biocatalysis and biotransformation in brazil: an overvie · 2020. 2. 11. · in another work,...

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Biotechnology Advances xxx (2015) xxx–xxx

JBA-06894; No of Pages 30

Contents lists available at ScienceDirect

Biotechnology Advances

j ourna l homepage: www.e lsev ie r .com/ locate /b iotechadv

Research review paper

Biocatalysis and biotransformation in Brazil: An overview

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Willian G. Birolli a,1, Irlon M. Ferreira a,1, Natália Alvarenga a,1, Darlisson A. dos Santos a,1, Iara L. de Matos a,1,João V. Comasseto b,c, André L.M. Porto a,1

a Laboratório de Química Orgânica e Biocatálise, Instituto de Química de São Carlos, Universidade de São Paulo, Av. João Dagnone, 1100, J. Santa Angelina, 13563-120, São Carlos, SP, Brazilb Instituto de Química, Departamento de Química Fundamental,Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo, SP, Brazilc Instituto de Ciências Ambientais, Químicas e Farmacêuticas,Universidade Federal de São Paulo, Av. Prof. Artur Riedel, 275, 09972-270 Diadema, SP, Brazil

E-mail addresses: [email protected] (J.V. Coma(A.L.M. Porto).

1 Tel.: +55 16 3373 8103; fax: +55 16 3373 9952.

http://dx.doi.org/10.1016/j.biotechadv.2015.02.0010734-9750/© 2015 Published by Elsevier Inc.

Please cite this article as: Birolli WG, et al, B10.1016/j.biotechadv.2015.02.001

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Keywords:Brazilian microorganismsBiotransformationBiocatalysisLipases

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RThis review presents the recent research in biocatalysis and biotransformations in Brazil. Several substrates werebiotransformed by fungi, bacteria and plants. Biocatalytic deracemization of secondary alcohols, oxidation ofsulfides, sp3 CH hydroxylation and biocatalytic epoxidation of alkenes were described. Chemo-enzymatic resolu-tion of racemic alcohols and amines were carried out with lipases using several substrates containing hetero-atoms such as silicon, boron, selenium and tellurium. Biotransformation of nitriles by marine-fungi, hydrolysisof epoxides bymicroorganisms of Brazilian origin and biooxidation of natural products were reported. Enzymaticreactions under microwave irradiation, continuous flow, and enzymatic assays using fluorescent probes werereported.

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Contents

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Reduction by Saccharomyces cerevisiae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Reduction by other microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Reduction by whole cells of plant and algae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Reduction of organic compounds containing heteroatoms (sulfur, selenium and silicon) by whole cells of microorganisms and vegetables . . 0

Biocatalytic oxidation of sulfides by microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic sp3 C-H hydroxylation with whole cells of microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic kinetic resolution by lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic deracemization of secondary alcohols using whole cells of microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic epoxidation of alkenes by lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biocatalytic reactions in organic compounds containing heteroatoms (silicon, boron, selenium and tellurium) . . . . . . . . . . . . . . . . . . . . 0

Miscellaneous biotransformation by microorganisms of Brazilian origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biotransformation of nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biotransformation of epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Biotransformation of natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Enzymatic assays using fluorescent probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

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sseto), [email protected]

iocatalysis and biotransforma

Introduction

The importance of biocatalysis in organic synthesis, especially inthe industrial synthesis of pharmaceuticals, is well established anddismisses further comments (Aldridge, 2013; Patel, 2008).

tion in Brazil: An overview, Biotechnol Adv (2015), http://dx.doi.org/

http://dx.doi.org/10.1016/j.biotechadv.2015.02.001

mailto:[email protected]

mailto:[email protected]

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Scheme 1. Reduction of cinnamaldehyde derivatives by S. cerevisiae.

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Although chemistry has experienced a notable development inBrazil over the last three decades, until the beginning of the presentcentury, the application of enzymes for performing synthetic transfor-mations had been explored by a reduced number of chemists in theacademy, and most of the work in this field was concerned with theuse of isolated lipases and baker's yeast to perform kinetic resolutionsof racemates and stereoselective reductions of ketones, respectively.

In 2002we started the organization of periodical meetings, bringingtogether Brazilian chemists and international professionals specializingin biocatalysis. Since then, a number of Brazilian laboratories started towork in this field using isolated enzymes, plants and microorganismsto perform chemical transformations. In the forthcoming pages wegive an overview of the works on biocatalysis and biotransformationsperformed in Brazil; most of them in the last five years. The articledoes not intend to be an exhaustive review, but just to give an ideaabout the state of the art of this field in the country, especially in theacademy.

Biocatalytic reactions

Reduction

Biocatalyzed stereoselective reduction is an important synthetictool, since it introduces chirality in an eco-friendly way in moleculesthat can be intermediates in the synthesis of pharmaceuticals, agro-chemicals and fragrances. It is well known that the biological activitiesof these compounds highly depend on their enantiomeric purity(Nakamura and Matsuda, 2006). In view of this fact, biocatalytic reduc-tions have attracted the attention of the synthetic organic chemists.

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Scheme 2. Reduction of 1-phenyl-1,

Scheme 3. Reduction of α-methyle

Please cite this article as: Birolli WG, et al, Biocatalysis and biotransforma10.1016/j.biotechadv.2015.02.001

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Reduction by Saccharomyces cerevisiaeOne of the first studies in biocatalysis developed in Brazil employed

Saccharomyces cerevisiae for the reduction of ketones. These workswere reported in the beginning of the 1990s by Rodrigues and Moran(Brenelli et al., 1990; De Carvalho et al., 1991). After that, a numberof studies emerged from this group, focusing in different aspects of thereaction, such as the development of immobilization methods, use ofbiphasic systems, as well as continuous processes to perform the car-bonyl reduction.

Free cells of S. cerevisiae were employed in the enantioselectivereduction of cinnamaldehyde derivatives, which can be used as chiralbuilding blocks for the synthesis of someHIV-protease inhibitors, yield-ing α-substituted-3-phenyl-1-propanol (Scheme 1) (Fardelone et al.,2004).

In another study, it was found that baker's yeast catalyzed the reduc-tion of 1-phenyl-1,2-propanedione giving a mixture of (R)-1-hydroxy-1-phenyl-2-propanone and anti-(1R,2S)-1-phenyl-1,2-propanediol(Scheme 2) (Lourenço et al., 2004).

Different approaches were employed by Chaves et al. (2013) toperform the reduction of methyl α-methylene-β-ketoesters com-pounds using free yeast strains. The reaction was carried out in water,employing Amberlite® XAD7HP or filter paper as the substrate support.The best results were obtained using S. cerevisiae with the substratesadsorbed on filter paper (Scheme 3). This study showed that a cellulosematrix can be successfully employed in these biocatalytic reactions andfree cells of S. cerevisiae can be employed in regio- and enantioselectivereductions of the ketones studied with excellent yields.

Ionic liquids, biphasic systems and several additives were employedby Silva et al. (2012) in the preparation of (1R,4R)-dihydrocarvone forthe reduction of the α,β-carbon_carbon double bond of (4R)-carvoneby Baker's yeast. Among the different approaches employed, it wasobserved that the best results were obtained in water using trehaloseas additive (Scheme 4).

In the reduction of α-haloenones to halohydrins, Zampieri et al.(2013) showed interesting results using ionic liquids, since the reac-tions performed in the biphasic system (water/[(bmim)PF6]) gavebetter diastereoselectivity and enantioselectivity than in pure water.However a slightly lower conversion was observed. The better conver-sions were performed by S. cerevisiae (Scheme 5), and the reactionswere also carried out with Candida albicans, Rhodotorula glutinis,Geotrichum candidum and Micrococcus luteus.

2-propanedione by S. cerevisiae.

ne-β-ketoesters by S. cerevisiae.




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Scheme 4. Reduction of (4R)-carvone in a biphasic system by S. ceresiae.

Scheme 5. Reduction of α-haloenones in a biphasic system with ionic liquids by S. ceresiae.

