Biocatalytic Methods for CC Bond Formation - Wiley Online Library

CHEMCATCHEM REVIEWS DOI: 10.1002/cctc.201200709

Biocatalytic Methods for C C Bond Formation Kateryna Fesko and Mandana Gruber-Khadjawi*[a]

2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Carbon-carbon bond formation is among the most challenging transformations in the organic synthetic chemistry. Enzymes capable to perform this reaction are of great interest. The enzymes for stereoselective C C bond formations have been investigated very intensively during the last two decades. New recombinant DNA technologies have paved the way for im-

proved catalysts and broaden the application scope of the already known enzymes and reactions. On the other side new discoveries have brought more enzyme players in the arena of C C bond formation reactions. Novel enzymatic C C bond formation reactions have been applied, implying the most important benefit of biocatalysis, namely the high selectivity.

Introduction Carbon-carbon bond formation reactions have always built the supreme discipline in synthetic organic chemistry and the same is true for enzyme catalyzed reactions. Although stereoselective C C bond formations catalyzed by enzymes (foremost by lyases) are well established applications,[1–3] novel biotransformations have been reported recently which involves enzymes from other classes.[4–6] In the present review we focus on the latest results regarding optimizations and applications of the well-known enzymes (lyases) and introduce new enzyme discoveries applied in enzymatic carbon-carbon bond formations. The enzymes in this review are classified by the size of chain elongation and the cyclizations that they perform.

Enzymes used for Carbon-Carbon Bond Formation Chain elongation by 3- and 2-carbon units (aldolases)

ters and usually only one isomer is obtained. Over the past years many aldolases have been explored for use as catalysts for the asymmetric synthesis of complex polyfunctional carbohydrates and amino acids.[7, 8] Although the function of aldolases in vivo is often related to the degradative cleavage of metabolites, the reactions are reversible and by choosing the proper conditions synthesis becomes favored. In combination with other enzymatic and chemical transformations aldolasecatalyzed reactions provide a powerful and convenient route to sugars, sugar analogs, glycoprocessing enzyme inhibitors, and carbohydrate probes.[7, 9] Mechanistically, two classes of aldolases can be recognized: 1) Class I aldolases form a Schiff base with the donor substrate and the w-NH2-group of an active site lysine residue attacks the carbonyl of the donor,[8c, 10] 2) Class II aldolases require a metal cofactor such as divalent zinc (sometimes Fe2 + or Co2 + ), which acts as a Lewis acid and activates the nucleophile.[8c] In some cases pyridoxal phosphate (PLP) is required as cofactor, which forms a Schiff base with the amino group of an amino acid substrate, thereby increasing the nucleophilicity of the a-carbon. Aldolases usually show relaxed specificities towards the electrophilic acceptor component, but are quite rigid for the nucle-

The aldol reaction is one of the most powerful tools in organic chemistry used to create carbon-carbon bonds stereoselectively. Natural aldolases catalyze the reversible stereoselective aldol addition of a donor compound nucleophile, which is usually a ketone, to an acceptor compound electrophile, which is an aldehyde. Depending on the nature of the reaction, aldolases belong either to the lyase class of enzymes (EC4) or to the transferase class (EC2).[7] Upon aldol condensation up to two new chiral centers are formed, thus four possible diastereomers can be produced. The reactions catalyzed by aldolases proceed with high levels of stereocontrol at the newly formed chiral cen- Scheme 1. Reactions catalyzed by aldolases and their donors in vivo (I) and conditions for non-physiological synthesis (II). [a] Dr. K. Fesko, Dr. M. Gruber-Khadjawi ACIB GmbH (Austrian Centre of Industrial Biotechnology) c/o Institute of Organic Chemistry Graz University of Technology Stremayrgasse 9, 8010 Graz (Austria) Fax: (+ 43) 316-873-1032410 E-mail: [email protected] Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://chemcatchem.org/open.


ophile donor substrate. Based on the donor specificity aldolases are divided into four main types (Scheme 1): A) dihydroxyacetone phosphate (DHAP) 1 dependent; B) pyruvate 2 dependent or phosphoenolpyruvate 3 dependent, C) acetaldehyde 4 and D) glycine 5 dependent aldolases.[7]

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Scheme 2. The in vivo catalyzed reactions of DHAP-dependend aldolases of synthetic interest and their stereospecificities.

DHAP-dependent aldolases Aldol reactions catalyzed by DHAP-dependent aldolases proceed with formation of two new stereocenters. This type of aldolases is extremely useful in biocatalysis as enzymes synthesizing all four possible stereoisomers with excellent enantioand diastereoselectivity are known (Scheme 2). Fructose-1,6-bisphosphate aldolases (FruA) is the most widely used DHAP dependent aldolase,[8c,d] which catalyzes formation of products with (3S,4R)-configuration. The class I FruA isolated from rabbit muscle (RAMA) is commercially available and most often employed for preparative synthesis. Fuculose1-phosphate aldolases (FucA) and rhamnulose-1-phosphate aldolase (RhuA) generate diol units with (3R,4R)- and (3R,4S)-configurations, respectively.[11] Only tagatose 1,6-bisphosphate aldolase (TagA) gives the (3S,4S) aldol product with lower stereoselectivity. Thus, this enzyme is synthetically not as useful as Kateryna Fesko (Lypetska) studied chemistry at the Moscow State University (Russia). In 2005 she started a PhD project on biocatalysis with threonine aldolases at Graz University of Technology (Austria) under supervision of Prof. H. Griengl. Since 2010 she has been working as a post-doctoral researcher at the Austrian Centre of Industrial Biotechnology (ACIB).

Mandana Gruber-Khadjawi obtained her PhD in Chemistry from Graz University of Technology in 1994 for research on asymmetric synthesis by application of chemo- and biocatalysis. She is researcher and project manager at ACIB GmbH. Her main research interests include biocatalysis and asymmetric synthesis.


other DHAP dependent aldolases. Each aldolase accepts a wide range of aldehyde acceptor substrates, such as unhindered aliphatic and aromatic aldehydes, a-heteroatom substituted aldehydes, monosaccharides, and their derivatives at a synthetically useful rate. Some aromatic, specially hindered aliphatic and a,b-unsaturates aldehydes are not accepted.[12] DHAP-dependent aldolases were applied for the production of nitrogen-containing, deoxy-, fluoro-, and high-carbon sugars.

Optimization of DHAP-dependent aldolases Having a broad substrate range, the application of DHAP dependent aldolases is suffering from their strict donor specificity regarding the expensive and not stable DHAP 1.[7] Moreover, the phosphate group in the product is not always desirable and has to be removed in an additional step. Thus during the last decade the main focus in this area was to find methods for the effective production of 1 or engineering of the enzymes with affinity towards the non-phosphorylated donor. An efficient method for the preparative application of 1 is still essential. Several chemical routes and enzymatic procedures were reported.[13] Among the chemical methods for the production of 1 the use of dihydroxyacetone dimer[14a,b] or 1,3-dibromacetone[14c] are the most frequently applied methods. However, the more popular approach is the application of multi-step enzyme catalysis for which 1 is produced in situ from dihydroxyacetone 10 (Figure 1). To overcome the DHAP 1 dependence of aldolases engineering of reaction conditions by in situ formation of arsenate[17a,b] or borate[18] complexes 14 were reported. These compounds are mimics for phosphate ester (Figure 1 d). This approach was successfully used for the one step synthesis of l-iminocyclitol precursors l-fructose and l-rhamnulose.[18] Recently, a bifunctional aldolase/kinase enzyme has been constructed by gene fusion, which consists of a monomeric FruA and a homodimeric dihydroxyacetone kinase. The fusion protein retains both kinase and aldolase activity and has been applied for the stereoselective C C bond formation starting from 10 as the initial donor and an aldehyde with 20-fold increase in the reaction rate compared to the multi-enzyme system of the free parent enzymes (Scheme 3).[19] Screening for a catalyst that accepts a non-phosphorylated donor gave the novel promising enzyme fructose-6-phosphate aldolase (FSA).[20] The enzyme does not belong to DHAP dependent aldolase group, but it catalyzes similar reactions utilizing 10 as a donor. The enzyme gives aldol products with (3S,4R)-configuration and can be considered as an alternative to FruA. Similar activities were obtained for the designed aldoChemCatChem 2013, 5, 1248 – 1272

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www.chemcatchem.org Asn29Asp was able to accept 10 as a donor, providing a stereocomplementary biocatalyst (3R,4S) to the FSA.[22] Application of DHAP-dependent aldolases

Figure 1. Methods for the in situ DHAP generation.

Scheme 3. Application of a bifunctional aldolase/kinase protein for the stereoselective C C bond formation.

