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Cite this: Green Chem., 2011, 13, 226

CRITICAL REVIEW

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Enzyme-mediated oxidations for the chemist Frank Hollmann,*a Isabel W. C. E. Arends,*a Katja Buehler,b Anett Schallmeyc and Bruno B¨uhlerb Received 23rd September 2010, Accepted 11th November 2010 DOI: 10.1039/c0gc00595a Biocatalysis is an enabling technology adding to organic oxidation chemistry. Especially the high selectivity of enzymatic oxidation coevally operating under mild conditions and not necessitating problematic solvents makes it a very valuable tool for (green) chemistry. The present state of the art in the use of enzymes and microorganisms for catalytic oxidation and oxyfunctionalization chemistry is reviewed.

1.

Introduction

1.1

What makes biocatalytic oxidation green?

Oxidation is a central transformation in organic chemistry. Starting off with stoichiometric toxic reagents such as chromates, it is coming of age now with catalytic procedures utilizing environmentally benign oxidants such as O2 or H2 O2 . In the past decades, tremendous advances in transition metal-catalyzed1–5 and organocatalytic6–8 oxidations and oxyfunctionalizations have been achieved. Next to these, biocatalysis is emerging as an additional pillar for environmentally benign oxidation catalysis. From a Green Chemistry point-of-view, selectivity is the key advantage of enzyme-catalyzed oxidation over the use of chemocatalysts. Throughout this review, examples will appear of, for example, regioselective oxidation of polyols, regioand enantioselective oxyfunctionalization of non-activated C– H and C C bonds and selective oxidation of one functional group in the presence of other, more reactive functionalities. For some of these examples there is not even a chemical equivalent available yet. Thus, if properly used in retrosynthesis, biocatalytic oxidation chemistry can help shortening synthesis routes, avoiding protection group chemistry, and reducing byproduct formation. Furthermore, biocatalysis generally operates under mild reaction conditions in terms of temperature and pressure and does not require problematic solvents. Overall, biocatalysis is an enabling technology with a tremendous potential of greening the way we perform organic (oxidation) chemistry.

a

Department of Biotechnology, Delft University of Technology, Julianalaan 136, 2628BL, Delft, The Netherlands. E-mail: [email protected], [email protected]; Fax: +31 (0)15 2781415; Tel: +31 (0)15 2781415 b Laboratory of Chemical Biotechnology, Department of Biochemical and Chemical Engineering, TU Dortmund, Germany c Junior Professorship for Biocatalysis, Institute of Biotechnology, RWTH Aachen University, Worringer Weg 1, 52074, Aachen, Germany

226 | Green Chem., 2011, 13, 226–265

1.2 Scope and limitations of biocatalytic oxidation for organic chemistry The major advantage of biocatalysis over many chemocatalytic counterparts consists in its selectivity. This is a consequence of the unique embedment of highly reactive metal- or organocatalysts in the well-defined three-dimensional framework of a protein. Furthermore, the latter does not serve as an innocent chiral ligand; rather it actively participates in the catalytic mechanism, for example by precise placement of the substrate towards the active catalyst and stabilization of transition states.9 As a consequence, enzymes generally are highly efficient catalysts with turnover frequencies of a few to thousands per second. While the enzymatic formation (and cleavage) of carbonyl carbon–heteroatom bonds is well-established,10–13 biocatalytic oxidation chemistry has just begun to unfold its scope and potential use for synthetic chemistry. The reasons for this delay are manifold. In some respects oxidoreductases are more difficult to handle than ‘simple’ hydrolases.14–19 Also their occurrence in specific metabolic and anabolic pathways concurs with sometimes rather narrow substrate scopes. Finally, their cofactor-dependency has for a long time been regarded as a major impediment en route to preparative application. These issues can be circumvented by using oxidoreductases as wholecell biocatalysts, which for many organic chemists still appear to be ‘too biological’ to be of preparative relevance.14 Many of the examples outlined in this overview deal with whole-cell biocatalysis, but they also impressively demonstrate that the traditional prejudice is no longer valid today. Using a wholecell biocatalyst often is not more demanding than, for example, using Schlenk techniques. However, the use of isolated oxidoreductases has also experienced a tremendous development during the past two decades. Today a broad range of techniques is available solving issues such as enzyme availability, ‘cofactor challenge’, enzyme stability and recycling.20–25 Similarly, for other previously identified limitations of biocatalysis, practical solutions have been developed: for example the confinement to aqueous reaction media, resulting in low This journal is © The Royal Society of Chemistry 2011

substrate loadings and poor space-time yields or issues of reactant toxicities, has been addressed and some practical solutions will be discussed here. Also the narrow substrate scope as well as enantioselectivity is nowadays efficiently addressed by protein engineering and examples for this will appear throughout this review.26–30 The aim of this review is to give the interested reader a realistic overview on the current state-of-the-art in oxidation biocatalysis: to emphasize the potential without disguising its present limitations. 1.4

The catalysts used

A variety of different enzyme classes are involved in biooxidation chemistry. An overview over the different redox transformations as well as the most relevant enzyme classes discussed here is given in Table 1. Enzymes utilizing other catalysts such as (multiple)Cu centers, pterines, and pyrroloquinoline quinone are, so far, of lesser importance.31–34 A detailed description of the catalytic mechanisms would significantly go beyond the scope of this contribution. The interested reader therefore is referred to some excellent recent reviews.16,18,32,34–48 1.4.1 Dehydrogenases. Dehydrogenases catalyze the reversible oxidation of alcohols and amines. The primary oxidant here is the oxidized nicotinamide cofactor (NAD(P)+ ). Naturally, two sorts of nicotinamides exist: phosporylated (NADP) and non-phosphorylated (NAD). They differ with respect to phosphorylation of a remote ribosyl-OH moiety (Fig. 1) but are indistinguishable from a mechanistic point-of-view. In nature, this distinction is important to separate metabolic and anabolic pathways which is also why many wild type enzymes are highly specific for either form. NAD(P) is a classical hydride transfer agent existing in an oxidized (NAD(P)+ ) and a reduced form (NAD(P)H). NAD(P)+ is the active oxidant abstracting a hydride from the alcohol-CH-group to the pyridinium moiety.

Fig. 1

Structure and basic redox-chemistry of the nicotinamide.

Alcohol dehydrogenases (ADHs) are by far the most popular catalysts for the oxidation of alcohols.11,12,49–51 ADHs are found in all kingdoms of life. Thus, every organism is a potential source This journal is © The Royal Society of Chemistry 2011

for novel ADHs and the number of newly described ADHs is constantly growing. A complete coverage of these, potentially very useful, ADHs would go significantly beyond the scope of this overview. In the following, some of the most important ADHs will be shortly discussed. One of the earliest ADHs used for organic chemistry is the ADH isolated from horse liver (HLADH). HLADH exhibits a broad substrate tolerance towards primary and secondary alcohols combined with an almost invariable (S)-stereoselectivity making it a highly predictable and therefore valuable tool for stereoselective oxidations. HLADH also exhibits appreciable stereoselectivity towards chiral centers other than the alcohol group being converted. Application in water-saturated organic media52–54 or under near-dry conditions in gas-phase reactions55,56 has been reported. Recently, a secondary ADH from Rhodococcus ruber DSM 44541 (ADH-A) has attracted considerable interest as an exceptionally solvent-stable ADH (vide infra).57–59 ADH-A converts a broad range of (S)-2-alkanols with E-values up to 100, also benzylalcohols are converted efficiently and highly stereoselectively, whereas cyclic alcohols are somewhat sluggish substrates. Redox enzymes attractive for organic synthesis are increasingly derived from thermophilic microorganisms.60 Interest stems from their thermostability and activity at high temperatures. Furthermore, these enzymes have also been found to be resistant toward common protein denaturants and organic solvents. For example the ADH from Thermoanaerobacter brokii (TBADH) is mostly recognized for its high stability even at 85 ◦ C61,62 and resistance to a range of water-miscible organic solvents;63 activity was observed in the presence of up to 87% (v/v) methanol, ethanol or acetonitrile.64 In addition to TBADH, a range of other ADHs originating from (hyper-)thermophilic host organisms such as the ADHs from Sulfolobus solfataricus,65 Thermus ethanolicus,66 or Thermus sp. ATN167–69 are worth mentioning. Next to the NAD(P)+ -dependent ADHs, quino-hemodehydrogenases (QH-ADHs),31,70–72 though less familiar to most researchers, are also involved in some important biotechnological oxidation processes (vide infra).

1.4.2 Oxidases. Oxidases are enjoying increasing popularity for the catalytic oxidation of alcohols and amines. A number of Cu2+ -dependent oxidases such a galactose oxidase (E.C. 1.1.3.9) are known,73–76 but their relevance falls back significantly behind the relevance of flavin-dependent AlcOxs. Here, FAD or FMN function as primary hydride acceptor (though the exact mechanism is still under debate) from which the excess reducing equivalents are eventually shuttled to molecular oxygen (Fig. 2). Aliphatic alcohol oxidases (AlcOx) from methylotrophic yeasts such as Candida, Hansenula, Pichia mostly accept primary alcohols, which are selectively oxidized to the aldehyde stage.77–80 Glucose oxidase (GluOx) is probably the most prominent oxidase.81 The flavoenzyme catalyzes the oxidation of bD-glucose to D-glucono-d-lactone, which spontaneously hydrolyzes to gluconic acid. Wild-type GluOx is highly specific for b-D-glucose. Thus, the preparative usefulness of GluOx is rather limited and it is mostly applied for bioanalytical82–84 and food applications (glucose and/or O2 removal).81 Green Chem., 2011, 13, 226–265 | 227

Table 1

Overview over oxidative biotransformations covered in this review

Transformation

Enzyme classes

Remarks

Section

ADH/AlcOx

Selective oxidation to the aldehyde

2.1

ADH/ADH+AldDH

Selective oxidation to the acid

2.1, 2.2, 5

ADH/AlcOx

Regioselective oxidation of polyols

2.3

ADH

Chiral alcohols via kinetic resolution, deracemization, and stereoinversion

2.4–2.6

AAOx/AADH

Chiral amines and amino acids via (dynamic) kinetic resolution

3

FlMO

Selective o- and p-hydroxylation of phenols

4.1

FlMO/peroxidase

Halogenation/nitration of phenols

4.2

FlOx

Benzylic hydroxylation of phenols

4.4

Laccase

Catechol oxidations

4.3

FlMO

Baeyer–Villiger oxidations

6

FlMO/P450/Perox/ AlkMO/lipase

Double bond epoxidation

8.1–8.2

DiOx/Perox

‘Ozonolysis’ reactions

8.3

DiOx

Aromatic cis-hydroxylation

9

P450/Perox

Hydoxylation of non activated C–H bonds

10

P450/Perox

Heteroatom oxygenation

11

ADH: Alcohol dehydrogenase; AlcOx: alcohol oxidase; AldDH: aldehyde dehydrogenase; AAOx: amino acid oxidase; AADH: amino acid dehydrogenase; FlMO: flavo-monooxygenase; P450: cytochrome P450 monooxygenase; AlkMO: non-heme-iron (alkane)monooxygenase; DiOx: dioxygenase; Perox: (heme thiolate) peroxidase.

228 | Green Chem., 2011, 13, 226–265

This journal is © The Royal Society of Chemistry 2011

Fig. 3

Fig. 2

Schematic oxygenation mechanism of flavo-monooxygenases.

Structure and basic redox-chemistry of the flavin group.

Polyol oxidases with a broader substrate scope than GluOx are of greater value for regio- and enantioselective oxidation. In this context, galactose oxidase (GalOx),76,85–88 pyranose-2oxidase (P2O),89–91 and alditol oxidase (AldO)92–95 are worth mentioning. Also glycolate oxidase (GlyOx)96–100 and cholesterol oxidase (ChOx)101–106 are of preparative value. Laccases belong to the so-called blue-copper oxidases predominantly found in fungi.107,108 Laccases catalyze hydrogen abstraction reactions from phenolic and related substrates resulting in corresponding phenoxy radicals.108,109 In addition, laccase can oxidize activated mediators such as ABTS, syringaldazine, b-diketones, and TEMPO and derivates. The resulting so-called laccase-mediator-systems (LMSs) have attracted some preparative interest in recent years. Here the laccase regenerates an oxidized mediator, which then oxidizes alcohols (Table 5). Many of these mediators are common oxidants widely used in organic synthesis,110 thus LMSs can be considered as a ‘green’ alternative to established routes using problematic terminal oxidants such as hypochlorite. However, the efficiency of the currently known LMSs is not high enough to enable preparative implementation, particularly the still low total mediator turnover numbers (seldom exceeding a few dozen) represent a major limitation.111–113 1.4.3 Oxygenases. Mono- and di-oxygenases catalyze reductive activation of molecular oxygen. The resulting organic (hydro-)peroxides and high-valent metal oxo complexes are very potent oxygenation agents. Hence, flavo monooxygenases form a 4-a-(hydro)peroxoflavin capable of epoxidation, phenol hydroxylation, and – most prominently – Baeyer–Villiger oxidation (Fig. 3).34,39,42 The so-called cytochrome P450 monooxygenases contain a heme iron complex belonging to the most powerful oxygen transfer reagents.34,47 The catalytically active oxyferryl species (compound I, but also other species are discussed) is formed through a sequence of (NAD(P)H-dependent) reduction and O2 activation (Fig. 4). Reactions catalyzed by such enzymes range from hydroxylation of alkanes (not methane) via heteroatom oxygenation to epoxidation reactions. This journal is © The Royal Society of Chemistry 2011

Fig. 4 Structure and highly simplified redox chemistry of P450 monooxygenases. The formation of the catalytically active compound I is achieved by reduction and activation of O2 . In addition to compound I also a FeIII -peroxo complex is discussed.

