Ethyl 3-oxobutanoate alcohol

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

Microwave-mediated transesterification of commercially available neat poly(styr-ene-co-allyl alcohol) with ethyl 3-oxobutanoate, ethyl 3-phenyl-3-oxopropanoate, and diethyl malonate provided the desired polymer-supported /i-dicarbonyl compounds (Scheme 12.18) [65]. Multigram quantities of these interesting building blocks for heterocycle synthesis were obtained simply by exposing the neat mixture of reagents to microwave irradiation in a domestic microwave oven for 10 min. 

Enolate anions of esters, such as ethyl 3-oxobutanoate or diethyl propanedioate, react with aeyl halides or anhydrides to give acylation products. These reactions are carried out best using sodium hydride instead of sodium ethoxide for production of the enol salt, because then no alcohol is liberated to react with the acyl halide or anhydride ... 

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. ... 

A Rh complex of JOSIPHOS, a non-C2 chiral diphosphine, is effective for asymmetric hydrogenation of ethyl 3-oxobutanoate [26]. Hydrogenation of methyl 3-oxobutanoate catalyzed by a BINAP-Ru complex and p-toluenesulfonic acid immobilized in a polydimethylsiloxane membrane matrix gives a chiral alcohol in 92% ee [27]. The reaction rate is comparable with that of the homogeneous system. 

One of the most studies a-chloroketones is ethyl 4-chloro-3-oxobutanoate. (Rj- and (S -enantiomers of the corresponding alcohol were produced by various micro-... 

Figure 16.2-49. Asymmetric reduction of ethyl-4-chloro-3-oxobutanoate catalyzed by an alcohol dehydrogenase (ADH) in recombinant E. coli. The necessary reduction equivalents were derived from the oxidation of isopropanol with the same enzyme.

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). 

For 30 years, Raney nickel, modified with optically active compounds, has been used as an efficient heterogeneous catalyst for the reduction of 3-oxo esters such as methyl or ethyl 3-oxobutanoate. Many optically active compounds as modifiers and many supports other than Raney nickel have been tested 62 63. However, the best system by far is Raney nickel modified with tartaric acid and sodium bromide 64 6t This heterogeneous catalyst gives enantioselectivities close to 90% cc for a broad range of 3-oxo esters (Table 9). The alkyl substituents in the alcohol moiety, as well as in the 4-position of 3-oxobutanoate, can be varied without changing the enantioselectivity of 86-88% ee66. 

The same reaction conditions can also be applied to iV-acyl-2-oxazolidinones, such as 3, and to an ester, methyl (S)-2-benzoylpropanoatc, giving the corresponding alcohols, each with d.r. > 99 1. However, it was not general for esters, giving a nonstereoselective reduction with ethyl 2-methyl-3-oxobutanoate 2. 

In a follow-up study [34] it was discovered that the condensation of cyanothioacetamide with ethyl 2-ethoxymethylene-3-oxobutanoate in the presence of piperidine in fact gave a 41 % yield of 3-cyano-5-ethoxycarbonyl-6-methylpyridine-2(l//)-thione (III.92), and not the isomeric 4-methyl derivative as previously thought [32]. Methylation of (III.92) (Mel-KjCOj-DMF) followed by reduction (LiAlH4-Et20), methoxymethylation, and oxidation with w-chlorobenzoic acid led to the alcohol (III.98) (50%), the ether (Ill.lOO)... 

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