DHAP dependent aldolases were mostly used for the preparation of the rare or unnatural monosaccharides which are known as useful non-nutritive sweeteners, glycosidase inhibitors and as important chiral building blocks for the synthesis of biologically active compounds. One of the most representative examples of the industrial application of DHAP-dependent aldolases is the synthesis of the macrolactone (+)-aspicillin 17 from 4-hydroxybutyraldehyde 15 and 1 using FruA (Scheme 4).[23] The enzymes have been used for the synthesis of rare ketose 1-phosphates, which are further dephosphorylated to produce the free ketosugars.[24] The last can then be converted to aldoses in a chemical or enzymatic (by ketol isomerases) step. The same approach was applied for the synthesis of l-fucose 18 analogs and l-rhamnose 19 from l-8 and its analogs using FucA and RhuA and the corresponding isomerases (FucI and RhaI) (Scheme 5).[10, 25] FSA is a promising catalyst for the preparation of monosaccharides. It has a broad substrate specificity and accepts 10 (but not 1), hydroxyacetone 22, and 1-hydroxy-butanone as donors, and several acceptors like hydroxyaldehydes, glycolaldehydes and their respective phosphorylated forms, which is unusual for aldolases.[26] Using hydroxyaldehydes (e.g. glycolaldehyde 20) allows the enzymatic cross-aldol addition of two aldehydes. Thus aldoses can be synthesized directly (Scheme 6 a).[27] FSA and newly designed TalBF178Y have been applied to the synthesis of deoxysugars using 22 as aldol nucleophile with simple carbonyl compounds or monosaccharides as acceptors (Scheme 6 b).[21c, 27] An improved mutant Ala129Ser with increased affinity towards 10 gave 17-fold improvement compared to the wild-type enzyme for the synthesis of polyhydroxylated compounds.[28] d-Xylulose and d-fructose were synthesized by this process, which was not possible with the wild-type enzyme. The industrial application of FSA was reported for the production of sweetener furaneol 26 from 22 and pyruvaldehyde 24 with in situ dehydration (Scheme 6 c).[29] One of the main applications of DHAP-dependent aldolases and FSA is the synthesis of iminocyclitols (iminosugars). Iminosugars are important compounds for therapeutic use as inhibi-

lase from transaldolase B Phe178Tyr and Phe178Tyr/Arg181Glu (TalBF178Y).[21] A directed evolution approach was successfully applied to engineer enzymes with broad substrate specificity to avoid the use of 1. Thus, after random mutagenesis and a proper selection system, RhuA Scheme 4. Stereoselective aldol synthesis of (+)-aspicillin building block 16 catalysed by FruA. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 8. Synthesis of furanoid 31 using FruA.

Scheme 5. Enzymatic synthesis of l-fucose 18 a and its analogs 18 b–d, and l-rhamnose 19.

Scheme 6. Synthesis of a) d-threose, b) 1-deoxy-d-ido-hept-2-ulose, and c) furaneol using FSA.

thiolated aldehydes[34] as well as some phosphonated sugars using a bioisosteric methylene phosphonate analog of 1 as donor.[15b, 35] Moreover, RAMA was used for the synthesis of five- and six-membered carbocycles.[36] New nitrocyclitols (e.g. 33) and aminocyclitols were stereoselectively synthesized in a one-pot/two-enzyme process whereby three reactions took place: RAMA-catalyzed aldolization, phytase-catalyzed phosphate hydrolysis, and intramolecular spontaneous nitroaldolization.[37] The nitro group can be reduced to give an analog of valiolamine 34, a natural inhibitor of g-glycosidases (Scheme 9). Recently, rare sugars such as d-psicose, d-sorbose, l-tagatose, and l-fructose were prepared with the l-fuculose-1-phosphate aldolase (FucA) from a thermophilic source in a one pot/ four enzymes approach starting from rac-glycerol-3-phosphate 12 and d- or l-glyceraldehyde.[38]

tors of glycosidases, glycosyltransferases and metalloproteinases.[30] The substrates are azido aldehydes and a-protected amino aldehydes 27, whereas the donor is 1 (or 10 for FSA) (Scheme 7). Using different DHAP-dependent aldolases, diastereomeric piperidine- and pyrrolidine derived iminocyclitols 29 Scheme 9. Synthesis of the aminocyclitol 34 analog of valiolamine using FruA. were prepared in good yields.[31] Stereoselectivity at C3 of iminosugars is controlled by the enzyme, however stereoselectivity at C4 deThe pyruvate- and phosphoenolpyruvate-dependent pends on the acceptor aldehyde used and could be manipulataldolases ed by choosing an enzyme or performing the reaction under Pyruvate-dependent aldolases mostly have a catabolic function kinetic control.[30b] Moreover, the conversions and diastereosein the degradation of sialic acids, or more general hexoses and lectivities depend on the nature of the protecting group and pentoses. Hence, the equilibrium is shifted towards retro-aldol the best results were obtained for the benzyloxycarbonyl (Cbz) side and synthetic reactions are usually driven by an excess of group.[32] The solubility of the substrates and conversions were improved by using water-in-oil emulsions.[32b] pyruvate 2 to achieve satisfactory conversions. The most famous members of this aldolase class are N-acetylneuraminic Aldolase-catalyzed bidirectional chain elongation of simple, acid aldolase (NeuA), 2-keto-3-deoxy-manno-octosonate aldoreadily available dialdehydes was developed into an efficient lase (KdoA), 2-keto-3-deoxy-6-phosphogluconate aldolase method for the production of several C-linked disaccharide (KDPG), and 3-deoxy-d-arabinose-heptulosonic acid 7-phosmimics and higher carbon sugar analogs (e.g. furanoids 31) by phate synthase (DAHP) (Scheme 10). The latter utilizes phosa simple one-pot procedure.[33] A single diastereomer can be phoenolpyruvate 3 instead of 2, which upon C C bond formaobtained through thermodynamic reaction control (Scheme 8). tion releases the inorganic phosphate and thus renders the Besides these examples DHAP-dependent aldolases have aldol addition essentially irreversible.[7] been used for the preparation of thiosugars from 2- and 3NeuA (sialic acid) aldolase catalyzes the synthesis of sialic acid 36 from 2 and N-acetylmannosamine (ManNAc) 35 and is the most intensively investigated enzyme among pyruvatedependent aldolases. The Scheme 7. Chemo-enzymatic synthesis of iminosugars 29. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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www.chemcatchem.org C4 only if a bulky protecting group is introduced into the substrate. After substrate engineering and the use of the structurally rigid glyceraldehyde acetonide instead of glyceraldehyde, KDG aldolase is able to induce stereocontrol into the aldol reaction.[45b] Recently, trans-o-hydroxybenzylidenepyruvate hydratase-aldolase (tHBP-HA) was isolated from bacteria and tested for the production of a,b-unsaturated carboxylic acids conjugated to an aromatic ring starting from 2 and an aldehyde, for example, salicylaldehyde 42 or benzaldehyde 67 (Scheme 11 a).[46] The SanM aldolase and an enzyme possessing the 4-hydroxy-3methyl-2-oxopentanoate aldolase activity (HPAL) were reported to accept 2-oxobutanoic acid 45 as aldol donor (Scheme 11 b).[47]

Scheme 10. The in vivo catalyzed reactions of pyruvate-dependent aldolases of synthetic interest and their stereospecificities.

enzyme has broad acceptor specificity towards sugar derivatives, including pentoses, hexoses, aminosugars, neutral monosaccharides, and some disaccharides.[39] Variations in the substrate include replacement of the natural d-manno configured substrate with derivatives containing modifications at positions C2, C4, or C6, as well as C5 and C9 modified N-acetylated derivatives. The N-acetyl group may also be either omitted or replaced by sterically demanding substituents such as N-Cbz without destroying the activity.[7, 39, 40] Only 2 and fluoropyruvate are accepted by NeuA as donors.[41] Stereospecificity in the aldol reaction catalyzed by NeuA usually depends on the acceptor substrate used and is controlled thermodynamically. KDO aldolase catalyzes the reversible condensation of 2 with d-arabinose 37 to form KDO 38. Besides the natural substrate, it accepts also trioses, tetroses, pentoses and hexoses. The enzyme prefers the substrates with (R)-configuration at C3 and gives rise to products with (R)-configuration at the newly formed center.[42] KDPG and KDPGal aldolases are stereocomplementary enzymes and catalyze the condensation of 2 with d-glyceraldehyde 3-phosphate 6 to form KDPG (4S)-39 or KDPGal (4R)-39 respectively.[43] Both enzymes are very specific for the natural phosphorylated acceptor. Several polar short-chain aldehydes can be accepted at reduced rates, whereas simple aliphatic and aromatic aldehydes are not accepted as substrates.[44] In contrast to other pyruvate aldolases, KDPG aldolase operates under kinetic control, providing access to the product with (S)configuration at C4, whereas KDPGal gives products with (4R)configuration. There are a few pyruvate dependent aldolases that do not use phosphorylated substrates, like 2-keto-4-hydroxyglutarate (KHG) and 2-keto-3-deoxy-d-gluconate (KDG) aldolases. These enzymes accept other derivatives of 2, such as a-ketobutyrate and bromopyruvate as donor substrates, however they show no diastereoselectivity for the natural substrate.[45] The KDG aldolase produces the ulosonic acids with high (S)-selectivity at 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Scheme 11. The in vivo catalyzed reactions of novel pyruvate-dependent aldolases.

