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TETRAHEDRON: ASYMMETRY Pergamon Tetrahedron: Asymmetry 14 (2003) 2659–2681 TETRAHEDRON: ASYMMETRY REPORT NUMBER 60 Recent developments in asymmetric reduction of ketones with biocatalysts Kaoru Nakamura,a,* Rio Yamanaka,a Tomoko Matsudab and Tadao Haradab b Institute for Chemical Research, Kyoto University, Uji, Kyoto 611 -0011, Japan Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520 -2194, Japan Received 14 April 2003; accepted 31 May
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  TETRAHEDRON:  ASYMMETRY  Tetrahedron: Asymmetry 14 (2003) 2659–2681 Pergamon TETRAHEDRON: ASYMMETRY REPORT NUMBER 60 Recent developments in asymmetric reduction of ketones withbiocatalysts Kaoru Nakamura, a, * Rio Yamanaka, a Tomoko Matsuda b and Tadao Harada b a Institute for Chemical Research , Kyoto University , Uji  , Kyoto 611 - 0011 , Japan b Department of Materials Chemistry , Faculty of Science and Technology , Ryukoku University , Otsu , Shiga 520  - 2194  , Japan Received 14 April 2003; accepted 31 May 2003 Abstract— Herein we review recent advances in the asymmetric reduction of ketones by biocatalysts. Included are discussions onrecent developments in methodologies to control enantioselectivities of catalytic reactions, and examples of practical applicationsthat reduce various types of ketones are also shown.© 2003 Elsevier Ltd. All rights reserved. Contents 1. Introduction 26601.1. Biocatalysts versus chemical catalysts 26601.2. Enzyme classification and reaction mechanism 26611.3. Hydrogen sources for reduction 26612. Methodologies 26622.1. Search for the biocatalyst 26632.1.1. Screening 26632.1.2. Overexpression 26652.1.3. Directed evolution 26652.1.4. Catalytic antibody 26652.2. Modification of the substrates 26662.3. Optimization of reaction conditions 26662.3.1. Acetone treatment of the cell 26662.3.2. Solvent engineering 26682.3.3. Inhibitors 26682.3.4. Reaction temperature 26683. Applications 26703.1. Reduction of aliphatic ketones 26703.2. Reduction of halogenated aromatic ketones 26723.3. Reduction of ethyl 4-chloro-3-oxobutanoate 26733.4. Reduction of diketones 26733.5. Reduction of hydroxy ketones 26753.6. Reduction of ketones containing sulfur functionalities 26763.7. Large-scale synthesis 26784. Conclusion 2678References 2679 * Corresponding author. / $ - see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016 / S0957-4166(03)00526-3  K  . Nakamura et al  . /  Tetrahedron :  Asymmetry 14 (2003) 2659  –  2681 2660 1. Introduction The asymmetric reduction of ketones is one of the mostimportant, fundamental and practical reactions for pro-ducing non-racemic chiral alcohols, which can be trans-formed into various functionalities, withoutracemization, to synthesize industrially importantchemicals such as pharmaceuticals, agrochemicals andnatural products. The catalysts for the asymmetricreduction of ketones can be classi fi ed into two cate-gories: chemical and biological methodologies. Bothhave their own peculiarities, and development of bothto enable the appropriate selection of the catalysts forparticular purposes is necessary to promote greenchemistry. In this review, methods using biocatalysts 1 will be discussed while comparing them with chemicalcatalysts. 1.1. Biocatalysts versus chemical catalysts Biocatalysts have unique characteristics when com-pared with chemical (homogeneous and heterogeneous)catalysts. Some features that distinguish biocatalystsfrom chemical catalysts are listed below. Selectivity :Very high enantio-, regio- and chemoselectivities can beachieved due to the strict recognition of the substrateby the enzyme. For example, very high enantioselectivi-ties can be achieved, even with the reduction of aliphatic ketones such as ethyl propyl ketone, whereaschemical catalysts can perform highly enantioselectivereductions usually when the two substituent groups of the carbonyl carbon of the ketones are signi fi cantlydifferent. Safety of the reaction :Biocatalytic reductions are generally safe. The reactionconditions are mild, the solvent is usually water, anddangerous reagents are not necessary. For example,ethanol and glucose etc. are used as hydrogen sourcesinstead of explosive hydrogen gas. Natural catalysts :The biocatalysts, i.e. microorganisms, plants, animals,or their isolated enzymes, are reproducible and can beeasily decomposed in the environment after use. Catalyst preparation :Some of the biocatalysts for reduction, isolatedenzymes and whole cells, are commercially availableand ready to use like chemical catalysts or hydrolyticenzymes (Fig. 1). Commercially available biocatalysts Figure 1. Biocatalysts for asymmetric reductions.  