Enzymatic Reduction of Ketones

Biocatalysis in organic synthesis has a longstanding history and wide applicability in the enantioselective reduction of ketones (150, 151], Many enzymatic protocols provide reliable, scalable, and inexpensive routes to optically active alcohols consequently, such transformations have been extensively employed in industrial applications. A few representative examples of enzymatic reductions of ketones on large scale, giving hydroxy acids 243 [147, 152) and 245 (153) with exceptional enantioselectivities and yields, are shown below (Equations 18 and 19). 

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Protease or lipase enzymes were useful for the regioselective aminoacylation of lobucavir. Lipase was also used for resolution of a synthon for the paclitaxel side chain. The paclitaxel side-chain ester was also prepared by reduction of a keto ester precursor. Enzymatic reduction of ketones to chiral alcohols is another reaction that has been widely applicable. C14-deacylase, ClO-deacety-lase, and C7-xylosidase were identified from microorganisms isolated from soil samples and were useful for converting complex mixtures of taxanes found in yew extracts primarily to 10-deacetyl baccatin III, a precursor for the semisynthesis of paclitaxel and analogs. 

Table 9.6 Enzymatic reduction of ketones in a scC02/buffer or hexane/buffer biphasic system.

Figure 7.25 Enzymatic reduction of a-halogenated propargylic ketones by LBADH...

Zhu, D. and Hua, L. (2006) Enantioselective enzymatic reductions of sterically bulky aryl alkyl ketones catalyzed by a NADPH-dependent carbonyl reductase. The Journal of Organic Chemistry, 71 (25), 9484—9486. 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

Surh YJ, Lee SS. (1992). Enzymatic reduction of shogaol a novel biotransformation pathway for the alpha, beta-unsaturated ketone system. Biochem Int. 27(1) 179-87. 

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

Enzymatic reduction of 23a with recLBADH and CPCR resulted in unsatisfactory results (60% and 49% ee) as well. The results mentioned above indicate that a bulky substituent at the alkyne moiety results in a higher selectivity of the reduction. Furthermore, Bradshaw et al. reported that Lactobacillus kefir ADH, an enzyme highly homologous to LB ADH, affords (R)-4-trimethylsilyl-3-butyn-2-ol [(R)-25j with an ee of 94% in 25% yield [39bj. In our investigations ketone 23b was reduced by recLBADH with almost quantitative conversion. The enantiomeric excess and absolute configuration of the product were determined by desi-lylation with borax converting alcohol (R)-25 into enantiopure (R)-3-butyn-2-ol [(R)-24j (Scheme 2.2.7.14). 

The enzymatic reduction of T-configured alkenones represents a valuable alternative to the enzyme-catalyzed reduction of the corresponding alkynone with subsequent partial reduction of the C-C triple bond. Nevertheless, since in our results the Z-configured vinylic alcohols are not accessible in enantiopure form by enzyme-catalyzed reduction of the olefinic ketones, for this class of compounds the two-step process via the propargylic alcohols is a highly valuable new strategy. 

Scheme 2.2.7.19 Chiral building blocks evolved from enantioselective enzymatic reduction of propargylic ketones D.

C. Wandrey, 1998, A novel reactor concept for the enzymatic reduction of poorly soluble ketones, J. Mol. Catal. B ... 

Substrate substituent effects on activity and enantioselectivity have been investi- gated in the enzymatic reduction of aryl ketones, using 24 recombinant ketoreduc-tases.308... 

A graduate student was studying enzymatic reductions of cyclohexanones when she encountered some interesting chemistry. When she used an enzyme and NADPH to reduce the following ketone, she was surprised to find that the product was optically active. She carefully repurified the product so that no enzyme, NADPH, or other contaminants were present. Still, the product was optically active. 

Pandit has provided evidence for the Lewis acid catalysis postulated to operate in these reduction reactions. The reduction of various cinnamoylpyridines by 1,4-dihydropyridine derivatives to the corresponding saturated ketones is catalyzed by zinc or magnesium cations. The reduction rate was fastest in the case of 2-cinnamoylpyridine, in which the metal ion can complex simultaneously to both the nitrogen and oxygen sites (Scheme 78). This example is regarded as a model of Lewis acid catalysis of the NADH-dependent enzymatic reduction of A -3-keto steroids. 

Reduction Phase I can also be accomplished by means of reductions. The reductive enzymes are localized both in the micro-somes and the cytosol. They trigger the enzymatic transformation of ketones, aldehydes, sulphoxides, nitro- and azo-linkages, etc. The intestinal flora also contributes to the reductive metabolism of foreign substances. 

Throughout the text most, but not all, of the 60 and 90 MHz nmr spectra have been replaced with 250 MHz proton spectra. A section on 2D nmr is included in the chapter on nmr spectroscopy, and procedures are given for the use of chiral nmr shift reagents to determine the optical purity of the product from the chiral enzymatic reduction of a ketone. 

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