BphI and HpaI are two pyruvate dependent class II aldolases that catalyze the reversible aldol cleavage of 4-hydroxy-2-oxopentanoate 47 and 4-hydroxy-2-oxo-1,7-heptanedioate 49 to 2, and acetaldehyde 4 or succinic semialdehyde 48, respectively (Scheme 11 c,d).[48a,b] Both aldolases are able to catalyze aldol addition reactions between 2 and aldehyde acceptors two to five carbons in length. HpaI is able to accept 2-ketobutanoate besides 2 as a carbonyl donor. However this enzyme does not show stereospecificity in the aldol reactions, whereas BphI gives only products with an (S)-configuration at C4.[48b]

Optimization of pyruvate- and phosphoenolpyruvate-dependent aldolases To overcome the limitation of unfavorable equilibrium in the aldol reactions catalyzed by pyruvate dependent aldolases, an excess of 2 is usually applied. In the transformations with NeuA shifting of the equilibrium was achieved by coupling the reaction with a sialyltransferase to produce sialyloligosaccharides.[49] Another approach was to introduce a mixture of 35 and N-acetylglucosamine (GlcNAc) for which the latter can be epimerized to 35 by chemical[50] or enzymatic means.[51] ChemCatChem 2013, 5, 1248 – 1272

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The substrate specificity of NeuA is limited to C5 and C6 aldehydes, whereas short aldehydes are poor acceptors. To optimize NeuA aldolases for other substrates directed evolution approaches were applied and the novel designed enzymes were used for the synthesis of potent influenza inhibitors like zanamivir,[51d] as well as tertiary amides[52] and different sialic acid mimetics 52 with high stereoselectivity, which can be switched by using a proper mutant (Scheme 12).[53]

Scheme 12. Parallel synthesis of sialic acid mimetics using a sialic acid aldolase variant. EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt = 1-hydroxy-benzotriazole hydrate.

Application of pyruvate- and phosphoenolpyruvate-dependent aldolases The pyruvate- and phosphoenolpyruvate-dependent aldolases are widely used for the synthesis of sugar acids, such as 36 and analogs, and short chain ulosonic acids.[5, 12] Recently it was found that NeuA can accept a variety of donor and acceptor substrates. This observation was used for the effective preparation of novel glycosylated sialic acids using disaccharides 54 as acceptors (Scheme 14).[59] Azasugars analogs of 36 were synthesized using 3-deoxy-3-azido analogs of 35, mannose, and glucosamine as acceptor substrates with NeuA.[8b, 60] The enzyme was also used for the production of 8-O-methylated sialic acids from the corresponding 5-O-modified six-carbon monosaccharides and 2.[61] Moreover, analogs of 2, such as fluoropyruvate can be accepted by NeuA as a donor to produce 3-fluorinated sialic acid derivatives.[41] In most cases (4S)-configurated products are obtained. The preparative application of KDO enzyme for the aldol synthesis suffers from the unfavorable equilibrium and attempts were mainly focused on the preparation of 38 analogs.

Using a directed evolution approach, NeuA was evolved to accept l-arabinose l-37 in order to alter the substrate specificity and to invert enantioselectivity. An efficient l-KDO aldolase variant was created by this means.[54] Scheme 14. Synthesis of glycosylated sialic acids using NeuA catalyzed reactions. KDPG aldolase from E.coli was mutated towards improved acceptance of non-phosphorylated and lconfigured substrates for the enzymatic synthesis of KDPG, KDPGal, and KDG aldolases were applied for the proboth d- and l-sugars.[55] KDPGal aldolase activity was improved duction of short chain ulosonic acids with high stereoselectivin the synthesis of 3-deoxy-d-arabinose-heptulosonic acid 7ity.[43, 44, 62] Thus, two enantiomers of the N-terminal amino acid phosphate (DAHP) 41 and was incorporated into a whole cell process for the synthesis of 3-dehydroshikimate 53 moiety 56 of the Nikkomycin antibiotics were synthesized (Scheme 13).[56] The KDPG was also evolved to recognize the from 2-pyridinecarboxaldehyde 44 using KDPG and KDPGal (Scheme 15).[44b] DAHP synthase has been applied for the large scale production of vanillin from glucose.[5]

Acetaldehyde dependent aldolases

Scheme 13. Application of KDPGal aldolase variant for the whole-cell production of 3-dehydroshikimate 53.

long chain acyl substrate 2-keto-4-hydroxyoctanoate.[57a] The double mutation T161S/S184 L in KDPG from E.coli enhanced the substrate specificity up to 450-fold towards hydrophobic substrates, for example, 2-pyridine carboxaldehyde.[57b] Double variants L87N/Y290F and L87W/Y290F of BphI aldolase were constructed and the resulting muteins showed reversed stereospecificity, exclusively utilizing (4R)- and not (4S)-47 as the substrate.[58]

2-Deoxy-d-ribose 5-phosphate aldolase (DERA) is the only known acetaldehyde dependent aldolase. DERA catalyzes the reversible condensation of acetaldehyde 4 and d-glyceraldehyde 3-phosphate d-6 to form d-2-deoxyribose 2-phosphate d-57 (Scheme 16). Interestingly, DERA catalyzes reactions for which both substrate and product are aldehydes, which is unusual among aldolases (with the exception of FSA). DERA accepts a number of unnatural aldehydes with up to four carbon atoms, and generates (R)-configured chiral centres.[7, 63] Propa-

Scheme 15. Synthesis of Nikkomycin K precursors using KDPG and KDPGal.


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www.chemcatchem.org acetone as donors.[63b] DERA was applied for the production of various purine- and pyrimidine-containing deoxyribonucleosides in a multienyzmatic industrial process.[63c]

Scheme 16. The in vivo catalyzed reactions of 2-deoxy-d-ribose 5-phosphate aldolase.

nal, acetone and fluoroacetone can replace 4 as the donor in the synthesis of variously substituted 3-hydroxyketones.[63c] Optimization of acetaldehyde dependent aldolases The optimization of the DERA-catalyzed reactions is focused on enzyme engineering towards increased substrate specificity. Thus, using structure-based mutagenesis DERA was evolved to accept non-phosphorylated substrates.[64] The mutation Ser238Arg showed significant influence on the substrate scope of DERA from E.coli and allowed the synthesis of azide derivatives. After optimization of the wild-type enzyme by directed evolution, the activity towards non-natural and toxic substrate chloroacetaldehyde 59 was improved for the synthesis of atorvastatin intermediate 60.[65]

Glycine dependent aldolases Glycine-dependent aldolases catalyze the reversible aldol reaction of glycine 5 with an aldehyde acceptor to form b-hydroxya-amino acids. The two known members of this group, serine hydroxymethyltransferase (SHMT)[69] and threonine aldolase (ThrA),[70] require PLP as cofactor for their activity. ThrAs play an essential role in the metabolism of the cells and catalyze the cleavage of threonine 64 to produce acetaldehyde 4 and 5 (Scheme 18). ThrAs are highly selective for the a-carbon of 64

Application of acetaldehyde dependent aldolases DERA is applied for the synthesis of deoxysugars, such as 2deoxy, dideoxy, trideoxy, thio, and azasugars.[66] The ability of the enzyme to catalyze cross-aldol addition reactions of two aldehydes makes DERA an important catalyst for the synthesis of building blocks of some anticancer drugs. Thus, the sequential asymmetric aldol addition reaction of three molecules of 4 forms (3R,5R)-2,4,6-trideoxyhexose 58 in a good yield (Scheme 17 a).[63a] The combination of two molecules of 4 with chloroacetaldehyde 59 results in (3R,5S)-6-chloro-2,4,6-trideoxyhexose 60, which is a precursor for statins (e.g. atorvastatin— a cholesterin lowering drug) (Scheme 17 b).[64, 67] When a- or bhydroxyaldehydes 8 or 62 are used as substrate, respectively, useful synthons of 1,3-polyols 61 and 63 are formed.[68a] The same strategy was applied for the synthesis of pyranose building blocks, that are intermediates of the anticancer agents epothilones A and C (Scheme 17 c).[68] Iminocyclitols were also prepared using DERA-catalyzed aldolization of 3-azido-2-hydroxypropanal as acceptor and 4 or

Scheme 18. The in vivo catalyzed reactions of glycine-dependend aldolases and their stereospecificities.

