Ethyl hexanoate reduction

Interactions between mannoproteins from yeast cell walls and aroma compounds have been studied by Langourieux and Crouzet (1997). They performed the experiments with crude mannoproteins extracts and observed no effect on the activity coefficient of isoamyl acetate, and a slight decrease on the activity coefficients of ethyl hexanoate and limonene. However, when they purified the mannoproteins or when they used a model glycopeptide, they did not observe any effect on limonene volatility. If the synthetic peptide was heat treated (50 °C), they observed a slight reduction on the activity coefficient of limonene. This was explained by an increase in the hydrophobicity of the glycopeptide after the thermal treatment. 

The reduction of harder substrates such as phenol requires harder catalysts (e. g., combinations with Lewis acids).The catalyst combination Co(2-ethyl hexanoate)2/ AlEtj allows the reduction of phenol to cyclohexanol to be carried out under mild conditions with over 90 % selectivity [Til]. 

In reaction 7.2.2.1, the reduction of Cr " to Cr " by AlEtj is accompanied by the production of ethane and ethylene. Reaction 1.2.22 is basically a ligand exchange reaction where the remaining ethyl hexanoate ligands are replaced by the chlorides. Finally, the catalytic intermediate 7.10 is produced according to reaction 7.2.2.3. In this reaction 2,6-dimethyl pyrrole (LH) loses a proton and coordinates to the metal. 

D. B. Brzozowski, R. L. Hanson, and L. J. Szarka, Enantioselective microbial reduction of 3,5-dioxo-6-(benzyloxy) hexanoic add, ethyl ester, Enzyme Microb. Technol. 1993, 15, 1014-1021. 

So far, most microorganisms and enzymes derived therefrom have been used in the reduction of a single keto group of p-keto or a-keto compounds [68-71], Recently, Patel et al. [72] have demonstrated the stereoselective reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester (41), to (3,S, 5R)-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester (42a) (Fig. 14). The compound (42a) is a key chiral intermediate required for the chemical synthesis of [4-[4a,6P(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one, compound R-( + )-(43), a new anticholesterol drug that acts by inhibition of HMG CoA reductase [73], Among various microbial cultures evaluated for the stereoselective reduction of diketone (41), cell suspensions of Aci-... 

The enantioselective reduction of the diketoester ethyl 3,5-dioxo-6-(benzyloxy) hexanoate (39) to the diol ethyl (31 ,5S)-dihydroxy-6-(benzyloxy)hexanoate (40a) has been demonstrated by Acinetobacter calcoaceticus SC 13876 in a yield of 85% with a diastereoselectivity of 97%. Cell extracts of A. calcoaceticus SC 13876 in the presence of NAD+, glucose, and glucose dehydrogenase reduced 39 to the corresponding isomeric monohydroxy compounds 42 and 43, which were further reduced to the compound 40a. A reaction yield of 92% and enantiomeric purity of 98% were obtained when the reaction was carried out at lOg/L in a 1-L batch (Patel et al., 1993). 

To determine the stereoselectivity of diastereotopic proton abstraction from the Pro-R methylene group of ACPC (9) in the fragmentation (occurring between Pro-S p-C and a-C), 2-ethyl-[3-Di]-ACPC (8a) was prepared with the ethyl side chain and deuterium substituent in cis relationship. Incubation of this compound followed by in situ reductive enzymatic trapping with (25)-lactate dehydrogenase yielded 2-hydroxy-[3-D]-hexanoate where the R,5-placement of D was analyzed by NMR and the D-content by mass spectrometry. These results had defined the stereoselectivity for )5-H-abstraction from the Pro-R methylene of 2-ethyl-ACPC (8) as the proton removal in the overall fragmentation process and by analogy the same in ACPC (9). These results place stereochemical constraints on the ACPC deaminase process and were accommodated in Scheme 10. 

S) fi"-D-Galactometasaccharinic Acid.—Kiliani and Sanda reduced their parasaccharinic acid in the usual manner with hydriodic acid and red phosphorus. The product was a hexanoic lactone whose boiling point (217.5°) was precisely intermediate between that (220°) of the n-hexanoic 1,4-lactone obtained by a similar reduction of a -D-galactometasaccharinic acid and that (215°) reported for 2-ethylbutyro-l, 4-lactone. Kiliani, however, chose the latter structure for his lactone, since the corresponding acid, like DL-(2-ethyl-4-hydroxybutyric acid) and unlike either the enantiomor-... 

FIGURE 16.17 Anticholesterol drug 64. Diastereoselective enzymatic reduction of 3,5-dioxo-6-(benzyloxy) hexanoic acid, ethyl ester 62. 