K  . Nakamura et al  . /  Tetrahedron :  Asymmetry 14 (2003) 2659  –  2681 2661 include baker ’ s yeast and the alcohol dehydrogenasesfrom baker ’ s yeast, Thermoanaerobium brockii  (TBADH), horse liver and the hydroxysteroid dehydro-genase from Pseudomonas testosteroni  and Bacillusspherisus . However, to obtain other biocatalysts, it isnecessary to cultivate cells from seed cultures that maybe commercially available. Large scale synthesis and space - time yield  :One of the disadvantages of using biocatalysts is thedif  fi culty encountered in large scale synthesis; (1) workupprocedures may be complicated, (2) large spaces for thecultivation of the cell may be necessary, or (3) thespace  – time yields are not high due to the low substrateconcentrations and long reaction times. However, thesedisadvantages have been surmounted by improving thebiocatalysts using genetic methods and by investigatingthe reaction conditions. 1.2. Enzyme classification and reaction mechanism Dehydrogenases and reductase, classi fi ed underE.C.1.1.1., are enzymes that catalyze the reduction of carbonyl groups. 2 The natural substrates of the enzymesare alcohols such as ethanol, lactate, glycerol, etc. andthe corresponding carbonyl compounds; however,unnatural ketones can also be reduced enantioselectively.To exhibit catalytic activities, the enzymes require acoenzyme such as NADH or NADPH from which ahydride is transferred to the substrate carbonyl carbon.There are four stereochemical patterns that enable thetransfer of the hydride from the coenzyme, NAD(P)H,to the substrate, as shown in Figure 2. 3a With E1 3 andE2 4 enzymes, the hydride attacks the si  -face of thecarbonyl group, whereas with E3 5 and E4 enzymes, thehydride attacks the re -face, which results in the forma-tion of ( R ) and ( S  )-alcohols, respectively. On the otherhand, E1 and E3 enzymes transfer the pro-( R )-hydrideof the coenzyme, and E2 and E4 enzymes use thepro-( S  )-hydride. Examples of the E1-E3 enzymes are asfollows:E1: Pseudomonas sp. alcohol dehydrogenase 3a Lactobacillus kefir alcohol dehydrogenase 3b E2: Geotrichum candidum glycerol dehydrogenase 4a  – c Mucor javanicus dihydroxyacetone reductase 4d E3: Yeast alcohol dehydrogenase 5a Horse liver alcohol dehydrogenase 5b  – e Moraxella sp. alcohol dehydrogenase 5f  1.3. Hydrogen sources for reduction Hydrogen sources are necessary to perform the reductionreaction. For biocatalytic reduction, alcohols such asethanol and 2-propanol, glucose, formic acid and dihy-drogen, among others, can be used. 1 An example of usingformic acid as a hydrogen source for the reduction of ethyl 4-chloro-3 oxobutanoate with Rhodococcus ery - thropolis is shown in Figure 3. 6 Reduction of the Figure 2. Stereochemistry of the hydride transfer from NAD(P)H to the carbonyl carbon on the substrate (S is a small group andL is a large group). Figure 3. NADH recycling using HCO 2 H as an hydrogen source for the reduction. 6  K  . Nakamura et al  . /  Tetrahedron :  Asymmetry 14 (2003) 2659  –  2681 2662 Figure 4. Utilization of light energy as the driving force of reduction. 7a  – c substrate accompanies the oxidation of the coenzymefrom NADH to NAD + . Before the next cycle of thereduction of the main substrate can occur, the coen-zyme has to be reduced to NADH, which is driven bythe formate dehydrogenase catalyzed oxidation of HCO 2 H to CO 2 .Photochemical methods 7 have been developed toprovide an environmentally friendly system, thatemploys light energy to regenerate NAD(P)H, forexample, by the use of a cyanobacterium, a photosyn-thetic biocatalyst. 7a  – c Using the biocatalysts, the reduc-tion of acetophenone derivatives occurred moreeffectively under illumination than in the dark (Fig. 4).The light energy harvested by the cyanobacterium isconverted into chemical energy in the form of NADPHthrough an electron transfer system, and, consequently,the chemical energy (NADPH) is used to reduce thesubstrate to the chiral alcohol (ee 96  – > 99%). The lightenergy, which is usually utilized to reduce CO 2 tosynthesize organic compounds in the natural environ-ment, was used to reduce the substrate in this case.When a photosynthetic organism is omitted, the addi-tion of a photosensitizer is necessary. 7d The methodsuse light energy to promote the transfer of an electronfrom a photosensitizer to NAD(P) + via an electrontransport reagent.Electrochemical regeneration of NAD(P)H is anotherinteresting and clean method. 8 The system involveselectron transfer from the electrode to an electronmediator, such as methyl viologen or acetophenoneetc., then to the NAD(P) + , which is catalyzed by anelectrocatalyst such as ferredoxin NADP + reductase oralcohol dehydrogenase, etc. 2. Methodologies Recent developments in methodology to fi nd the mostsuitable reactions and to control enantioselectivities of those reactions are presented in this section, with asummary given in Figure 5. The methods can beclassi fi ed into three categories: (1) search and creationof the biocatalysts, (2) modi fi cation of the substrate,and (3) optimization of the reaction conditions. Figure 5. Summary of the methodology in biocatalytic reduc-tion.
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