation. Final-... 

Michael additions. In this sense, the preferred formation of the (S)-diastereomers of the Michael adducts 17 generated from the enolate 15 of the diacetone-glucose dithiane-2-carboxylic acid ester with arylidene malonic acid esters 16 can be explained by assuming that the electrophile attacks from the lithium site in a way, which minimizes the steric repulsion between the dithiane ring and the aryl group ( formula A) ... 

Sodium and Potassium.—Although Li bases, because of their solubility, availability, or ease of preparation, are most popular for formation of reactive anions, occassions arise when basic Na or K compounds have advantages. For example, the reaction depicted in Scheme 8 occurs in 80% yield using the potassium enolate of ethyl cyanoacetate, but proceeds further to give unwanted products with the lithium enolate. Also, potassium enolates of vinylogous carboxylic acid derivatives are alkylated to give y-alkyl products more efficiently than the lithium enolates. ... 

Later, Yamamoto and coworkers developed the axially chiral ester 183 for asymmetric acetate aldol additions. After formation of the lithium enolate with LDA, the reaction with various aldehydes yielded P-hydroxy esters 184 in very high diastereoselectivity. It was shown, for two adducts, that a nearly quantitative saponification leads to P-hydroxy carboxylic acids 176 and liberates phenol 185 in nearly quantitative yield and undiminished optical purity (Scheme 4.40) [100]. The authors discuss a twist-boat as well as an open transition state for rationalizing the preferred Re-face attack to the aldehyde, observed with (R,R)-configured acetate 183. Yamamoto s procedure is impressive because of its stereoselectivity, but one has to be aware that the chiral auxiliary 185 is by far not as readily accessible as others also enabling the asymmetric acetate aldol addition. 

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