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Ferreira and Simonelli (1990) described the asymmetric total syn-thesis of (2S,8S)- and (2S,8R)-8-methyl-2-decanol propanoates startingfrom (S)-(+)-4-iodo-2-butanol, which was prepared from ethyl (S)-(+)-3-hydroxybutanoate obtained by the selective reduction of ethylacetoacetate by baker's yeast (Scheme 6). In another work Baraldiet al. (2002) described the enantioselective synthesis of (R)- and (S)-2-methyl-4-octanol, a sugarcane weevil pheromone. The key step wasthe asymmetric reduction of ethyl 5-methyl-3-oxohexanoate to its cor-responding alcohol by S. cerevisiae in good yield and high enantiomericexcess (Scheme 6).

Immobilization of S. cerevisiae cells were employed in several reac-tions (Jegannathan et al., 2008). Traditional techniques such as adsorp-tion, covalent bonding, entrapment, encapsulation and cross-linkinghave long been used for immobilization of enzymes and can be usedfor the immobilization of whole cells (Zajkoska et al., 2013).

Alginate was the most employed support for immobilization ofS. cerevisiae cells, as described in the following examples. The immobili-zation in calcium alginate pellets with double gel layers was employedin the bioreduction of 3-bromo-2-oxoalkanoates. The syn-(2R,3S)-β-bromo-α-hydroxy esters were obtained regioselectively (Scheme 7).These chiral bromohydrinswere cyclized to the corresponding epoxides,which were transformed into oxazolidines and finally opened by acidichydrolysis to give syn-(2S,3S)-β-amido-α-hydroxy esters (Rodrigueset al., 2005).

S. cerevisiae immobilized in alginate was also employed in the regioand enantioselective reduction of α-methyleneketoesters for the

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Scheme 6. Reduction of ethyl acetoacetates by S. cerevisiae.


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excesses (Clososki et al., 2007). In the same way, ethyl 2-methylene-3-oxo-3-arylpropanoates were transformed with good conversions togive C_C and C_O reduction products (Scheme 8).

The bioreduction of ethyl 3-halo-2-oxo-4-phenylbutanoatewas alsoperformed using S. cerevisiae which was immobilized in calcium algi-nate beads with double gel layers (Scheme 9) (Milagre et al., 2006).

Another material used for immobilization of S. cerevisiae cells wasmontmorillonite. The reduction of (E)-1-phenyl-1,2-alkanedione 2-(O-methyloxime), by S. cerevisiae immobilized in this support, gave opticallyactive R-alcohols (Scheme 10) (Kreutz et al., 2000).

The use of continuous flow processes has increasingly attracted im-portance in organic synthesis and biocatalysis (Hartman et al., 2011). Itis noteworthy that the biocatalyst immobilization is crucial for the suc-cess of biocatalytic processes using continuousflow, because under suchconditions, protein lixiviation is always a concern and should be takeninto account throughout the process development and immobilizationprotocol (Itabaiana et al., 2013). An alternative approach developedto minimize this problemwas the use of whole cells immobilized on al-ginate (Yadav et al., 1996). This material was employed in a continuousflow process byMilagre et al. (2005). The immobilization of S. cerevisiaewhole cells in calcium alginate was applied in the reduction of ethylbenzoylformate producing ethyl (R)-mandelate (Scheme 11) (Milagreet al., 2005).

In another work, ketone reduction using continuous flow processwas also performed using S. cerevisiae immobilized on chrysotile fibersin a packed-bed-reactor (Scheme 11) (Wendhausen et al., 1998).

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Reduction by other microorganismsThe screening of new microorganisms is an important method for

discovering efficient biocatalytic reactions, and several methods havebeen developed for the selection of suitable biocatalysts which lead tothe products with high yields and enantiomeric excesses (Nakamuraet al., 2003).

Pichia stipitiswas used in the reduction of ketones with high chemoand enantioselectivity. The preparation of (S)-2-ethyl-1-phenylprop-2-en-1-ol by the reduction of 2-ethyl-1-phenylprop-2-en-1-one adsorbedon Amberlite™ XAD-7 was reported by Conceição et al. (2003)(Scheme 12).




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Scheme 7. Synthesis of syn-(2R,3S)-β-amido-α-hydroxy esters using S. cerevisiae as biocatalyst.

Scheme 8. Reduction of ethyl methylene arylpropanoates by S. cerevisiae.

Scheme 9. Reduction of ethyl 3-halo-2-oxo-4-phenylbutanoate by S. cerevisiae.

Scheme 10. Reduction of (E)-1-phenyl-1,2-alkanedione 2-(O-methyloxime) by S. cerevisiae immobilized on montmorillonite.


Please cite this article as: Birolli WG, et al, Biocatalysis and biotransformation in Brazil: An overview, Biotechnol Adv (2015), http://dx.doi.org/10.1016/j.biotechadv.2015.02.001



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Scheme 11. Reduction of ethyl benzoylformate in continuous flow by S. cerevisiae.


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In another study, P. stipitiswas employed in the reduction of (Z)-4-phenyl-3-halo-3-buten-2-ones. However, it was observed the for-mation of 4-phenylbutan-2-one through the dehalogenation of 3-halo-4-phenylbutan-2-one by an electron transfer mechanism. Theaddition of 1,3-dinitrobenzene to the reaction mixture avoids thedehalogenation reaction, and under this condition, the corresponding(2S,3S)-halohydrins were obtained by a hydride transfer mechanism(Scheme 13) (Zampieri et al., 2011).

Different substrates were reduced by R. glutinis CCT 2182 andTrichosporon cutaneum. R. glutinis CCT 2182 promoted the enantio-selective reduction of 2-X-1-(1,3-benzodioxol-5-yl)-1-ethanone (X =Cl, Br, N3) to the corresponding (R)-alcohols (Scheme 14) (Antuneset al., 2004).

T. cutaneumwas employed in the diastereo- and enantioselectivereductions of (±)-2-hydroxy-1-tetralone to the correspondingenantiopure (1S,2R)-cis-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene(Scheme 15). Kinetic studies showed that a deracemization occurredduring the reduction process (Lunardi et al., 2007).

Strains of marine fungi were screened for the asymmetric reductionof 1-(4-methoxyphenyl)ethanone to 1-(4-methoxyphenyl)ethanol.Aspergillus sydowii Ce15 and Bionectria sp. Ce5 produced the enantiopureanti-Prelog (R)-alcohol in N99% ee and, the fungi Beauveria felina CBMAI738 and Aspergillus sclerotiorum CBMAI 849 gave the Prelog (S)-alcoholin N99% ee (Scheme 16) (Rocha et al., 2012a). This reduction was alsoperformed using immobilized cells in silica gel, silica xerogel and chito-san. Enhanced selectivities were observed, immobilized whole cells ofthemarine fungus Penicillium citrinum CBMAI 1186 on chitosan affordedthe (R)-alcohol in 95% yield and N99% ee after 9 days of reaction (Rochaet al., 2012b).

Marine fungal cells were also employed in the chemoselective re-duction of chalcones. Whole mycelia of the marine fungus P. citrinumCBMAI 1186, both free and immobilized on cotton (Gossypium sp.),fibroin (Bombyx mori) and a local kapok (Ceiba speciosa), catalyzed thechemoselective reduction of the chalcone C_C bonds in good yields.The immobilized fungus and free whole mycelium showed a similarbehavior in the conversion of chalcones with different substituents.The enzymes involved in the reduction are enoate reductases, whichwere more effective than the alcohol dehydrogenases in the competi-tion for the substrate (Scheme 17) (Ferreira et al., 2014).

Alginate beads immobilization of Pichia kluyveri, P. stipitis andCandida utilis were employed for the reduction of benzoylacetates. Theaddition of glucose and α-chloroacetophenone to the reaction mediumincreased the yields and ee. Under optimized condition, enantiomericexcess of N99% and yields up to 85% were achieved. The optimizedconditions were employed in a scaled up process (1.0 g of substrate

Scheme 12. Reduction of 2-ethyl-1-phenylprop-2-en-1-one adsorbed on Amberlite™XAD-7 by P. stipitis.


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per batch) in a 400 mL stirred-tank reactor using benzoylacetate, p-nitrobenzoylacetate and p-methoxybenzoylacetate as substrates. Theproducts were obtained in good yields and selectivities for all substratestested (Scheme 18) (Milagre et al., 2009).

