Peroxidase-catalyzed asymmetric oxidation

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

The rates of asymmetric sulfoxidation of thioanisole in nearly anhydrous (99.7%) isopropyl alcohol and methanol catalyzed by horseradish peroxidase (HRP) were determined to be tens to hundreds of times faster than in water under otherwise identical conditions (Dai, 2000). Similar effects were observed with other hemo-proteins. This dramatic activation is due to a much higher substrate solubility in organic solvents than in water and occurs even though the intrinsic reactivity of HRP in isopropyl alcohol and in methanol is hundreds of times lower than in water. In addition, the rates of spontaneous oxidation of the model prochiral substrate thioanisole in several organic solvents was observed to be some 100- to 1000-fold slower than in water. This renders peroxidase-catalyzed asymmetric sulf-oxidations synthetically attractive. 

Enzymes, in particular peroxidases, catalyze efficiently the enantioselective oxidation of alkyl aryl sulfides and also dialkyl sulfides, provided that the alkyl substituents are sterically differentiable by the enzyme. The peroxidases HRP, CPO, MP-11, and the mutants of HRP, e. g. F41L and F4IT, were successfully used as biocatalysts for the asymmetric sulfoxidation (Eq. 14). A selection of sulfides. 

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. 

Oxometalloporphyrins were taken as models of intermediates in the catalytic cycle of cytochrome P-450 and peroxidases. The oxygen transfer from iodosyl aromatics to sulfides with metalloporphyrins Fe(III) or Mn(III) as catalysts is very clean, giving sulfoxides, The first examples of asymmetric oxidation of sulfides to sulfoxides with significant enantioselectivity were published in 1990 by Naruta et al, who used chiral twin coronet iron porphyrin 27 as the catalyst (Figure 6C.2) [79], This C2 symmetric complex efficiently catalyzed the oxidation... 

This catalytic asymmetric oxidation yielded J -methylphenylsulfoxide with a productivity of30g/l/day andane.e. >98% [35]. Chloroperoxidase is the most versatile peroxidase with better stability compared to other peroxidases, because spontaneous oxidation can be suppressed in the presence of ascorbic acid or dihydroxyfu-maric acid, and with better enantioselectivity because substrate access to the heme iron and ferryl oxygen favors stereoselective oxygen transfer [36]. Chloroperoxidase has been used for catalyzing the oxidation of cis-cydopropylmethanols with much higher enantioselectivity than trans-isomers [37]. 

Another reaction of heteroatom oxidation is that of S-oxidation, which leads to the synthesis of sulfoxides, a reaction not very common in the plant cell biochemical factory. Enantiomerically pure sulfoxides are important chiral synthons in asymmetric synthesis, in particular in enantio-selective carbon-carbon bond formation [77]. The sulfoxide functional group is involved in different biological activities, and optically pure sulfoxides are of great pharmaceutical interest [82]. However, plant peroxidases, such as horseradish peroxidase, catalyze the enantio-selective sulfoxidation of alkyl aryl sulfides ... 

Lutz, S., Steckhan, E. and Liese, A. (2004) First asymmetric electroenzymatic oxidation catalyzed by peroxidase. Electrochemistry Communications, 6, 583-587. 

Flavoprotein oxidases do not catalyze directly the oxidation of prochiral sulfides, but these biocatalysts have been used in combination with other oxidative enzymes to perform asymmetric sulfoxidations. Thus, flavoprotein oxidases are able to generate hydrogen peroxide in situ as a byproduct, which will be used as an oxidant by, for example, peroxidases or peroxygenases. This cascade methodology enhances the operational stability of peroxidases when compared with the one-pot addition of hydrogen peroxide. The direct addition of peroxides often leads to rapid inactivation of the employed enzyme [18]. 

---