In addition to the heme-dependent enzymes also a broad variety of mono- and multi-nuclear Fe-monooxygenases are known. Similar to the P450 monooxygenases, the active species for, for example, alkane hydroxylation (including methane), epoxidation, aromatic cis-dihydroxylation etc. follows a sequence of reduction and O2 activation. 1.4.4 Peroxidases. Peroxidases depend on H2 O2 to regenerate their oxidized, catalytically active prosthetic group comprising either protoporphyrin IX (heme peroxidases), selenium (glutathione peroxidase),114 vanadium,115–119 or manganese.120,121 Heme peroxidases are particularly interesting for preparative application as they catalyze P450-monooxygenase-like reactions; especially if the proximal iron ligand stemming from the protein backbone is a cysteine (like in P450 monooxygenases).122,123 For two decades the peroxidase from Caldariomyces fumago (CPO) has been the preferred enzyme for peroxide-driven oxidation and oxyfunctionalization chemistry. However, the catalytic performances reported fall back by orders of magnitude to be of economic value. Recently, Hofrichter and coworkers reported a novel heme-peroxidase (AaP from the agaric basidiomycete Agrocybe aegerita) which might take over CPO’s significance as preparative peroxidase.123–135 1.5 Enzyme regeneration A basic feature of (bio)catalytic oxidation is its redox character. As a consequence, electrons have to be removed from the Green Chem., 2011, 13, 226–265 | 229

Table 2

Selection of NAD(P)+ regeneration systems

Waste/g mol-1 Ref.

Cosubstrate

Coproduct Catalyst

ketone

alcohol

ADHa

58

141,142

pyruvate

lactate

lactate-DH

90

143

glutamate-DH

146

144

a-ketoglutarate glutamate

145–148

O2

H2 O/H2 O2 NADH oxidaseb 18/34

O2

H2 O

LMSc

O2

H2 O 2

FMN, quinones 34

150–154

anode/mediator —

155,156

electrochemical

18

149

acceptable terminal electron acceptor becomes available. Furthermore, the high thermodynamic driving force of O2 reduction is favorable to shift the thermodynamic equilibrium. Like ADHs, oxidases also catalyze hydride abstraction from the substrate with an oxidized flavin prosthetic group being the primary acceptor. The stored reducing equivalents are then transferred to molecular oxygen yielding the catalytically active flavin and hydrogen peroxide (i.e. direct aerobic regeneration of the prosthetic group). At a first glance, this seems a simpler oxidation procedure compared to the coenzyme dependant dehydrogenases. However O2 reduction generally leads to hydrogen peroxide, a known enzyme inactivator. This can be dealt with by catalase-catalyzed dismutation of H2 O2 . But in cases when the production enzyme is highly H2 O2 -sensitive, it is desirable to fully circumvent its formation. Fortunately, many oxidases are not very selective with respect to O2 as electron acceptor but can also transfer electrons to a range of chemical mediators. To enable catalytic use of these chemical mediators, they can be reoxidized in situ by either using an anode157–159 or by laccasecatalyzed reoxidation (Fig. 5).89,160–162

a

Due to the reversibility of ADH reactions, often a significant molar surplus of the cosubstrate has to be applied to shift the equilibrium. b Usually highly selective for either NADPH or NADH. c LMS: laccase mediator system.

enzymes’ active sites (or provided to them as in case of monoand dioxygenases) to close the catalytic cycle. In nature this is achieved by a range of electron transport proteins and small molecules (mediators) which themselves are regenerated via the cellular metabolism. This ‘cofactor challenge’ can be approached in two ways. Whole-cell biotransformations are one option. Alternatively, redox enzymes may also be used as isolated catalysts coupled to a regeneration system. The advantage of whole-cell biocatalysis is that enzyme regeneration is principally not an issue. However, working with living organisms still is not straight forward to chemists. Also issues such as reactant metabolization (lowering yields), toxicity, and productivity of whole-cell processes have to be addressed. Often, microbial cells contain various variants of the actual production enzyme exhibiting complementary selectivity. Sometimes poor (enantio)selectivities can be the result.136–139 Therefore, significant research efforts have been devoted to the development of efficient ‘artificial’ regeneration systems enabling the use of isolated enzymes. In the following, a brief overview over the most relevant approaches is given. Dehydrogenases depend on the oxidized nicotinamide cofactor, which for economic and thermodynamic reasons has to be used in catalytic amounts and recycled from its reduced form in situ.23,25,50,140 From an environmental point-of-view classification of the many reported regeneration systems according to the amount and quality of the by-products formed is reasonable. Table 2 gives an overview over the most important NAD(P)+ regeneration systems. Each of these systems has specific advantages and disadvantages. There is however a trend towards aerobic regeneration systems. Thus, O2 as an environmentally 230 | Green Chem., 2011, 13, 226–265

Fig. 5 Hydrogen peroxide-free regeneration of oxidases either via the laccase mediator system (LMS) or via indirect electrochemical regeneration.

Oxygenases catalyze the reductive activation of molecular oxygen. As a result, reducing equivalents are necessary to sustain the catalytic cycle. Generally these are derived (more or less directly) from reduced nicotinamide cofactors. Enzymatic NAD(P)H regeneration systems are preferred. For example, approaches based on ADH,163–167 formate dehydrogenase (FDH)168–171 or phosphite dehydrogenase (PDH)172,173 have been reported. Compared to these, chemical174–176 and electrochemical177,178 alternatives are less popular (Table 3). In many cases electrons are not directly delivered from NAD(P)H to the oxygenase’s active site but through a sequence of redox proteins. As these electron transport chains are usually not involved in the catalytic oxygenation mechanism, shortcutting by directly delivering electrons to the oxygenase could dramatically simplify cell-free oxygenase catalysis (Fig. 6). However, at present most of the reported chemical,179–181 electrochemical,182–193 and photochemical194–196 approaches are still at a rather early stage of development. The preparatively relevant heme-thiolate peroxidases utilize H2 O2 or organic peroxides to regenerate the catalytically active oxyferryl species.197 However, in the presence of excess H2 O2 they are also rapidly inactivated due to oxidative degradation of the heme moiety.198 Various reaction engineering approaches such as immobilization,199–202 encapsulation in polymersomes,203 use of antioxidants and/or radical scavengers,204–207 ionic liquids208–210 This journal is © The Royal Society of Chemistry 2011

Table 3

Overall, it can be concluded that the so-called ‘cofactor challenge’ is solved. For any given enzymatic oxidation reaction, a range of regeneration approaches is available from which the most suitable can be chosen. It should be mentioned here that, despite the significant research efforts on artificial cofactor regeneration systems, current industrial practice is almost entirely based on whole-cell systems with their ‘built-in’ regeneration systems (vide infra).

Selection of NAD(P)H regeneration approaches

Cosubstrate

Coproduct

Catalyst

Waste/ g mol-1 Ref.

alcohol

ketone

ADH

58

163,164

formate

CO2

FDH

44

168–171

174,175

[Cp*Rh(bpy)(H2 O)]2+ glucose

gluconic acid GDH

196

165–167

phosphite

phosphate

PDH

95

172,173

H2

H2 O

hydrogenasea

18

172,173

anode/mediator



177,178

electrochemical a

1.6

Biocatalytic oxidations in industry

Reliable information on the use of redox biocatalysis within real industrial practice is difficult to obtain, especially if it comes to absolute numbers. A representative overview, however, can be attained from the excellent compendium by Liese and coworkers.12 Accordingly, bioredox catalysis accounts for one third of all commercialized enzymatic processes. From these, approximately half comprise oxidation processes. Interestingly, (seemingly) simpler alcohol and amine oxidations are only a minor fraction (22%) compared to enantiospecific oxyfunctionalisations such as hydroxylations, dihydroxylations, epoxidations and Baeyer– Villiger oxidations (Fig. 8).

Not demonstrated for monooxygenases yet.

Fig. 8 Distribution of reaction types amongst the industrial biocatalytic oxidation reactions (22 in total) listed in Liese et al.12 Fig. 6 Comparison of the traditional, biomimetic regeneration of oxygenases with the direct, artificial approach.

or the use of organic hydroperoxides such as tert-butyl hydroperoxide (tBHP) have been reported.211,212 Also protein engineering to some extent yielded stabilized peroxidase variants.213,214 In situ generation of H2 O2 from O2 appears the most convenient and promising approach to maintain H2 O2 at optimal levels not compromising enzyme activity nor stability. For this a range of enzymatic,215–220 (electro)chemical,221–223 and photochemical224 approaches are available (Fig. 7).

Fig. 7 In situ generation of H2 O2 by catalytic reduction of O2 to promote peroxidase catalysis.

This journal is © The Royal Society of Chemistry 2011

One explanation for this discrepancy might be due to the clear superiority of biocatalysis over traditional chemistry in the area of specific oxyfunctionalization. Thus, a chemically unpredecendent, highly regio- and enantiospecific biocatalytic reaction also represents an economically viable option. In contrast, there is an existing optimized toolbox for the oxidation of, for example, alcohols, so that here transition to biocatalysis is less attractive. Also the alcohol oxidations mentioned by Liese et al. deal with highly regioselective oxidation of polyols. Obviously, selectivity represents the characteristic of biocatalysis most appreciated by industry. Another interesting feature becomes clear from Liese et al. With the exception of one example (an oxidase-catalysed reaction), all industrial oxidation processes are based on whole, metabolically active cells. The generally assumed higher price of isolated and (partially) purified enzymes probably is only part of the explanation as the majority of all hydrolase-based processes makes use of isolated enzymes. More likely, the abovediscussed regeneration approaches have not (yet) reached a development stage suitable for commercial implementation. Additional factors such as complicated molecular architecture Green Chem., 2011, 13, 226–265 | 231

and poor long-term stability of isolated enzymes under oxidising conditions may further complicate the use of isolated enzymes.

2.

Oxidation of alcohols

Oxidation of alcohols is a pivotal reaction in organic chemistry. Thus, it is not astonishing that also the biocatalysis community has been paying an ever increasing attention to this reaction. In the following section, examples of biocatalytic alcohol oxidations will be presented. First, the focus will be on the selective oxidation of primary alcohols to either the aldehyde or acid stage. Oxidation of secondary alcohols has for a long time been neglected as here chirality is destroyed rather than generated. However, regioselective oxidation of polyols (sugars) is an excellent playground for biocatalysis. Furthermore, oxidation of secondary alcohols plays a key role in the preparation of enantiopure alcohols by means of (dynamic) kinetic resolution, deracemization, and desymmetrization. 2.1

Table 4 Control over the selectivity of acetic acid bacteria-catalyzed oxidation of primary alcohol by choice of the reaction conditions233

Substratea

Synthesis of aldehydes from alcohols

The major challenge encountered if selective oxidation to the aldehyde stage is desired is the high reactivity of the product. Especially over-oxidation to the acid stage is thermodynamically favored. This is a challenge particularly when applying whole cell biocatalysis where oxidation of aldehydes adds to the organism’s energy balance by regenerating one equivalent of NADH. But also when using isolated enzymes such as ADHs or AlcOxs, enzymatic ‘over-oxidation’ may be observed. One elegant solution to this problem is to make use of in situ product removal from the reaction phase. Usually, a second liquid and less polar organic phase is applied. Thus, the aldehyde preferentially partitions into the more hydrophobic organic solvent and is thereby extracted from the reaction mixture (Fig. 9).

Fig. 9 Prevention of over oxidation by in situ removal of the intermediate aldehyde to an organic phase. At the same time the organic phase also serves as substrate reservoir.