A chemo-enzymatic approach to obtain α-hydroxy-β-methyl-γ-hydroxy esters with three continuous stereogenic centers in highenantio- and diastereoselectivity was developed by Milagre et al.(2010). Two distinct linear routes were proposed, the key steps in bothroutes consisted of an initial stereocontrolled ketoester bioreductionusing P. kluyveri, S. cerevisiae, R. glutinis or T. cutaneum. In Scheme 19are shown the results obtained using P. kluyveri (Route A) andS. cerevisiae (Route B). Route A gave the product with the 3R,4R,5Sconfiguration exclusively, whereas route B gave two products with the3R,4R,5S and 3R,5S,5R configurations.

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Microorganisms, such as fungi and bacteria have been long exploredas biocatalysts. However, plants and therefore their enzymes have notbeen extensively studied for transformations of xenobiotic substratesfor synthetic purposes. The enzymes present in plants cells may haveunknown and interesting properties that would allow new approachesin biocatalysis (Cordell et al., 2007; Matsuda et al., 2009).

The asymmetric reduction of carbonyl groups for the productionof chiral alcohols has significant importance for the development ofdrugs and agrochemicals. Bearing this fact in mind, Lens culinaris seedswere employed as biocatalyst for the asymmetric reduction of carbonyland nitro groups. The enzymatic reduction of bromoacetophenones byL. culinaris resulted in the (S)-alcohols with excellent conversions andenantioselectivities (Scheme 20) (Ferreira et al., 2012a).

In addition, the carbonyl group of benzaldehyde and furfuraldehydewas completely reduced by whole cells of L. culinaris, leading to thecorresponding alcohols with high yields (Ferreira et al., 2012a). In com-pounds containing nitro and carboxyl substituents in the aromatic ring,high conversions were obtained for the compounds with the groups atthe para position (Scheme 21) (Ferreira et al., 2012b).

Chemoselectivity was observed when whole seeds of Linumusitatissimum were employed in the reduction of nitroacetophenones.The nitro group was preferentially reduced and the best results wereobtained for ortho and para-nitroacetophenones (Scheme 22) (Tavareset al., 2014).

Plant cells from coconut (Cocos nucifera), sugar cane (Saccharumofficinarum) and passion fruit (Passiflora edulis) were reported as re-ducing and esterifying agents, resulting in the formation of the prod-ucts with regio and enantioselectivity (Assunção et al., 2008, 2009;Fonseca et al., 2009; Machado et al., 2008a). In the enantioselectivereduction of prochiralβ-keto-esters, ethyl 3-oxobutanoatewas reducedby C. nucifera, S. officinarum and P. edulis leading to the (+)-(3S)-hydroxy-ethyl-butyrate. The product was formed with S-configurationexclusively (Scheme 23) (Fonseca et al., 2009).

Bioreduction and biooxidation reactions using plants as biocatalystswere reported by Andrade et al. (2006). The Arracacia xanthorrhizaprovided the best results and, in general, acetophenone derivativeswere bioreduced with good conversions and high enantiomeric ex-cesses (up to 98% ee) (Scheme 24). It is noteworthy that ketones werealso formed from secondary alcohols oxidation using edible plants ascatalysts.




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Scheme 13. Reduction of (Z)-4-phenyl-3-halo-3-buten-2-ones by P. stipitis.

Scheme 14. Reduction of 2-X-1-(1,3-benzodioxol-5-yl)-1-ethanone by R. glutinis.

Scheme 15. Reduction of (±)-2-hydroxy-1-tetralone by T. cutaneum.

Scheme 16. Enantiocomplementary reduction of 1-(4-methoxyphenyl)ethanol by marine fungi.

Scheme 17. Chemoselective reduction of chalcones by the marine fungus P. citrinum CBMAI 1186.





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Scheme 20. Reduction of bromoacetophenone derivatives by L. culinaris.Scheme 18. Reduction of benzoylacetates by P. kluyveri.


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Algal biomass was also employed in bioreduction reactions.Acetophenone derivatives were reduced by Bostrychia tenella andBostrychia radicans yielding enantiomerically pure alcohols. Bacterialstrains associatedwith these algaewere isolated and identified as Bacillusgenus and were also able to catalyze the reduction of acetophenonederivatives with high enantiomeric excess (Scheme 25) (Mouad et al.,2011). In addition the bioconversion of acetophenone derivatives wasinvestigated using whole cells of marine fungy isolated from algaeB. radicans and Sargassum sp. (Mouad et al., 2012).

Reduction of organic compounds containing heteroatoms (sulfur, seleniumand silicon) by whole cells of microorganisms and vegetables

Organic selenium compounds have been proposed as importantsynthetic intermediates in total synthesis (Wirth, 2011) and potentialdrugs for the treatment of pathologies in a variety of experimentalmodels (Koppula et al., 2012). Andrade et al. (2004) synthesized a seriesof organoselenium acetophenones, which were reduced to the corre-sponding alcohols using whole cells of Rhizopus oryzae CCT 4964,Aspergillus terreus CCT 3320, A. terreus CCT 4083 and Emericella nidulansCCT 3119. These microorganisms showed Prelog and anti-Prelogstereoselectivity, leading to arylselenoalcohols in moderate to highenantiomeric excesses and high conversions (Scheme 26). In thiswork (Andrade et al., 2004), it was observed that for the series ofseleno-containing acetophenones tested, the carbonyl group at theortho-position to the seleno group did not suffer reduction. Probably,

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Scheme 19. Biocatalytic synthesis of α-hydroxy-β-meth


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an intramolecular interaction between the oxygen of the carbonylgroup and the selenium atom is responsible for this result (Pandaet al., 2001).

Daucus carota root promoted the reduction of the carbonyl groupof organoselenium acetophenones, leading to the correspondingbenzyl alcohols in good yields and enantiomeric excesses (Scheme 27)(Comasseto et al., 2004). The ortho-methylseleno and ortho-phenylselenoacetophenones were not biotransformed into the respec-tive chiral alcohols when treated with carrot roots, in the same way ascommented above for the reduction by fungi.

Ferraz et al. (2008) used D. carota root in the reduction reaction of(±)-α-tetralone, in aqueous phosphate buffer, employing acetonitrileand ethanol for the solubilization of the substrates. The correspondinghomochiral alcohols were formed in conversions ranging from 9 to90% in good enantiomeric excesses (Scheme 28).

Piovan et al. (2008) obtained enantiopure compounds containingselenium by biocatalytic reduction of racemic selenocyclohexanoneusing basidiomycetes native of Brazil. Five strains of white-rot basidio-mycetes, such as Irpex lacteus CCB 196, Pycnoporus sanguineus CCB196, Trametes rigida CCB 285, Trametes versicolorCCB 202 and Trichaptumbyssogenum CCB 203, were examined. Cells of T. rigida CCB 285 gave cis-(R,S) and trans-(S,S) selenoalcohols in high enantiomeric excesses andgood conversions (Scheme 29).

Piovan et al. (2008) also observed that the chemoselective reductionof (±)-2-(phenylthio)cyclohexanone by T. rigida CCB 285 afforded

yl-γ-hydroxy esters with three stereogenic centers.




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Scheme 21. Biotransformation of aldehydes, aromatic carboxylic acids and aromatic nitrocompounds by L. culinaris.

Scheme 24. Reduction of acetophenone derivatives by A. xanthorrhiza.


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exclusively the (+)-cis-(1R,2S) and (+)-trans-(1S,2S) diastereoiso-mers of 2-(phenylthio)cyclohexanol with high enantiomeric excesses(Scheme 30). This transformation was chemoselective since theenzymes present in this microorganism have not biotransformed thesulfide group.

The reduction of aroyltrimethylsilanes by Baker's yeast was de-scribed by Patrocínio et al. (1999). Aromatic acylsilanes were reducedto optically active α-silyl alcohols in 20–70% yield and 43–88% ee(Scheme 31) showing that the biocatalytic reduction by S. cerevisiaecan be a important method for the reduction of organic compoundscontaining silicon, which was important in the control of the reaction.

Biocatalytic oxidation of sulfides by microorganisms

A. terreus CCT 3320 transformed sulfides into a mixture of sufoxidesand sulfones. Whole cells of A. terreus CCT 3320 were immobilized onchrysotile and cellulose/TiO2 enabling the cells to reuse with similaractivity as that of the free cells for at least three months (Scheme 32)(Porto et al., 2002).

In another work, whole cells of I. lacteus, P. sanguineus, T. byssogenum,T. rigida, Trametes versicolor and Trametes villosa catalyzed the oxidationof aryl alkyl sulfides into (S)-sulfoxideswith varying yields (30–42%) andenantioselectivities (0–99% ee) (Ricci et al., 2005).

