Ethyl acetate enolate

A relatively concise synthesis of a compactin lactone (99) derivative makes use of 590 as the source of chirality (Scheme 93) [142]. Addition of ethyl acetate enolate to 590 produces a 1 1 mixture of aldols 633 in 58% yield. After silylation of the hydroxyl group, cleavage of the acetonide furnishes lactone 635 as a crystalline solid. Tosylation of the primary alcohol and separation of the isomers furnishes 636 (47% yield) and 637 (44% yield). The desired isomer 636 is a suitably protected and functionalized version of compactin lactone . 

It is readily prepared by the action of metallic sodium on dry ethyl acetate. The reaction, which occurs only in the presence of a trace of ethanol, is complex, but may be considered (in effect) as a condensation of two molecules of ethyl acetate under the influence of sodium ethoxide, the sodium derivative of the enol form being thus obtained. Clearly, only a trace of ethanol is thus initially... 

Step 1 Proton abstraction from the a carbon atom of ethyl acetate to give the corresponding enolate... 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

Strategy A mixed Claisen reaction is effective when only one of the two partners has an acidic cy hydrogen atom. In the present case, ethyl acetate can be converted into its enolate ion, but cliethyl oxalate cannot. Thus, ethyl acetate acts as the donor and diethyl oxalate as the acceptor. 

Our first experiments were performed with benzene as solvent, which generally provides very good yields.3 Use of the less hazardous solvent ethyl acetate gives inferior yields if the silyl enol ether contains triethyiamine. Ethyl acetate was distilled from potassium carbonate. 

The Mechanism of the Ethyl Acetoacetate Synthesis—Before the tautomerism of ethyl acetoacetate is discussed we must consider the mechanism of its formation, which for decades has been the subject of lively discussion and was conclusively explained only in recent years (Scheibler). It has been found that even the C=0-group of the simple carboxylic esters, although in other respects inferior in activity to the true carbonyl group, can be enolised by alkali metals. Thus ethyl acetate is converted by potassium into the potassium salt of the tautomeric enol with evolution of hydrogen ... 

It is not only the esters of organic acids which combine, in the manner of the ethyl acetoacetate synthesis , with the enolates of ketones and of esters an analogous behaviour is shown by the esters of nitrous and nitric, acids. The process which leads to the formation of isonitroso-and atinitro-compounds yields products fundamentally similar to those already described just as with ethyl acetate the group CO.CHs enters, so here, the NO- and N02-groups are involved, and enolise " exactly as does >O=0 ... 

Or, the conversion of the ketonic form of ethyl acetic ester to the enolic form can be explained ... 

Methyllithium (4.0 mmol, 1.0 M in diethyl ether, 4.0 mL) was added to a suspension of CuCN (2.0 mmol, 0.18 g) in THF (10 mL) at -75°C. The reaction mixture was then stirred until a clear solution was obtained and allowed to warm to room temperature. The appropriate (Z)-vinylic telluride A (2.0 mmol) or B (1.0 mmol) was added and stirred for 45 min. The solution was cooled back to -75°C and the corresponding enone (2.2 mmol) was added. After 20 min, chlorotrimethylsilane (2.6 mmol, 0.60 g) diluted in THF (5 mL) was added. The reaction mixture was stirred for 1 h, allowed to warm to room temperature and then treated with 1 1 solution of saturated aqueous NH4CI and NH4OH (20 mL), extracted with ethyl acetate (3x20 mL), dried, evaporated and the residue was purified by Kiigelrohr distillation affording the silyl enol ethers. 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

Acetyl-CoA is a good biochemical reagent for two main reasons. First, the a-protons are more acidic than those in ethyl acetate, comparable in fact to a ketone, and this increases the likelihood of generating an enolate anion. As explained above, this derives from sulfur being larger than oxygen, so that electron donation from the lone pair that would stabilize the neutral ester is considerably reduced. This means it is easier for acetyl-CoA to lose a proton and become a nucleophile. Second, acetyl-CoA is actually a better electrophile than ethyl acetate. 

Alternatively, and much more satisfactory from a synthetic point of view, it is possible to carry out a two-stage process, forming the enolate anion first. We also saw this approach with a mixed aldol reaction (see Section 10.3). Thus, ethyl acetate could be converted into its enolate anion by reaction with the strong base EDA in a reaction that is essentially irreversible (see Section 10.2). 

Let US use a systematic approach to consider what product is most likely to result when a mixture of an ester and a ketone, both capable of forming enolate anions, is treated with base. For example, consider an ethyl acetate-acetone mixture treated with sodium hydride in ether solution. 

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. 

Chiral P-formyl-p-hydroxycarboxylic esters were also obtained by the employment of either lithium or zinc enolate of ethyl acetate in place of Grignard reagents in the above-mentioned reaction in moderate to excellent optical purity (62 to 92 % e.e.)122). 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

Mechanism. Removal of an a-hydrogen from the ethyl acetate by NaOEt produces a resonance-stabilized enolate anion. 

Nucleophilic attack of the enolate anion to the carhonyl carhon of another ethyl acetate gives an alkoxide tetrahedral intermediate. The resulting alkoxide reforms the carhonyl group hy ejecting the ethoxide anion. This ethoxide anion deprotonates the a-hydrogen, and produces a new enolate anion of the resulting condensed product, which is protonated in the next step upon acidification during work-up and yields the ethyl acetoacetate. 

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