A-Hydroxy-P-keto esters

HYDROXY CARBOXYLIC ACIDS Dicyclohexylborane a -HY DROXY-a, [J-ENONES m-Chloropcrbcnzoic acid y-HYDROXY-a,B-ENONES Potassium peroxomonosulfate. a HYDROXY ESTERS Tris(phenylthio)methyllithium. a-HYDROXY-p-KETO ESTERS ... 

P-hydroxy esters Aceto(carbonyl)cyclo-pentadienyl(triphenylphosphine)iron. (S)-(—)-Menthyl p-toluenesulfinate. 7-hydroxy esters Titanium(IV) chloride. a-HYDROXY- P-keto esters Lithium diiso-propylamide. 

Furthermore, they demonstrated that the optically active a-hydroxy-P-keto esters 105 obtained undergo diastereoselective reduction giving anti-a,P-diols. 

Therefore, they accomplished the reduction of a-hydroxy-P-keto ester 25 by baker s yeast immobilized over calcium alginate at pH 4.0 (Scheme 12.12). The produced dihydroxy ester 2Sc was then converted to optically active owti-(4S,51 )-5-hydroxy-Y-decalactone 26 [25a]. 

Application of the Ritter reaction conditions on y-hydroxy-a,P-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or y-A-acylamino-P-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The y-A-acylamino-P-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCI3 <06TL4385>. 

The enzyme recLBADH is the first catalyst that has been found to allow the highly regio- and enantioselective synthesis of 5-hydroxy-P-keto esters by reduction of the respective diketo esters. This enzymatic reaction is of enormous preparative value. The substrates are readily available by acylation of P-keto ester bisenolates and the reaction only requires a simple batch technique which is easy to scale up. Reduction of the chlorinated compound la has been performed routinely on a 75 g scale in our laboratory (8 L fed batch), yielding (S)-2a in an isolated yield of 84% [10]. 

The surface chemistry of Ca in y-BL and MF is very similar to that of Li in these solvents. In y-BL, the surface species include Ca butyrate, derivatives of y-hydroxy butyrate, and a cyclic P-keto ester calcium salt (see Table 3). In MF, calcium formate is the major surface species. 

Reduction of a-alkoxy-p-keto esters.1 t-Butoxy esters of a-alkoxy-/i-keto acids are reduced by NaBH4 in 2-propanol selectively to erythro-a-a.lkoxy-fi-hydroxy curboxylates. The report suggests that the selectivity results from reduction of an intermediate five-membered chelate involving Na+ and, in fact, no stereoselectivity is observed if a crown ether is present. 

Hydrogenation of racemic a-monosubstituted P-keto esters normally results in four possible stereoisomeric hydroxy esters. Under appropriate conditions, however, a single stereoisomer with two contiguous stereogenic centers can be ob-... 

HYDROXY-P-KETO ESTERS Titanium(IV) chloride. a-HYDROXYMETHYL KETONES Formaldehyde. 

Reformatsky reactions. A practical synthesis of P-hydroxy-a,a-difluoroalkanoic esters involves halodifluoroacetic esters and induction by Smij. a-Bromoalkanoic esters undergo self-condensation, and if they are quenched by carbonyl compounds, 5-hydroxy-p-keto esters are formed as products. ... 