Biocatalytic sp3 C-H hydroxylation with whole cells of microorganisms

The selective oxyfunctionalization of sp3C–H bonds in saturatedorgano compounds by traditional chemicalmethods represents a formi-dable challenge for the synthetic organic chemists (Hollmann et al.,

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Scheme 22. Chemoselective reduction of nitrocetophenones by L. usitatissimum.

Scheme 23. Reduction of ethyl 3-oxobutanoate by plant cells.


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2011). In these reactions, biocatalysis gained attention, since enzymescatalyze regio and stereoselective functionalization of organic com-pounds under mild reaction conditions (Lewis et al., 2011). For exam-ple, the hydroxylation of hydrocarbons (indan and tetralin) wasperformed using whole cells of Mortierella isabellina (Scheme 33),Micromucor ramanniana andBeauveria bassiana (Limberger et al., 2007).

Whole cells of fungi were also employed in hydroxylation reactionsfor obtaining menthanetriols. (R)-Carvone gave p-menthane-2,8,9-triols by action of Lasiodiplodia theobromae and Mucor circinelloides(Scheme 34). In addition, the microbial biotransformation of carvoneenantiomers (R and S) by L. theobromae, Trichoderma harzianum andM. circinelloides fungi also showed dihydrocarveol and dihydrocarvoneas products (Nunes et al., 2013).

Biocatalytic kinetic resolution by lipases

Enzymatic kinetic resolution is an excellent strategy for obtainingenantiomerically pure organic compounds from their racemates. Theenzymatic kinetic resolution of alcohols, for example, has been ofgreat synthetic interest because they are key pieces in a variety of syn-thetic routes. The kinetic resolution of racemates has been performedwith different methodologies, such as the use of whole cells of microor-ganisms, free and/or immobilized isolated enzymes, microorganisms orenzymes in ionic liquids, enzymes immobilized in magnetic nanoparti-cles and immobilized enzymes in continuous flow processes.

Among the most widely employed biocatalysts used for kineticresolutions we can highlight the lipases. Rocha et al. (2010) report-ed the kinetic resolution of (±)-iodophenylethanols using Candidaantarctica (CAL-B) lipase as biocatalyst. High enantiomeric excesseswere observed for the (R)-acetates and (S)-alcohols (up to N98% ee)(Scheme 35).

CAL-Bwas also employed in enzymatic kinetic resolution of sulcatol.Ferreira et al. (2010) described high enantiomeric excesses for the (S)-sulcatol and (R)-sulcatyl acetate, in a short reaction time using vinylacetate as acyl donor group (Scheme 36). In another study, Ferreiraet al. (2012a,b,c) reported the efficient kinetic resolution of aliphatic

Scheme 25. Reduction of the iodoacetophenones by marine algae.




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Scheme 26. Reduction of 1-(4-(methylselanyl)phenyl)ethanone by whole cells of fungi.


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alcohols using CAL-B, vinyl acetate as acyl donor and hexane as solvent.The productswere obtainedwith high yields and enantiomeric excesses(N99% ee).

Lipases, in special CAL-B have high versatility for regioselectivemodifications. This enzyme was considered the most suitable one forthe regioselective production of the biologically active compoundschloramphenicol and thiamphenicol esters (Bizerra et al., 2011; DaSilva et al., 2014a). Araujo et al. (2009) described the chemoenzymaticsynthesis of the antitumoral agent (S)-5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione employing CAL-B and Pseudomonascepacia PSL-I lipase. In this study, the biologically active (S)-alcohol hasbeen isolated in its enantiopure form (Scheme 37).

Complex structures such as propargylamine derivatives are impor-tant for the syntheses of optically active molecules such as alkaloidsand aminoacids (Reginato et al., 1996). Melgar et al. (2010) synthesized(±)-hydroxypropargylpiperidone in good yield via a three-componentone-pot procedure. Then, the product was submited to chemoenzymaticresolution with CAL-B generating the enantiomerically enrichedpropargylpiperidinone derivatives. These experiments were performedin hexane as solvent and vinyl acetate as acyl donor (Scheme 38).

The enzymatic kinetic resolution of (±)-propargylic alcohols byCAL-Bwas described by Raminelli et al. (2004). The best reaction condi-tions (hexane, vinyl acetate, 40 min and 32 °C) were then applied todifferent alcohols with high enantiomeric excesses in some cases. Theresults indicated that compounds with R = Me showmoderate kineticresolution under the conditions employed (Scheme 39).

(±)-α-Tetralolswere submitted to CAL-B-catalyzed enzymatic acet-ylation employing vinyl acetate as acyl donor. The reactions were per-formed in hexane at 32 °C. The resulting acetates were obtained inhigh yields and excellent enantiomeric excesses (Scheme 40) (Ferrazet al., 2007).

Da Silva et al. (2014b) investigated the catalytic activity ofthe Rhizomucor miehei lipase in the kinetic resolution of amido esters(N-protected group). The best results were obtained using methyl andallyl ester derivatives of N-acetyl-phenylalanine as substrates, intransesterification reactions with butyl butyrate in acetonitrile at30 °C. The activity and stereoselectivity of the reaction were depen-dent on the amino esters structure. In this way, high and moderatestereoselectivities were observed for the para- and meta-nitro amidoesters, respectively, whereas the ortho-nitro amido ester did not react(Scheme 41).
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491Scheme 27. Reduction de organoseleno acetophenones by D. carota.


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Immobilized enzymes or enzyme complexes from plants were usedfor the esterification of alcohols. Immobilized enzymes from sugar cane(S. officinarum), cassava (Manihot esculenta) and passion fruit (P. edulis)were used for the acetylation of secondary alcohols. Enzymes fromM. esculenta and P. eduliswere immobilized in calcium alginate, respec-tively. These biocatalysts promoted the acetylation of racemic alcohols,wherein the R enantiomer was acetylated in all the compounds investi-gated (Machado et al., 2009). The immobilized enzymes of sugar canejuice on calcium alginate showed biocatalytic activity for producingacetates in good to high yields (Scheme 42) (Assunção et al., 2009;Machado et al., 2008a,b).

Microwave irradiation (MW) is being applied to improve biocatalyt-ic transformations (Mahapatro and Negron, 2013). An example ofthe application of this technique was given by Ribeiro et al. (2013).The enzymatic kinetic resolution of (±)-organofluorine alcohols usingCAL-B under microwave irradiation, gave higher conversions and enan-tiomeric excesses and occurred in shorter reaction times than the sametransformation under conventional heating (CH) (Scheme 43) (Ribeiroet al., 2013). The kinetic resolution of (±)-mandelonitrile was also car-ried out using CAL-B undermicrowave irradiation in toluene, producingthe (S)-mandelonitrile acetate with high selectivity (Ribeiro et al.,2012).

Microwave irradiation was also applied for the kinetic resolution of(±)-sec-butylamine by free and immobilized lipase on starch or gelatinfilms. For the free lipase from Aspergillus niger, the conversionwas threetimes higher under microwave irradiation than under conventionalheating. When the same enzyme immobilized on starch was employedunder microwave irradiation, the (R)-amidewas obtained with conver-sion degrees lower than those using the free lipase, but the selectivitywere better than under conventional heating. In general, better resultswere obtained under microwave irradiation than under conventionalheating (Scheme 44) (Pilissão, 2012).

The same authors employed ionic liquids as co-solvents in the acyl-ation of (R,S)-phenylethylamine by lipases. Higher conversion degreesand E-valueswere obtained using CAL-B. The two-phase system formedby [BMIm][Cl]/dichloromethane or [BMIm][Cl]/chloroform, using CAL-Bas biocatalyst showed a better selectivity than the reaction in organicsolvents (Scheme 45) (Pilissão et al., 2009).

Ionic liquids as co-solvents were also applied in the enzymaticresolution of (±)-methyl mandelate using lipases and n-butylaminein organic solvents. The best results were achieved when CAL-B wasused in a mixture of chloroform or tert-butanol and [BMIm][BF4](Scheme 46) (Pilissão and Nascimento, 2006).

