Enantioselective reduction aromatic compounds

Electroenzymatic reactions are not only important in the development of ampero-metric biosensors. They can also be very valuable for organic synthesis. The enantio- and diasteroselectivity of the redox enzymes can be used effectively for the synthesis of enantiomerically pure compounds, as, for example, in the enantioselective reduction of prochiral carbonyl compounds, or in the enantio-selective, distereoselective, or enantiomer differentiating oxidation of chiral, achiral, or mes< -polyols. The introduction of hydroxy groups into aliphatic and aromatic compounds can be just as interesting. In addition, the regioselectivity of the oxidation of a certain hydroxy function in a polyol by an enzymatic oxidation can be extremely valuable, thus avoiding a sometimes complicated protection-deprotection strategy. 

Peroxidases are ubiquitous, and many are b-type heme proteins. Several good reviews summarize years of peroxidase research and describe peroxidase applications [57 -61]. Some of the reactions catalyzed by peroxidases are listed in Tab. 10.2 and include oxidation of aromatic and heteroatom compounds, epoxidation, enantioselective reduction of racemic hydroperoxides, free radical oligomerizations and polymerizations of electron-rich aromatics, and the oxidative degradation of lignin [58, 60],... 

The enantioselective reduction of ketones has become a key reaction not only for the production of chiral alcohols, but for the production of fimctionalized compounds in general, thanks to the versatility of the hydroxyl fimctionality. The oxazaborolidine-catalyzed borane reduction of ketones [2] has become an important reaction due to the fact that the stereochemistry of the alcohols can be predicted and because of the wide substrate acceptance of this catalytic system (it works with aromatic as well as with aliphatic ketones). Among all the known oxazaboroUdine catalysts, the proline-based one is very interesting not only because it is one of the most selective catalysts, but also because another related reagent, the 4-hydroproline, is commercially available and possesses a functional group which could be used for the linkage to a polymer. 

Peroxidases are foimd in nature in plants, microorganisms, and higher organisms. Common peroxidases and their various biological fimctions are shown in Table 2 [24]. Peroxidases are able to catalyze the oxidation of aromatic compounds, the oxidation of heteroatoms, epoxidation, and the enantioselective reduction of racemic hydroperoxides [12,16-20,22,24,35]. Typical reactions catalyzed by peroxidases are listed in Table 3 [24]. 

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,... 

The F-C reactions of aromatic compounds can provide a practical synthetic route for chiral a-trifluorobenzylalcohols of synthetic importance (Scheme 1). In previous asymmetric syntheses of a-trifluorobenzylalcohols, the asymmetric reductions of trifluoromethyl ketone were used as a key step 30-34). In this F-C reaction, the catalytic activity and enantioselectivity of BINOL-Ti catalysts (55-57) were found to be critically influenced by the substituents of BINOL derivatives (Table I). 1) (i )-6,6 -Br2-BINOL-Ti catalyst was the most effective catalyst. This F-C reaction did not proceed easily as compared with the carbonyl-ene reaction (7,8) or the Mukaiyama-aldol reaction (7) with fluoral. Therefore, the role of the electron-witiidrawing group at the 6,6 -position of BINOL is very important for increasing the Lewis acidity (runs 1 3). Relatively high enantio-... 

As with the reduction of aldehydes and ketones (16-23), the addition of organometallic compounds to these substrates can be carried out enantioselectively and diastereoselectively. Chiral secondary alcohols have been obtained with high ee values by addition to aromatic aldehydes of Grignard and organolithium compounds in the presence of optically active amino alcohols as ligands. ... 

Since the electroreduction of ketones shown in Scheme 29 has been well established [1-3, 12, 62-65], one more recent interest in the electroreduction of carbonyl compounds is focused on the stereo-selective reduction of ketones. For example, the diastereo-selective cathodic coupling of aromatic ketones has been reported. In the presence of a chiral-supporting electrolyte, a low degree of enantioselectivity has been found [66] (Scheme 30). 

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

The enantioselective hydrogenation of olefins, ketones and imines still represents an important topic and various highly enantioselective processes based on chiral Rh, Ru or Ir complexes have been reported. However, most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of aromatic and heteroaromatic compounds and examples of efficient catalysts are rare. This is especially the case for the partial reduction of quinoline derivatives which provide 1,2,3,4-tetrahydroquinolines, important synthetic intermediates in the preparation of pharmaceutical and agrochemical products. Additionally, many alkaloid natural products consist of this stmctural key element. 

The major synthetic problem associated with the synthesis of compounds such as NK-104 is the stereoselective construction of the lactone moiety and its connection to an aromatic or ethylenic core. This has been overcome by Minami and colleagues with the enantioselective synthesis of methyl 6-oxo-3,5-isopropylidenehexanoate (52) by ozonolysis of the ester 53, followed by reductive workup using dimethyl sulfide (Scheme 11,14).54 With the required aldehyde 52 now formed, further reaction could permit the production of NK-104 51 to take place enantioselectively. 

Enantioselective Ketone Reduction. After the pioneering work of Itsuno et al., Corey s group isolated the 1,3,2-oxazaborolidine derived from chiral a,a-diphenyl-2-pyrrolidinemethanol (2) and applied it (and also other related B-alkyl compounds) to the stereoselective reduction of ketones with borane-tetrahydrofuran, borane-dimethyl sulfide (BMS) or catecholborane.It was named the CBS method (after Corey, Bakshi, and Shibata). Since then, the CBS method has become a standard and has been extensively used, specially for aromatic and a,p-unsaturated ketones, not only in academic laboratories but also in industrial processes. ... 

Examples of efficient catalysts for the asymmetric hydrogenation of aromatic and heteroaromatic compounds are quite rare, even with hydrogenation procedures catalyzed by chiral Rh, Ru, and Ir complexes. Therefore an important breakthrough was by Rueping s group in 2006 the development of an enantioselective phosphoric acid-catalyzed partial reduction of quinoline derivatives [62]. This represents the first example of a metal-free reduction of heteroaromatic compounds. (/ )-(—)-9-phe-nanthryl-l,l -binaphthyl-2,2 -diyl hydrogenphosphate was selected as chiral element of choice to perform stereocontrol (97% ee. Scheme 15.29). 

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