and thus l- and d-specific ThrAs have been recognized. The different selectivities at the b-position for l-ThrA result in either l-, l-allo- or l-low-specificity ThrA. The last type does not show any selectivity. Only d-low specificity ThrA have been found in nature so far. SHMT is a folate-dependent enzyme and catalyzes the synthesis of 5 from serine 66 in vivo (Scheme 18). In the absence of tetrahydrofolate SHMT also catalyzes reactions similar to lThrA, such as retroaldol cleavage of l-64 and other b-hydroxy-a-amino acids.[71] Recently a reaction mechanism was proposed for the folate-independent aldol reactions catalyzed by SHMT.[69c] Besides natural substrates, ThrA and SHMT accept a wide range of aliphatic (up to ten carbon atoms) and aromatic aldehydes as acceptor in the aldol reaction to produce enanScheme 17. Application of DERA-catalyzed reaction for the synthesis of useful synthons. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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CHEMCATCHEM REVIEWS tiopure b-hydroxy-a-amino acids.[71–73] Best substrates are aldehydes with electron-withdrawing groups.[73, 74] In general, the reactions proceed with complete stereocontrol at the a-carbon of the product, whereas a mixture of syn and anti diastereomeres is usually obtained. Optimization of glycine dependent aldolases The main drawbacks in the application of glycine depended aldolases are unfavorable reaction equilibrium position and low selectivity at b-carbon of the formed b-hydroxy-a-amino acids leading to the thermodynamic mixture of syn/anti isomers. The yields for the direct synthesis strongly vary with the aldehyde used and can be improved by using an excess of 5.[70d] The combination of ThrA catalyzed reaction with an irreversible step (e.g. decarboxylation) shifts the equilibrium towards product side and improves the yields. Thus, the tandem use of the l-low specificity ThrA from Pseudomonas putida and high selective l-tyrosine decarboxylase from Enterecoccus faecalis in the one pot/two enzyme system leads to the quantitative conversion of benzaldehyde 67 and the low b-carbon selectivity was improved yielding enantioenriched (R)-2-amino-1-phenylethanol (R)-69 (ee 77 %) (Scheme 19).[75] Diastereoselectivity can also be manipulated in a kinetic mode of reaction.[74] Thus products with high diastereoselectivity are obtained in a short reaction time[74, 76] or by lowering the reaction temperature.[73a] The reaction protocol at industrial scale was further improved by employing a whole-cell, high-density bioreactor, as it was shown for the synthesis of l-syn-3,4-dihydroxyphenylserine (DOPS).[77] Moreover, the diastereoselectivity of l-low specificity ThrA from S. coelicolor was improved using directed evolution to produce l-syn-DOPS with 55 % de.[78] The product range of glycine dependent aldolases was limited to b-hydroxy-a-amino acids for a long time, owing to the high specificity of the enzymes to the donor component accepting only 5. However, using the screening methodology of the natural enzymes towards novel substrate specificities new SHMTs and ThrAs were found which accept other amino acids

www.chemcatchem.org than 5 (e.g. alanine, serine or cysteine) as donor to produce valuable a,a-disubstituted b-hydroxy-a-amino acids.[79] Application of glycine dependent aldolases Glycine-dependent aldolases are mostly applied for the stereoselective production of multi-functional b-hydroxy-a-amino acids 70, which are components of many complex natural products such as antibiotics and immunosuppressants.[80] The excellent enantiospecificity of a ThrA was successfully exploited for the kinetic resolution of a racemic mixture of chemically produced DL-syn-70 (Scheme 20).[81] The applications of natural

Scheme 20. A chemo-enzymatic process for the synthesis of optically pure b-hydroxy-a-amino acids.

aldolases in this aspect include the resolution of aryl serines by l-ThrA, a DOPS precursor and resolution of the racemic 4methylthio-phenylserine (MTPS) by d-ThrA. The products are usually obtained in quantitative yields and almost 100 % ee and de. The direct asymmetric synthesis starting from an aldehyde and 5 was also exploited for the preparative synthesis of 70. Thus, using highly selective d-ThrA from Alcaligenes xylosoxidans the d-syn-phenylserine d-syn-68 and its derivatives can be obtained with excellent selectivity (ee > 99 %, de up to 95 %) under kinetic reaction control.[73] l-allo-TA from the yeast Candida humicola has been used for the direct aldol synthesis of (S,S,R)- and (S,S,S)-3,4-dihydroxyprolines,[82] Polyoxin analogs[72b, 83] and for the preparation of a chiral building block towards the synthesis of the immunosuppressive lipid mycestericin D.[76, 84] Further, the first enantioselective synthesis of iminodigitoxose and imino-deoxydigitoxose was reported using this enzyme.[83b] The l-ThrA from E.coli has been applied for the synthesis of polyfunctional w-carboxy-bScheme 19. Synthesis of 2-amino-1-phenylethanol 69 using l-threonine aldolase and l-tyrosine decarboxylase in hydroxy-l-a-amino acids 72,[85] tandem. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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CHEMCATCHEM REVIEWS and l-syn-b-hydroxy-a,w-diamino acid derivatives (Scheme 21).[71] The yield and stereoselectivity were improved by elegant medium engineering. Moreover SHMT from Streptococcus thermophilus catalyzes the same reactions, but gives diastereocomplementary l-anti products. Further derivatization of the product compound allows fast separation of the two diastereomers.[72]

Scheme 21. Synthesis of w-carboxy-b-hydroxy-l-a-amino acids 72 using lThrA from E.coli.

SHMT was also used to produce a range of l-70 compounds as diastereomeric mixtures from 5 and several aldehydes.[86] SHMT from Klebsiella aerogenes and E.coli have been applied for the industrial biocatalytic synthesis of l-66 starting from formaldehyde 65 and 5.[87] It was employed for the synthesis of l-anti-2-amino-3-hydroxy-1,6-hexane dicarboxylic acid, a potential precursor for carboxylic b-lactams and nucleotides.[88] The SHMT with a broad donor specificity was named a-methylserine aldolase and was applied for the synthesis of abranched amino acids from 65 and l-alanine l-73 a or l-2-aminobutyric acid.[79b,c] l-allo-ThrA from Aeromonas jandaei and d-ThrA from Pseudomonas sp. were found to possess broad donor specificity and to catalyze the aldol condensation of d-amino acids (alanine 73 a, serine 73 b and cysteine 73 c) with a range of aldehydes to form a-substituted-b-hydroxy-a-amino acids 74, which are difficult to obtain by standard chemical methods (Scheme 22).[79a] The products are obtained with excellent enantioselectivity (eeL > 99 % for LTA, eeD > 99 % for DTA) and moderate diastereoselectivity (de up to 90 %). Applying the bi-enzymatic protocol by using l-ThrA from Pseudomonas putida and l-tyrosine decarboxylase from Enterococcus faecium in a one pot synthesis, a range of aromatic 1,2-

www.chemcatchem.org amino alcohols 76 which are important chiral building blocks of numerous drugs were synthesized starting from the corresponding aldehydes 75 and 5 (Scheme 23).[89] Enantioenriched (S)-octopamine and (S)-noradrenaline were successfully produced using this protocol. Aldol reactions as promiscuous activity The lipase from Candida antarctica CALB and its variant Ser105Ala were the first examples of hydrolase-catalyzed aldol addition of aliphatic aldehydes (propanal and hexanal).[90] Several lipases have the ability to catalyze asymmetric aldol reactions in water.[91] The lipase from porcine pancreas (PPL) and pepsin catalyze the asymmetric aldol reaction between acetone and 4-nitrobenzaldehyde in the presence of water, and the product was obtained with a remarkable enantioselectivity (ee 50 %) and high yield.[91b] A cysteine protease chymopapain, nuclease p1, alkaline protease BLAP and acidic protease AUAP display promiscuous activity to catalyze the direct asymmetric aldol reaction of aromatic and heteroaromatic aldehydes with cyclic ketones 77 (Scheme 24).[92]

Scheme 24. Promiscuous aldolase activity of proteases.

Recently promiscuous aldolase activity was found for the enzyme macrophomate synthase (MPS), which catalyzes the addition of pyruvate enolate derivative 80 diastereoselectively to a wide range of structurally complex aldehydes to produce various 3-deoxysugars. The advantages of this promiscuous aldol reaction over known pyruvate aldolases is the broad substrate spectrum, which can accept differently protected sugars and yield products, which can further be selectively manipulated downstream in a chemical synthesis (Scheme 25).[93] A promiscuous aldolase activity was reported for the enzyme 4-oxalocrotonate tautomerase (4-OT) to catalyze the aldol condensation of acetaldehyde with benzaldehyde to form cinnamaldehyde. This low-level aldolase activity was improved 16-fold Scheme 22. Aldol synthesis of a-alkyl-b-hydroxy-a-amino acids 74 using l- or d-threonine aldolase. with a single point mutation.[94] A single point mutation Tyr265Ala at PLP-dependent alanine racemase from Geobacillus stearothermophilus enhanced the promiscuous activity and the enzyme was able to catalyze reactions similar to that of dthreonine aldolase with the Scheme 23. Bi-enzymatic stereoselective synthesis of aminoalcohols 76. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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www.chemcatchem.org

Scheme 25. MPS-catalyzed synthesis of 2-keto-3-deoxy-d-glycero-d-galacto-nonulosonic acid (KDN) 82.

83. The addition of a second aldehyde 86 to the “active aldehyde” yields 2-hydroxy ketones 87 (Scheme 26). Pyruvate decarboxylase (PDC) was the first enzyme found to catalyze the acyloin reaction. The synthetic application of this reaction increased enormously as it became evident, that the enzymes accept simple aldehydes as substrates instead of ketoacids (Scheme 27).[99a] Very recently a detailed mechanistic study on PDC from yeast was reported.[99b] Benzoylformate decarboxylase (BFD) shows a broader substrate range. While acetaldehyde as the acceptor substrate yields (S)-configured products, aromatic aldehydes lead to (R)-hydroxy ke-

rates and substrate specificities comparable with the native enzyme.[95]

Chain elongation by 2-carbon units

Scheme 27. Acyloin condensation of benzaldehyde and acetaldehyde catalyzed by PDC.