Magnetic nanoparticles were employed in enzymatic kinetic resolu-tions in order to improve and/or allow the use of enzymes for severalturnovers (Netto et al., 2013). Netto et al. (2009) immobilized CAL-Bdirectly into functionalized superparamagnetic nanoparticles. The enzy-matic activity was preserved and the nanoparticles were used in theenantioselective transesterification of (±)-1-phenyl-ethanol deriva-tives (Scheme 47). The immobilized enzyme was easily recovered bymeans of a magnet, allowing its reuse with a negligible loss of theactivity.

Other methodologies were used for the immobilization of lipases onmagnetic nanoparticles. The immobilization of Burkholderia cepacia




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Scheme 28. Reduction of (±)-α-tetralone by Daucus carota root.

Scheme 29. Chemoselective reduction of (±)-selenocyclohexanone by fungi.

Scheme 30. Chemoselective reduction of (±)-2(phenylthio)cyclohexanone by T. rigida CCB 285.

Scheme 31. Reduction of aroyltrimethylsilanes by Baker's yeast.





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Scheme 32. Enantioselective oxidation of sulfides by A. terreus.


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lipase (BCL) on superparamagnetic nanoparticles was performedusing three different methodologies: adsorption, chemisorption withcarboxybenzaldehyde and chemisorption with glutaraldehyde. Theimmobilized enzyme was employed for the kinetic resolution of (±)-α-bromoethanol. In general, the immobilization of B. cepacia lipase ledto an improvement of its catalytic performance. The best results for thekinetic resolution were obtained using the B. cepacia lipase immobilizedvia glutaraldehyde on themagnetic nanoparticles (Scheme48) (Andradeet al., 2010b).

Miranda et al. (2013a) made use of a continuous flow techniquein the kinetic resolution of an imidazole derivative. Candida antarticaB lipase immobilized on an acrylic resin was used as the catalyst(Scheme 49).

The continuous flow process approach was also used by Manoelet al. (2013) for the kinetic resolution of (±)-1,2,4-tri-O-benzyl-myo-inositol catalyzed by CAL-B. Under continuous flow, the productivitywas 531 times higher than that observed for the corresponding batchprocess, and the catalyst maintained the stability for 9 consecutivecycles (Scheme 50).

Miranda et al. (2013b) employed continuous flow technics in theresolution of (±)-1-phenylethylamine. The immobilized CAL-B couldbe used for more than 9 consecutive turnovers (Scheme 51).

Biocatalytic deracemization of secondary alcohols using whole cells ofmicroorganisms

Deracemization by enantioselective stereoinversion of an alcoholracemate yielding an enantiomerically enriched product is an importanttool in the production of optically active alcohols (Chen et al., 2008).

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OBiocatalytic deracemizations can be performed by isolated enzymes orby whole cells of microorganisms, however, only a limited number ofmicroorganism are capable of successfully promoting this reaction(Chen et al., 2008; Mantovani et al., 2009).

A deracemization processwas developed using strains ofA. niger CCT1435, C. albicans CCT 0776 and Bacillus pumilus CBMAI 0008 and (±)-epoxyoctane. A. niger and C. albicans produced the enantioenriched(S)-diol. Kinetic resolution was also promoted by B. pumilus. In thiscase the (S)-diol was obtained along with an equal amount of 1-hydroxy-2-octanone (Scheme 52) (Chen et al., 2008).

A deracemization process of (±)-1,2-octanediol to yield (S)-1,2-octanediol in high enantiomeric excesses was developed using strainsof A. niger CCT 1435, C. albicans CCT 0776 and B. pumilus CBMAI 0008.A. niger and C. albicans produced only the (S)-diol, whereas kinetic res-olution was promoted by B. pumilus. In this case, the (S)-diol was ob-tained with an equal amount of 1-hydroxy-2-octanone (Scheme 52).These data suggest that the (R)-alcohol was selectively oxidized to 1-hydroxy-2-octanone by all microorganisms. However, while A. nigerand C. albicans reduced the 1-hydroxy-2-octanone by the action of(S)-stereoselective oxidoreductases increasing the conversion of the(S)-alcohol, B. pumilus seems not to have these oxidoreductases,resulting in the accumulation of 1-hydroxy-2-octanone (Chen et al.,2008).

Mantovani et al. (2009) also employed the strain C. albicans CCT0776 in the deracemization of (±)-phenylethanol. The stereoinversiongave (R)-phenylethanol in 96% conversion and 99% ee. To evaluate themechanism of deracemization, acetophenone was used as substrate inthe biotransformation with C. albicans resulting in the preferentialformation of the (S)-alcohol in low ee. The (S)-alcohol was selectivelyoxidized to the corresponding ketone, and after many cycles, the (R)-alcohol was enantiomerically enriched in high yields (Scheme 53)(Mantovani et al., 2009).

C. albicans CCT 0776 was also applied in the deracemization ofsecondary alcohols, such as (±)-4-benzyloxy-1,2-butanediol, (±)-2-nonanol and (±)-2-undecanol. C. albicans produced the (S)-4-benzyloxy-1,2-butanediol. (±)-2-Nonanol and (±)-2-undecanol werederacemized providing the (R)-alcohols in 99% ee (Scheme 54)(Mantovani et al., 2009).

Comasseto et al. (2004) studied the deracemization of arylethanolsin the presence of A. terreus CCT 4083. In the reaction of (±)-(p-nitro-phenyl)ethanol the deracemization process occurred leading to (S)-(p-nitrophenyl)ethanol in 86% conversion and 99% ee. This result indi-cated that A. terreus CCT 4083 promoted the oxidation of (R)-(p-nitro-phenyl)ethanol, forming the p-nitroacetophenone, while (S)-(p-nitrophenyl)ethanol was not oxidized. Then, the p-nitroacetophenonewas reduced to the (S)-alcohol, promoting the enantiomeric enrich-ment (Scheme 55) (Comasseto et al., 2004).

C. albicans CCT 0776 was used in deracemization by stereoinversionof racemic 1-(4-substituted phenyl)-1,2-ethanediol. Cazetta et al.




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Scheme 34. Biotransformation of carvone by fungi.

Scheme 35. Kinetic resolution of iodophenylethanols by CAL-B.

Scheme 36. Kinetic resolution of (±)-sulcatol by CAL-B.

Scheme 37. Kinetic resolution of (±)-5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione by lipases.

Scheme 38. Synthesis and enzymatic resolution of (±)-hydroxypropargylpiperidones by CAL-B.





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Scheme 39. Kinetic resolution of (±)-propargylic alcohols by CAL-B.

Scheme 40. Kinetic resolution of (±)-α-tetralols by CAL-B.


RREC(2014) observed that (±)-1-phenyl-1,2-ethanediol was quantita-

tively converted to (S)-1-phenyl-1,2-ethanediol. When only the(R)-enantiomer was incubated with C. albicans, it was observed theformation of α-hydroxyacetophenone followed by its reduction to the(S)-1-phenyl-1,2-ethanediol 99% ee. When (S)-1-phenyl-1,2-ethanediolwas incubated with C. albicans, no biotransformation was observed.These experiments showed that the deracemization occurred by selectiveoxidation of (R)-1-phenyl-1,2-ethanediol to α-hydroxyacetophenone,which was then reduced to (S)-1-phenyl-1,2-ethanediol (Scheme 56)(Cazetta et al., 2014).

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Scheme 41. Transesterification of am


Biocatalytic epoxidation of alkenes by lipases

The chemo-enzymatic epoxidation of citronellol followed by esteri-ficationwas reported byDa Silva andNascimento (2012). Dependingonthe reaction conditions, high yields of products citronellol oxide or citro-nellol oxide ester were obtained (N99%). CAL-B was the most effectivecatalyst in this reaction. For the epoxide, the highest yields of 80%and 77% were obtained at 20 °C and 25 °C, respectively, using urea–hydrogen peroxide (H2O2–UHP) as an oxidizing agent and octanoicacid as an acyl donor (Scheme 57).

ido esters by R. miehei lipase.




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Scheme 42. Kinetic resolution of (±)-secondary alcohols by immobilized lipases from M. esculenta and P. edulis.

Scheme 43. Kinetic resolution of organofluorine alcohols by CAL-B under MW irradiation.


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In another study, Da Silva et al. (2013) reported the regioselectiveepoxidation of β-caryophyllene by CAL-B in the presence of oxidizingagents (H2O2) and urea-hydrogen peroxide (UHP). The reaction pro-duced the mono- and the di-epoxides in high yields. When n-hexanewas employed as the solvent, the mono-epoxide was obtained withN99% conversion, whereas in ethyl acetate or toluene, the di-epoxidewas obtained with N99% of conversion (Scheme 58).