Additionally, this strategy is beneficial for downstream processing, which is greatly facilitated and overall higher substrate payloads are possible than under one-phase conditions. Also toxic and inhibitory effects of substrates and products can be alleviated by the second phase keeping the in situ aldehyde concentration in the biocatalyst phase low. ¨ This concept was elegantly used by Buhler et al. for the selective oxidation of pseudocumene to 3,4-dimethyl benzaldehyde using recombinant E. coli.225–229 By using dioctylphthalate 232 | Green Chem., 2011, 13, 226–265

a

Yield acid in pure H2 O [%]

Yield aldehyde in H2 O/isooctane [%]

>97

93

>97

90

>97

91

16

29

97

96

20

24

[substrate]0 = 2.5 g L-1 .

as second organic phase, both toxic effects of the reagents and undesired over-oxidation to the acid could be efficiently circumvented. Overall, product titers of up to 0.22 M at 70% isolated yield were achieved. A similar application of the two liquid phase concept was also demonstrated by Molinari and coworkers.230–233 Using acetic acid bacteria as biocatalysts, a range of primary alcohols was converted selectively either to the aldehyde or the acid, depending on the reaction medium used (Table 4). Another possibility to remove the reactive aldehyde is to subject it to a sequential chemical or enzymatic reaction. For example, undesired over-oxidation could be circumvented in case of conversion of glycolic acid into glyoxylic acid by in situ removal of glyoxylic acid as imine.96,98,137,234 The latter reaction was applied to establish a chemo-enzymatic route to N-(phosphonomethyl)glycine.100 Another nice example was reported recently by Siebum and coworkers: AlcOx from Pichia pastoris was used to in situ generate the reactive aldehyde substrate for 2-deoxyribo-5-phosphate aldolase (DERA)-catalyzed synthesis of b-hydroxyketones (Fig. 10).74 Similarly, Wong and coworkers integrated the GalOxcatalyzed oxidation of glycerol to L-glyceraldehyde into a This journal is © The Royal Society of Chemistry 2011

Table 5

Selection of LMS-catalyzed oxidation of alcohols

Product

Mediator/laccase

Ref.

VA/LTv

236

ABTS/LPc; TEMPO/LTv

237–240

TEMPO/LTv

238

R = alkyl, alkoxy, halo, nitro

As early as 1985, Wong and coworkers reported on a cellfree system for the kinetic resolution of 1,2-diols and amino alcohols to produce optically pure a-hydroxy acids and amino acids (Table 7). Here, HLADH was used in combination with an aldehyde dehydrogenase and GluDH-mediated cofactor regeneration.148,242 Recently, Ohta and coworkers reported on a similar in vitro oxidation system combining purified alcohol138 and aldehyde139 dehydrogenases from Brevibacterium sp.148 for the oxidation of various primary alcohols to the corresponding acids. For in situ regeneration of the oxidized nicotinamide cofactor the H2 O-forming NADH oxidase from Lactobacillus brevis was used.243 Also, hexanoic acid production using a yeast ADH (YADH) coupled to NADH oxidase-cofactor regeneration was just reported.244 A very interesting variation of the ‘through oxidation’ of alcohols comprises the HLADH-catalyzed oxidation of 1,4- and 1,5-diols. The primary aldehyde product spontaneously cyclises forming a hemiacetal which is further oxidized by HLADH, giving access to enantiopure lactones. Very successfully, mesodiols have been desymmetrized (Table 8). 2.3 Regioselective oxidation of polyols

TEMPO, HPI, HBT/LTva

241

LTv: laccase from Trametes villosa; LTb: laccase from Trametes pubescens; LPc: laccase from Pycnoporus coccineus; VA: violuric acid; TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxyl; ABTS: 2,2¢-azinobis(3-ethylbenzthiazoline-6-sulfonic acid; HPI: N-hydroxyphthalimide; HBT: hydroxybenzotriazole.a Starting from the ether compound.

Next to stereoselectivity also regioselectivity of enzymes is one of the key-advantages of biocatalysis over conventional counterparts. High regioselectivity is especially appreciated when it comes to oxidation of carbohydrates. The poly-functionality of the starting material makes extensive protection/deprotection steps inevitable in order to achieve regioselective oxidation. Polyol dehydrogenases and oxidases, on the other hand, exhibit an intrinsic high to exclusive regioselectivity, which is exploited in a range of preparative and industrial applications.86,263–266 The so-called ‘Cetus-process’ comprises a chemoenzymatic route for the synthesis of fructose from glucose. In the first step, glucose is converted into the corresponding 2-keto-glucose by immobilized P2O and subsequently hydrogenated into practically pure D-fructose (Fig. 11).267,268

Fig. 10 Two-step, one-pot reaction, combining an oxidase and an aldolase.74

four-enzyme one-pot cascade reaction to produce fructose from simple precursors.235 Also the previously mentioned laccase mediator system (LMS) has been used for oxidation of primary alcohols selectively to the aldehyde stage. Some representative examples of applications of the LMS for the selective oxidation of the most activated alcohol functionality in the substrate molecule are given in Table 5. 2.2

Fig. 11 Chemoenzymatic transformation of glucose into fructose in the so-called ‘Cetus process’.267,268

In the Reichenstein process for the production of ascorbic acid from glucose, Gluconobacter oxidans catalyzes the keytransformation (Fig. 12).269

Synthesis of acids from alcohols

Various examples of biocatalytic ‘through oxidations’ of primary alcohols to the corresponding acids have been reported over the years. In this field, whole cell biotransformations (mostly using acetic acid bacteria) clearly dominate over the use of isolated enzymes. A representative selection of whole cell transformations is given in Table 6. This journal is © The Royal Society of Chemistry 2011

Fig. 12 Gluconobacter oxydans-catalyzed selective oxidation of sorbitol as the key-step of the ‘Reichenstein-process’.269

Other applications of Gluconobacter oxydans comprising selective oxidation of, for example, glycerol,270 ribitol,271 and N-butylglucamine272 are summarized in Fig. 13. Green Chem., 2011, 13, 226–265 | 233

Table 6

Selection of whole-cell through oxidations of alcohols to the corresponding acids

Catalyst

Substrate

Acetobacter

Product

Yield/ee [%] 23 g L

-1

Ref. 245

100 mM (E = 16)

137,246,247

2.5 g L-1 (>90% ee)

248

1 g L-1 (E > 200)

249

25 g L-1 (>97% ee)

250,251

60 g L-1

231

45 g L-1

231

76 g L-1

252

10 g L-1 (>99%)

253

Comamonas testosteroni

5 g L-1 (E = 49)

137

Nocardia corallina

9 g L-1

254

Rhodococcus sp

6 mM (85% ee)

255

Cupriavidus basilensis/Pseudomonas putida

30 g L-1

256

Cucurbita maxima

Low

257

Gluconobacter oxydans

2.4

Kinetic resolutions of alcohols

Oxidation of chiral secondary alcohols goes hand in hand with the elimination of a chiral center. Using an enantioselective oxidation catalyst (enzyme) allows accumulation of only one enantiomer in a kinetic resolution. The intrinsic disadvantage of kinetic resolutions however is the maximal yield of only 50% (provided the catalyst exhibits perfect enantioselectivity). Thus, from the point-of-view of enantioselective synthesis, 234 | Green Chem., 2011, 13, 226–265

enantiospecific reduction of the prochiral ketones is usually preferred (100% yield). Nevertheless, a range of oxidative kinetic resolutions have been reported which are summarized in Table 9. The intrinsic disadvantage of kinetic resolutions can be easily overcome by using symmetrical, prochiral alcohols which upon oxidation are transformed into a chiral product. Using this ‘meso-trick’, on the one hand, enables full conversion of the starting material. On the other hand, the number of meso-compounds is naturally limited. Nevertheless, quite This journal is © The Royal Society of Chemistry 2011

Table 7 Enantiopure a-hydroxy- and HLADH-catalyzed kinetic resolution258

a-amino

acids

through

Table 8 diols

Selection of HLADH-catalyzed lactone-formation from 1,4-

Product Substrate

Ratea

ee [%]b

1

>97

3–6

>97

29.5

>97

30

>97

33

>97

16

84

11

0

50

0

Yield/ee [%]

259

87/>97a

259

94/>99.5a , b

260,261

79/>99.5a , c

260

> 68/>99.5a

261

>60/21–90a

260

81/>99.5a

262

86/>97

HLADH: ADH from horse liver; AldDH: aldehyde dehydrogenase from yeast; GluDH: glutamate DH.a Relative rates. b Of the acid product.

Regeneration ketoadipate.

Ref.

a

system:a FMN/O2 ;

b

ABTS/anode;

c

GluDH/

Fig. 13 Preparative-scale applications of Gluconobacter oxydans for the regioselective oxidation of ribitol (upper), glycerol (middle) and Nbutylglucamine (lower).

efficient desymmetrization of syn-cyclohexanediol using GDH278 and of 2,3-butanediol using Gluconobacter asaii248 have been reported. Desymmetrization of meso-2,5-hexanediol was reported using ADH-A from Rhodococcus ruber yielding (R)-5-hydroxy-2hexanone at 88% conversion within 2 h (ee > 99%) (Fig. 14). Here, E. coli recombinantly expressing ADH-A was used as biocatalyst.279 This journal is © The Royal Society of Chemistry 2011

Fig. 14 Desymmetrisation of meso-2,5-hexanediol using ADH-A from Rhodococcus ruber.279

2.5 Deracemizations of alcohols The basic requirement for redox-deracemization obviously is that at least one of the steps, either oxidation or reduction, proceeds enantioselectively. Ideally, both steps occur with high Green Chem., 2011, 13, 226–265 | 235

Table 9

Some representative biocatalytic kinetic alcohol resolutions

Product

Catalyst/s

Yield/ee [%]

Scale/g L-1

Ref.

Rr

49/97.2

100

57

Rr

49.4/97.8

100

57

Rr

46.7/98.5

100

57

CpADH

48.5/95

25

273

Re

48.5/>98

0.5

274

Rr

49.7/95.7

100

57

Rr

49.3/98.2

100

57

Rr

44.4/77.8

100

57

As

6–40/96–99

analytical

275

GDH

40/95

analytical

276

Pp

>44/>95

0.5

277

Nc

Up to 86

analytical

266

GlyOx

49/>98

analytical

96

GlyOx

50/99

analytical

96

GlyOx

47/86

analytical

96

Rr: Rhodococcus ruber; As: Acinetobacter sp.; Pp: Pseudomonas paucimobilis; Nc: Nocardia corallina B-276; Re: Rhodococcus erythropolis; CpADH: from Candida parapsilosis rec. in E. coli; GlyOx: glycolate oxidase. Het = (2-furanyl), (5-methyl-2-thiophenyl), (2-benzothiazolyl), (3-methyl-5isoxazolyl), (4,4-dimethyl-2-(D2 )-oxazolinyl), (2-(D2 )-thiazolinyl), (4-methyl-2-thiazolyl).

236 | Green Chem., 2011, 13, 226–265

This journal is © The Royal Society of Chemistry 2011

and complementary selectivity. Thus, only one redox cycle is necessary to achieve complete deracemization (stereoinversion of the undesired enantiomer). However, also if one step is unspecific, gradual enrichment of one enantiomer occurs during each cycle. As a consequence, more redox cycles have to be performed to achieve sufficiently high enantiomeric excess of the product. Deracemizations are thermodynamically slightly uphill. Since both, racemic starting material and enantiopure (or at least enriched) products are secondary alcohols, the enthalphic term (DH) of the Gibbs-free-energy change is zero. The entropic term (DS) however calculates as DS = Rln2, being ca. 0.4 kcal mol-1 at 20 ◦ C.280,281 As a consequence thermodynamic driving force has to be added to the system in order to drive any deracemization reaction to completion. The use of two, enantiocomplementary ADHs has gained considerable interest in recent time (Fig. 15).280,282–285

3. Oxidation of amines 3.1

Oxidation of amino acids

Early examples of amine oxidation comprise amino acid dehydrogenases (AADH) such as L-alanine DH.291 Due to their high L-selectivity, AADHs are useful catalysts for the kinetic resolution of racemic a-amino acids (e.g. as derived from Strecker synthesis). AADHs are NAD(P)+ -dependent thus, similarly to the ADH-catalyzed oxidation of alcohols, additional thermodynamic driving force has to be added to drive the equilibrium reaction to completion. A very elegant solution for this was reported by Moiroux and coworkers (Fig. 16).292 They reported the stereoinversion of L-alanine using L-Ala-DH as stereoselective catalyst. Regeneration of the oxidized nicotinamide cofactor was achieved by direct anodic oxidation of NADH. Ala-DH-catalyzed oxidation of L-Ala yields pyruvate, which in the presence of large molar NH3 surpluses lies in equilibrium with the corresponding imine. The latter is reduced cathodically to racemic alanine. Overall, a chemoenzymatic dynamic kinetic resolution of alanine yielding enantiopure Dalanine is achieved. However, imine formation is overall ratelimiting making the whole process comparably slow.

