Enantioselective biocatalytic reduction

Retrosynthetic considerations reveal an approach (Scheme 1.2.6) in the first step based on disconnections of the C -Cy and C12-C13 double bonds. Those can be built up using highly B-selective Wittig olefinations between allyltributylphos-phorous ylides derived from the corresponding allylic bromides 29 and 31 [31]. The aldehyde 30 is accessible from the keto ester 33, which can be prepared in high enantiomeric purity by a biocatalytic enantioselective reduction of a... 

Prochiral aryl and dialkyl ketones are enantioselectively reduced to the corresponding alcohols using whole-cell bioconversions, or an Ir1 amino sulfide catalyst prepared in situ.695 Comparative studies show that the biocatalytic approach is the more suitable for enantioselective reduction of chloro-substituted ketones, whereas reduction of a,/ -unsaturated compounds is better achieved using the Ir1 catalyst. An important step in the total synthesis of brevetoxin B involves hydrogenation of an ester using [Ir(cod)(py) P(cy)3 ]PF6.696... 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

The asymmetric syntheses of various chiral compounds have already been compared with regard to their applicability on a technical scale. For example, Blaser and coworkers compared four technically feasible routes (A-D) for the large scale preparation of the chiral building block ethyl (R)-2-hydroxy-4-phenylbutyrate (10) (Scheme 4.13) [53]. The stereogenic centre is introduced via enantioselective reduction, either via biocatalytic or nonenzymatic methods. 

Two biocatalytic routes were also developed to the pilot stage by Ciba-Geigy, namely the enantioselective reduction of the corresponding a-keto acid with immobihzed Proteus vulgaris (route A in Scheme 12.10) and with D-LDH in a membrane reactor (route B), respechvely. It was therefore of interest to compare the four approaches. The EATOS (Environmental Assessment Tool for Organic Syntheses) program was used to compare the mass consumption (kg input of raw materials for 1 kg of product) as well as other parameters [28]. 

Non-standard equipment was necessary for all enantioselective reductions for the hydrogenations, a high pressure reactor, for the biocatalytic processes sophisticated continuous reaction systems with various feedback loops. 

The biocatalytic reduction of the keto group to the alcohol group proceeds with a great tolerance of other functional groups in the substrate, for example, the enantioselective reductions of ketoesters to chiral hydroxyesters [70-73] or of... 

A selection of biocatalytic deoxygenation reactions is shovm in Figure 1.8. The reducing power of baker s yeast in an ethanol-water mixture and sodium hydroxide at 60° C has been found effective for the rapid and selective reduction of a series of N-oxides like aromatic and heteroaromatic N-oxide compounds [118]. DMSO reductase from Rhodobacter sphaeroides f sp. denitrificans catalyzed the (S)-enantioselective reduction of various sulfoxides and enabled the resolution of racemic sulfoxides for the synthesis of (R)-sulfoxides with >97% ee [119,120]. Purified dimethyl sulfoxide reductase from Rhodobacter capsulatus resolved a racemic mixture of methyl p-tolyl sulfoxide by catalyzing the reduction of (S)-methyl p-tolyl sulfoxide and gave enantio-merically pure (J )-methyl p-tolyl sulfoxide in 88% yield, while whole cells of E. coli,... 

Wong,)., Huisman, G., Tfuesdell, S., and Lalonde, (. (2010) Highly enantioselective reduction of a small heterocyclic ketone biocatalytic reduction of tetrahydrothiophene-3-one to the corresponding (R)-alcohol. Org. Proc. Res. Dev., 14, 188-192. 

Since stereoselectivities of biocatalytic reductions are not always satisfactory, modification of biocatalysis are necessary for practical use. This section explains how to find, prepare, and modify the suitable biocatalysts, how to recycle the coenzyme, and how to improve productivity and enantioselectivity of the reactions. 

Organometallic aldehydes can be reduced enantioselectively with dehydrogenases. For example, optically active organometallic compounds having planar chiralities were obtained by biocatalytic reduction of racemic aldehydes with yeast [22c,d] or HLADH [22e] as shown in Figure 8.29. 

Anderson, B.A., Hansen, M.M., Harkness, A.R. et al. (1995) Application of a practical biocatalytic reduction to an enantioselective synthesis of the 5H-2,3-benzodiazepine LY300164. Journal of the American Chemical Society, 117, 12358-12359. 

Most catalysts originally developed for C=C bonds show a rather poor performance for the hydrogenation of many ketones. However, this situation changed dramatically when it was found that selected Ru-binap and later Ru-binap-dia-mine complexes achieve excellent enantioselectivities, as well as very high TONs and TOFs, for a variety of ketones [92]. Since then, it has been demonstrated that many a- and yS-functionalized, as well as aromatic ketones, are suitable substrates for hydrogenation with industrially viable catalytic results. For the reduction of various ketones biocatalytic methods are an industrially viable alternative to chemocatalysts [15]. 

In what appears to be a particularly irmovative development in the area of UV/ Vis-based ee screening systems, the determination of the enantiomeric purity of chiral alcohols 9 is based on a new concept of using two enantioselective enzymes to modify the product (84). The method allows the determination of ee values independent of the concentration, which may be of significant advantage in directed evolution projects. It can be used in three different biocatalytic processes, namely biohydroxylation of alkanes, reductase-catalyzed reduction of ketones, and lipase-or esterase-catalyzed ester hydrolysis. 

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