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Scheme 44. Kinetic resolution of (±)-sec-butylam


Moreira et al. (2005) reported the in situ epoxidation of octanoicacid by hydrogen peroxide in the presence of CAL-B to the corre-sponding peroxy octanoic acid, which promoted the epoxidation ofcyclohexene to cyclohexene oxide (Scheme 59). Interesting resultswere also obtained using Amano Rhizopus oryzae lipase and the ionicliquid 1‐butyl‐3‐methylimidazolium tetrafluoroborate (Moreira et al.,2005).

ine under CH or MW by lipase from A. niger.




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Scheme 45. Kinetic resolution of (±)-phenylethylamine by CAL-B in a biphasic system.

Scheme 46. Aminolysis of (±)-methyl mandelate by CAL-B.


The auto oxidation of linoleic acid was catalyzed by CAL-Bimmobilized in microemulsion-based organogels of hydroxyl–propyl–methyl cellulose in presence of H2O2. The regioselective oxidationyielded the mono- and di-epoxides depending on the experimentalconditions (Scheme 60). The biocatalyst was reused for 7 consecutive

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Scheme 47. Kinetic resolution of 1-phenylethanol derivatives by i

Scheme 48. Kinetic resolution of (±)-α-bromoethanol


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times with excellent conversions during the first 4 reuses. After that,the conversion was significantly reduced (Zanette et al., 2014).

Bitencourt and Nascimento (2009, 2010) developed a highly effi-cient chemo-enzymatic system for the oxidation ofN-alkyliminesmedi-ated by lipases. N-alkylimines were oxidized by hydrogen peroxide

mmobilized CAL-B on functionalized magnetic nanoparticles.

by immobilized lipase on magnetic nanoparticles.




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Scheme 49. Kinetic resolution of 5H-pyrrolo[1,2-a]imidazol-7-ol,6,7-dihydro under continuous flow by CAL-B.

Scheme 50. Kinetic resolution of (±)-1,3,6-tri-O-benzyl-myo-inositol under continuous flow by CAL-B.

Scheme 51. Kinetic resolution of (±)-1-phenylethylamine in continuous flow by CAL-B.


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catalyzed by CALB leading to the corresponding oxaziridines. The influ-ence of organic solvents, acyl donor and lipase amount were evaluated,and no oxidation product was detected in the absence of lipases.The chemo-enzymatic formation of oxaziridines involves firstly, theenzymatic formation of peracids by the carboxylic acids or esters andhydrogen peroxide, followed by the attack of the C_N double bond ofan imine to the electrophilic oxygen of the peracid, resulting in anoxazirane ring (Scheme 61).

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Scheme52.Deracemization of (±)-1,2-octanediol by A. niger CCT 1435 and C. albicansCCT0776 (k1 ≫ k2; k − 2 ≫ k − 1) and kinetic resolution with B. pumilus CBMAI 0008(k1 N k2 N k − 1 and k − 2).


Biocatalytic reactions in organic compounds containing heteroatoms (silicon,boron, selenium and tellurium)

Organic compounds containing heteroatoms such as boron, silicon,seleniumand telluriumhave been submitted to biocatalytic transforma-tions with high selectivities. It was also noteworthy that in most casesthe heteroatom remained untouched.

(±)-Aryltrimethylsilyl alcoholswere submitted to kinetic resolutionusing P. cepacia lipase (PS-C II) as catalyst. The reaction with meta andpara substituted benzyl alcohols gave good results (Scheme 62). Theortho isomer did not react under the employed conditions (Palmeiraet al., 2011).

The use of enzymes as catalysts for obtaining optically pure boroncompounds was reported by Andrade et al. (2009a). The kinetic resolu-tion of boron-containing chiral alcohols was performed using CAL-Bwith excellent E values (N200) and high enantiomeric excesses (up toN99% ee) of both alcohols and acetates (Scheme 63) (Andrade et al.,2009).

The enantioselective acetylation of primary amines containingorganoboron in the structure was also reported by Andrade et al.(2010b). Different reaction conditions were evaluated to achievemaximum conversion in the enantioselective acylation of theamines. CAL-B was the best biocatalyst for the acetylation reaction(Scheme 64).

Brondani et al. (2011) reported the use of Baeyer–Villiger mono-oxygenases (BVMOs) in the chemo- and enantioselective oxidationof a number of boron-containing aromatic and vinylic compounds.




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Scheme 53. Deracemization of (±)-phenylethanol by C. albicans CCT 0776.

Scheme 54. Deracemization of (±)-alcohols by C. albicans CCT 0776.


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Several BVMOs were used in this study. The degree of chemoselectivitydepended on the type of BVMO employed, which preferred the boron–carbon oxidation over the Baeyer–Villiger oxidation. Phenylacetonemonooxygenase (PAMO) performed the kinetic resolution of boron-containing compounds with phosphite dehydrogenase (PTDH) for the

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Scheme 55. Deracemization of (±)-(p-nitro


reduction of NADP+. The (S)-borane was oxidized to the corresponding(S)-alcohol, and the (R)-borane was recovered with a moderate enan-tiomeric excess (Scheme 65).

Reis and Andrade (2012) reported the kinetic resolution of chiralβ-borylated carboxylic esters via lipase-catalyzed hydrolysis and

phenyl)ethanol by A. terreus CCT 4083.




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Scheme 56. Deracemization of 1-phenyl-1,2-ethanediol by C. albicans CCT 0776.


transesterification reactions. The enantioselective hydrolysis catalyzedby CAL-B led to the β-borylated carboxylic acid with reasonable enan-tiomeric excess. In addition, the methyl carboxylic ester was recoveredwith excellent selectivity (Scheme 66).

Reis et al. (2013) investigated the asymmetric reductive aminationof aryl-ketones bearing boronic ester using enantiocomplementary ω-transaminases (ω-TAs) as catalysts and an alanine dehydrogenase as acofactor recycling system. When the ω-transaminase derived fromChromobacteriumviolaceum andA. terreuswasused, the (R)-enantiomerof the amino-aryl boronates was formed, whereas when the ω-transaminase derived from P. fluorescens and Arthrobacter citreus wasemployed, the (S)-enantiomer was obtained (Scheme 67).

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Scheme 57. Chemo-enzymatic epox

Scheme 58. Chemo-enzymatic epoxida


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The kinetic resolution of organoselenides and tellurides has beenexplored (Comasseto and Gariani, 2009) to obtain these compoundsin pure enantiomeric form for synthetic purposes. The enzymatic kineticresolution of β-hydroxyselenides was reported by Costa et al. (2004).A comparative study on the effect of temperature, solvent, enzymesand the structure of the substrates in the resolution was presented.The best result for (±)-1-phenylselanyl-propan-2-ol was obtained byCAL-B (Scheme 68).

The kinetic resolution of racemic organoseleno-1-arylethanols byC. antarctica lipase was reported by Omori et al. (2007). In some cases,enantiomeric excesses of up to 99%were obtained for alcohols and ace-tates (Scheme 69).
E
idation of citronellol by CAL-B.

tion of β-caryophyllene by CAL-B.




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Scheme 59. Chemo-enzymatic epoxidation of cyclohexene by CAL-B.


Andrade et al. (2006) investigated a series of organoseleniumamines in the enzymatic kinetic resolution by acetylation mediated byCAL-B to give the corresponding chiral amides in enantiomericallypure form (Scheme 70).

An efficient method for the chemoenzymatic dynamic resolutionof selenium-containing chiral amines was developed by Andradeet al. (2009b) leading to the corresponding amides in excellent

UNCO

RRECTScheme 60. Chemo-enzymatic epoxi

Scheme 61. Chemo-enzymatic epoxid

Scheme 62. Kinetic resolution of (±)-arylt


OO

F

enantioselectivities and high yields. This one-pot procedure employedtwo different types of catalysts, the PdSO4 as the racemisation catalystand CAL-B as the resolution catalyst (Scheme 71).