ThDP- and TPP-dependent enzymes Acyloin condensation catalyzed by thiamine diphosphate (ThDP)-dependent enzymes is an enzymatic C C bond formation tool which leads to stereoselective formation of diverse 2-hydroxyketones via decarboxylation.[96–98] The activation step is deprotonation of the cofactor ThDP 83 at C-2 to form the ylide in the active site of the enzyme as an effect of conformational and electrostatical interactions. In the first step the carbonyl group of 85 reacts with the ylide form of ThDP 83 and the 2-hydroxy acid adduct is built. After CO2 release the active aldehyde is formed which upon protonation releases the corresponding aldehyde 84 and restores to ylid

Scheme 26. Proposed mechanism for ThDP-dependent enzyme catalyzed acyloin condensation.


Scheme 28. BAL catalyzed asymmetric acyloin formation.

tones.[100] Benzaldehyde lyase (BAL) shows the broadest range for aromatic donor substrates and is enantiocomplimentary to BFD (Scheme 28).[101] Further ThDP-dependent enzymes in acyloin condensation reactions are phenylpyruvate decarboxylase[102] and indole-3-pyruvate decarboxylase.[103] The first example of an enzymatic cross-coupling reaction between an aldehyde and a ketone was performed by using a thiamine diphosphate-dependent enzyme (Scheme 29).[104] The range of acceptor substrates is very broad including cyclic and openchain ketones, diketones, a- and b-ketoesters. An enzymatic Stetter reaction was reported for a ThDP-dependent enzyme. In contrast to the enzyme from Yersinia pseudotuberculosis YerE, PigD another ThDP-dependent enzyme from Serratia marcescens did not catalyze the formation of 1,2-adducts with ketones as acceptor substrates. Instead 1,4-selectivity was observed with a,b-unsaturated ketones (ee values > 99 %). In the case of aldehydes as acChemCatChem 2013, 5, 1248 – 1272

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www.chemcatchem.org Application of ThDP- and TPP-dependent enzymes

Scheme 29. Enzymatic cross coupling reaction for the preparation of tertiary alcohols.

The ThDP-dependent enzymes have found applications in many synthetically valuable reactions such as benzoin condensation,[101a, 113] asymmetric cross-benzoin condensation,[101b,c] racemic resolution of 2-hydroxyketones,[114] synthesis of bis(2-hydroxy ketones)[100] and homocoupling of aliphatic aldehydes.[115] Transketolases of ThDP- and TPP-dependent enzymes

Scheme 30. PigD catalyzed acetylation of a a,b-unsaturated ketone (1,4-addition).

Transketolases (TKs) catalyze in vivo the reversible transfer of the hydroxyacetyl group from d-xylulose 5-phosphate 95 to dribose 5-phosphate 96 and generates d-sedoheptulose 7-phosphate 97 and d-glyceraldehyde 3-phosphate 6. The new built stereogenic centre (C3) has (S)-configuration (Scheme 31). Transketolases require the cofactor thiamine pyrophosphate (TPP) and Mg2 + for their activity.

ceptors both enzymes catalyze 1,2-addition reactions (Scheme 30).[105] The ThDP-dependent enzyme 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase (MenD) from E.coli, which catalyzes the decarboxylation of a-ketoglutarate and the following addition of succin- Scheme 31. The in vivo catalyzed reaction of transketolases. yl to isochorismate, was tested A wide range of non-phosphorylated, as well as phosphoryas a C C-bond formation catalyst. Condensation of a-ketoglulated hydroxyaldehyde acceptors can be used, however the tarate after decarboxylation to a broad range of aldehydes enzyme is strictly specific towards (R)-configuration of the acgave a-hydroxyketones with yields up to 87 % and ee values ceptors, thus only d-threo (3S,4R) ketoses can be obup to 98 % for aromatic aldehydes. In the condensation of atained.[10, 116] The best substrates are a-hydroxyaldehydes and ketoglutarate and pyruvate inverted regioselectivity was [106] obtained. aldoses. Transketolases can accept xylulose 5-phosphate 95, sedoheptulose 7-phosphate 97, fructose 6-phosphate and hydroxypyruvate (HPA) 99 as donor substrates. When HPA is Optimization of ThDP- and TPP-dependent enzymes used, its decarboxylation and loss of carbon dioxide renders the overall condensation reaction irreversible. Thus, this donor Introducing an A28S mutation into BAL from Pseudomonas fluorescens allows the enzyme to decarboxylate benzoylis frequently applied for the asymmetric synthesis catalyzed by formate.[107] transketolases. The carboligase activity of the BFD enzyme from Pseudomonas putida has been increased 5-fold after several rounds of diOptimization of transketolases rected evolution.[108] Studies revealed L461 as a hot spot for The application of transketolases was limited, owing to limited stereoselectivity in BFD. Exchange to alanine and glycine reavailability of the catalyst and expense of the donor substrate sulted in variants that catalyze the (S)-stereoselective addition HPA. The donor can be produced in situ from serine using of larger acceptor aldehydes, such as propanal with benzaldea serine hydroxygenase. A robust and scalable synthetic procehyde and its derivatives, which are not catalyzed by the wilddure for the production of hydroxypyruvate 99 has been detype enzyme.[109] Benzoylformate decarboxylase from Pseudoveloped recently.[117] The use of transketolases has been facilimonas putida was engineered and some of the variants showed improved decarboxylation activity toward 2-ketohexatated by recombinant protein expression and the large-scale noate, 2-ketopentanoate and 2-ketobutanoate.[110] The formasynthesis of ketol donors. TK variants with improved activities towards non-natural substrates like propionaldehyde,[118] nontion of (S)-2-hydroxy-1-(2-substituted-)phenyl propan-1-one [111] was performed by BFD variants L476Q and M365L/L461S. phosphorylated aldehydes,[119] linear and cyclic aliphatic aldehydes[120] have been obtained by directed evolution. For the synthesis of 2-hydroxypropriophenone (HPP) with enhanced enantioselectivity (up to 80 %) reaction engineering was applied next to mutagenesis. Reactions performed at high Application of transketolases benzaldehyde concentrations and high pressure conditions showed increase in (R)-2-HPP formation catalyzed by BFD varTransketolases give similar products to those obtained by aldoiants F464I, A460I, A460I/F464I.[112] lase-catalyzed reactions. DHAP-dependent aldolases, such as 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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CHEMCATCHEM REVIEWS FruA, and transketolases are complementary tools for the enzymatic synthesis of monosaccharides and analogs, but need different starting materials.[121] Thus, choose of the appropriate catalyst depend on the availability of the corresponding acceptor substrate. FruA creates two asymmetric centres, while only one asymmetric centre is created by a transketolase. The products have the same stereoconfiguration. The main advantage of TK over FruA is the acceptance of non-phosphorylated substrates, thus the additional step of dephosphorylation is not required. Moreover, the use of HPA as a donor shifts the equilibrium to the product side due to the decarboxylation step (Scheme 32).

www.chemcatchem.org Chain elongation by 1-carbon unit Hydroxynitrile lyases Enzyme catalyzed methods for the preparation of chiral cyanohydrins are applied frequently[127] and show higher enantioselectivities compared to chemical methods. Hydroxynitrile lyases (HNLs) catalyze the reversible formation of cyanohydrins (Scheme 34) from HCN and aldehydes or ke-

Scheme 34. Cyanohydrin formation (R1 = acyclic, cyclic, aromatic and heteroaromatic hydrocarbons, R2 = H, alkyl)

Scheme 32. Application of transketolase catalyzed reactions with hydroxypyruvate as donor.

The alternative stereoselective synthesis of ulosonic acids KDO and 3-deoxy-d-arabino-2-heptulosonic acid (DAH) - potential antibacterial and herbicide agents - was performed using RAMA and TK respectively, staring from a-hydroxyaldhehydes as substrates and DHAP (for RAMA) or HPA (for TK) as donor.[121b] The stereospecific C2 elongation catalyzed by TK has been used for the synthesis of various chiral products, such as fructose analogues and other monosaccharides, as well as azasugars.[116, 121, 122] It is often applied in multi-enzyme approaches for the synthesis of sugars, for example, d-xylulose 5phosphate 95 starting from DHAP 1 and hydroxypuruvate 99 with triosephosphateisomerase and recombinant transketolase (Scheme 33).[122b, 123, 124] The synthesis of d-xylulose 5-phosphate 95 was performed before by Fessner and co-workers starting from fructose-1,6-diphosphate 7 as the substrate for fructose diphosphate aldolase.[125a] The new approach with transketolase became an attractive alternative compared to the aldolase method because meanwhile dihydroxyacetone phosphate 1 can be synthesized efficiently[125b] and converted to glyceraldehyde 3-phosphate 6 using triosephosphate isomerase. In another study a transketolase was used for the preparation of a,a’-dihydroxyketones.[126]

tones. HNL from almonds was the first hydoxynitrile lyase to be isolated and characterized[128] and ever since used for the preparation of enantiomerically enriched (R)-cyanohydrins from aromatic and aliphatic aldehydes. The first (S)-selective hydroxynitrile lyase was detected in 1960 in millet seedlings.[129] Today, a broad spectrum of both (R)- and (S)-selective hydroxynitrile lyases is available.[130] A wide range of substrates is accepted and some of the enzymes can be obtained in large quantities by overexpression which made synthetic applications in industrial scale possible. (R)-Selective HNLs

