4-Chloroacetoacetate ethyl ester

Production of Chiral 4-Chloro-3-Hydroxybutanoate Ethyl Ester by Microbial Asymmetric Reduction of 4-Chloroacetoacetate Ethyl Ester... 

The reduction of 4-chloroacetoacetate ethyl ester (CAAE) to 4-chloro-3-hydroxy-butanoate ethyl ester (CHBE) usually proceeds stereospecifically [54, 55]. This activity is widely distributed in yeasts, molds and bacteria, most of which give the (S)-enantiomer. Sporobolomyces salmonicolor was found to produce the (l )-enan-tiomer predominantly (62% e. e.) with high molar conversion [54,55], and several Candida yeasts formed (S)-CHBE of high optical purity (> 90% e. e.) [54,55]. 

Bromo- and 4-chloroacetoacetic ethyl ester react in the same manner as do a-halo ketones (78JHC401 80JHC1321 91AP49). 

Chlormolysis of tetraethylthiuram disulfide, 35, 55 Chloroacetamide, 30, 22 Chloroacetic acid, 39, 78 a-Chloroacetoacetic acid, ethyl ester, 33, 43, 45... 

Aryl-4-formylsydnone 4 -phenylthiosemicarbazones 183 were treated with ethyl 2-chloroacetoacetate and 2-bromoacetophenone in buffer systems of sodium acetate and acetic acid, to produce anti-oxidants 2-[(3-arylsyd-non-4-ylmethylene)-hydrazono]-4-methyl-3-phenyl-2,3-dihydrothiazole-5-carboxylic acid ethyl esters 184 and 3,4-diphenyl-2-[(3-arylsydnon-4-ylmethylene)hydrazono]-2,3-dihydrothiazoles 185 in good yields (Scheme 71) <2004BMC4633>. 

Meguro and co-workers used this method, among others, to prepare a variety of potential antidiabetic agents. For example, cyclization of cyclohexanecarbox-amide with ethyl 4-chloroacetoacetate gave 2-cyclohexyl-4-oxazoleacetic acid 199, albeit in poor yield (Scheme 1.54). Similarly, Ohkubo and co-workersprepared 4-(nitrophenyl)-2-phenyl-5-oxazolecarboxylic acid ethyl esters 200a and 200b as precursors to potential cerebral protective agents. 

A first group of ISPR systems, most commonly with reductions, is those using the addition of a resin or porous adsorbent to remove the product. Early work on ketone reduction showed already that hydrolysis and also loss of ee could be overcome by maintaining low concentrations of the substrate in the reaction. One successful approach involves the controlled release of the substrate from a resin placed in the reaction media. For example, Amberlite XAD-2 resin enhanced the asymmetric reduction of ethyl 4-chloroacetoacetate to (S)-4hydroxybutyric acid ethyl ester catalyzed by yeast [34]. In the subsequent development of the technolt, the approach was extended to simultaneous substrate supply and product removal. A similar approach was developed for the asymmetric reduction of 6-bromo-P-tetralone [35]. 

GL 4] [R 5] [P 5] The rate of the fluorination of y0-keto esters is usually correlated with the enol concentration or the rate of enol formation as this species is actually fluorinated [15, 16]. For the fluorination of ethyl 2-chloroacetoacetate in a micro reactor, much higher yields were found as expected from such relationships and as compared with conventional batch processing which has only low conversion. Obviously, the fluorinated metal surface of the micro channel promotes the enol formation. 

Related methods. The replacement of 3-chloro-2-butanone (or of similar a-halogenated ketones) by ethyl a-chloroacetoacetate [Graffenried and Kostanecki, 1910) gives aryloxyacetoacetates (77)]. Cyclodehydration of esters (77) (with H2S04) gives good yields (60-70%) of coumarilic esters (78),232 which are sometimes difficult to synthesize by other methods. 

The ammonium formate in formic acid procedure has rendered possible the first preparation of isomeric 4,5-disubstituted oxazoles.03101 Bredereck, Gompper, and Reich101 have reported the anomalous behavior of certain long-chain a-bromo ketones a single a-bromo ketone on reaction with ammonium formate in formic acid gives a mixture of two isomeric oxazoles. Refluxing of a-bromo ketones or of a-chloro-/3-keto esters with ammonium acetate in acetic acid results in the formation of substituted 2-methyl-oxazoles.40 102 Ethyl a-chloroacetoacetate on heating with ammonium carbonate or formamide in formic acid yields 4-methyloxazole-5-carboxylic ester.40 103... 

Interestingly, reduction of ethyl 4-chloroacetoacetate with Baker s yeast gave predominantly the corresponding (5)-alcohol (i.e. the opposite configuration from that of the alcohol from ethyl acetoacetate itself) (7.103), but the corresponding octyl ester gave almost entirely the (/f)-alcohol. The stereochemistry of the reduction depends on the shape of the molecule and it is likely that the yeast contains at least two different oxidoreductase enzymes which produce the two enantiomeric alcohols at different rates. 

Essential for the economics of the overall process is a simple way to make the amino-component available. A pivotal intermediate is therefore the R)-4-cyano-3-hydroxybutyrate ester, which is accessible by various routes. [397] In variant a) ethyl 4-chloroacetoacetate is reduced enantioselectively with a ketoreductase, and the chlorine is replaced enzymatically by cyanide (Codexis technology). [398]... 

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