Biomethylation of organoselenium compounds by whole cells ofA. terreus was observed by Da Costa et al. (2007). A. terreus CCT 3320and A. terreus URM 3571 catalyzed the biotransformations of organicβ-hydroxyphenyl selenides through oxidation and methylation reac-tions. The biotransformation of (±)-1-(phenylseleno)-2-propanol gavephenyl methyl selenide in 40% yield and (+)-(S)-1-(phenylseleno)-2-propanol in 50% yield and N99% ee. It was proposed that the biotransfor-mation of (±)-1-(phenylseleno)-2-propanol by A. terreus involved amulti-enzymatic sequence of oxidoreduction reactions that leads tothe kinetic resolution of the alcohol. The oxidation of the R-enantiomerfollowed by the elimination of the propyl moiety and subsequentmethylation of the presumed intermediate, led to the formation ofmethylphenyl-selenide, whereas the (S)-enantiomer was not bio-transformed, being recovered in N99% ee (Scheme 72).

A systematic study on the enzymatic kinetic resolution ofhydroxyalkylltellurides was studied by Dos Santos et al. (2006). CAL-Bprovided the best conversions, leading to both enantiomers with highenantiomeric purity (Scheme 73). The (R)-acetate was easily trans-formed to the corresponding (R)-alcohols by hydrolysis.

ED P

Rdation of linoleic acid by CAL-B.

ation of N-alkylimine by CAL-B.

rimethylsilyl alcohols by lipase PS-CII.




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RRECTED P

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OFScheme 63. Kinetic resolution of boron-containing chiral alcohols by CAL-B.

Scheme 64. Kinetic resolution of (±)-boron-containing amines by CAL-B.

Scheme 65. Kinetic resolution of (±)-borane catalyzed by PAMO.

Scheme 66. Hydrolysis of (±)-β-borylated carboxylic ester by CAL-B.





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Scheme 67. Reductive amination of aryl-ketones bearing boronic ester by ω-transaminases.

Scheme 68. Kinetic resolution of (±)-1-phenylselanyl-propan-2-ol by CAL-B.

Scheme 69. Kinetic resolution of (±)-organoseleno-1-arylethanols by CAL-B.


NCOThe obtained enantiomerically enriched (R)- and (S)-alcohols were

transformed into the corresponding lithium dianions by reaction withn-BuLi. Subsequent treatment with carbon dioxide and HCl afforded(S)- and (R)-valerolactones (Scheme 74).

The enantiomerically enriched hydroxytellurides were employed inthe synthesis of chiral lactones (Dos Santos et al., 2007) and chiral insectpheromones (Ferrarini et al., 2009).

U

Scheme 70. Kinetic resolution of org


Bassora et al. (2007) submitted a (±)-hydroxy vinylic telluride to anenzymatic screening aiming to perform its kinetic resolution. Threelipases were investigated in three solvent systems. The enantioenriched(R)-acetates were obtained in high enantiomeric excess using CAL-Band porcine pancreatic lipase (PPL). On the other hand, the enantiomer-ic excess of the unreacted (S)-alcohols was good in the presence of CAL-B using hexane as solvent andmoderate in a 1:1mixture of THF/hexane.

anoselenium amines by CAL-B.




ECTED P

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Scheme 72. Biotransformation of (±)-1-(phenylseleno)-2-propanol by A. terreus.

Scheme 71. Kinetic dynamic resolution of selenium-containing chiral amines by palladium and CAL-B.


NCO

RROn the other hand, Amano Pseudomonas sp. lipase (PSL) provided poor

results in the kinetic resolution reaction (Scheme 75). The chiralhydroxy vinylic tellurides prepared as described in Scheme 75 wereemployed in the enantioselective synthesis of butano- and butenolides(Ferrarini et al., 2012).

Enzymatic kinetic resolution of hydroxychalcogenides (Se, Te) in sc-CO2 was reported by Gariani et al. (2011). The reaction conditions wereoptimized to obtain the productswithmaximumenantiomeric excesses(Scheme 76).

In another work, Raminelli et al. (2005) obtained enantiomericallypure propargylic alcohols by means of a kinetic resolution using CAL-B.

U

Scheme 73. Kinetic resolution of (±


The enantiomerically pure propargylic alcohols were transformed intothe corresponding enantiomerically pure vinylic tellurides, which werecoupled with alkynes under Pd catalysis to provide enantiomericallypure allylienynols (Scheme 77).

Miscellaneous biotransformation by microorganisms of Brazilianorigin

Brazil has a very rich, but scientifically unexplored biodiversity.Recently this biodiversity became the object of intensive study by theBrazilian scientific community. The exploitation of microorganisms for

)-hydroxytellurides by CAL-B.




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Scheme 75. Kinetic resolution of (±)-vinylic telluride by lipases.

Scheme 74. Chemo-enzymatic synthesis of (S)- and (R)-valerolactones from S- and R-hydroxytellurides.


NCO

RREC

synthetic purpose is even more recent, and in the forthcoming sectionswe will comment on the most recent developments in biotransforma-tion in Brazil employing native microorganisms.

Biotransformation of nitriles

Nitriles constitute a versatile class of organic compoundswhichmaybe used as intermediate for the synthesis of a wide variety of com-pounds, such as amides, carboxylic acids, aldehydes and ketones. Enzy-matic nitrile hydrolysis is important not only for the treatment of toxicresidues of nitriles in industry, but also by a synthetic point of view,since this reaction usually generates the corresponding carboxamidesand carboxylic acids (De Oliveira et al., 2013, 2014).

Whole cells ofmarine fungiwere employed in the biotransformationof 2-phenylacetonitrile to 2-hydroxyphenylacetic acid. A. sydowii Ce15,A. sydowii Ce19, A. sydowii DR(M3)2, A. sydowii Gc12, Bionectria sp. Ce5and Penicillium raistrickii DR(B)2 promoted the complete biotransfor-mation of 2-phenylacetonitrile by the action of nitrilases. It was pro-posed that the phenylacetonitrile was hydrolyzed to phenyl aceticacid and then biooxidized at the ortho position of the aromatic ring(Scheme 78) (De Oliveira et al., 2013).
U
Scheme 76. Kinetic resolution of (±)-hydr


E

In another study, methylphenylacetonitriles were also bio-transformed by marine fungi showing good yields in the formation ofcarboxylic acid derivatives (Scheme 79) (De Oliveira et al., 2014).

Biotransformation of epoxides

Epoxides and vicinal diols are important intermediate for thesynthesis of biologically active compounds. Epoxide hydrolases (EH)are the enzymes responsible for the hydrolysis of epoxides with forma-tion of enantioenriched diols and the residual oxirane (Beloti et al.,2013). The use of epoxide hydrolases allows the enantiospecific epoxideopening under mild conditions in an eco-friendly process and thisfact has stimulated the research in epoxide biotransfomation usingmicroorganisms.

Martins et al. (2011, 2012) employed whole cells of marine-derivedfungi in the biotransformation of glycidyl ether derivatives. A. sydowiiGc12 transformed (±)-2-(benzyloxymethyl)oxirane (benzyl glycidylether, BGE) into the corresponding diol (absolute configuration wasnot determined) and promoted the enantiomeric enhancement of the(R)-epoxide. On the other hand, Trichoderma sp. Gc1 exhibited an

oxychalcogenides in sc-CO2 by CAL-B.




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Scheme 77. Chemo-enzymatic synthesis of chiral Z-vinylic telluride and synthesis of enantiopure Z-enynes.


UNCO

Ropposite preference, giving the (R)-diol and (S)-BGE (Scheme 80)(Martins et al., 2011).

Trichoderma sp. Gc1whole cellswere also employed in the enzymat-ic hydrolysis of (±)-2-((allyloxy)methyl)oxirane (allylglycidyl ether,AGE). Trichoderma sp. Gc1 promoted the enrichment of the (S)-AGEenantiomer and produced the (R)-diol in low enantiomeric excess(Scheme 81) (Martins et al., 2012).

The epoxide-hydrolase activity of three microorganisms, isolatedfrom the Atlantic rain forest and from a Guava tree were evaluated(Cagnon et al., 1999). In the presence of (±)-cyclohexene oxide,A. niger CCT 4846 produced (1R,2R)-trans-diol whereas A. niger CCT

Scheme 78. Biotransformation of phen


3086 biotransformed (±)-l,2-epoxyoctane to (2R)-l,2-octanediol andpromoted the enantiomeric enrichment of the sample in (2S)-l,2-epoxyoctane. The yeast R. glutinis CCT 2182, transformed (±)-l,2-epoxyoctane lead to (2R)-1,2-octanediol. (±)-Styrene oxidewas almostcompletely converted into the corresponding diol in the presence ofA. niger CCT 4846, A. niger CCT 3086 and R. glutinis CCT 2182, but withno selectivity (Scheme 82) (Cagnon et al., 1999).

