Enantioselective enzymatic reduction

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

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. 

Substituted 1,3-diols are valuable intermediates in the synthesis of drugs and natural products [18]. Starting from the regio- and enantioselective enzymatic reduction of diketo esters described above, various methods to obtain enantio-merically pure 3,5-dihydroxy esters were developed. 

Scheme 2.2.7.11 Chiral building blocks evolved from diketo ester la via regio- and enantioselective enzymatic reduction.

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

ENANTIOSELECTIVE ENZYMATIC REDUCTIVE AMINATION OF 2-(3-HYDROXY-1-ADAMANTYL)-2-OXOETHANOIC ACID... 

ENANTIOSELECTIVE ENZYMATIC REDUCTION OF N,N-DIMETHYL-3-KETO-3-(2-THIENYL)-1-PROPANAMINE... 

Figure 3. Enantioselective enzymatic reduction of 2-oxo-4-phenylbutyric acid to ( )-2-hydroxy-4-phe-nylbutyric acid (using EMR technology).

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

Synthesis o/lOO.- with a Cf Building Block from the Chiral C Pool and an Enantioselective Enzymatic Reduction of a Cg Building Block... 

The active form of the catalyst must transfer the electrons or the hydride ion to NAD(P)+, but not directly to the substrate. Otherwise, this non-enzymatic reduction will lead to low chemoselectivity and/or low enantioselectivity. 

Enzymatic reduction of carbonyl compounds and enzymatic enantioselective transformation of racemic or meso alcohols (25,43.) are two methodologies that have proven to be beneficial in the preparation of optically active hydroxyl compounds, key chiral building blocks used in carbohydrate and natural product syntheses (44-45. Our interest in this area is to develop enzymatic routes to optically active glycerol and furan derivatives, and hydroxyaldehydes. 

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... 

Reduction of l-(chloro or bromo) -3-butyn-2-one (27e,f) with recLBADH affords enantiopure R-alcohols 28e,f, resulting in an interesting switch of the enantioselectivity of the enzymatic reduction. As the enantiomers (S) -28e,f can be obtained by recLBADH-catalyzed reduction of 27b-27d and subsequent removal of the si-lyl-protecting group, this enzyme offers unique access to a pair of enantiomers via the same oxidoreductase. Due to the high volatility of the substrates (27e,f) these transformations were only performed on an analytical scale. 

Stereoselective enzymatic hydrolyses of esters represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion is illustrated in Scheme 15. Starting from the racemic (l-acetoxyethyl)silane rac-11, the optically active (l-hydroxyethyl)silane (5)-41 was obtained by a kinetic racemate resolution using porcine liver esterase (PLE E.C. 3.1.1.1) as the biocatalyst7. The silane (5)-41 (isolated with an enantiomeric purity of 60% ee bioconversion not optimized) is the antipode of compound (R)-41 which was obtained by an enantioselective microbial reduction of the acetylsilane 40 (see Scheme 8). 

Scheme 15)62. After terminating the reaction at a conversion of 38% (relative to total amount of substrate rac-78), the product (S)-43 was separated from the nonreacted substrate by column chromatography on silica gel and isolated on a preparative scale in 71% yield (relative to total amount of converted rac-78) with an enantiomeric purity of 95% ee. Recrystallization led to an improvement of the enantiomeric purity by up to >98% ee. The biotransformation product (S)-43 is the antipode of compound (/ )-43 which was obtained by enantioselective microbial reduction of the acylsilane 42 (see Scheme 8)53. The nonreacted substrate (/ )-78 was isolated in 81% yield (relative to total amount of nonconverted rac-78) with an enantiomeric purity of 57% ee. For further enantioselective enzymatic hydrolyses of racemic organosilicon esters, with the carbon atom as the center of chirality, see References 63 and 64. 

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

Fig. 34 Enzymatic reduction in biphasic media. Ketones are reduced enantioselective to the corresponding (S)-alcohols by ADH from Rhodococcus erythropolis. Regeneration of the cofactor NADH is carried out by FDH from C. boidinii. The introduction of a biphasic system allows higher substrate concentrations...

As before, the enzymatic reduction is the method of choice for the enantioselective reduction of purely aliphatic ketones and only in the case of fert-butyl methyl ketone could the bench mark of 90 % ee be crossed by the transfer hydrogenation and both other catalytic hydrogenation methods. However, substantial success in the hydrogenation of aromatic ketones by transition metal complexes with respect to the enantioselectivity and the activity (TON) strengthens the confidence that further progress is possible, enabling us to use some advantages of these nonenzymatic processes for extended application in the near future, for example in the facilitation of product isolation. 

Baker s yeast reduces conjugated nitro compounds to nitroalkanes and also the C=C unit of conjugated ketones. Other enzymatic reductions are possible. A reductase from Nicotiana tabacum reduced a conjugated ketone to the saturated ketone, with excellent enantioselectivity. Enzyme YNAR-I and NADP-H reduces conjugated nitro compounds to nitroalkanes. ... 

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