The natural substrate of hydroxynitrile lyase from Rosaceae (e.g. Prunus sp.) is (R)-mandelonitrile.[131] (R)-HNL is used for the synthesis of cyanohydrins from aliphatic, unsaturated, aromatic and heteroaromatic aldehydes as well as ketones.[132] Utilizing the natural source, unpurified almond meal in organic solvents with small amounts of aqueous phase (4 %), provides products with ee values of up to 99 %.[133] (R)-HNL from apple seed meal accepts sterically hindered aldehydes (e.g. pivalaldehyde) as substrates with ee values better than 90 %.[134] A (R)-hydroxynitrile lyase was reported for the catalysis of the asymmetric synthesis of d,e-unsaturated cyanohydrins with yields 70 % and ee values up to 98 %.[135] The same HNL was reported to be active for sterically demanding aromatic aldehydes like 3phenoxybenzaldehyde leading to good yields and very good selectivities.[136] Nowadays recombinant PaHNL (HNL from Prunus amygdalus) is available from the yeast Pichia pastoris.[137] The crystal structure of this enzyme was resolved by the Kratky group in 2001.[138] The knowledge about crystal structure and the expression of recombinant PaHNL paved the way for the preparation of variants for specific applications by enzyme engineering. Solis and coworkers reported the addition of cyanide to imines, prepared from substituted aromatic aldehydes and aniline catalyzed by HNL from mamey. The obtained a-amino nitriles show moderate enantioselectivity (23 % ee).[139] The substrate scope of PaHNL regarding ketones ranges from acyScheme 33. Two step synthesis of d-xylulose 5-phosphate from d-fructose1,6-bisphosclic aliphatic ketones, methyl phenyl ketones, to phate using FruA and transketolase. 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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CHEMCATCHEM REVIEWS cyclic, bicyclic, and heterocyclic compounds and silicon-containing compounds.[140, 157] Another class of (R)-selective hydroxynitrile lyases (LuHNL) has been isolated from flax (Linum usitatissimum).[141] Using this enzyme, it is possible to synthesize (R)-butan-2-one cyanohydrin with an enantiomeric excess (ee) up to 88 %. This is remarkable, owing to the relatively small steric difference between the methyl and ethyl groups in the neighborhood of the carbonyl functional group of the substrate 2-butanone. LuHNL catalyses the addition of HCN to various aliphatic ketones and aldehydes, while aromatic ketones were reported not to be converted.[142] In 2007, Roberge and coworkers reported the conversion of aromatic ketones to optically active cyanohydrins by LuHNL with inverted stereoselectivity ((S)products were obtained).[143] Meanwhile also LuHNL with high specific activity is produced recombinantly.[144] PhaHNL from Phlebodium aureum built the third class of (R)specific HNLs, with (R)-mandelonitrile as its natural substrate. The enzyme is suitable for synthesis of (R)-cyanohydrins in organic media.[145] In 2006, Han and coworkers reported about a (R)-HNL found in the defatted seed meal of vetch (Vicia sativa a Fabaceae). Under micro-aqueous conditions a quantitative yields of mandelonitrile with 99 % ee was achieved. With some other aromatic aldehydes yield of 52–97 % and ee values of 3–97 % were obtained, an aliphatic aldehyde tested was not converted.[146] 2007, a (R)-selective HNL was found in Arabidopsis thaliana (AtHNL),[147a] which belongs to the a/b-hydrolase fold superfamily.[147b,c] It shows high activity towards mandelonitrile, the substrate range is similar to the (S)-selective HNLs from Hevea brasiliensis and Manihot esculenta including aromatic and aliphatic aldehydes. The selectivity of AtHNL is high.[147] (S)-Selective HNL HNL from Sorghum bicolor (SbHNL) was the first (S)-HNL used in an organic solvent for the preparation of (S)-cyanohydrins. The natural substrate is (S)-4-hydroxymandelonitrile. Its major drawback is the limited substrate tolerance, only aromatic and heteroaromatic aldehydes are accepted, while aliphatic aldehydes or ketones are not converted. For a wide range of 3and 4-substituted aromatic aldehydes excellent selectivities were obtained.[140d, 148] HNL from Hevea brasiliensis (HbHNL) was isolated from the leaves of the tropical rubber tree. The gene has been cloned and overexpressed in several microorganisms and the enzyme was isolated in an active form, enabling the production of recombinant purified biocatalyst. The natural substrate of HbHNL is acetone cyanohydrin. Many different starting materials such as aromatic, heteroaromatic, aliphatic, unsaturated and branched aldehydes, a- and b-oxygenated aldehydes derived from Diels–Alder reactions and even unusual substrates such as formylferrocene (99 % ee) as well as methyl and heterocyclic ketones have been transformed to the corresponding cyanohydrins.[149] Here again, the knowledge about crystal structure and the expression of recombinant HbHNL opened the way for the preparation of enzyme variants for specific applications by 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemcatchem.org enzyme engineering.[150] Similar results were obtained for the (S)-HNL from Manihot esculenta.[151] This enzyme is highly homologous (77 % sequence identity) to HbHNL. MeHNL has also been produced as recombinant protein.[152] Several different carbonyl substrates could be converted to the corresponding cyanohydrins catalyzed by MeHNL. While aldehydes yield cyanohydrins with high enantioselectivities, the ketones provide the products less selectively. Guanabana (Annona muricata) sead meal is reported as a source of (S)-HNL for the synthesis of aromatic, heteroaromatic and a,b-unsaturated (S)-cyanohydrins.[153] N-heteroaryl carboxaldehydes are not the appropriate substrates for the known HNLs regarding stereoselectivity. Here the selectivity could be increased by the concept of substrate engineering. N-substituted pyrrole-2- and -3-carboxaldehydes gave moderate to good enantiopurities, 91 % ee with both PaHNL and HbHNL was achieved with N-benzylpyrrole-3-carboxaldehyde.[154] Concerning (S)-ketone cyanohydrins, impressive results were achieved with aliphatic and aromatic ketones, for example, acetophenone cyanohydrin. The latter was obtained using the hydroxynitrile lyase from Hevea brasiliensis (40 % conversion, 99 % ee)[155] or Manihot esculenta HNL (87 % conversion, 98 % ee).[156] 4-Substituted cyclohexanones were subjected to enzymatic cyanohydrin synthesis with PaHNL and MeHNL in order to get access to starting materials for substituted tetronic acids. While PaHNL catalyzed almost completely the formation of the trans isomers with all the tested ketones, MeHNL favors the cis isomers.[157] Five- and six-membered cyclic ketones, namely tetrahydrofuran-3-one and tetrahydro-2H-3-pyranone have been subjected to the synthesis of hydroxynitrile lyase catalyzed cyanohydrins. Both substrates were accepted by PaHNL and HbHNL yielding moderate ee values (up to 81 %).[158] Detailed mechanistic studies concerning PaHNL, HbHNL, MeHNL and AtHNL have been reported. A general acid-base catalysis is the mechanism of the hydroxynitrile lyase catalyzed reaction involving all types of (R)- and (S)-selective HNLs, which differ regarding details for each enzyme.[159, 147c] Optimization of HNLs Although many HNLs are well characterized enzymes and already made their way to industrial applications, there is still room for improvements. Not all substrates can be converted in sufficient amounts and enantiopurity. Substrate engineering attempts were reported for HNLs.[160] An example of a coupled approach of substrate and enzyme engineering published recently showed impressive results regarding both activity (10– 20 times less enzyme amount) and selectivity (ee increased from 10 % to about 90 %).[150] Glieder and coworkers have improved the HNL from Prunus amygdalus starting from (R)-HNL isoenzyme 5 for synthesizing (R)-pantolactone, which is used in vitamin B5 synthesis. (R)-pantolactone can be synthesized from hydroxypivalaldehyde and HCN catalyzed by PaHNL. The ee and the amount of enzyme needed for the reaction was not ChemCatChem 2013, 5, 1248 – 1272

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CHEMCATCHEM REVIEWS satisfying. The enzyme was subjected to saturation mutagenesis at several positions, identified by molecular modeling. The ee could be increased from 89 to 97 %.[161] Another success story regarding PaHNL improvement is mutein PaHNL5L1QA111G. The large-scale production of (R)-2-chloromandelic acid—the chiral building block for the drug Clopidogrel—via (R)-2-chlorobenzaldehyde cyanohydrin was hindered by low turnover rates and moderate ee both in the enzymatic and metal catalyzed reaction. The rationally designed mutation of alanine to glycine at position 111 raised the yield enormously.[162] Another improved HNL is the “tunnel-variant” W128A of MeHNL.[163] Based on the crystal structure and reaction mechanism of MeHNL, a tryptophan residue at the entrance to the active site was supposed to play a crucial role regarding enzyme activity. The exchange of the bulky amino acid by sitedirected mutagenesis to the smaller amino acid alanine leads to the enhanced activity.[164] In two other examples the HNLs were highly improved by single point mutations to convert sterically demanding substrates[137b] and increase the enantioselectivity.[165] The enzymatic synthesis of enantiopure cyanohydrins has been brought to a high stage of development. Both (R)- and (S)-cyanohydrins are accessible for a broad variety of substrates in as a rule excellent yield and enantiopurity. Progress in recombinant protein production makes enzymes available in quantities needed for synthetic applications even in industrial scales.[130] The procedures for safe handling of cyanides are well established so that they do not restrict the exploitation of HNLs. Application of HNLs Next to the many synthetic applications described above, hydroxynitrile lyases have also been applied as catalysts for resolution of racemic cyanohydrins. It is possible to treat a racemic cyanohydrin 102 with a (R)- or (S)-HNL to decompose selectively one enantiomer of this mixture (Scheme 35). The (R)-HNL from Prunus amygdalus was used for the resolution of racemic

www.chemcatchem.org a similar way the (S)-cyanohydrin was afforded from racemic 2methyl-2-hydroxyhexanenitrile with P. amygdalus HNL in more than 90 % ee.[133d, 168] The transhydrocyanation of aromatic and aliphatic aldehydes with acetone cyanohydrin 103 catalyzed by (R)-HNL to give cyanohydrins is a method which enables the avoiding the use of free and highly toxic HCN as the cyanide source.[133c, 169] (Scheme 36)

Scheme 36. The concept of transhydrocyanation.