Fig. 15 Bi-enzymatic redox-deracemization utilizing enantiocomplementary ADHs.280,282–285

ADH-1 catalyzes the kinetic resolution of the racemate producing 0.5 eq. of the desired enantiomer and 0.5 eq. of ketone which is then transformed by enantiospecific reduction catalyzed by ADH-2. One drawback of this methodology is that both ADHs need to differ in their cofactor requirements to prevent undesired cross-activities. Likewise the corresponding cofactor regeneration systems need to be selective for either the phosphorylated or the non-phosphorylated nicotinamide cofactor. Cross-activities lead to futile cycles and eventually heat-generation by unnecessary consumption of the respective co-substrates. In addition to the aforementioned fully enzymatic deracemization systems, also a range of chemo-286 and electroenzymatic155 approaches have been reported. In both cases enantioselective enzymatic oxidation is accompanied by an unselective reduction regenerating a fraction of the previous racemate. A selection of biocatalytic deracemization reactions is given in Table 10. 2.6

Stereoinversions

Mechanistically, stereoinversions are closely related to the above-discussed deracemizations. From a chemical point-ofview they represent the biocatalytic counterpart of the Mitsunobu reaction.287 Compared to deracemizations however, little attention has been paid to stereoinversions. Geotrichium candidum,288 Cyanidioschyzon merolae,289 and Candida albicans290 have been evaluated for the stereoinversion of some substituted arylethanols. Recently, Riva and coworkers reported on an oxidation/reduction sequence involving stereoinversion at C-7 of cholic acid.284 Very selective stereoinversion of disaccharides was reported for the combination of P2O and aldose reductase.89 This journal is © The Royal Society of Chemistry 2011

Fig. 16 Electroenzymatic alanine.292

deracemization/stereoinversion

of

Compared to the above-mentioned AADHs, amino acid oxidases (AAOxs) represent the more useful catalyst class as, for example, no cofactor dependency issues have to be addressed.310 Furthermore, AAOxs combine broad substrate spectra with a generally high stereoselectivity thereby making them highly interesting catalysts for the production of chiral a-amino acids. An industrial example for D-AAOx is the oxidative deamination of cephalosporin C as the first step in the so-called 7-aminocephalosporanic acid (7-ACA) process (Fig. 17). This process is running at GlaxoSmithKline who also did a full life cycle assessment to quantify the environmental benefits of the enzymatic process compared to the preexisting chemical one.311

Fig. 17

The 7-ACA process.

Green Chem., 2011, 13, 226–265 | 237

Table 10 Product

Representative selection of microbial and enzymatic deracemization reactions. If wavy bonds are shown, both enantiomers are reported Catalyst/s

Yield/ee [%]

Scale/g L-1

Ref.

Sp

99/99

8–15

280,282

Rs

89/99

8

280,282

Rs

99/60

9

280,282

Cr

99/99

1.25

296

99/99

10

298–300

Lactate oxidase/NaBH4 ; LDH/cathode; GlyOx/Catalase/LDH/FDH

90–99/>97.5

1

96,97,155,286,301

(1) Pp; (2) Mf

60/99

45

303,304

Cp

>50/99

0.25

307–309

Rs

99/99

10

280,282

Rs

99/99

9

280,282,293

At; Ax; Ps; Zo

86/99

0.5

285,294,295

Ro

99

>97

312

L-AAOxa , b /NH3 -BH3 /HCO2 NH4 /Pd/C

97

>99

314

L-AAOxa /NH3 -BH3

79

>99

314

L-AAOxa /NH3 -BH3

83

93

314

L-AAOxa /NH3 -BH3

87

93

314

D-AAOxc /NaCNBH3

86

99

315

D-AAOxc /NH3 -BH3

78

99

316

D-AAOxd /NH3 -BH3

82

99

316

D-AAOxe /NaCNBH3

66

99

316

From Proteus myxofaciens (rec. in E. coli). b Also other amino acids such as proline, methionine, tryptophan, phenylalanine, valine, histidine, tyrosine, etc. c From porcine kidney. d From snake venom. e From Trigonopsis variabilis.

a

a carbonyl-cosubstrate serves as NH2 -acceptor from the amine enantiomer converted by the transaminase (Fig. 20). Challenges met using transaminases are the reversibility of the amino group transfer reaction and a sometimes pronounced product inhibition. Truppo et al. developed a kinetic resolution protocol using commercially available transaminases.329 The reversibility issue was approached by using pyruvate as amine acceptor together with AAOxs. Thus, the resulting alanine is irreversibly 240 | Green Chem., 2011, 13, 226–265

re-transformed into pyruvate, which therefore can be used in catalytic amounts. Overall, the AAOx-catalyzed reduction of O2 to H2 O2 drives the reaction to completion (50% conversion of the racemate) (Fig. 20). Efficient resolution of a range of benzylamines to enantiopure (R)- and (S)-amines was reported. Coevally, Kroutil and coworkers have developed a two-step deracemization protocol.330,331 In the first step, a transaminasecatalyzed kinetic resolution of the racemic amine is performed This journal is © The Royal Society of Chemistry 2011

Table 12

Selected examples for dynamic kinetic amine deracemizations

necessary to achieve high optical purity of the product. Even though this methodology is quite complicated it was successfully applied to a fairly broad range of racemic amines with generally excellent optical purity and reasonable to good overall yields (60–99%). Also application for the synthesis of Mexiletine, an antiarrhytmic agent, was reported.332

4. Oxidation of phenols Product

Catalyst/reducing agent Yield [%] ee [%] Ref. MAO /NH3 -BH3 n.d.

>99

318

MAOa /NH3 -BH3 n.d.

>99

318

MAOa /NH3 -BH3 n.d.

>99

318

MAOb /NH3 -BH3 n.d.

>99

320

MAOb /NH3 -BH3 >95

97

321

a

Several types of oxidoreductases accept phenols enabling specific ortho- and para-hydroxylation, benzylic hydroxylation and desaturation, oxidative polymerization and even nitration and halogenation reactions.125 Some preparatively relevant examples will be discussed in the following. 4.1 Hydroxylation of phenols Aromatic o- and p-hydroxylation of phenols has been reported with Cu-containing tyrosinases.333,334 Tyrosinases exhibit different chemical reactivity towards phenols. In the first half reaction (phenolase activity) phenols are ortho-hydroxylated yielding a CuII -coordinated catecholate. The catalytically active (O2 activating) CuI -species is regenerated in the second half reaction (catecholase activity) producing the corresponding o-quinone. Overall, phenols are hydroxylated/oxidized to highly reactive o-quinones which, for example, can be exploited for the covalent crosslinking of proteins.335,336 Waldmann and coworkers reported the use of tyrosinase to in situ generate o-quinone as dienes for Diels–Alder reaction with various dienophiles (Fig. 21), representing an early example for a chemoenzymatic cascade reaction.337,338 Recently, a similar approach using laccases has been reported.339

a

MAO from Aspergillus niger mutant Asn336Ser. b MAO from Aspergillus niger mutant Ile246Met/Asn336Ser/Met348Lys/ Thr384Asn/Asp385Ser. Fig. 21 Chemoenzymatic conversion oxabicyclo[2.2.2]oct-5-en-3-ones.337,338

of

catechols

to

However, generally the tyrosinase-catalyzed over-oxidation is not desired and is suppressed by the addition of reducing agents such as ascorbic acid or hydroxylamine. Thus, selective o-hydroxylation of various substituted phenols has been reported.340,341 The hydroxylation of tyrosine yielding L-DOPA and derivates has received special interest (Fig. 22).342,343 Fig. 20 Kinetic resolution of racemic amines using a transaminase with catalytic quantities of pyruvate and an AAOx.329

using stoichiometric amounts of pyruvate as amine acceptor. In the second step, a stereocomplementary transaminase is used to re-reduce the carbonyl group formed in the first step using alanine also originating thereof as amine donor. The equilibrium is shifted towards full conversion by reductive removal of pyruvate with lactate dehydrogenase and in situ NADH regeneration using glucose dehydrogenase. Between step 1 and 2, thermal inactivation of the primary transaminase is This journal is © The Royal Society of Chemistry 2011

Fig. 22 Tyrosinase-catalyzed o-hydroxylation of tyrosine yielding LDOPA. One equivalent of ascorbic acid is added to prevent quinone formation.

Green Chem., 2011, 13, 226–265 | 241

Next to tyrosinases, also some flavin-dependent monooxygenases have gained some attention for selective phenol hydroxylation. 2-hydroxybiphenyl-3-monooxygenase (HbpA) from Pseudomonas azelaica is among the best-characterized flavo monooxygenases. HbpA catalyzes the selective o-hydroxylation of a broad range of 1-substituted phenols. The substrate scope of the native enzyme was broadened significantly by protein engineering.344,345 For practical application, HbpA’s cofactor dependence has to be addressed, which was done extensively by Schmid and coworkers. Whole-cell approaches bear the advantage of integrated cofactor regeneration via the microbial metabolism.346,347 However, also toxic effects of the reactants on the microbial catalysts have to be considered and can be partially overcome by in situ product extraction (e.g. to a solid resin). Cellfree applications of HbpA became possible upon the setup of a scalable production/partial purification protocol. Using the well-known FDH-NADH regeneration system combined with a two-liquid phase approach for the in situ substrate feed and in situ product removal, full conversion of various phenols was achieved.168,348 Also chemical and electrochemical NADH regeneration using the organometallic catalyst [Cp*Rh(bpy)(H2 O)]2+ was coupled to HbpA-catalysis.175–177,349 Other flavo monooxygenases capable of selective o-hydroxylation such as hydroxybenzoic acid hydroxylase350 or phenol hydroxylase351–354 are known. However, to date, preparative applications are rather limited. Peroxidases were reported as phenol hydroxylation catalysts as early as 1961 but have not yet reached preparative relevance.126,355–357 p-Hydroxylations are comparably scarce with the exception of the microbial transformation of 2-phenoxypropionic acid into the corresponding 2-(4-hydroxyphenoxy) propionic acid reported by Hauer and coworkers.358 The optimized Beauveria bassiana strain was implemented at BASF (Ludwigshafen, Germany) for the large-scale (120 m3 ) production of this herbicide (Fig. 23). The biocatalyst has a fairly relaxed substrate scope; if the p-position to the alcohol/ether moiety is alkyl substituted, benzylic oxidation occurs.

Fig. 23 Microbial p-hydroxylation of phenylethers using Beauveria bassiana at BASF.

4.2

Halogenation/nitration of phenols

Halogenation/nitration at the aromatic ring has also been reported for a range of enzymes. Peroxidases have been used as catalysts for the oxidation of nitrite (NO2 - ) to NO2 + or NO2 ∑ at near-neutral pH reacting with various phenolic compounds (Table 13).359–361 Another approach for the production of nitroarenes using peroxidases is based on the oxidation of the corresponding anilines.362–365 Once considered as little more than a curiosity, a large number of enzymatic halogenation reactions have been discovered in 242 | Green Chem., 2011, 13, 226–265

Selection of enzymatic phenol nitration reactions359–361

Table 13

Substrate

Product

natural systems.366,367 The most common mechanism for enzymatic halogenation is the oxidative conversion of halogenides to enzyme-bound or free diffusible hypohalogenide species. Heme iron peroxidases and vanadyl bromoperoxidases represent the classical biocatalysts.366,368–370 Vanadium-containing haloperoxidases, frequently found in marine organisms,371 might turn out to be potent catalysts.115–118,372,373 Chloroperoxidase from Caldariomyces fumago (CPO) is the best-known haloperoxidase and a variety of aromatic halogenations have been reported with CPO.214,374–376 In addition halogenations with haloperoxidase from Agrocybe aegerita,124,131 lignin,377 manganese,378 soybean,379 and horseradish peroxidases380 have been reported. However, the use of haloperoxidases as halogenation catalysts is limited because they share a lack of inherent selectivity. As frequently hypohalogenides are excreted to the reaction medium, the selectivity of the halogenation reaction is determined by the chemical reactivity of the substrates and not influenced by the enzyme. Highly selective halogenations have been reported with a number of flavin-dependent halogenases. For example, selective tryptophane-5-, 6-, and 7-halogenases are known.369 The catalytic mechanism of these enzymes still is under debate but This journal is © The Royal Society of Chemistry 2011

more and more evidence exist that hypohalogenides are formed from halogenides reacting with a flavin-hydroperoxide. These hypohalogenides, however, are not released from the enzyme but are channeled through to the enzyme-bound substrates ensuring highly selective halogenation.366,368–370,381–384 As classical monooxygenases, flavin-dependent halogenases need molecular oxygen and reducing equivalents for catalysis.180 As in the haloperoxidases, hypohalogenides represent the actual oxidizing agents. As a consequence, only electron-rich substrates such as phenols, indoles, and pyrroles can be converted.385 A fourth class of halogenating enzymes, a-ketoglutarate-dependent, FeII containing monooxygenases presumably transfer halogen radicals thereby also making inactivated methyl groups principally available for enzymatic halogenation.386–388 The known members however are not (yet) practical. As part of polyketide synthesis pathways they exhibit a very high substrate specificity for their natural substrates. Once, this is overcome, exciting new developments in the enzymatic halogenation may be expected.

4.3

Oxidation of p-alkylphenols

Oxidation at the benzylic position of p-alkylphenols has been reported especially for the enzyme vanillyl alcohol oxidase (VAO), which has been investigated in great detail by van Berkel and coworkers.40,400,401 The catalytic mechanism comprises in the reductive half reaction, FAD-mediated hydride abstraction at the benzylic position yielding an intermediate p-quinone methide together with the reduced prosthetic group (FADH2 ). The catalytic active prosthetic group is regenerated by aerobic reoxidation whereas the p-quinone methide either rearranges to a styrene derivate or is attacked by water in a Michael-type reaction yielding (R)-a-hydroxy benzyl phenols (Fig. 24).402–405

Fig. 24 VAO-catalyzed phenols.402–405

Oxidation of catechols

The (enzymatic) oxidation of o- and p-catechols generates highly reactive quinones reacting with suitable nucleophiles as Michael acceptors. In recent years, the chemoenzymatic transformation of catechols, especially into heterocycles has gained increasing interest. Some representative examples are summarized in Table 14.