A new epoxide hydrolase from Aspergillus brasiliensis CCT1435(AbEH) was cloned and overexpressed in Escherichia coli cells. In thefluorogenic assays using O-(3,4-epoxybutyl)umbelliferone the AbEHoptimimum conditions were found to be pH 6.0 and 30 °C. These

ylacetonitrile by A. sydowii Ce19.




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Scheme 79. Biotransformation of methyl-phenylacetonitrile derivatives by the marine fungus A. sydowii CBMAI 934 in the presence of 2-phenylacetonitrile.

Scheme 80. Hydrolysis of (±)-BGE by Trichoderma sp. Gc1 and A. sydowii Gc12.

Scheme 81. Enzymatic resolution of (±)-AGE by Trichoderma sp. Gc1.


RECconditionswere employed in the hydrolysis of (R,S)-styrene oxide (SO).

AbEH hydrolyzed 66% of 8 mM racemic styrene oxide (SO) and the re-maining (S)-SO exceeded 99% ee (Beloti et al., 2013). The AbEHenantioselective hydrolysis were also evaluated with enantiopure (S)-SO and (R)-SO, showing that the hydrolysis of (R)-SO was faster thanthe hydrolysis of (S)-SO, demonstrating that in both enantiomersthe water attack occurred in the Cβ, with no configuration inversionand no enantio-convergent process to the formation of the 1,2-diol(Scheme 83). Therefore, this new epoxide hydrolase presented a

UNCO

R

Scheme 82. Hydrolysis of epoxides by fungi isolated in Brazil.


potential for the preparation of enriched or enantiopure epoxides orvicinal diols (Beloti et al., 2013).

816

817

818

819

820

821

822

Biotransformation of natural products

Oxygenated terpenes are valuable for the production of fragrances,since they are responsible for the floral and woody notes of essentialoils. These compounds can be obtained by biotransformation of otherterpenes by the action of oxygenases, which belong to the oxidoreduc-tases class and promote the oxidation of organic compound by insertionof molecular oxygen (Pinheiro and Marsaioli, 2007).

Whole cells of T. cutaneum CCT 1903were employed for biooxidationof natural products. Stereoselective oxidation of cis-jasmone formedthe 4-hydroxyjasmone, 7,8-epoxyjasmone and 7,8-dihydroxyjasmone(Scheme 84) (Pinheiro and Marsaioli, 2007).

Scheme 83. Hydrolysis of (R,S)-styrene oxide by an epoxide hydrolase cloned fromA. brasiliensis CCT1435.




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Scheme 84. Biotransformation of cis-jasmone by T. cutaneum CCT 1903.

Scheme 85. Biotransformation of (R)-(−)-carvone by T. cutaneum CCT 1903.


The biotransformation of (R)-(−)-carvone by T. cutaneum CCT 1903cells yielded 4 different compounds (Scheme 85) (Pinheiro andMarsaioli, 2007). This study indicated that T. cutaneum CCT 1903 is agood source of oxygenase enzymes.

Marine fungi catalyzed the biooxidation of the natural products (−)-ambrox®, (−)-sclareol and (+)-sclareolide. A. sydowii CBMAI 934,Botryosphaeria sp., Eutypella sp. and Xylaria sp. presented active oxidore-ductases, and catalyzed the regioselective hydroxylation in the naturalproducts. The hydroxylated metabolites obtained were: 1β-hydroxy-ambrox (14%, A. sydowii CBMAI 934), 3β-hydroxy-ambrox (17%,Botryosphaeria sp.; 11%, Eutypella sp.), 3β-hydroxy-sclareol (31%, Xylaria

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Scheme 86. Biooxidation of natur


ED P

R

sp.; 69%, Botryosphaeria sp.; 55%, Eutypella sp.), 18-hydroxy-sclareol(10%, Xylaria sp.) and 3β-hydroxy-sclareolide (34%, Botryosphaeria sp.;7%, Eutypella sp.) (Scheme 86) (Martins et al., 2015).

Enzymatic assays using fluorescent probes

The search for new biocatalysts has been limited by time-consumingprocedures of classical methodologies for screening the enzymaticactivity of microorganisms whole cells. Protocols of miniaturized enzy-matic assays using fluorescent probes have been described for purifiedenzymes, and the method was successfully adapted for the enzymatic

al products by marine fungi.




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Scheme 87. Fluorogenic probes hydrolysis to assay esterase activity in bacterial strains.


RREC

activity screening with whole cells (Bicalho et al., 2004; Mantovaniet al., 2010). The general principle of the technique using fluorescentprobes involves a sequence of steps in which a substrate is transformedby hydrolases into a diol, which undergoes chemo-enzymatic transfor-mations, releasing the umbelliferone anion,whichproduces thefluores-cent signal, used as probe for the presence of the evaluated enzymes(Scheme 86) (Beloti et al., 2013; Mantovani et al., 2010).

64 Soil bacterial strains were screened in a miniaturized enzymaticassay usingfluorescent probes to reveal esterase activity in thesemicro-organisms. 6 Strains presented preference only for 4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]butane-1,2-diyldiacetate, showing a high level ofacetate hydrolyses, followed by the release of the fluorescent anion.Three strains were more efficient for propionate hydrolyses (4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]butane-1,2-diyl dipropionate), and agroup of six strains showed activity for hydrolyzing both acetate andpropionate (Scheme 87) (Mantovani et al., 2010).

UNCO

Scheme 88. Epoxide hydrolysis used as fluoro


ED

For the longer chain acyl esters, 4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]butane-1,2-diyldioctanoate, only two strains presented esterase ac-tivity. This substrate is probably more adequate to test lipases which re-quire a higher level of lipophilicity in the substrate for a good reactivity.

1-Phenylethanol acyl derivatives were used to validate these resultswith non-fluorogenic compounds, showing an agreement to the bio-transformation experiments and the fluorescent enzymatic assay. Thistechnique is an important tool for a quick screening of enzymes activityof whole cells in miniaturized scale, saving time and unnecessary sol-vent wastes (Mantovani et al., 2010).

A study usingfluorescent probeswas also developed by Bicalho et al.(2004), adapting a protocol originally designed for purified hydrolyticenzymes to screen microbial whole cells for epoxide hydrolase (EHs).The methodology consists in a high throughput screening fluorogenicassay, which allowed the selection of three new microbial sources ofEH (Agrobacterium tumefaciens, P. stipitis, and T cutaneum) screened

genic probe assay for epoxide hydrolases.




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for the hydrolysis of the epoxides 7-(2′-oxiranyl-ethoxy)-2H-1-benzopyran-2-one and 7-(2-(3-ethyloxiran-2-yl)ethoxy)-4-methyl-2H-chromen-2-one (Scheme 88) (Bicalho et al., 2004).

Extremophile enzymes present in microorganisms isolated from adeep-water petroleum reservoir at high temperatures (62–85 °C)were investigated using fluorescent probes. Among the 82 isolatedbacteria, 35 presentedmonooxygenase and 28 presented hydrolase en-zymatic activities using fluorescent probes in high throughput screen-ing assays. The use of epoxides and esters as fluorescent probes forlipases and esterases identified strong activity for 10 strains (Da Cruzet al., 2010). Automated and miniaturized assays offer advantages forbiocatalytic screening for new enzymes from diverse environments.

Conclusion

From the works commented in this overview, it can be concludedthat biocatalysis is becoming an active area of research in Brazil. Thenext step for the improvement of this important branch of organicchemistry in the country should be the formation of multidisciplinaryteams composed by synthetic organic chemists, microbiologists, molec-ular biologists, experts in bioinformatics, enzymologists, among otherspecialists, aiming to discover and to improve the performance of newenzymes derived from the Brazilian biodiversity. The introduction ofhigh-throughput tools as routine practice for screening new enzymesis fundamental for this end. These recommendations are essential tobring the biocatalysis in Brazil to a more advanced level.

Uncited references

Andrade and Silva, 2008Andrade and Barcellos, 2009Andrade et al., 2010a

Acknowledgments

The authors thank Prof. Rodrigo O. M. de Souza for the invitation towrite this overview. CNPq, FAPESP and CAPES are acknowledged forthe financial support.

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