Asymmetric Synthesis of Aliphatic 2‐Hydroxy Ketones by Enzymatic Carboligation of Aldehydes

Marı́a, Pablo Domı́nguez de; Pohl, Martina; Gocke, Dörte; Gröger, Harald; Trauthwein, Harald; Stillger, Thomas; Walter, Lydia; Müller, Michael

doi:10.1002/ejoc.200600876

Cited by 55 publications

(33 citation statements)

References 29 publications

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“…At this point, 8 m m of benzoin remained uncleaved and 28 m m of the initial 300 m m benzaldehyde was unconverted (91 % conversion). Negligible amounts of acetoin can be detected (<5 m m ), which results from the carboligation of two acetaldehyde molecules catalyzed by BAL . Upon the addition of cosubstrate and buffer after 25.25 h (after the BAL‐containing “teabags” were exchanged with RasADH‐containing bags), the analyte concentrations decreased because of dilution.…”

Section: Resultsmentioning

confidence: 99%

“…Negligible amounts of acetoin can be detected (< 5mm), which results from the carboligation of two acetaldehyde molecules catalyzed by BAL. [37] Upon the addition of cosubstrate and buffer after 25.25 h( after the BALcontaining "teabags"w ere exchanged with RasADH-containing bags), the analyte concentrationsd ecreased because of dilution. The followingo xidoreduction yieldeda96 %c onversion of (R)-HPP.T he resulting final diol concentration of 32.9 g L À1 (216 mm)c an be considered to be in the lower industrially relevant order of magnitude.…”

Section: Application Of the Spinchem Reactor For Ao Ne-pot Two-step Dmentioning

confidence: 99%

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Modularized Biocatalysis: Immobilization of Whole Cells for Preparative Applications in Microaqueous Organic Solvents

et al. 2015

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The use of whole‐cell biocatalysts enables catalyst application in microaqueous reaction systems, in which the liquid phase consists of high substrate loadings in organic solvents, to enable access to high concentrations of easy‐to‐purify product. One current research focus is the modularization of single reaction steps to (i) enable flexible combinations into multi‐step enzyme reactions, (ii) investigate ideal reaction conditions, and (iii) facilitate catalyst handling and recycling. Therefore, we published the easy‐to‐apply encapsulation of a lyophilized whole‐cell catalyst in a polymeric membrane recently. These catalytic “teabags” were demonstrated to enable flexible catalyst combinations for multi‐step reactions and excellent recyclability during repeated batch experiments. We now describe the applicability of these “teabags” on a larger scale by using the new SpinChem reactor and a classical stirred‐tank reactor model. As an alternative, we investigate the described alginate entrapment approach and compare the results. The carboligation reaction towards (R)‐benzoin, using lyophilized E. coli that enclose Pseudomonas fluorescens benzaldehyde lyase (EC 4.1.2.38), served as a model reaction. It was demonstrated that the catalytic “teabags” are scalable and perform equally on the investigatory 5 mL scale and the preparative 140 mL reactor scale. Tested in a more advanced application, the “teabags” were proven to be useful in a one‐pot two‐step reaction for the gram‐scale production of 1‐phenylpropane‐1,2‐diol by using the SpinChem reactor, which allowed to reach an industrially relevant product concentration (32.9 g L−1) and space–time yield (8.2 g L−1 d−1).

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Section: Resultsmentioning

confidence: 99%

Section: Application Of the Spinchem Reactor For Ao Ne-pot Two-step Dmentioning

confidence: 99%

Modularized Biocatalysis: Immobilization of Whole Cells for Preparative Applications in Microaqueous Organic Solvents

et al. 2015

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“…BAL catalyzes this reaction with a specific activity of 0.05 U/mg resulting in the formation of (R)-27 (ee 80 %). [21,22] Thus, although the activity of KdcA is distinctly lower for this transformation it opens the way to both enantiomers of aliphatic acyloins. Surprisingly, KdcA is not able to catalyze the selfcarboligation of isobutyraldehyde (19) in detectable amounts, although 19 is the reaction product of the physiological decarboxylation of 3-methyl-2-oxobutanoic acid (1) and should therefore fit into the active center.…”