Table 14 Laccase-generated quinones as in situ generated Michael acceptors389–399

Substrates

4.4

hydroxylation/desaturation

of

p-alkyl-

Primary and activated alcohols are further oxidized to the corresponding aldehydes/ketones.406 For wild-type VAO, the ratio of hydroxylation/dehydrogenation depends on the size of the aliphatic chain with short chains (up to 3 C atoms) favoring (R)-hydroxylation. This ratio can be controlled to some extent by medium engineering (e.g. low-water content organic media, presence of small anions blocking the water binding site thereby favoring dehydrogenation).407 On the other hand, protein engineering resulted in two VAO-variants favoring hydroxylation and dehydrogenation, respectively.408 Also inversion of the stereoselectivity from (R) to (S) was reported.409 A very interesting cascade reaction combining amidases with VAO for the one-pot conversion of capsaicin (the active component of chilli peppers) to vanillin was reported (Fig. 25).410

Product

Fig. 25 Bi-enzymatic cascade for the synthesis of vanillin from capsaicin.410

Next to VAO, p-cresol methylene hydroxylase (PCMH) and p-ethylphenol methylene hydroxylase (EPMH)411–413 have also received some attention as benzylic hydroxylation/oxidation catalysts. Though both enzymes share significant structural homology to VAO they do not accept molecular oxygen as terminal oxidant.40 Rather, cytochrome c414 or azurin415 as well as a range of synthetic electron acceptors such as organic dyes416 and ferrocenes417–419 also can be used for preparative applications. In contrast to VAO and EPMH, wt-PCMH is (S)-selective. Finally, oxidative polymerization of phenols is worth mentioning here. Especially peroxidases and laccases have been reported to perform a hydrogen atom abstraction on phenolic compounds. The resulting phenoxy radicals then can initiate a non-enzymatic polymerization.420,421 Such polymers might be This journal is © The Royal Society of Chemistry 2011

Green Chem., 2011, 13, 226–265 | 243

interesting alternatives to conventional phenol/formaldehyde resins. Also, polyflavonoids obtained from laccase-initiated polymerization may be interesting, as they represent more potent radical scavengers than the corresponding monomers.422

5.

Oxidation of aldehydes

Compared to the oxidation of alcohols, the oxidation of aldehydes is less popular. Thus, it is not astonishing that comparably few biocatalytic aldehyde oxidation procedures have been reported. ADHs have been observed to catalyze NAD(P)+ -dependent aldehyde oxidation. This was first reported for HLADH, which was shown to oxidize, for example, formaldehyde423,424 and butanal or octanal.425 In the presence of equimolar amounts of aldehyde and oxidized nicotinamide cofactor, HLADH catalyzes the slow but near-quantitative formation of the corresponding acid.424 However, NADH-dependent aldehyde reduction represents a common side-reaction.426 Mechanistically, the ADH-catalyzed aldehyde oxidation is suspected to proceed via the gem-diol thereby presenting an abstractable hydride to the oxidized nicotinamide cofactor (Fig. 26).

Fig. 26 Reaction scheme of the sequential oxidation of alcohol to the corresponding carboxylic acid catalyzed by TBADH as proposed by Henehan and Oppenheimer.425

By now various other ADHs from different species have been described, which are capable of the sequential oxidation of alcohol to the corresponding carboxylic acids. These include ADHs from Drosophila melanogaster,427 TADH68 and TBADH,428 both isolated from extremophile bacteria, HLADH, YADH from yeast429 and HpCAD, an alcohol dehydrogenase isolated from Heliobacter pylori.430 Aldehyde dehydrogenases (AldDH) represent the ‘natural’ aldehyde oxidation catalysts. Their main mechanistic difference to the aforementioned ADHs is that they contain a nucleophilic cysteine in their active site. Thus, an intermittently formed thiohemiacetal exposes an ‘alcohol substrate’ to the enzymebound nicotinamide cofactor enabling ADH-like oxidation. After hydride abstraction, the thioester is hydrolyzed thereby releasing the acid product.431 Examples for preparative AldDH applications are scarce. An AldDH from yeast was applied to oxidize (Z,Z)-nona-2,4dienal, yielding the corresponding w-hydroxy carboxylic acid.432 Recycling of the necessary cofactor NAD+ was achieved in situ by addition of an alcohol dehydrogenase, reducing (Z,Z)-nona2,4-dienal to the corresponding alcohol. Since both reactions are stoichiometrically linked via NAD, this corresponds to an overall disproportionation of the aldehyde (Fig. 27) as described above. This concept was extended to industrially relevant metabolites of linoleic acid, which is an important 244 | Green Chem., 2011, 13, 226–265

Fig. 27 Enzymatic disproportionation of (Z,Z)-nona-2,4-dienal by and NAD-coupled ADH-/AldDH-cascade.432

building block for polymers and detergents. No isomerization of the double bonds and yields up to 90% were reported. Higher vertebrates possess retinal-specific aldehyde dehydrogenases, which often occur in various isoforms. The main substrate of these enzymes is retinaldehyde, which is converted to the corresponding carboxylic acid.433 Also very interesting because of a broad substrate spectrum is the benzaldehyde dehydrogenase II from Acinetobacter calcoaceticus. The best substrate for this enzyme was benzaldehyde, but it also converted other derivatives of benzaldehyde as well as aliphatic aldehydes.434,435 Aldehydes are rather untypical substrates for oxidases. An exception is xanthin oxidase, a two-component, molybdenumiron-sulfur flavoprotein hydroxylase. It oxidizes a wide variety of purines, pyrimidines, pterins and aldehydes. Interestingly, xanthine oxidase and xanthine dehydrogenase represent alternate forms of the same gene product. While the natural electron acceptor for xanthin oxidase is molecular oxygen, the dehydrogenase form accepts NAD+ .436 The oxidation of aldehydes catalyzed by xanthin oxidase was described as early as 1938 and was accomplished under anaerobic conditions using dyes like methylene blue, phenazine methosulfate or ferricyanide as artificial electron acceptors.437 Dastoli and coworkers transferred this reaction to nonpolar solvents with solid enzyme, which also worked at acceptable rates.438 From a preparative point-of-view, monooxygenases are negligible as aldehyde oxidation catalysts. However, it is interesting to note that the so-called luciferases (E.C. 1.14.14.3), a class of flavin-dependent monooxygenases, catalyze the NADPHdependent oxidation of some aldehydes yielding light emission as a by-product, thereby accounting for many forms of bioluminescence observed in nature.439 Luciferases have been described from a number of different species, mainly of marine origin, like Photobacterium fisheri,440 Latia neritoides,441 and many others. In addition, a number of P450-monooxygenase-catalyzed aldehyde oxidations (to corresponding acids)442–444 as well as oxidative decarboxylations have been reported.445,446

6. Baeyer–Villiger oxidations Enzymatic Baeyer–Villiger oxidations are catalyzed by the socalled Baeyer–Villiger monooxygenases, BVMOs. All known BVMOs are NAD(P)H-dependent, flavin (FAD or FMN)containing enzymes. According to the generally accepted mechanism, the reduced flavin reacts with molecular oxygen to form a deprotonated 4-a-peroxoanion, which nucleophilically attacks the carbonyl group to form the Criegee adduct.439,447 This journal is © The Royal Society of Chemistry 2011

Table 15 Representative examples for BVMO-catalyzed desymmetrizations of cyclobutanones45

R

Catalyst

ee [%]

Yield [%]

Ph

CHMOa CHMOb HAPMOc CHMOa fBVMOd CHMOa HAPMOc CHMOa fBVMOd

43 (-) 98 (-) 92 (+) 85 (+) 98 (-) 82 (-) 44 (+) 55 (+) 98 (-)

70 73 12 88 30 57 26 90 74

p-ClPh Bn CH2 OBn

a Cyclohexanone monooxygenase from Acinetobacter calcoaceticus NCIMB 9871. b Cyclohexanone monooxygenase from Brevibacterium HCU. c Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB. d fBVMO: fungal BVMO from Cunninghamella echinulata NRRL 2655.

BVMOs have gained strong interest as more selective alternatives to the existing chemical toolbox while at the same time operating under milder reaction conditions. The selectivity was nicely demonstrated by Mihovilovic and coworkers by chemoselective transformation of heterocyclic ketones.448 Though BVMOs are capable of heteroatom oxygenation, only the carbonyl function was converted to the corresponding lactone. The most valuable synthetic applications of BVMOs cover the desymmetrization of prochiral substrates, the (dynamic) kinetic resolution of chiral ones, and the generation of ‘abnormal lactones’, which will be discussed in the following. 6.1

R



Catalyst

ee [%]

Yield [%]

Me

H

Me

OH

Et

OH

Me Allyl OH OMe CH2 OH Cl

Me H H H H H

Br

H

I

H

CHMO CPMO CHMO CPMO CHMO CPMO CHMO CHMO CHMO CHMO CHMO CHMO CPMO CHMO CPMO CHMO CPMO

>98 (-) 46 (+) 97 (-) 76 (+) 94 (-) 42 (+) n.d. 95 (-) 10 (-) 78 (-) 98 (-) 95 (-) 34 (+) 97 (-) 64 (+) 97 (-) 82 (+)

83 68 48 54 54 52 61 62 73 84 80 56 64 63 70 60 65

CHMO: cyclohexanone monooxygenase from Acinetobacter calcoaceticus NCIMB 9871; CPMO: cyclopentanone monooxygenase from Comamonas sp. NCIMB 9872.

mentary resolutions can be achieved. For example, resolution of a-substituted cyclopentanone yielded the corresponding enantiopure lactone and the enantiomeric non-converted starting material, thus giving access to both antipodes of the pheromone component from Vespa orientalis, 5-hexadecanolide (Fig. 29).452

Desymmetrization reactions

Desymetrizations of various p-substituted cyclobutanones and cyclohexanones giving corresponding lactones in excellent yields and optical purities have been reported.45 Some representative examples are summarized in Table 15 & Table 16. Especially chiral butyrolactones are valuable chiral building blocks. In the case of 4-hydroxy cyclohexanone, the initially formed 7-membered lactone spontaneously rearranges into the thermodynamically more stable butyrolactone, which is a valuable starting material for natural product synthesis such as Calyculin or Tirandamycin (Fig. 28).449–451

Fig. 28 Rearrangement of hydroxylketones after Baeyer–Villiger oxidation.45

6.2

Table 16 Representative examples for BVMO-catalyzed desymmetrizations of cyclohexanones45

Kinetic resolutions

Also a broad range of kinetic resolutions have been reported using BVMOs.45 By choice of suitable catalysts stereocompleThis journal is © The Royal Society of Chemistry 2011

Fig. 29

Kinetic resolution of racemic a-undecylcyclopentanone.452

An interesting case of kinetic resolution often is observed especially with fused cyclobutanones.45,453 While in enzymatic Baeyer–Villiger oxidations the more nucleophilic carbon atom of unsymmetrical ketones usually migrates, a fundamentally different behavior is observed in the case of bicyclic cyclobutanones. Especially in case of the CHMO-type BVMOs, one substrate enantiomer is converted into the ‘normal’ lactone while its antipode is transformed into the ‘abnormal’ lactone (Table 17).453,454 This regiodivergent oxidation offers an elegant entrance to chiral building blocks used for natural product synthesis as exemplified with bicyclo[3.2.0]hept-2-ene-6-one (Fig. 30). Using recombinant E. coli expressing CHMOAcineto an in situ substrate feed/product removal approach proved to be efficient Green Chem., 2011, 13, 226–265 | 245

Table 17

Substrate

Selected examples for regiodivergent Baeyer–Villiger oxidations453

Catalyst

Normal lactone [abs. conf./ee]

Abnormal lactone [abs. conf./ee]

Conversion/ratio

CHMORhodo

(1S,5R)/99

(1R,5S)/>99

83/(50 : 50)

CPMOComa CHMOAcineto CHMOArthro

— (1S,5R)/95 (1S,5S)/>99

(1R,5S)/>99 (1R,5S)/>95 (1R,5S)/>99

61/(3 : 97) 63 (49 : 51) 85 (49 : 51)

CHMOBrevi CHMOAcineto

(1S,5S)/>99 (1S,6S)/60

(1R,5S)/>99 (1S,6R)/>95

83 (50 : 50) 48 (35 : 65)

CPMOComa CHMOAcineto

— n.d./44

(1S,6R)/>99 n.d./>99

80 (4 : 96) 84 (30 : 70)

CHMORhodo CHMOArthro

n.d./73 (1S,5R)/12

n.d./>99 n.d./98

88 (42 : 58) 98 (3 : 97)

CHMOBrevi CHMOAcineto

(1S,5R)/42 (4S,7S)/high

n.d./92 (3R,6S)/high

90 (20 : 80) n.d.455

CHMORhodo : CHMO from Rhodococcus; CPMOComa : CPMO from Comamonas sp.; CHMOAcineto : CHMO from Acinetobacter; CHMOArthro : CHMO from Anthrobacter; CHMOBrevi : CHMO from Brevibacterium.