The attempt to use racemic 2-methyl-2-hydroxyhexanenitrile as the cyanide donor was rewarded by obtaining aliphatic wbromo cyanohydrins from the corresponding aldehydes in 90– 97 % ee.[168] In 2002 the concept was applied to w-hydroxyalkanals[170] and the ee values could be improved slightly performing the transformation in a micro-aqueous medium. Transhydrocyanation was also applied to silicon-containing aliphatic ketones with (R)-hydroxynitrile lyase from apple seed meal showing better activity and selectivity than almond meal.[171] The transhydrocyanation concept was further modified by the application of ethyl cyanoformate as cyanide donor. In a chemoenzymic one-pot reaction of ethyl cyanoformate with benzaldehyde, catalysed by PaHNL, ethoxycarbonylated (R)mandelonitrile was formed.[172] Meanwhile transhydrocyanation was also applied to ketones. As a biocatalyst (R)-hydroxynitrile lyase was used.[167] Today (S)- and (R)-mandelic acids derived from cyanhydrin precursors and subsequent acidic hydrolysis are produced on an industrial scale. The chiral acids are mainly used for racemate resolution. (R)-2-chloromandelic acid (250 g L 1 d 1, ee 95 %)[173] as well as (R)-2-hydroxy-4-phenylbutyronitrile are further large scale products of “improved” HNLs.[174]

Methyltransferases

Scheme 35. Kinetic resolution of racemic cyanohydrins with (R)- or (S)-selective HNLs.

cyanohydrins. Employing a biphasic system, namely citrate buffer/diisopropyl ether (40:1) at 39 8C, catalytic amounts of PhNH2 and semicarbazide were added for aldehyde capture. In this manner the (S)-cyanohydrin of 3-phenoxybenzaldehyde was obtained with 91 % ee at 50 % conversion.[166] Almond meal was used for the resolution of rac-2-hydroxy-2-phenylpropanenitrile. Under the optimized conditions, (S)-2-hydroxy-2phenylpropanenitrile as the less reactive enantiomer was obtained in 98–99 % ee at approximately 50 % conversion.[167] In 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

The enzymatic equivalent of Friedel–Crafts alkylation catalyzed by S-adenosyl-l-methionine (SAM) dependent methyltransferases is a novel biocatalytic C C bond formation reaction reported for two C-methyltransferases CouO and NovO. By application of chemically modified cofactors (artificial SAM analogs) 106 the alkylation could be extended beyond the natural methylation reaction (Scheme 37). Though the substrate range of the enzymes is not very broad, it is not restricted to the natural substrates.[175] The application of SAM-dependent methyltransferases with modified cofactors is manifold. Weinhold et al. demonstrate in many reports during the last years that site-specific modifications of DNA and RNA, as well as protein labeling can be performed precisely. By attaching a “reporter-residue” like a fluoChemCatChem 2013, 5, 1248 – 1272

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www.chemcatchem.org In a sulfate reducing enrichment culture genes for putative naphthalene carboxylases and in a strictly anaerobic iron-reducing culture benzene carboxylating enzymes were identified. The proteins built potential candidates as biocatalysts.[184]

Scheme 37. Alkylation of aromatic compounds catalyzed by methyltransferases using modified cofactors.

rescence tag to the modification residue, the target compound or residue can be captured and identified.[176]

Carboxylases Faber et al. describe in a review from 2010 the possibility of establishing the carboxylation reaction (CO2 fixation) as a novel C C bond formation reaction in biocatalysis by using enzymes which are involved in detoxification pathways in vivo. These enzymes are assumed to have rather relaxed substrate specificities and catalyze low-energy reactions.[177a] In a very recently published communication a highly regioselective carboxylation of phenols and styrene derivatives using (de)carboxylases in carbonate buffer is reported (Scheme 38). While benzoic acid (de)carboxylases selectively formed o-hydroxybenzoic acid derivatives 108, phenolic acid (de)carboxylases acted at the bcarbon atom of styrenes giving (E)-cinnamic acids 109. The substrate tolerance of benzoic acid decarboxylases is remarkably broad while the phenolic acid decarboxylases are more selective.[177b] In Xanthobacter Py2 an epoxide carboxylase transformed epoxypropane in the presence of CO2 to 3-oxobutyrate, which was converted further to poly-b-hydroxyalkanoates.[178] Electron-rich aromatic compounds like phenols and heteroaromatics are degraded in anaerobic bacteria starting with a carboxylation step to enhance the solubility. Regioselective para-carboxylation of phenylphosphate in Thauera aromatica[179] and ortho-carboxylation of phenol in the yeast Trichosporon moniliiforme WU-0401[180] and pyrrole in Bacillus megaterium[181] as well as catechol by 3,4-dihydroxybenzoate decarboxylase of Enterobacter cloacae P[182] are examples for biocatalytic carboxylations. Even in the case of aliphatic compounds the pyruvate decarboxylase which requires thiamine pyrophosphate is successfully applied for the reverse carboxylation reaction to yield pyruvic acid 2 from acetaldehyde.[183]

Scheme 38. Application of decarboxylases for the reversed reaction direction.


Chain elongation by n·5carbon units

Prenyltransferases catalyze a reaction starting with elimination of the diphosphate ion from an allylic diphosphate to build an allylic cation, which is attacked subsequently by the isopentenyl diphosphate (IPP) 111 molecule with stereospecific removal of a proton to form a C C bond and a newly formed double bond in the product (Scheme 39).[185] By repeating the conden-

Scheme 39. Isoprenoid chain elongation (geranyl diphosphate synthesis shown as an example).

sation step, prenyl diphosphates with certain chain length and stereochemistry are synthesized depending on the specificity of the prenyltransferase involved. The enzymes are classified into four different groups. Prenyltransferase I are short-chain prenyldiphosphate synthases, class II are medium-chain synthases, class III long-chain (E) prenyl diphosphate synthases and prenyltransferase IV belongs to the (Z)-polyprenyl diphosphate synthases. Most prenyltransferases require a divalent metal ion, like Mg2 + or Mn2 + . The group I prenyltransferases is involved in the biosynthesis of steroids, carotenoids and prenylated proteins. Terpenes are classified based on the number of C5 isoprenoid units in their structure. Monoterpenes comprise two, sesquiterpenes three, diterpenes four and polyterpenes from nine up to 30 000 connected isoprenoid units. Terpenoids show great structural and functional diversity. They built the essential part of fragrances and flavors. All terpenes are derived from allylic diphosphates. Isopentenyl pyrophosphate (IPP) 111 is the precursor of all terpenes. The IPP can be converted by an isomerase to dimethylally pyrophosphate (DMAPP) 110. Prenyltransferase use one molecule of DMAPP and IPP to form geranyl pyrophosphate (GPP) 112 (Scheme 39), which was believed to be the precursor of all monoterpenes.[186] In 2009 it could be shown with convincChemCatChem 2013, 5, 1248 – 1272

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ing results that GPP 112 is not the only native substrate (transoid) of monoterpene synthases. Neryl diphosphate (NPP), the (Z)-isomer (cisoid) of GPP is the native substrate of a monoterpene synthase from tomato.[187]

