Metal enolates carboxylic acid derivative

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. 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

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. 

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). 

Catalytic and highly enantioselective fluorination of acyl chlorides was reported by Lectka et al. where O-benzoyl quinidine (O-Bz-QD), is combined with a transition metal-based cocatalyst, (l,3-dppp)NiCl2 or trans-(PPh3)2PdCl2, to generate chiral ketene enolates from acyl chlorides, which are fluorinated with NFSI to produce ot-fluorinated carboxylic acid derivatives. These derivatives are then in situ reacted with different nucleophiles such as methanol, water or variety of amines affording a-fluoro esters, acids... 

The direct aldol reaction of carboxylic acid derivatives and aldehydes (or ketones) is very difficult. Recently, Kobayashi and co-workers (146) extended the ketones to amides as suitable candidates successfully for the direct aldol reaction. The screening of metal sources revealed that Ba(0-tBu)2 was the better catalyst than Sr(0-iPr)2, Ca(0-iPr)2, or Mg(0-iPr)2, whereas rare earth metals (eg, La(0-iPrls) are catalytically inactive in the presence of p-methoxyphenol. In this aldol reaction, barium enolate formed in situ from barium alkoxide and acylamide and... 

As carboxylic acid derivatives, the enolates derived from N-acyl oxazolidinones approximate the reactivity patterns of thioesters the derived alkali metal enolates display moderate nucleophilicity [82]. Investigations of these systems have revealed that there is a pronounced difference in alkylation rates between the various alkali metal enolates. Thus, although the reactivity of the lithium enolates is limited (reaction temperatures = 0°C), the corresponding sodium enolates undergo allcylation at lower temperatures (-78 °C). This feature resulted in higher observed diastereoselectivity for the corresponding sodium enolates in the alkylation reactions. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

Returning to the main theme in this section, another case where chelation to a metal centre controls reactions involving enolates is seen in complexes of amino acid derivatives. Amino acids are commonly found in metal complexes as the chelated anions in which the carboxylate oxygen and the amino group are co-ordinated to the metal. The co-ordinated amino acid anion could be in the keto (5.6) or enolate (5.7) form. 

Alkylations of acyclic enolates containing a collection of chiral auxiliary groups have been used successfully for the asymmetric synthesis of carboxylic acids. The chiral, nonracemic substrates that have been used include amides, imides, esters, imine derivatives of glycinates and acyl derivatives of chiral transition metals. In these systems either extraannular or chelate-enforced intraannular chirality transfer may control the sense of the alkylation step. 

The dilithium derivatives 19 of carboxylic acids 17 are much more inclined to alkylation at the y position7 to give 20 though a-alkylation is by no means uncommon,8 while extended enolates 22 of amides such as 21 occupy a midway position, ratios of 23 24 varying from 67 33 to 98 2 for different R groups. In both these last two examples the metal can be exchanged for copper to improve y-selectivity, as it seems copper favours conjugate addition both for nucleophiles and for electrophiles.9... 

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... 

The enantioface selective protonation of prochiral enol derivatives is a simple and attractive route for the preparation of optically active carbonyl derivatives. Reports of stoichiometric protonation of metal enolates by a chiral proton source at low temperature leads to optical yields from 20 to 85% ee and yeast esterase catalyzes the hydrolysis of 1-acetoxycycloalkenes with enantioselectivi-ties between 41 and 96% for enol protonation [17,18]. These reactions involve enolates under basic conditions. Hydrolysis of enol ethers under acidic conditions proceeds via a rate-determining carbon protonation and is catalyzed by carboxylic acids [19,20]. Raymond et al. [21] reasoned that a complementary... 

Other derivatives of carboxylic acids and some unusual catalyst systems have found favor. Diarylboryl hexachloroantimonates activate acyl chlorides, carboxylic anhydrides and acyl enolates. A number of metal oxides have been successfully employed. It is worth noting at this point that the chloroacetylium and bromoacetylium ions, which can be prepared in either Freon 113 or sulfur dioxide, are more stable than the acetylium ion and have been shown to give high yields of ketones at low temperatures. ... 

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