Fig. 30 Chiral building block synthesis exploiting the CHMOcatalyzed regiodivergent oxidation of bicyclo[3.2.0]hept-2-ene-6-one.

to circumvent poor substrate solubility and was brought to pilotscale production.456–458 Another interesting example for regiodivergent conversion of chiral cyclic ketones was reported recently.459 The chirality in bposition determined the regioselectivity of CHMO- and CPMOcatalyzed Baeyer–Villiger oxidation. Thus, O-insertion for one enantiomer occurred at the ‘proximal’ C–C bond, whereas the other enantiomer was converted to the ‘distal’ lactone. Recently, Bornscheuer and coworkers reported on kinetic resolutions of acyclic b-hydroxyketones460,461 and b246 | Green Chem., 2011, 13, 226–265

acetamidoketones offering novel and potentially very useful access to b-aminoalcohols and b-amino acids as well as the corresponding hydroxy analogues.462 One major limitation of kinetic resolutions, of course, is the maximal theoretical yield of 50% (perfect enantiodiscrimination of the catalyst provided). At least for a-substituted substrates this can be overcome by in situ substrate racemization leading to a dynamic kinetic resolution (Fig. 31). Excellent conversions and optical product purities have been reported for this approach.463–465 6.3 Novel BVMOs Until recently, only a handful of BVMOs were accessible, thereby restricting the number of preparative applications largely to those BVMOs mentioned above, especially the cyclohexanone monooxygenase from Acinetobacter calcoaceticus. Fortunately, the number of potentially useful BVMOs is growing rapidly, e.g. by identifying novel BVMOs from genome sequences.466,467 One This journal is © The Royal Society of Chemistry 2011

7. Oxidation of carboxylic acids

Fig. 31 Dynamic kinetic resolution of racemic ketones via in situ racemization combined with enantioselective BVMO-oxidation.

BVMO deserving special attention is phenylacetone monooxygenase (PAMO) from the mesothermophilic actinomycete Thermobifida fusca. Discovered by a genome mining approach,466 the thermostable enzyme was the first BVMO of which a crystal structure became available,468 thereby opening up new possibilities for mechanistic understanding of enzymatic Baeyer– Villiger oxidations469 as well as enabling structure-guided protein engineering to enlarge the substrate scope.470–473 Also in the case of BVMOs the cofactor challenge represents a major impediment en route to cell-free application and confining BVMO-catalysis largely to whole cell approaches with all the problems associated with them. Promising approaches using enzymatic474 or transition metal-based cofactor regeneration174 have been reported but still are at an early development stage. Another very promising approach was developed by the Fraaije group. They recently reported on the generation of a PAMOPDH (PDH = phosphite dehydrogenase)475 fusion protein as a self-sufficient BVMO catalyzing enantioselective, phosphite driven Baeyer–Villiger oxidations (Fig. 32).172,173

Fig. 32 A PAMO/PDH fusion protein as self-sufficient BVMO for phosphite-driven Baeyer–Villiger oxidations.172,173

Using crude cell extracts of this novel bifunctional catalyst even made external NADP addition unnecessary thereby pointing towards a very economical reaction setup. Alternatively, direct non-NADPH-dependent regeneration of PAMO is also possible by direct introduction of reducing equivalents to the prosthetic FAD group.194,195 Though most simple in its setup, the efficiency is not yet sufficiently high (mainly due to the oxygen dilemma, vide infra). It remains to be shown to what extent this approach represents a valid alternative to the established cofactor regeneration methodologies. This journal is © The Royal Society of Chemistry 2011

Comparatively few oxidations of carboxylic acids of preparative value can be found in the literature. The oxidation of formic acid has received considerable interest and application as in situ NAD(P)H regeneration reaction. Using formate dehydrogenase (FDH) the reducing equivalents obtained from formic acid can be transferred specifically to oxidized nicotinamide cofactors, thereby yielding the enzymatically active reduced 1,4-NAD(P)H isomers. The importance of this reaction to catalyze NAD(P)H-dependent reduction and oxyfunctionalization reactions has been reviewed extensively in some excellent recent review articles.23–25,476 The oxidation of pyruvate can be used to in situ promote cellfree regeneration of ATP. Pyruvate decarboxylase catalyzes the decarboxylative oxidation of pyruvate yielding CO2 , H2 O2 , and the activated anhydride acetylphosphate. The latter can be used by the enzyme acetate kinase, which catalyzes the transphosphorylation of ADP to the activated triphosphate.477–479 This reaction can be applied in vitro to regenerate ATP in ATP dependent enzymatic reactions such as in vitro protein biosynthesis.480

8. Oxidation of C

C double bonds

The oxidative conversion of C C double bonds mainly covers their epoxidation. In addition, halohydroxylation, cisdihydroxylation, and ozonolysis-like oxidative cleavage will be discussed shortly here. Epoxidations are of special interest for organic synthesis as they typically lead to the formation of up to two new chiral centers. Especially in the area of enantioselective epoxidation, biocatalysis offers a broad repertoire of very selective catalysts. 8.1

Epoxidation of aliphatic C C bonds

Diverse classes of monooxygenases and peroxidases catalyze epoxidations of aliphatic alkenes. Most reports on the biocatalytic epoxidation of aliphatic olefins involve heme-dependent (P450)-monooxygenases and non-heme diiron monooxygenases. Next to their cofactor dependency, these enzymes typically exhibit a very complicated molecular architecture comprising multicomponent systems, which makes their application as isolated enzymes very complicated.21,22 Therefore, the majority of studies focus on whole-cell biotransformation, often even using the wild type organisms. Alkane monooxygenases (AMOs) as expressed by alkane degrading Pseudomonas putida are very powerful epoxidation catalysts.481,482 The catalytically active component of AMO is a membrane-bound, non-heme diiron monooxygenase also enabling AMOs for C–H hydroxylation reactions.483–486 Interestingly, the selectivity of AMO-catalyzed epoxidation reaction differs from the chemical reactivity of the C C double bond. Thus, terminal C C double bonds are converted exclusively, leaving higher substituted and cyclic alkenes untouched. In recent years, various other microbial epoxidation systems have been identified (Table 18). Toxicity of the reactants is an issue frequently observed in whole-cell biocatalysis. Especially reactive epoxides can be a significant limitation to the stability of the biocatalyst. A very simple approach to circumvent this undesired inhibition is to keep the epoxide concentration low Green Chem., 2011, 13, 226–265 | 247

Table 18

Substrate

Examples for selective microbial alkane epoxidations

Catalyst

ee [%]

Ref.

Mycobacterium sp.

98 (R)

493

Norcardioides sp.

98 (R)

494

Norcardia sp.

98 (R)

493

Xanthobacter

88 (R)

495

Mycobacterium sp.

98 (S)

493

Norcardia sp.

98 (S)

493

Mycobacterium sp.

86 (R)

493

Mycobacterium sp.

88 (R)

496

Norcardia sp.

84 (R)

496

Burkholderia cepacia

>99 (R)

497

P450BM3 (variant RH47)

60 (R)

498

P450BM3 (variant SH44)

74 (S)

498

P450BM3 (variant RH47)

84 (R)

498

P450BM3 (variant SH44)

56 (S)

498

Rhodococcus rhodochrous

86 (R)

499

Rhodococcus rhodochrous

86 (R)

499

Rhodococcus rhodochrous

82

499

by continuous extraction to a second, organic phase.487 Thereby, the low aqueous solubility of the hydrophobic substrates also can be overcome as there is also a continuous substrate feed from the organic phase. Overall product concentrations of 150 g Lorg -1 could be achieved.488 In another approach, substrate feeding and product removal was performed via the gas phase in a continuous, closed-gas loop reactor.489 Moreover, the use of microbial biofilms may be an interesting approach for highly robust biocatalyst preparations. Biofilms are known to be more resistant to external stress factors (such as toxic compounds).490 Promising proof-of concept studies have established that biofilms are indeed highly robust catalysts (>50 days operational stability).491,492 Further challenges in whole-cell biocatalysis may be the presence of different, stereocomplementary epoxidation systems which may impair the optical purity of the final product. This was exemplified with Mycobacteria where the stereochemical outcome of propene and butene epoxidation strongly depended on the culture conditions. Mycobacteria grown on alkenes 248 | Green Chem., 2011, 13, 226–265

exhibited (R)-selectivity, whereas in the presence of ethane as carbon and energy source (S)-selectivity was observed, pointing to the presence of multiple differently regulated AMOs with different enantioselectivities.495 Generally, further metabolization is undesired as it decreases the yield. However, the epoxidation of 2-butene with Micrococci was accompanied by enantioselective hydrolysis of the undesired enantiomer thereby increasing the optical purity of the desired product.500 Stereospecific epoxidation of aryl allyl ethers into (R)-aryl glycidyl ethers as chiral building blocks for adrenergic receptor inhibitors was reported with some Pseudomonads and Mycobacteria (Fig. 33).501,502

Fig. 33 Microbial (R)-epoxidation of aryl glycidyl ethers as key step in the synthesis of metoprolol.

The Japan Energy Corporation (formerly Nippon Mining) has commercialized the Rhodococcus rhodochrous B-276-based epoxidation platform.503,504 A broad range of terminal alkenes were converted to the corresponding (R)-epoxides with optical purities reaching 90% (depending on the substrate chain length). Product titers of up to 80 g L-1 at 4 m3 scale were reported. Epoxidation of cis-propenylphosphonic acid yields the antibiotic fosphomycine. Various microbial strains have been reported for this reaction.505–507 Also, the as-yet only example of a BVMOcatalyzed epoxidation reaction was reported for this reaction.508 The chemoenzymatic conversion of sulcatol to the pheromone pityol is also of pharmacological interest (Fig. 34).509

Fig. 34

Chemoenzymatic conversion of sulcatol to pityol.

With respect to cytochrome P450 monooxygenases, Bacillus megaterium was one of the first organisms, which has been reported to catalyze P450-dependent epoxidation reactions such as the epoxidation of unsaturated fatty acids.510,511 The responsible P450 monooxygenase (P450BM3 ) was the target of many directed evolution studies aiming at the hydroxylation and epoxidation of ‘unnatural’ P450BM3 substrates.512 Thus, P450BM3 variants capable of styrene, cyclohexene, and propene epoxidation are available.498,513 A P450BM3 variant capable of specific amorpha4,11-diene epoxidation was reported as a step towards the antimalaria drug artemisinin.514 Camphor monooxygenase from Pseudomonas putida (P450cam ) is similarly popular as an epoxidation catalyst, with which, for example, limonene epoxidation was studied extensively by Wong and coworkers.515,516 Practical application of P450BM3 and P450cam as epoxidation catalysts This journal is © The Royal Society of Chemistry 2011

is hampered by their generally low selectivity. For example, conversion of limonene,515 pinene,517 and valencene518 using these enzymes generally leads to multiple epoxidation, hydroxylation, and over-oxidation products (Fig. 35) which may be overcome in the future by protein engineering.191,512,518–522

Table 19

Alkene

Fig. 35 Product distributions of P450-catalyzed transformations of apinene, limonene, and valencene.

Epoxidation of (-)-a-pinene using P450BM3 heterologously coexpressed with glucose dehydrogenase (to ensure efficient NADPH regeneration) and a glucose uptake facilitator in E. coli was reported by Schrader and coworkers.517 20 mg apinene oxide per gram of biocatalyst (next to hydroxylation products verbenol and myrtenol) were obtained. Some peroxidases (mostly heme-thiolate peroxidases) are known to catalyze the epoxidation of C C double bonds,123,523 of which chloroperoxidase from Caldariomyces fumago (CPO) is the most commonly used enzyme.197,524,525 Especially aliphatic cis-alkenes and gem-substituted alkenes, not too far away from the terminus are efficiently epoxidized by CPO reaching high enatiomeric purities for the products (Table 19).211,524,526,527 Lower enantioselectivities are observed with trans-alkenes and internal C C double bonds. One very interesting application of CPO is reported for the synthesis of (R)-(2)-mevalonolactone (Fig. 36).528

Fig. 36 Chemoenzymatic synthesis of (R)-(2)-mevalonolactone with CPO-catalyzed epoxidation as the key chiral step.

Finally, also lipases have been reported as biocatalysts in chemoenzymatic epoxidation reactions.529,530 This approach makes use of the perhydrolase activity of some lipases. Thus, the covalent enzyme-acyl product can also be cleaved by hydrogen peroxide releasing peracids that can epoxidize C C double bonds (Fig. 37). An advantage of this approach is that lipases are rather robust enzymes withstanding comparably harsh reaction conditions. On the other hand, however, as a chemoenzymatic variant of This journal is © The Royal Society of Chemistry 2011

Epoxidation of different olefins by chloroperoxidase

Epoxide

ee [%]

Yield [%]

Ref.

96

78

526

92

82

526

95

23

527

94

34

527

89

22

527

62

61

211

88

93

211

95

89

211

87

33

211

50

42

211

94

33

526

66

28

526

74

10

526

50

81

526

100

95

524

40

95

524

95

20

524

Green Chem., 2011, 13, 226–265 | 249

Table 20

Fig. 37 Lipase-catalyzed formation of peracids as a biocatalytic entry to the Prilezhaev reaction.