Cyclizations Terpenoid cyclases Terpene synthases (cyclases) are a family of enzymes responsible for the formation of terpenoid compounds, which are structurally and stereochemically very divers. All terpenoids derive from their respective 10-, 15- or 20-carbon atom prenyl diphosphate precursors.[188] Two pathways to cyclic terpenes are Scheme 41. Terpenoid cyclases, GPP (C10) geranyl diphosphate 112, FPP (C15) farnesyl known (all-trans pathway and cis-trans-pathway) diphosphate 113, GGPP (C20) geranylgeranyl diphosphate 122. (Scheme 40).[189] The enzymes catalyze complex cyclisation cascades which are started by the formation of a highly reactive carbocation in a polyisoprene substrate[189] and convert simple, linear hydrocarbon phosphates into an assembly of chiral carbocyclic skeletons. The enzyme provides a template for binding and stabilizing the acyclic flexible substrate in a precise orientation, which is required for catalysis and cyclisation (Scheme 41).[190] Lanosterol synthase, for example, catalyzes the precise cyclisation of the precursor (S)-2,3-oxidosqualene 126 to lanosterol 127, one out of 128 possible stereoisomers (Scheme 42).[190b] The precision is the main characteristic of these enzymes (one enzyme one product). The structure–function relationship Scheme 42. Lanesterol synthase catalyzed cyclisation. is proposed through building a template for the substrate, triggering carbocation formation, convoying the conformations of the application of a squalene hopene cyclase from Zymomonas intermediates and stabilization thereof in order to yield mobilis in intramolecular Friedel–Crafts alkylations. Although a single product. Very recently Hauer and coworkers reported the conversions are low, the enzyme accepted substrates with different chain length and size, showing flexibility in this regard.[191] With more than 55 000 members, the family of terpene or terpenoid natural products shows an impressive collection of molecular diversity. The class I terpenoid synthases contain a conserved metal binding motif that coordinates to a trinuclear metal cluster, with different functions. The cluster binds and orients the isoprenoid substrate in a pre-catalytic Michaelis complex next to the release of the diphosphate leaving group to generate a carbocation and to start the catalysis. Further conserved hydrogen bond donors support the metal cluster in its function.[192] The X-ray crystal structure of recombinant epi-isozizaene synthase (EIZS), a sesquiterpene cyclase from Streptomyces coelicolor and variants were determined, which provided a view of conformational changes required for substrate binding and catalysis in a terpenoid cyclase. Aromatic amino acids appear to be responsible for stabilizing carbocation intermediates in the cyclisation cascade through pScheme 40. Regio- and stereospecific reactions catalyzed by terpene synthases.[188] 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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www.chemcatchem.org Application of cyclases

Scheme 43. Proposed catalytic mechanism of taxadiene synthase.[195]

cation interactions. Mutagenesis studies of terpene synthases have provided mechanistic insight and structure–function relationships for specific enzyme residues.[193] Mutations can cause alternative binding orientations of the carbocation intermediate leading to an alternative new product.[194] Recently the X-ray crystal structure of a truncation variant of taxadiene synthase was published.[195] The enzyme is responsible for the first step in taxol biosynthesis of Pacific yew (Taxus brevifolia), namely the cyclisation of the linear isoprenoid substrate geranylgeranyl diphosphate (GGPP) 122 to form taxa4(5),11(12)-diene 125 (Scheme 43). The enzyme comprises of a class I terpenoid cyclase fold at the carboxy-terminal domain, which binds and activates the substrate with a three metal ion cluster and a class II terpenoid cyclase fold at the N-terminus. Optimization of cyclases Terpene cyclases are of great interest for industrial applications, as they enable the in vitro synthesis and production of terpenoid compounds independently from natural sources. Essential oils isolated from natural sources often vary in quality and quantity. In the recent years considerable effort has been applied in the engineering of terpenoid biosynthesis in microorganisms and plants in order to reduce the costs and even the varying compositions in natural sources.[196] For example, a patent on terpene synthases from sandalwood has been recently applied. The wood fragrance contains essential oils, which are used as fixative in many high end perfumes. Now the production of terpenoids from sandalwood can be performed in the lab and there is no need to isolate the oil from its natural source (tree).[197] Engineering of terpene biosynthesis in microorganisms or plants might also provide access to new compounds, naturally not occurring in oil compositions.[196] 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Next to applications as fragrance and flavor compounds, methods for the production of terpenes and terpenoids for use as fuel molecules from genetically engineered recombinant terpene synthases have been described.[198] Another approach for biofuel production is the photosynthetically produced isoprene by a recombinant strain expressing isoprene synthase. Isoprene is built from carbon dioxide via sunlight and a genetically engineered photosynthetic microorganism.[199] Very recently the genome sequence of Omphalotus olearius was reported, which revealed a diverse network of sesquiterpene synthases and two metabolic gene clusters associated with the anticancer sesquiterpenoids illudin biosynthesis. The results from characterization of the sesquiterpene synthases shall facilitate discovery and biosynthetic production of unique pharmaceutically relevant bioactive compounds from Basidiomycota.[200] Diels–Alderases The existence of natural Diels–Alderases for intermolecular [4+2] cycloadditions is still a matter of debate. In 2001 the existence of Diels–Alderases was reported in a highlight article.[201] The proof was the catalyzed synthesis of lovastatin with a purified enzyme. The enzyme catalyzed reaction furnished a product spectrum different from the non-catalyzed cyclization.[202] 2004 three natural Diels–Alderases were reported.[203] All of them have been purified and characterized. Two of them (solanopyrone synthase and macrophomate synthase) catalyze intramolecular Diels–Alder reactions, while the third one (lovastatin nonaketide synthase) catalyzes an intermolecular Diels–Alder reaction. The crystal structure of macrophomate synthase is resolved and a mechanism for catalysis proposed.[204] Macrophomate synthase is believed to produce a reactive substrate and act as an entropy trap for [4+2] cycloaddition.[205] Recently, the solanopyrone synthase as a Diels–Alderase was revised and classified as iterative type I polyketide synthase.[206] Enzymes catalyzing intramolecular Diels–Alder reactions are reported in Aspergillus species, suggesting that each species has evolved enantiomerically distinct Diels– Alderases.[207] Recently the development of an artificial enzyme Diels–Alderase was reported. The protein was designed in silico, genes encoding the desired protein were synthesized and expressed in E.coli. Two enzymes showed activity in the cyclohexene ring formation (Scheme 44).[208] ChemCatChem 2013, 5, 1248 – 1272

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www.chemcatchem.org followed by an intramolecular N-heterocycle formation (1benzylisoquinoline derivatives, e.g. 137).

Berberine bridge enzyme Scheme 44. A designed enzyme for performing Diels–Alder cyclizations.

Polyketide synthases Nature uses decarboxylating claisen condensation reactions for C C-bond formation not only in the biosynthesis of fatty acids, but also for polyketides.[209] The enzymes catalyzing the biochemical claisen condensations share a common 3-dimensional fold and concomitantly small similarity in amino acid sequence.[210] Determination of biosynthetic pathways in the formation of polyketides has been highly investigated during the last decade to enhance our understanding of the mechanisms involved in the complex cascade reactions.[211] The enzymes catalyzing these reactions consist of modules. For example, type III polyketide synthases catalyze iterative decarboxylative condensations of malonyl units with a CoA-linked starter molecule to produce structurally divers secondary metabolites with remarkable biological activities.[212]

The flavine-dependent berberine bridge enzyme (BBE) is a redox enzyme which catalyzes the formation of benzophenanthridine alkaloids (berberines) 139 via an intramolecular Friedel–Crafts alkylation reaction. The C C-bond formation is an oxidative coupling reaction (Scheme 46).[214]

Miscellaneous Halohydrin dehalogenase A halohydrin dehalogenase enzyme was used as a catalyst for the epoxide ring opening by the nuclephile cyanide. The enantioselective formation of a b-hydroxynitrile 141 was achieved (Scheme 47).[215]

Scheme 47. Enantiopure 2-hydroxynitrile 141 formation catalyzed by a halohydrin dehalogenase.

Pictet-Spenglerases These enzymes are classified as lyases and called synthases. The enzymes are involved in the synthesis of natural products bearing a condensed tetrahydropyridin ring in an electronrich aromatic system (Scheme 45).[213] The C C-bond formation is initiated by the condensation of an electronrich aryl ethylamine (e.g. 135) and an aldehyde (e.g. 136) to form an imine

Tyrosine phenol lyase Tyrosine phenol lyase is a PLP (pyridoxal 5-phosphate)-dependent enzyme which catalyzes the carbon-carbon bond cleavage of tyrosine to form phenol, pyruvate 2 and ammonia 143. The enzyme was applied in the reverse direction for the synthesis of tyrosine derivatives 144. The variant M379V was the most active mutein for the preparation of 3’-substituted tyrosines derived from ortho-substituted phenols (Scheme 48).[216]

Scheme 45. Norcoclaurine synthase catalysed C C-bond formation.

Nitroaldolase

Scheme 46. Biocatalytic oxidative C C-bond formation catalyzed by BBE, The (S)-configured product 139 is the main product of the kinetic resolution. The remaining substrate is (R)-138.


A biocatalytic enantioselective nitroaldol (Henry) reaction[217] catalyzed by HbHNL[218] (Scheme 49) and AtHNL[219] has been reported. AtHNL yields (R)and HbHNL (S)-configuration of the hydroxyl-bearing carbon atom. A broad range of aromatic, heteroaromatic and aliphatic aldehydes have been transformed to the corresponding nitro alcohols.[220] Intensive stud-

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www.chemcatchem.org M.G.-K. acknowledges financial support from the Austrian Science Foundation (FWF) through projects P24135-N17. The autors want to express their special thank to Herfried Griengl for proof reading and his thoughtful comments on the manuscript.

Scheme 48. Tyrosine phenol lyase catalyzed synthesis of 3’-substituted tyrosines 144.

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Received: October 9, 2012 Published online on February 21, 2013

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