Alcohol dehydrogenase catalyzed reductions

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method for the production of chiral alcohols. HLAD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates (Table 11). It efficiendy reduces all simple four- to nine-membered cycHc ketones and also symmetrical and racemic cis- and trans-decalindiones (167). Asymmetric reduction of aUphatic acycHc ketones (C-4—C-10) (103,104) can be efficiendy achieved by alcohol dehydrogenase isolated from Thermoanaerohium hrockii (TBADH) (168). The enzyme is remarkably stable at temperatures up to 85°C and exhibits high tolerance toward organic solvents. Alcohol dehydrogenases from horse Hver and T. hrockii... 

Table 11. Alcohol Dehydrogenase-Catalyzed Reductions on Ketones...

Alcohol dehydrogenase-catalyzed reduction of ketones is a convenient method lor the production nf chiral alcohols. HI.AD, the most thoroughly studied enzyme, has a broad substrate specificity and accommodates a variety of substrates. 

In contrast to the multiplicity of examples of diastereotopic face discriminations in combination with other enzyme specificity discussed later, there are relatively few alcohol dehydrogenase catalyzed reductions that involve diastereotopic face selectivity alone. However, whenever a carbonyl group is present in a single chiral stereoisomer, diastereotopically face-selective reductions are possible. The reductions of the L-homocysteine derivative (47) (48), and of the (-)-oxocineole (15,4/ )-(49) (50), are two... 

The above principle is amply illustrated by the small molecule systems discussed in Section III. The roles proposed for zinc ion in the three enzyme systems discussed in Section IV also adhere to this principle. The accumulated experimental evidence makes it highly probable that zinc ion has a Lewis acid catalytic function both in the horse liver alcohol dehydrogenase-catalyzed reduction of aldehydes, and in the carboxypeptidase A-catalyzed hydrolysis of peptides. In contrast, the accumulated experimental evidence supports a role for zinc ion involving the enhancement of water nucleophilicity via inner sphere coordination in the carbonic anhydrase-catalyzed hydration of CO 2. The substrates for... 

Scheme 19.20 One-pot synthesis of allylic alcohols based on combination of Wittig reaction and alcohol dehydrogenase-catalyzed reduction.

Dodds, D.R. and Jones, J.B. (1988) Enzymes in organic synthesis 38. Preparations of enantiomericaDy pure chiral hydroxydecalones via stereospedfic horse liver alcohol dehydrogenase catalyzed reductions of decalindiones. 

Smith and Hendlin [51] suggested that there are two systems competing for benzaldehyde in the yeast cell. The first is the phenylacetyl carbinol-synthesizing system and the second is alcohol dehydrogenase, catalyzing reduction of benzaldehyde to benzyl alcohol. These researchers found that the increase in phenylacetyl carbinol production is accompanied by a decrease in the formation of benzyl alcohol and vice versa [78]. 

Alcohol dehydrogenases catalyze oxidation of alcohols in a reaction dependent on the pyridine nucleotide NAD+ [Eq. (5)]. Since the reaction is reversible, alcohol dehydrogenases also catalyze the reduction of aldehydes by... 

Reductions ofketones -alcohol dehydrogenase-catalyzed pNZYMES IN ORGANIC SYNTHESIS] (Vol 9)... 

The initial rates (v in juM/min) of liver alcohol dehydrogenase-catalyzed ethanal reduction are measured in the presence of pyrazole as an inhibitor at the constant concentration of NADH (0.02 M) and the constant concentration of ethanal (2.0 mM), respectively. Propose respective inhibition types and estimate their inhibition constants. 

By means of capillary gas chromatographic determination of the optical purities of formed products we could demonstrate that yeast alcohol dehydrogenase catalyzes not only the oxidation of racemic secondary alcohols but also the reduction of the corresponding methyl ketones in highly stereoselective manner. 

Figure 6. Fornation of optically pure secondary alcohols by yeast alcohol dehydrogenase catalyzed oxidation of racemic mixtures of alkan-2-ols and reduction of alkan-2-ones.

The yeast-induced reduction of (5e) —> (6e), (R = substituted phenyls, R = Me) is one of the very first preparative-scale alcohol dehydrogenase catalyzed reactions to have been reported. While the transformations of (5a-j) demonstrate that broad structural mlerances are possible in the substrate ketones, the enzymes are sometimes very discriminating. For example, while the BY-catalyzed reductions of the 2-, 3- and 4-substituted pyridyl ketones (5g) proceed smoothly with high stereospecificitythe analogous furanyl and thiophenyl ketones give virtually racemic product alcohols, and 2-acetylpyrrole is not a substrate at all. ... 

ALCOHOL DEHYDROGENASE-CATALYZED REACTIONS Stereoselective reduction of aldehydes and ketones... 

Figure 2. Preparation of (R) and (S)-3-fluoro-2-hydroxypropanal via (a) opening of (R)-glycidal diethylacetal, (b) lipase-catalyzed resolution of a racemic precursor, (c) alcohol dehydrogenase-catalyzed asymmetric reduction...

The stereochemical aspects of many enzyme-catalyzed reactions have been determined. The enzyme alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde by removing the pro-R hydrogen (abbreviated as H ). When the same enzyme catalyzes the reduction of acetaldehyde to ethanol, hydrogen is transferred to the Re face. 

Nakata T, Kuwabara T, Tani T, Oishi T (1982) Total synthesis of (+)-oudemansin. Tetrahedron Lett 23 1015-1016 Nambiar KP, Stauffer DM, Kolodziej PA, Benner SA (1983) A mechanistic basis for the stereoselectivity of enzymatic transfer of hydrogen from nicotinamide cofactors. J Am Chem Soc 105 5886-5890 Ng GY, Yuan L-C, Jakovac IJ, Jones JB (1984) Enzymes in organic synthesis. 29. Preparations of enantiomerically pure cis-2,3- and 2,4-dimethyl lactones via horse liver alcohol dehydrogenase-catalyzed oxidations. Tetrahedron 40 1235-1243 Oae S, Nagata T, Yoshimura T, Fujimori K (1982) Reduction of diaryl disulfides with 1-benzyl-1,4-dihydronicotinamide. Tetrahedron Lett 3189-3192... 

Figure 1.2 Prelog s rule stereospedfic product formation by alcohol dehydrogenase-catalyzed ketone reduction, assuming the large group having higher priority in CIP rules than the small group.

The analysis of reaction enantioselectivity for asymmetric reductions is key for the process development and an interesting combined use of high-performance liquid chromatography and circular dichroism has led to an efficient procedure for alcohol dehydrogenase-catalyzed asymmetric reduction of l-phenyl-2-propyn-3-trimethyl-silyl-l-on [133]. 

Alcohol dehydrogenase-catalyzed regeneration of NAD(P)H by oxidation of alcohols certainly represents the most widespread regeneration method currently applied. Especially if the desired production reaction is an ADHsubstrate-coupled regeneration approach excels in simplicity, as only one biocatalyst has to be used for the whole reaction (Scheme 8.8). Another advantage of this methodology is that the nicotinamide cofactor does not have to leave the... 

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