1- hexanoate, enzymatic

Xie, Z., Feng, J., Garcia, E. et al. (2006) Cloning and optimization of a nitrilase for the synthesis of (3S)-3-cyano-5-methyl hexanoic acid. Journal of Molecular Catalysis B Enzymatic, 41, 75-80. 

Eor example, in the intestinal tract and liver of both humans and animals DEHP is rapidly hydrolyzed by esterases to yield mono-(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol [25]. The latter metabolite is subsequently oxidized enzymatically to 2-ethyl hexanoic acid (2-EHXA) [26]. MEHP, 2-hethylhexanol, and/or their metabolites are the immediate inducers of the majority of enzymes known to be affected by exposure of DEHP [27]. Due to the high importance of the primary and secondary PAE metabolites in the human exposure smdies, during the last years a big number of smdies have been conducted to prove that some of them are appropriate biomarkers to calculate human PAE intake [28-30] and that their determination is easier than calculate it through food intake, which are more time consuming and subjects to several error sources. 

The flavour of distillates from apple and pear is characterised by typical aroma compounds from these fruits formed by enzymatic degradation of fatty acids to C6-fragments like hexanol, trans-2-hexenol, as well as ethyl esters and acetates of hexanoic acid. In distillates of pears, especially of the variety Bartlett pear, the characteristic pear flavour is mainly dominated by the ethyl and methyl esters of frans-2-czs-4-decadienoic acid and trans-2-trans-A-decadienoic acid [27-29], The biogenesis of these monounsaturated, diunsaturated, and triunsaturated esters may be explained by -oxidation of unsaturated linoleic and linolenic acid in the fruits. The sesquiterpene compound a-farnesene, which is formed during postharvest ripening and storage of Bartlett pears [28], shows that quality and intensity of distilled pear spirits is mainly influenced by the quality and degree of ripeness of the fruits. 

Fruity flavor in dairy products is the result of ethyl ester formation, usually catalyzed by esterases from psychrotrophic or lactic acid bacteria. Ester formation by P. fragi involves liberation of butyric and ca-proic acids from the one and three positions of milk triglycerides and the subsequent enzymatic esterification of these fatty acids with ethanol (Hosono et al. 1974 Hosono and Elliott 1974). Consequently, among the esters formed, ethyl butyrate and ethyl hexanoate predominate. Pseudomonas-produced fruity flavor can occur in fluid milk, cottage cheese, and butter. 

Whereas several anti-cholestemic drugs are produced wholly by fermentation, the side chain of several others is accessible through enzymatic synthesis. (3R,5S)-Dihydroxyhexanoate, a key intermediate of fluvastatin, is accessible by reduction of the diketo acid, either by bioreduction with whole cells (85% yield, 97% e.e.), or cell extracts (72% yield, 98.5% e.e.), or, for syn-(3h,5.S)-dihydroxy-6-Cl-hexanoate, regioselective and (ft)-specific reduction with ADH to yield (5S)-6-chloro-3-ketohexanoate. 

Figure 11 Synthesis of chiral synthon for ceranopril enzymatic conversion of CBZ-L-lysine (31) to (S)-hydroxy-6-(carbobenzyloxyamino)-hexanoic acid (30).

Initial scale up of the enzymatic resolution for production of kilogram quantities of (R)-2-amino-2-ethylhexanoic acid was performed in a batch process. The oil of ethyl 2-amino-2-ethyl-hexanoate was suspended in an equal volume of water containing the enzyme. The enantioselective hydrolysis of the ester proceeded at room temperature with titration of the produced acid by NaOH through a pH stat (Figure 6.4). 

ENZYMATIC SYNTHESIS OF ETHYL (3/ ,5S)-DIHYDROXY-6-(BENZYLOXY) HEXANOATE... 

Figure 18.13. Enzymatic synthesis of ethyl (31 ,55)-dihydroxy-6-(benzyloxy)hexanoate (40a).

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. 

Enzymatic hydrolysis rates for different positional and structural esters of lincomycin were determined in dog serum and simulated USP intestinal fluid (75). In general, the hydrolysis rates were faster in simulated intestinal fluid than in dog serum, indicating a higher esterase activity in simulated intestinal fluid. The 2- propionate ester of lincomycin was hydrolyzed slower than the longer chain 2 hexanoate ester, with the greatest difference in rates occuring in simulated intestinal fluid. Sterically hindered esters were hydrolyzed at extremely slow rates. 

In this resolution involving transesterification, the enzyme is catalysing the acetylation by vinyl acetate of the hydroxyl group of 42 with S configuration. This use of vinyl acetate is now fairly common in enzymatic resolution (see Chadha and Manohar12) hexanoic anhydride is also sometimes used in this context. 

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

FIGURE 16.18 Anti-Alzheimer s drug 70. Enantioselective enzymatic reduction of 5-oxo-hexanoate 71 and 5-oxohexanenitrile 72. 

Novo Nordisk showed in the synthesis of (-)-Ormeloxifene (48), a drug candidate for the treatment and prevention of osteoporosis, that the enzymatic asymmetric hydrolysis of potential intermediates can be carried out using Candida rugosa lipase (CRT) immobilized on Accurel (Scheme 15) [74]. Racemic czs-hexanoate mc-46 was subjected to enzymatic hydrolysis in aqueous acetonitrile and gave the phenol ds-(3R,4S)-47 in 95% ee. This transformation is a nice example to demonstrate that the enzyme can recognize and use remote stereocenters. The reaction was run on a 10 g scale, and it was even possible to recycle hexanoate (3S,4R)-46. Simple recovery of the immobilized enzyme by... 

In addition to the enzymatic pathway of aroma formation, a thermal route also exists. At high temperatures, interactions of amino acids and sngars resnlt in the formation of various aldehydes. After thermal treatment, the tea becomes more tasty and pleasant, and has a better aroma. An essential source of secondary volatiles, formed during tea leaf processing, is oxidative. o-Quinone resulting from the oxidation of catechins can oxidize, besides amino acids and carotenes, unsaturated fatty acids as well. Linoleic and linolenic acids can be converted into hexenal and trans-hex-2-enal, respectively, and in addition, small amounts of other volatile compounds, especially hexanoic acid and trani-hex-2-enoic acid, can be formed from the same acids, respectively. Also the monoterpene alcohols, linalool and geraniol, play an important role in the formation of the aroma of black tea [38]. 

R = n-CgH, conditions /-octane, hexanoic acid. Pseudomonas sp. lipase Scheme 2.7 Sequential enzymatic resolution via hydrolysis and esterification... 

Cholesterol-Lowering Agents Enzymatic Preparation of Ethyl (3S,5R)-dihydroxy-6-(benzyloxy)hexanoate 72... 

Pregabalin enzymatic synthesis of ethyl (S)-3-cyano-5-methyl-hexanoate. 

CHOLESTEROL-LOWERING AGENTS ENZYMATIC SYNTHESIS OF (3S,5/ )-DIHYDROXY-6-(BENZYLOXY) HEXANOIC ACID, ETHYL ESTER... 

Cholesterol-lowering agents enzymatic synthesis of (3S,5/ )-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester. 

Fischer JJ, Aoyagi Y, Enoki M, Doi Y and Iwata T, Mechanical properties and enzymatic degradation of poly([R]-3-hydroxybutyrate-co-[R]-3-hydroxy hexanoate) uniaxially cold-drawn films. Polymer Degradation and Stability, 2004, 83 453—460. 

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