Substrate scope of styrene monooxygenase (StyAB)

Product

ee [%]

the Prilezhaev reaction, racemic products are formed.531–533 The use of chiral carboxylic acids has been proposed to exceed chiral induction.534 8.2

Yield [%] (mass/g)

Ref.

99.5

76.3 (12.6)

182,183,543,545,546

99.9

46.5 (8.7)

545

96.7

74.8 (11.3)

169,182,545

99.8

87.2 (15.4)

169,182,545

99.4

87.3 (18.3)

182,545

99.4

72a

179

98.1

35a

179

05.6

27a

179

98.5

53.0 (10.2)

182,545

98.0

47.9 (11.0)

545

Epoxidation of vinylaromatic compounds

The preferred catalysts for the epoxidation of styrenes are flavinand heme-dependent monooxygenases as well as peroxidases. In addition to their well-described activity as Baeyer–VilligerOxidation catalysts,34,42 flavin-dependent monooxygenases have been reported to be capable of epoxidizing activated, vinylaromatic C C double bonds.39 These so-called styrene monooxygenases have been described from various sources such as Pseudomonas,535–538 Rhodococcus539,540 or metagenome screenings.541 Styrene monooxygenase (StyAB) from Pseudomonas sp. strain VLB120 was the first enzyme of this class, which was examined in detail for biocatalysis over more than a decade. The twocomponent enzyme consists of a FADH2 -dependent oxygenase (StyA), which transforms a broad range of styrenes into the corresponding (S)-epoxides (Table 20) via reductive activation of molecular oxygen, and a reductase component (StyB) catalyzing the transfer hydrogenation between reduced nicotinamide cofactors and oxidized FAD.536 Toxicity issues related to the reactive product could be (partially) overcome by use of the two liquid phase approach with recombinant E. coli allowing for up to 72 g Lorg -1 .535,542,543 Scalability and economic as well as ecological feasibility have been evaluated.544 In addition to the promising whole cell approaches, also the cell-free application of StyAB was evaluated. Using catalytic amounts of NAD+ together with the formate dehydrogenase regeneration system, Hofstetter et al. performed gram-scale epoxidation of various styrenes at excellent enantioselectivities and rates.169 The rather complicated electron transport chain delivering reducing equivalents can be drastically simplified by using either a transition metal complex transferring electrons from formate to the oxidized flavin cofactor,179 or even more simple by direct cathodic flavin reduction.182,183 Challenges related to the latter approach comprise the undesired direct cathodic reduction of molecular oxygen resulting in the formation of reactive oxygen species which impair biocatalyst stability. Using an optimized electrochemical cell, Ruinatscha et al. could significantly reduce this undesired side-reaction and thereby improve the productivity and robustness of the electroenzymatic process.183 Further significant improvements are expected for the near future. The heme-containing monooxygenase P450cam from Pseudomonas putida also has received some attention as a styrene 250 | Green Chem., 2011, 13, 226–265

a

Analytical scale.

epoxidation catalyst. Especially the Y96F mutant showed significantly improved activity and selectivity for styrene epoxidation compared to the wild type enzyme.186 To avoid the addition of the costly nicotinamide cofactor, Vilker and coworkers chose an electrochemical strategy wherein the natural electron donor This journal is © The Royal Society of Chemistry 2011

for P450cam , putidaredoxin, was regenerated by direct cathodic reduction. Molecular oxygen required for the monooxygenase reaction was generated by anodic oxidation of water. This also proved to be necessary to suppress the undesired reoxidation of putidaredoxin (Fig. 38). Quite promising turnover frequencies for the monooxygenase component of 10 min-1 were observed. However, putidaredoxin had to be applied in huge molar surpluses, probably to compensate for the oxidative uncoupling reaction.

Fig. 38 Cathodic regeneration of reduced putidaredoxin (PDx) to promote P450cam -catalyzed styrene epoxidation.

Instead of performing reductive activation of molecular oxygen, heme-dependent enzymes are also capable of using hydrogen peroxide to regenerate the catalytically active oxyferryl heme-species. Particularly, this is true for heme-dependent peroxidases (vide infra). But also P450 monooxygenases such as P450BM3 from Bacillus subtilis,513,547 or P450s from thermophilic organisms548,549 have been evaluated as styrene epoxidation catalysts utilizing the peroxide shunt pathway. The major challenge encountered here is the poor stability of the heme group in the presence of hydrogen peroxide. Thus, oxidative degradation severely limits enzyme stability and thereby the applicability of this approach. Another class of heme-dependent enzymes, which has received some attention as styrene epoxidation catalysts, are natural O2 -transporting proteins such as hemoglobin and myoglobin. Especially the group around Rusling has been very active in designing enzyme-modified cathodes for bioelectrocatalytic applications such as styrene epoxidation.192,550,551 Direct reduction of the electrode-adsorbed enzymes followed by activation of molecular oxygen thereby competes with direct regeneration via the hydrogen peroxide shunt pathway by hydrogen peroxide generated at the electrode. With this approach, only analytical transformations have been reported so far, but exciting future developments may be expected. CPO was also reported as selective epoxidation catalyst for the epoxidation of styrenes (Table 21). 8.3

Oxidative cleavage of C C bonds

Oxidative cleavage of C C double bonds producing aldehydes or ketones plays an important role in plant metabolism. From a synthetic point of view these reactions are also highly interesting as they give access to some interesting bioactives and flavor compounds such as b-ionone from comparably cheap starting material.552 As an example, Fig. 39 shows the cleavage of b,bcarotene by a carotenoid cleavage dioxygenase from Arabidopsis This journal is © The Royal Society of Chemistry 2011

Table 21 Substrate

Epoxidation of various styrenes using CPO as biocatalyst Product

Conversion [%] ee-value [%] Ref. 67

96

526

85

97

526

89

49

526,527

55

89

527

90

30

554

95

n.d.

555

90

n.d.

555

92

n.d.

555

Fig. 39 b,b-carotene 9,10(9¢,10¢)-cleavage by, for example, carotenoid cleavage dioxygenase (Ccd) from Arabidopsis thaliana.

thaliana at the 9,10-and 9¢,10¢-double bonds giving b-ionone and apo-10,10¢-carotendial as the oxygenated products.553 Such dioxygenases from plants or cyanobacteria have been reported to cleave a variety of carotenoides including, b,bcarotene, z-carotene, lycopene, torulene, a-carotene, zeaxanthin, lutein, violaxanthin, and neoxanthin.556 Depending on the enzyme and the substrate, different double bonds are cleaved Green Chem., 2011, 13, 226–265 | 251

Table 22 Phenylalkenes cleaved by Trametes hirsute FCC 047 in buffer (pH6) at 2 bar oxygen pressure. Adapted from Lara et al.559

R1

R2

R3

R4

Conversion [%]

Chemoselectivitya [%]

p-OMe p-NH2 p-OMe H H p-CH3 p-tBu m-NO2 m-CH3 m-Cl o-Cl o-CH3 H H H

H H H H H H H H H H H H CH3 H H

CH3 H H CH3 H H H H H H H H H C3 H7 CN

H H H CH3 H H H H H H H H H H H

>99 3 55 13 22 33 23 5 20 49 77 20 27 27 1

>99 >99 90 83 >99 94 92 67 92 80 85 91 >99 64 >99

Fig. 40 Lipoxygenase-catalyzed dioxygenation of polyunsaturated fatty acids (e.g. linoleic acid).

a

9. Aromatic cis-dihydroxylation

leading to the corresponding aldehydes and/or ketones. In vitro dioxygenase catalysis has been performed in aqueous micellar reaction systems containing water miscible solvents and enzyme solubilisation by means of surfactants has been reported to play a crucial role.557 Another very interesting C C double bond cleaving enzyme activity was reported by Kroutil and coworkers, who found that whole cells or cell-free extracts of the wood-degrading fungus Trametes hirsute FCC 047 cleave C C double bonds adjacent to an aromatic ring by use of molecular oxygen as the sole oxidant to yield the corresponding carbonyl compounds.558–560 A broad range of phenylalkenes was shown to be converted typically with a high chemoselectivity (Table 22). Indene, 1,2dihydronaphthalene, isosafrole, and 2-(prop-1-enyl)thiophene also were cleaved at the double bond adjacent to the aromatic ring. Finally, allylic hydroperoxidation catalyzed by lipoxygenases is worth mentioning here.561 Lipoxygenases are non-heme iron dioxygenases acting on (Z,Z)-1,4-pentadienoic moieties of poly unsaturated fatty acids producing allyl hydroperoxides of migrated E,Z C C double bonds. (Fig. 40). The initially formed hydroperoxides are usually further transformed into aldehydes (C–C cleavage), alcohols and ketones representing interesting starting materials for flavors and fragrances but also for bioactive compounds. Preparative examples comprise for example the specific dihydroperoxidation of arachidonic acid yielding 5(S)-15(S)-di-hydroperoxy eicosatetraenoate, a key intermediate for the total synthesis of 6(R)lipoxin A,562 or a chemoenzymatic approach for the epoxidation of retinol, b-ionone etc.563 Further examples for the use of lipoxygenases in total synthesis can be found in the excellent review by Nanda et al.561

Dihydroxylation of arenes represents a nice example of biocatalysis complementing the chemical toolbox. While chemical methods for the controlled dihydroxylation of aromatics are still missing, nature has come up with a class of selective oxygenases capable of regio- and stereoselective cis-dihydroxylation of benzene-derivates, representing the first step of the so-called ‘lower arene degradation’ pathway. Since the first description of microbial degradation of aromatic hydrocarbons564,565 more than 300 different cis-diols have been reported.566–570 In the majority of cases these cis-diols are enantiopure thus potentially representing an enormous source of chiral building blocks. Despite this, the synthetic potential of only few cis-dihydrodiols, mainly derived from benzene, its alkylated and halogenated derivatives as well as napthalene has been exploited.568,571–573 For example, cis-dihydrodiols have been used for the synthesis of cyclohexanoids such as (+)-pinitol,574 rare carbohydrates like D- and L-erythrose, and various alkaloids as lycoricidine or pankratistatin.575–578 Bacterial dioxygenases are mainly classified according to the aromatic hydrocarbon used first for bioremediation studies. Thus among others, benzene, toluene, chlorobenzene, napthalene, and benzoate dioxygenases have been described. A representative, though by far not exhaustive, representation of cisdiols accessible is given in Table 23. Dioxygenases usually are found within microbial arene degradation pathways in combination with further metabolizing enzymes such as dioldehydrogenases transforming the primary product into corresponding catechols. Using wildtype strains, this of course represents an undesired reaction which can be overcome by recombinant expression of only the dioxygenase genes, e.g. in E. coli.585,586 On the other hand, the usually high stereoselectivity of these dehydrogenases may also be used to polish the optical purity of the cis-diols. Using an engineered (dehydrogenase-deficient) Pseudomonas strain, fluorobenzene was converted into the corresponding cis-diol, albeit at low enantioselectivity (60–80% ee). However, this was increased significantly by feeding this raw product to a

The chemoselectivity is given as the ratio of formed aldehyde/ketone to all compounds formed.

252 | Green Chem., 2011, 13, 226–265

This journal is © The Royal Society of Chemistry 2011

Table 23 Selection dihydrodiols566–568,571

of

representative

dioxygenase-derived

cis-

Product TDO566,579,580

NDO581

BZDO582

BPDO583,584

TDO: toluene-DO; NDO: naphthalene-DO; BZDO: benzoate-DO; BPDO: biphenyl-DO.

wild-type Pseudomonas containing the (highly enantioselective) dehydrogenase.587 Sinisterra et al. reported on the preparative-scale transformation of toluene into the corresponding cis-diol.588 One challenge was the high toxicity of the substrate which was overcome by using the two-liquid-phase concept and thereby keeping the aqueous toluene concentration at acceptable values for the microorganism (P. putida immobilized in alginate beats). Overall more than 80 g L-1 of enantiopure cis-diol could be obtained. Furthermore, a number of other cis-dihydrodiols have been obtained in high space-time yields (up to 20 g L-1 h-1 ) from whole-cell fermentations using toluene dioxygenase recombinantly expressed in E. coli. Here, substrate concentrations were kept below toxicity levels by continuous feed.577,585,586 Despite the currently few preparative examples for dioxygenase-catalysis, exciting future applications are expected due to the great versatility of the product class available through them. This journal is © The Royal Society of Chemistry 2011