The most important esters in connection with Li batteries are y-butyrolactone (BL) and methyl formate (ME). Li is apparently stable in both solvents due to passivation. Electrolysis of BL on noble metal electrodes produces a cyclic P-keto ester anion which is a product of a nucleophilic reaction between a y-butyrolactone anion (produced by deprotonation in position a to the carbonyl) and another y-BL molecule. FTIR spectra measured from Li electrodes stored in y-BL indicate the formation of two major surface species the Li butyrate and the dilithium cyclic P-keto ester dianion. The identification of these products and related experimental work is described in detail in Refs. 150 and 189. Scheme 3 shows the reduction patterns of y-BL on lithium surfaces (also see product distribution in Table 3). In the presence of water, the LiOH formed on the Li surfaces due to H2O reduction attacks the y-BL nucleophilically to form derivatives of y-hydroxy butyrate as the major surface species [18] [e.g., LiO(CH2COOLi)]. We have evidence that y-BL may be nucleophilically attacked by surface Li20, thus forming LiO(CH2)3COOLi, which substitutes for part of the surface Li oxide [18]. MF is reduced on Li surfaces to form Li formate as the major surface species [4], LiOCH3, which is also an expected reduction product of MF on Li, was not detected as a major component in the surface films formed on Li surfaces in MF solutions [4]. The reduction paths of MF on Li and their product analysis are presented in Scheme 3 and Table 3. 

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

Xu and coworkers reported several robust carbonyl reductases discovered via in silico data rnining approaches and developed a set of water-based bioreduction processes for efficient synthesis of functionalized optically active a- and P-hydroxy esters [2-4]. As shown in Table 9.1, several a- and P-keto esters were asymmetrically reduced at high loads using a carbonyl reductase mined from Candida abrata... 

Marine microalgae have also been used for the stereoselective reduction of a- and P-keto esters to the corresponding hydroxy esters [30]. The marine algae were photoautotrophically cultivated in synthetic seawater at 20 °C under constant aeration and illumination by white fluorescent light. In particular, Nannochloropsis sp. catalyzed the reduction of ethyl 2-methyl-3-oxobutanoate 20 to the anti-hydroxy ester (2S,3S)-20b with high conversion, excellent diastereoselectivity syn/anti = 1 99), and high enantioselectivity (anti >99%, syn 98%) (Scheme 12.14). 

In 2000, the group of Stewart in Florida reported the asymmetric synthesis of P-hydroxy esters and a-alkyl-P-hydroxy esters by recombinant E. cdi expressing enzymes from baker s yeast [32]. In all cases, a single diastereomer was produced (Scheme 12.15). Both strains yielded the syn-(3S)-alcohols 20a, 21a, 23a, and 28a, with high ee values and in moderate chemical yields. When racemic a-substituted P-keto esters 20, 21, 23, and 28 were employed as substrates, DKRs resulted in almost complete conversion of the substrate, due to facile racemization at the a-position. 

A few years later, the same research group demonstrated the bioreduction of a-chloro-P keto esters 29-33. The production of at least two of the four possible a-chlorO P-hydroxy ester diastereomers with high stereoselectivities, by using whole cells of an E. coli strain overexpressing a single yeast reductase identified from screening studies, was successfully accomplished (Scheme 12.16) [33]. 

The same enzymes were also applied to the DKR of a-alkyl-P-keto esters, such as 20, 21, 43, and 44, for the preparation of the corresponding hydroxy esters with excellent chemical and optical purity, as shown in Scheme 12.22 [55a,57j. In this case, substrate 43 was selected for the asymmetric chemoenzymatic synthesis of the aggregation pheromone 45 (sitophilate) of the granary weevil Sitophilus granarius (Scheme 12.23) [57]. 

Shimizu et al. have reported the synthesis of the 4-hydroxy-6-lactone component of mevinic acid by lactonization of a 6-hydroxy ester [53] (Scheme 16). Reaction of lithio-fcrt-butylacetate with p-trichloromethyl-p-lactone 80 gave 6-hydroxy-p-keto ester 81. A stereoselective syn reduction of the ketone, lactcmization, and protection of the secOTidaiy alcohol provided the lactone. The trichloromethyl group was reduced with tri- -butyltin hydride to furnish 6-chloromethyl lactone intermediate 84. 

Note also that if another ester, of general formula R-COOCjHj, were used in place of benzaldehyde in the above reaction, a similar complex would be formed, and on acidification would give an unstable p-hydroxy-P-ethoxy ester, which would very readily lose ethanol with the formation of a 3-keto-ester. 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

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