Enolate anions from enols

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

Bromination of the enolate anion from the reaction of 3j -acetoxypregna-5,16-dien-20-one (1) with methylmagnesium bromide in the presence of cuprous chloride affords (after treatment with sodium iodide to dehalo-genate any 5,6-dibromide) a mixture of 17a-bromo- and 17)5-bromo-16a-methyl compounds (11) and (12) in a ratio 9 1. The 17a-iodides can be obtained in an analogous reaction. 

FORMATION AND ALKYLATION OF SPECIFIC ENOLATE ANIONS FROM AN UNSYMMETRICAL KETONE 2-BENZYL-2-METHYLCY-CL0HEXAN0NE AND 2-BENZYL— 6-METHYLCYCLOHEXANONE, 52,... 

We now have examples of the generation of enolate anions from carbonyl compounds, and their potential as nucleophiles in simple Sn2 reactions. However, we must not lose sight of the potential of a carbonyl compound to act as an electrophile. This section, the aldol reaction, is concerned with enolate anion... 

Enolate anions from carboxylic acid derivatives... 

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. 

ENOLATE ANIONS FROM CARBOXYLIC ACID DERIVAHVES... 

Nucleophilic addition of an enolate anion from a carboxylic acid derivative onto an aldehyde or ketone is simply an aldol-type reaction (see Section 10.3). 

The Claisen reaction may be visualized as initial formation of an enolate anion from one molecule of ester, followed by nucleophilic attack of this species on to the carbonyl group of a second molecule. The addition anion then loses ethoxide as leaving group, with reformation of the carbonyl group. 

In Box 10.12 we saw that nature employs a Claisen reaction between two molecules of acetyl-CoA to form acetoacetyl-CoA as the first step in the biosynthesis of mevalonic acid and subsequenfiy cholesterol. This was a direct analogy for the Claisen reaction between two molecules of ethyl acetate. In fact, in nature, the formation of acetoacetyl-CoA by this particular reaction using the enolate anion from acetyl-CoA is pretty rare. 

The nucleophile will be the enolate anion from ethyl acetoacetate, which attacks the P-carbon of the electrophile, generating an addition complex that then acquires a proton at the a-position with restoration of the carbonyl group. The product is a 8-ketoester with an ester side-chain that has a... 

It is conceptually easier to consider initially the aldol reaction rather than the reverse aldol reaction. This involves generating an enolate anion from the dihydroxyacetone phosphate by removing a proton from the position a to the ketone group. This enolate anion then behaves as a nucleophile towards the aldehyde group of glyceraldehyde 3-phosphate, and an addition reaction occurs, which is completed by abstraction of a proton, typically from solvent. In the reverse reaction, the leaving group would be the enolate anion of dihydroxyacetone phosphate. 

The utility of the creation of a y-lactone enolate through 1,4-addition of a carbanion and its interception by an electrophile has also been demonstrated in other classes of natural products, e.g., in the enantioselective synthesis of 10-oxa-l 1-methyl PGE2 analogues22. This synthesis starts with 1,4-addition of the sulfone-stabilized anion from 27 to ( + )-(S )-4-methyl-2-buteno-lide which has been prepared in three steps from (—)-(S)-l,2-epoxypropane. The intermediate enolate 28 is reacted with the acetylenic iodide to give the trisubstituted diastereomeric mixture of lactones 29, which is eventually converted into the pure compound 30, both reactions occurring with high diastereoselectivity. 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

Reaction of that with potassium tert-butoxide affords the corresponding carbanion this is thought to first add to the enone in (5-3). The anion from the reaction with a second equivalent of base then adds to the enone function to form the spiw ring. The fact that the product from this reaction has the same relative stereochemistry as the natural product is attributed to the better overlap of the enolate with the triple bond in the transition state leading to that isomer. The product from the reaction is thus + griseo-fulvin (5-6) [5]. 

The succinct synthesis of warfarin starts with condensation of ort/zo-hydroxy-acetophenone (1-2) with ethyl carbonate to give the (3-ketoester (1-3) as the presumed intermediate shown in the enol form. Attack of the phenoxide on the ester grouping will lead to cyclization and the formation of the coumarin (1-4). Conjugate addition of the anion from that product to methyl styryl ketone (1-5) gives the corresponding Michael adduct and thus warfarin (1-6) [1]. 

Thus, treatment of the benzamide (35-1) from 2-phenethylamine with phosphorus oxychloride probably results in an initial formation of a transient enol chloride this then cycUzes to (35-2) under reaction conditions. The imine is then reduced with sodium borohydride. Resolution by means of the tartrate salt affords (35-3) in optically pure form. Acylation of that intermediate with ethyl chloroformate leads to carbamate (35-4). Reaction of this last with the anion from chiral quiniclidol (35-5) interestingly results in the equivalent of an ester interchange. There is thus obtained the anticholinergic agent solifenacin (35-6) [40]. 

Reaction of phthalic anhydride (70-1) with the ylide from ethyl triphenylphos-phoniumacetate leads to the condensation product (70-2), which in effect consists of a cyclic enol anhydride. Treatment of this product with hydrazine leads to the hydrazone-hydrazide (70-3). Alkylation of the anion from removal of the hydrazide proton with the substituted benzyl bromide (70-4) affords the alkylation product (70-5). Saponification then leads to the aldose reductase inhibitor ponalrestat (70-6) [79]. 

The 1carbanions1 we formed using the carbonyl group are like enols and are called enolate anions. Draw the enolate anion from this ketone 0... 

Now form the enolate anion from this ketone ... 

The enolates from p-dicarbonyl compounds are so easily formed that they can be used in a very simple carbon-carbon bond forming reaction outside our general scheme. Consider what would happen if you made the enolate anion from the compound below and reacted it with methyl iodide. 

BUILDING ORGANIC MOLECULES, 5 6 Make the enolate anion from acetaldehyde and add it to the carbonyl group of another molecule of acetaldehyde. 

A kind of enolic component we haven t mentioned yet is the acid anhydride. If you wanted to make the enolate anion from acetic anhydride, what base would you recommend ... 

Draw the enolate anion from cyanoacetic ester EtOOC.CH2.CN, and show how it is stable. 

Strong bases in dry solvents are usually used in organic synthesis to generate reactive enol anions from ketones. Nevertheless, the kinetic studies discussed here were mostly performed on aqueous solutions. Apart from the relevance of this medium for biochemical reactions and green chemistry, it has the advantage of a well-defined pH-scale permitting quantitative studies of acid and base catalysis. 

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