Ethyl 2- -3-oxobutanoate formation

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

The reaction of diketene with some 4-substituted 3-oxobutanoate esters also provides a route to pyran-4-ones, though some attention to the reaction conditions is necessary to avoid the competitive formation of ethyl 2,4-dihydroxybenzoates (79JCS(Pi)529). The two products are considered to arise from a common intermediate (419), cyclization of which can be envisaged through nucleophilic attack by an oxyanion or a carbanion (Scheme 139). 

While enantioselectivity during reduction of ethyl 3-oxobutanoate by baker s yeast (Saccharomyces cerevisiae) to ethyl (S)-3-hydroxybutanoate was found to exceed 99%, yields did not exceed 50-70% (Chin-Joe, 2000). Elimination of two of three causes, evaporation of substrate and product esters and absorption or adsorption of the two esters by the yeast cells, increased the yield to 85%. Alleviation of hydrolysis of the two esters by yeast enzymes could increase the yield even more. Low supply rates of glucose as an electron donor provided the most efficient strategy for electron donor provision and yielded a high enantiomeric excess of ethyl (S)-3-hydroxybutanoate, low by-product formation and biomass increase, with a low oxygen requirement(Chin-Joe, 2001). 

While in the presence of 2-oxoglutaric acid neither decarboxylation nor acyloin condensation had been observed, as expected from previously published results (75), we succeeded in the enzymatic conversion of the mono ethyl ester 3 to ethyl 4-oxobutanoate 4, using both whole yeast cells (Saccharomyces cerevisiae) and purified PDC. The oxo ester 4 served as substrate for a second reaction catalyzed by PDC. Formation of a new carbon-carbon bond was accomplished in the presence of pyruvic acid which acted as donor of a C2-unit. Thus, ethyl 4-hydroxy-5-oxohexanoate 5 was obtained for the first time as the result of an enzymatic acyloin condensation. Finally, traces of acid induced the lactonization of hydroxyester 5, indicating it as direct precursor of solerone 1 (Figure 1). 

The biogenesis of solerone 1 and related compounds was successfully rationalized by biomimetic model reactions. As key step we established the pyruvate decarboxylase catalyzed acyloin condensation of pyruvic acid with ethyl 4-oxobutanoate 4 or ethyl 2-oxoglutarate 3 with acetaldehyde. The importance of the ethyl ester function in 3 and 4 serving as substrates for the enzymatic formation of a-hydroxy ketones 5 and 6 was demonstrated. The identification of six yet unknown sherry compounds including acyloins 5 and 6, which have been synthesized for the first time, confirmed the relevance of the biosynthetic pathway. Application of MDGC-MS allowed the enantiodifferentiation of a-ketols and related lactones in complex sherry samples and disclosed details of their biogenetic relationship. 

Cyclopropyl isocyanates react effectively with various nucleophilic reagents. Ammonia and amines yield urea derivatives, " alcohols and phenols afford carbama-tg5,i5 5,164,181,184,185 )V )y-dimethylhydrazine gives a semicarbazide derivative, whereas cyclo-propylammonium chlorides are obtained in refluxing hydrochloric acid. The yields are usually very good. When more highly functionalized nucleophiles are employed, such as the enolate from ethyl 4-chloro-3-oxobutanoate, more complex molecules can be obtained, e.g. the formation of furanone derivative 15. ... 

In 1887, Claisen and Lowman reported that the condensation of 2 mol of an ester, such as ethyl acetate, in the presence of base gave the p-keto ester, ethyl acetoacetate (ethyl 3-oxobutanoate equation 1). The intramolecular equivalent was recognized by Dieckmann in 1894. He found that heating an adipic acid ester with sodium and a trace of alcohol led to cyclization, with the formation of a cyclopentanone (equation 2). The reaction was, at an early stage, extended to the acylation of ketones. Claisen himself reported the base-catalyzed reaction of acetophenone and ethyl benzoate to give dibenzoylmethane in 1887. This reaction, too, has an intramolecular parallel. The acylation of ketones with esters and other acid derivatives is sometimes called a Claisen condensation, although this usage is criticized by some writers and avoided by others. A widely used example of ketone acylation is the synthesis of a-formyl (hydroxymethylene) ketones (equation 3). Intramolecular variants of this reaction include the classical synthesis of dimedone (Scheme 1). 

Formation of the dianion of ethyl 3-oxobutanoate 5 with two equivalents of lithium diisopropylamide (LDA) in tetrahydrofuran followed by alkylation with allyl or propargyl bromide provided jS-keto esters 6a,b in 62% and 75% yield, respectively. Condensation of these esters with methyl or phenyl hydrazine in refluxing ethanol yielded the corresponding pyrazol-3-ones 7a,b in excellent yield (99TL3535) (Scheme 2). 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

Scheme 14.20. A pathway for the formation of 2,3-dunethylpyrrole-2-carboxyaldehyde from ethyl acetoacetate (ethyl 3-oxobutanoate). DMF = A,A-dimethylformamide.

A similar reaction was published by Song et al. in 2013 (Scheme 13.29) [47]. 2-Hydroxynaphthoquinone 75 was reacted with aromatic aldehydes 97 and ethyl 4,4,4-lrifluoro-3-oxobutanoate 98 catalyzed by a mixture of ammonium acetate and acetic acid (25mol% each). A Knoevenagel-Michael addition sequence was followed by hemiketal formation to give the desired product 99 in moderate to good yields. Dehydration of the product yielded the 4 f-pyran derivatives. 

Step 2. Enamine formation of ammonia with ethyl 3-oxobutanoate... 

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