Enolization of carboxylic acid derivatives

Among the enolates of carboxylic acid derivatives, esters are the most widely used. Ester enolates cannot be used in crossed aldols with aldehydes because the aldehyde is both more enolizable and more electrophilic than the ester. It will just condense with itself and ignore the ester. The same is true for ketones. A specific enol equivalent for the ester will therefore be needed for a successful ester aldol reaction. 

ALKYLATIONS OF METAL ENOLATES OF CARBOXYLIC ACID DERIVATIVES... 

Although carboxylic acids and their derivatives are somewhat weaker carbon acids than aldehydes and ketones, it is generally possible to quantitatively convert them to the corresponding metal enolates with dialkylamide bases, the most popular of which is LDA. - - Thus, monoanions of saturated esters, lactones, nitriles, /VA -dialkylamides and V-alkyllactams and dianions of carboxylic acids and V-unsub-stituted amides and lactams are easily prepared in aprotic solvents such as THF and C-alkylated with a variety of simple and functionalized SN2-reactive alkylating agents at room temperature or below. When more-hindered systems are involved, the basicity of the metal dialkylamide and the reactivity of the metal enolate can be enhanced by the addition of HMPA. Of course, many of the indirect methods used for the generation of aldehyde and ketone enolates are also applicable to the preparation of enolates of carboxylic acid derivatives (Section 1.1.2.1). O-Alkylations or dialkylations at carbon generally are of minimal importance with metal enolates of carboxylic acid derivatives. 

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. 

Diasteroselective Alkylations of Exocyclic and Endocyclic Enolates of Carboxylic Acid Derivatives... 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

In the first part of this chapter we saw how specific enol equivalents could be used to control aldol reactions. We now need to look at the same type of control in the acylation of enolates and extend our discussion to specific enolates of carboxylic acid derivatives. 

One of the most attractive options for asymmetric aldol reactions available to the synthetic chemist is to use enolates of carboxylic acid derivatives (inter alia ester, amide, or imide) with an appended chiral auxiliary (alcohol, amine, urethane). An early example of this approach dates back to 1938, when McKenzie reported that benzaldehyde undergoes addition by (-)-menthyl malonate (42) to give propanoic acid derivative 43 in 21 % ee (Equation 4) [43]. The modest selectivity was attributed to the conformational flexibility of ester enolates (cf. 44). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

Enolate hydroxylation is a problem of long standing. Direct oxygenation succeeds with the fully substituted enolates of certain a,a-disubstituted ketones and a variety of carboxylic acid derivatives (ester anions, acid dianions, amide anions), but the reaction of enolates, RCH = C(0 )R or CH2 = C(0 )R, with oxygen results in complex products of overoxidation. The stable... 

Enolates prepared by deprotonation of carboxylic acid derivatives can also undergo elimination to yield ketenes. This is rarely seen with amides, but esters, thiolesters, imides, or N-acylsulfonamides can readily decompose to ketenes if left to warm to room temperature (Scheme 5.58). At -78 °C, however, even aryl esters can be converted into enolates stoichiometrically without ketene formation [462, 463],... 

This protocol has been successfully applied to the reactions of carboxylic acid derivatives such as thioamides and thione esters (cqs 3 and 4). 3-Acetylthiazolidine-2-thiones are quite suitable substrates for the tin(ll) enolate mediated asymmetric aldol reaction and various optically active p-hydroxy 3-acetylthiazolidine-2-thiones are obtained by using chiral diamine 1 (eq 5). ... 

Extraannular and chelate-enforced intraannular chirality transfer in enolate alkylations of carboxylic acid derivatives may occur in cases where (i) the chiral center, e.g. a 3-carbon atom, is present and remains in the carboxylic portion of the molecule or (ii) the substrate contains a chiral auxiliary, e.g. the alcohol portion of an ester or the amine portion of an amide, which is removed after the alkylation to generate a chiral carboxylic acid. Alkylations of the former type will be discussed in this section. Alkylations of systems containing chiral auxiliaries are described in Section 1.1.6.4. 

A more direct version is the treatment of vinyl-lithiums with carboxylic acids.10 Vinyl-lithium itself reacts with EtC02H in DME (DiMethoxyEthane) to give the enone 56 in high yield.11 The first molecule of vinyl-lithium forms the lithium salt 54 and the second molecule adds to give the di-lithium derivative 55, an intermediate which might remind you of the lithium enolates of carboxylic acids discussed in the previous three chapters. Hydrolysis during normal work-up gives the enone 56. 

Perhaps the only true homoenolates used in synthesis are derived by metallation of derivatives of 3-haloacids. The acids themselves 12 give lithium 3-halocarboxylates 13 and hence by metallation the homoenolate which probably exists as 15, an analogue of the dilithium enolates of carboxylic acids (chapter 2). Reaction 16 with aldehydes or ketones gives y-lactones 19, by a homoaldol reaction via y-hydroxyacids 18, common products from addition of acid homoenolates to carbonyl compounds.3... 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) ... 

It is generally true that restrictions on conformational mobility minimize the number of competing transition states and simplify analysis of the factors that affect selectivity. Chelation of a metal by a heteroatom often provides such restriction and also often places the stereocenter of a chiral auxiliary in close proximity to the a-carbon of an enolate. This proximity often results in very high levels of asymmetric induction. A number of auxiliaries have been developed for the asymmetric alkylation of carboxylic acid derivatives using chelate-enforced intraannular asymmetric induction. The first practical method for asymmetric alkylation of carboxylic acid derivitives utilized oxazolines and was developed by the Meyers group in the 1970 s (Scheme 3.16a), whose efforts established the importance and potential for chelation-induced rigidity in asymmetric induction (reviews [77-79]). In 1980, Sonnet [80] and Evans [81,82] independently reported that the dianions of prolinol amides afford more highly selective asymmetric alkylations (Scheme 3.16b). 

Expanding upon these results, Schultz et al. analyzed the oxidation of enolates produced via the Birch reduction of carboxylic acid derivatives.15 It was found that when 21 was reduced and treated with (+)-5, 22 was obtained with only marginal yield and modest enantioselectivity. The enantioselectivity increased when 23 was deprotonated and then treated with (+)-5. 

Asymmetric alkylation of carboxylic acid derivatives has been studied intensively for about 20 years. [1] Numerous auxiliaries, tailor-made structures with high steric demands for effective RelSi face differentiation, have been synthesized and their efficiency tested. [1, 2] In recent years besides the preparative aspects of enolates, physico-chemical investigations into their structure-reactivity relationships have gained interest. [3] Crystal structure analyses, osmometric measurements, and NMR studies in solution are helpful in the investigation of the factors that may control enolate reactions. [3-5]... 

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