10. C–H bond oxyfunctionalizations The specific oxyfunctionalization of non-activated C–H bonds can be considered as particular playground for biocatalysis. Chemical oxyfunctionalization catalysts are often too reactive to exhibit significant selectivity. Enzymes often circumvent this reactivity challenge by precise positioning of the substrates within the active site. As a consequence, only one substrate moiety is exposed to the reactive oxygen transferred. It should be mentioned here that the selectivity strongly depends on the natural function of the oxyfunctionalization catalyst. Monooxygenases found in anabolic pathways (e.g. steroid synthesis)589 often exhibit a comparably narrow substrate scope combined with high selectivity. Enzymes involved in xenobiotic detoxification however convert many different substrates albeit sometimes at the expense of selectivity.47 Cytochrome P450 monooxygenases16,47,590 and mono- or binuclear non-heme iron monooxygenases591–596 represent the most thoroughly investigated enzyme class for selective hydroxylation of sp3 -hybridized carbon atoms. A representative collection of monooxygenase-catalyzed hydroxylations is given in Fig. 41. Industrial applications17,47 of P450 monooxygenases mainly comprise steroid and terpenoid hydroxylations589 such as the 11b-hydroxylation of 17,21-dihydroxypregn-4-ene-3,20-dione (Reichstein S) to hydrocortisone, the transformation of progesterone to cortisone,597,598 or the synthesis of artemisic acid.599 But also alkane functionalizations for the synthesis of a,wdicarboxylic acids have been reported.16,600,601 Selective hydroxylation of hydrocarbons also include, for example, the conversion of compactin into pravastatin,602 the conversion of limonene to perillyl alcohol,603–605 selective p-hydroxylation358 or benzylic hydroxylation of alkylaromatics.606 Among the vast number of P450 monooxygenases characterized, especially the P450 monooxygenases from Bacillus megaterium (P450BM3 ) and the camphor monooxygenase from Pseudomonas putida (P450cam ) have gained considerable interest as synthetic catalysts.16,46–48,607,608 Sometimes poor selectivity and narrow substrate range can be one major obstacle en route to practical applicability. Protein engineering, however, has frequently demonstrated its potential for overcoming such limitations.26,30,614–616 For example, P450cam hydroxylates its natural substrate camphor exclusively in 5-exo-position, whereas the structurally related a-pinene is transformed with poor selectivity yielding a complex product mixture.617 Based on semi-rational design, Wong, Rao and coworkers could generate P450cam mutants with significantly increased selectivity for either of the products.617 Similarly, the product distribution of P450cam -catalyzed conversion of the natural sesquiterpene (+)-valencene could be modulated.518 Other P450cam mutants useful, for example, for the hydroxylation of polycyclic aromatics,612 indole,618 chlorinated aromatics,619 or even ethane620 have been reported. Engineering of P450BM3 was studied to a similar extent. The natural substrates seem to be fatty acids, which however are not transformed with high regio- and stereoselectivity.607 Extensive directed evolution performed by Arnold and coworkers resulted in P450BM3 variants with significantly increased w or (w-1) preference in the hydroxylation of C6 –C10 alkanes.621 Furthermore, variants converting Green Chem., 2011, 13, 226–265 | 253

Fig. 41

Representative examples for P450-catalyzed hydroxylation reactions.184,186,358,518,597,598,600–605,609–613

shorter alkanes (up to ethane) could be generated.622,623 P450BM3 variants converting indole,624 valencene,518 phenols625 and bionone626 have been generated as well. In addition to these protein engineering approaches, substrate engineering following the so-called docking/protecting group concept has also been reported for selective C–H bond hydroxylations.627–632 The concept is based on the reversible covalent modification of the substrate of interest with a docking/protection group. In the reported cases, substrates that were either not converted at all or underwent significant side reactions could be selectively hydroxylated in vivo. In some cases chiral induction by the docking/protection group was observed. Two representative examples for the docking/protection group concept are shown in Fig. 42.

precise control over the compound concentration experienced by the microorganism, thereby minimizing toxicity effects and undesired metabolization while affording overall high substrate loadings. The organic phase also serves as product sink thereby facilitating downstream processing. A very elegant application of the two-liquid phase approach was reported by Schmid and coworkers.227,229 Xylene monooxygenase from Pseudomonas putida heterologously expressed in E. coli225,226 was used for the selective transformation of pseudocumene into 3,4-dimethyl benzaldehyde. By using dioctyl phthalate as second organic phase, substrate/product levels could be maintained below toxic levels allowing for stable oxidation activity of the E. coli catalysts. Furthermore, the desired aldehyde product was efficiently extracted into the organic phase thereby circumventing microbial over-oxidation to the acid (Fig. 43).

Fig. 42 Representative examples for the docking/protecting group concept.

Due to their cofactor-dependency, monooxygenases are almost exclusively used in whole cell systems. Thus, reducing equivalents needed for the reductive activation of molecular oxygen are provided by the microbial metabolism.16,17,229,607,633 A range of other complications derive from the whole cell approach: The majority of interesting substrate/product pairs is poorly water-soluble and/or toxic for the living cells. Organic/aqueous two-liquid phase systems present a suitable technique to overcome this limitation. This concept allows for 254 | Green Chem., 2011, 13, 226–265

Fig. 43 Two-step oxygenation of pseudocumene catalyzed by recombinant E. coli expressing the xylene monooxygenase (XylM) genes. The two-liquid phase system allows the exploitation of the multistep reaction kinetics for exclusive aldehyde formation by simply controlling the substrate concentration.

This journal is © The Royal Society of Chemistry 2011

Table 24

Product

a

Selection of microbial, O2 -independent N-o-hydroxylations

Catalyst

Isolated yield/g L-1

Achromobacter xylosoxidans

74

642

Pseudomonas fluorescens

191

635

Agrobacterium sp.a

301

636

Proteobacterium

6.4

643

Comamonas testosteroni

45

644

Ref.

Starting from corresponding nitrile.

Here, also the selective o-hydroxylation of pyridines should be mentioned. Particularly, nicotinic acid dehydrogenases are worth mentioning here as they have found industrial application, for example, for the synthesis of 5-hydroxypyrazinecarboxylic acid, 6-hydroxypicolinic acid and 6-hydroxynicotinic acid.634–640 As suggested by the nomenclature, the nicotinic acid dehydrogenase-catalyzed hydroxylation does not involve reductive activation of molecular oxygen, thereby representing an interesting alternative mechanism. Indeed, NADP+ dependent water incorporation could be demonstrated by isotope labeling.641 A representative selection of microbial ohydroxylations of N-aromatics is given in Table 24. Significant efforts have been devoted to establish cell-free hydroxylation reactions using isolated enzymes. The goal here is to obtain enzyme-based hydroxylation protocols of a comparable simplicity as already established for simple hydrolytic enzymes. The major challenge is to set up efficient supply of the monooxygenases with reducing equivalents. The obvious approach here is to use the natural nicotinamide cofactor together with a suitable in situ regeneration approach. Urlacher and coworkers have reported such a ‘traditional’ regeneration approach using P450BM3 combined with an NADP+ -specific dehydrogenase. Though multiple turnovers were observed for the enzyme in the hydroxylation of b-ionone, significant improvements are still necessary to obtain true catalytic turnover of the cofactor.171 A similar system was reported recently using an ADH-based regeneration system achieving a few dozen turnovers for NADP.645 Cell-free application of monooxygenases is complicated due to the often very complex molecular architecture of these enzymes. Though NAD(P)H serves as stoichiometric reductant, the reducing equivalents are usually This journal is © The Royal Society of Chemistry 2011

delivered to the oxygenase subunit via complex electron transport chains comprising various enzymes and electron transport proteins.646 The situation is further complicated by the so-called oxygen dilemma.22 Thus, spontaneous reaction of O2 (necessary for the monooxygenase reaction) with reduced components of the electron transport chain not only leads to a waste of reducing equivalents due to the decoupling of the regeneration reaction from the oxygenation reaction, but also this decoupling reaction generates reactive oxygen species that can significantly impair enzyme stability. Envisaging more simple and efficient cell-free biocatalytic monooxygenation reactions, a range of direct and indirect electrochemical regeneration approaches have been developed.181,184–189,191,647–656 It should be mentioned here that most of these investigations are still at an early level of development. Unfortunately, almost all studies report superstoichiometric use of the redox mediator and therefore are not yet applicable for preparative purposes.20–22 Most likely this can, again, be attributed to the oxygen dilemma. There are, however, some mediators which are O2 -stable in their reduced form and therefore represent a possible solution to the oxygen dilemma. For example deazaflavins have been demonstrated recently as promising mediators.136,196 Further investigations are currently ongoing. One approach worth mentioning here is the so-called hydrogen peroxide shunt pathway. Here, the catalytically active species within the enzyme is generated directly from hydrogen peroxide547,657,658 or organic peroxides.624,659 Thus, challenges related to the reductive activation of molecular oxygen are elegantly circumvented. However, H2 O2 also is a very reactive oxidant that can irreversibly inactivate enzymes. Thus, either improved enzyme variants have to be generated with an increased resistance towards H2 O2 657 and/or practical in situ H2 O2 generation systems have to be developed controlling H2 O2 levels for high productivity while minimizing inactivation rates. Overall, it can be asserted that enzymatic hydroxylation has a great potential for organic chemistry. At present, this potential is practically only accessible via whole-cell catalysis thereby confining its usefulness for preparative organic chemistry. Improvements in cell-free regeneration of the isolated enzymes are expected to make the wealth of biocatalytic oxyfunctionalization also accessible for the preparative working chemist.

11. Heteroatom oxidations Compared to the oxidation/oxyfunctionalization reactions outlined in this article, heteroatom oxyfunctionalization reactions play a minor role. Mostly, sulfoxidation (of thioanisole) is chosen as an easy model reaction to characterize and optimize reaction parameters. This is astonishing insofar as chiral heteroatom oxides are valuable chiral auxiliaries and building blocks in organic synthesis.660,661 Furthermore, biocatalysis offers an attractive alternative to existing chemical oxygenation technologies, not only from the point of view of stereodiscrimination but also of functional group tolerance and regioselectivity. For example, CHMO catalyzes highly stereoselective oxygenation of aromatic662,663 and aliphatic662 sulfides leaving other functional groups such as nitriles or C C double bonds untouched. 1,3-Dithioacetals are selectively monooxygenated.663 Also enantiocomplementarity can be achieved by suitable choice of the catalyst system.664–666 Green Chem., 2011, 13, 226–265 | 255

Also stereospecific oxygenation of boron,667 tertiary amines,668 and selenides669 have been reported. Especially the latter reaction might represent an interesting access to chiral allyl alcohols (Fig. 44). Unfortunately, using CHMO as catalyst yielded only racemic products and, to the best of our knowledge, this approach was not followed up with other enzymes.

Fig. 44

A chemoenzymatic method to allyl alcohols.

Amongst peroxidases, again CPO is the catalyst of choice for enantiospecific (R)-sulfoxidation of thioanisole and its derivates.197,201,203,221,223,670–676 Cytochrome P450 monooxygenases are also capable of heteroatom oxidation but this activity is hardly exploited for synthetic purposes,677,678 whereas many pharmacological studies on the metabolism of sulfur- and nitrogen-containing compounds (drugs, xenobiotics) by mammalian P450 monooxygenases can be found in the literature.679–681 Very recently, Zhang et al. reported a new self-sufficient bacterial P450 monooxygenase that converted a range of aryl aliphatic sulfides. The corresponding (S)-sulfoxides were obtained with good to high enantiomeric excess.678 However, the applicability of the enzyme on preparative scale still has to be demonstrated.

12. Concluding remarks Organic redox biocatalysis is slowly growing from being a mere lab curiosity. Already today a number of oxidoreductase processes are running on industrial scales where especially selectivity and the absence of similarly efficient chemical catalysts is the ‘key to success’. On the laboratory scale, preparative applications are as-yet far less prevalent. But the scope, as outlined in the current contribution, is significant. Previous limitations such as biocatalyst availability and prices are solved. An ever increasing number of new oxidoreductases are commercialized. Furthermore, the timelines from biocatalyst discovery, via characterization and optimization to heterologous expression at scale are going down from years to several months. Knowledge on how to use oxidoreductases beyond their natural environments and for other reactions than naturally designed is steadily growing. From a preparative point of view the stage is set to let redox biocatalysis become an integrated part of organic chemistry and to overcome the rather artificial distinction between (homogeneous and heterogeneous) chemocatalysis on the one hand and biocatalysis on the other hand. To let this become reality not only more and more intense collaborations between organic chemists 256 | Green Chem., 2011, 13, 226–265

and enzymologists and microbiologists are necessary. For this, a common language and terminology is indispensable. Terms such as ‘efficient’ or ‘stable’ should be used carefully and they should mean the same to a chemist as well as to an enzymologist, only then we will really understand each other correctly. A very interesting advance in this direction was proposed recently.682 From an environmental point-of-view, biocatalysis has a lot to offer. It is true that one benefit of biocatalysis lies in the mild reaction conditions. However, this is not generally true and it is by far not the only gain. Biocatalytic conversions of dilute aqueous substrate solutions take advantage of the benign reaction conditions and the green solvent used. However, these advantages may be easily over-compensated by downstream processing and waste water treatment (let alone industrial attractiveness of such processes). Also a biocatalyst is not per se more ecofriendly than, for example, a transition metal catalyst. The whole picture including catalyst preparation, performance in terms of total turnover, recyclability, and disposal needs to be taken into account. Thus, the green potential of enzymatic oxidation catalysis is immense. However, great care has to be taken when denoting a biocatalytic reaction green or greener than a chemical counterpart. Such statements will only be valid if quantified. At present, studies considering the full environmental impact of a biocatalytic oxidation reaction are few.311,544,683

Acknowledgements This work was financially supported by the Marie Curie ITN ‘Biotrains’ (grant agreement number 238531).

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