Selective reduction. A soln. of borane in tetrahydrofuran added dropwise at -18 during 19 min. to a mixture of adipic acid monoethyl ester and tetrahydrofuran, stirred and allowed to warm to room temp, during 16 hrs. -> ethyl 6-hydroxy-hexanoate. Y 75-88%. - Other functional groups such as cyano, halogeno, keto, or nitro, are likewise retained during this highly convenient reduction. F. e., also reduction of sterically hindered acids, s. N. M. Yoon, H. C. Brown et al., J. Org. Chem. 38, 2786 (1973) 2-aminoalcohols from a-aminocarboxylic acids s. M. L. Anhoury et al., Soc. Perkin 11974,191 via reduction with aq. NaBH of enolesters obtained from the acids and N-ethyl-5-phenylisoxazolium 3 -sulfonate (s. Synth. Meth. 16, 448) s. P. L. Hall and R. B. Perfetti, J. Org. Chem. 39, 111 (1974). 

Ethyl (3R,5S)-dihydroxy-6-(benzyloxy)hexanoate 72 (Figure 11.1) is a key chiral intermediate for the s)mthesis of Atorvastatin 12, and Rosuvastatin 13, anticholesterol drugs that act by inhibiting HMG CoA reductase [132-134]. The enantioselective reduction of a diketone, ethyl 3,5-dioxo-6-(benzyloxy) hexanoate 73 to ethyl (3R,5S)-dihydroxy-6-(benzyloxy) hexanoate 72 (Figure 11.21) was demonstrated by cell suspensions of Acinetobacter calcoace-ticus sc 13876 [135,136]. On reduction of 73 by cell suspensions, the syn-4 and anti-8 dihydroxy esters were formed in the ratio of about 87 13, 83 17, 76 24 after 24 h at 2, 5 and 10 g/L of substrate input, respectively. There was no significant peak due to a monohydroxy ester. Chiral HPLC determined that the desired syn-(3R,5S)-72 was the major product wdth 99.4% ee. Almost complete (>95%) conversion of the diketoester 73 to dihydroxy ester 72 in 24 h... 

Three different ketoredurtases were purified to homogeneity from cell extracts of A. ealcoaceticus SC 13876 and their biochemical properties were compared. Reductase I only catalyzes the reduction of ethyl diketoester 73 to its monohydroxy products whereas reductase II catalyzes the formation of dihydroxy products from monohydroxy substrates. A third reductase (111) was identified which catalyzes the reduction of diketoester 73 to syn-(3R,5S)-dihydroxy ester 72 [136]. Reductase III has been cloned and expressed in E. coli [137] and reduced the diketoester 73 to syn-(3R,5S)-dihydroxy ester 72 in 99.3% yield, 100% ee, and 99.8% de [137]. Ethyl (3R,5S)-dihydroxy-6-(benzyloxy) hexanoate 72 is the precursor of Kaneka alcohol 77, a key intermediate for the synthesis of Arotvas-tatin 12, and Rosuvastatin 13. 

An enz3unatic process was developed for the reduction of a diketone, 3,5-dioxo-6-(benzyloxy) hexanoic acid, ethyl ester 105 to (3R,5S)-dihydroxy-6-(benzyloxy) hexanoic acid, ethyl ester 103 (Figure 4.29) by cells ot Acinetobacter calcoaceticus SC 13876 [133,134]. Both the si/n-4 and anti-8 dihydroxy esters were formed in the ratio of about 76 24 after 24h at lOg/1 of substrate 105 input. There was no significant peak due to a... 

Regio- and enantioselective reduction of diketones have been conducted successfully by biocafalysis. Examples for the reduction of diketones to hydroxyl ketones and diols are shown in Figure 11.11. Figure 11.11a shows the preparation of a key intermediafe for the synthesis of terpenoids by a baker s yeast-catalyzed reduction of a o-cyclohexanedione. DMSO (10%) was used to solubilize the substrate [67]. Figure 11.11b shows the reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid ethyl ester by Acinetobacter sp. SC 13874 to the corresponding si/n-(3R,5S)-diol, potential intermediates for die s)mthesis of HMG-CoA reducfase inhibitors, in 99.4% ee with 52-74% de depending on substrate concentrations (74% de in 2g/l and 52% de in lOg/1) [66]. After the reaction, XAD-16 resin was added to facilitate the recovery process by adsorbing the product. 

Guo Z, Chen Y, Goswami A, Hanson RL, Patel RN. Synthesis of ethyl and t-butyl (3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction. Tetrahedron Asymmetry 2006 17 1589-1602. 

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