Section: Carboligation Of Aliphatic Aldehydesmentioning

confidence: 98%

Branched‐Chain Keto Acid Decarboxylase from Lactococcus lactis (KdcA), a Valuable Thiamine Diphosphate‐Dependent Enzyme for Asymmetric CC Bond Formation

et al. 2007

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The thiamine diphosphate-dependent, branched-chain 2-keto acid decarboxylase from Lactococcus lactis sup. cremoris B1157 (KdcA) is a new valuable enzyme for the synthesis of chiral 2-hydroxy ketones. The gene was cloned and the enzyme was expressed as an N-terminal hexahistidine fusion protein in Escherichia coli. It has a broad substrate range for the decarboxylation reaction including linear and branched-chain aliphatic and aromatic keto acids as well as phenyl pyruvate and indole-3pyruvate. The dimeric structure of recombinant KdcA is in contrast to the tetrameric structure of other 2-keto acid decarboxylases. The enzyme is stable between pH 5 and 7 with a pH optimum of pH 6-7 for the decarboxylation reaction. While KdcA is sufficiently stable up to 40 8C it rapidly looses activity at higher temperatures. In this work the carboligase activity of KdcA is demonstrated for the first time. The enzyme shows an exceptionally broad substrate range and, most strikingly, it catalyzes the carboligation of different aromatic aldehydes as well as CH-acidic aldehydes such as phenylacetaldehyde and indole-3-acetaldehyde with aliphatic aldehydes such as acetaldehyde, propanal, and cyclopropanecarbaldehyde, yielding chiral 2-hydroxy ketones in high enantiomeric excess. Noteworthy, the donor-acceptor selectivity is strongly influenced by the nature of the respective substrate combination.

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“…Enzymatic carboligation of linear aldehydes has been reported recently by Trauthwein and M ü ller et al resulting in high conversions and enantioselectivities of up to 80% ee [148] . This reaction has also been known for a long time for acetoin condensation.…”

Section: Benzoin Condensation and Related Reactionsmentioning

confidence: 95%

Enzyme‐Catalyzed Asymmetric Synthesis

Gröger

2010

Catalytic Asymmetric Synthesis

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INTRODUCTIONBiocatalysis has been recognized over the past decades as a highly valuable tool for organic chemists to prepare enantiomerically pure molecules, so -called chiral building blocks, in a highly effi cient way. Besides a multitude of academic work, it is noteworthy that enzyme catalysis belongs to the standard repertoire in industry when facing challenging enantioselective synthetic routes. A broad range of biocatalytic methods is already in use in particular for large -scale manufacture of drug intermediates [1] .The research in the fi eld of enzyme catalysis has already been comprehensively reviewed some years ago [2] . Thus, the focus of the current review is on a selection of (particularly recently developed) enantioselective enzymatic reactions, which turned out to be highly useful and applicable in organic synthesis, fulfi lling criteria such as high productivity, substrate concentrations, conversions, and enantioselectivities. The presented methods are an interesting complementary tool to existing " classic organic " or " chemocatalytic asymmetric " methodologies. Among biocatalytic reactions, both resolution of racemates and asymmetric synthesis starting from prochiral substrates are attractive routes already applied, in part, in industry. A third type of biotechnological approach, which is not a subject of this review, are fermentation processes. A graphical summary of these three types of so -called " white biotechnology " methodologies is given in Scheme 6.1 .Hydrolases are the enzyme class most commonly applied as biocatalysts in organic chemistry. This is mainly due to the accessibility of these enzymes (used, e.g., in the textile and detergents industry), their suitability for transformations in organic media Catalytic Asymmetric Synthesis, Third Edition, Edited by Iwao Ojima 269 270 ENZYME-CATALYZED ASYMMETRIC SYNTHESIS (in particular when using lipases), and the lack of a need for cofactors. However, in recent years, we have also seen an increasing tendency to apply redox enzymes in organic syntheses as well as lyases in C -C bond formations and transferases. Isomerases also turned out to be very useful in particular in combination with hydrolases for dynamic kinetic resolutions. Thus, a broad range of biotransformations is available for organic chemists. A challenge, however, is the use of ATP cofactor -dependent enzymes, which contribute to only a negligible number of typical organic biotransformations (e.g., due to the high price of ATP).The fi eld of biocatalysis benefi ted signifi cantly from the tremendous progress in molecular biology. Highly effi cient methods for screening and optimization of biocatalysts (by, e.g., directed evolution in the latter case) have been developed, which allows access to tailor -made enzymes. Furthermore, the design of recombinant microorganisms gives access to highly productive whole -cell catalysts, which contain only the desired enzymes in large amount, thus signifi cantly reducing the required biomass for biotransformations compared with the use of...

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Asymmetric Synthesis of Aliphatic 2‐Hydroxy Ketones by Enzymatic Carboligation of Aldehydes

Cited by 55 publications

References 29 publications

Modularized Biocatalysis: Immobilization of Whole Cells for Preparative Applications in Microaqueous Organic Solvents

Modularized Biocatalysis: Immobilization of Whole Cells for Preparative Applications in Microaqueous Organic Solvents

Branched‐Chain Keto Acid Decarboxylase from Lactococcus lactis (KdcA), a Valuable Thiamine Diphosphate‐Dependent Enzyme for Asymmetric CC Bond Formation

Enzyme‐Catalyzed Asymmetric Synthesis

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