Benzaldehyde Lyase-Catalyzed Enantioselective Carboligation of Aromatic Aldehydes with Mono- and Dimethoxy Acetaldehyde

Demir, Ayhan S.; Şeşenoğlu, Özge; Dünkelmann, Pascal; Müller, Michael

doi:10.1021/ol034415b

Cited by 78 publications

(43 citation statements)

References 33 publications

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“…The a-heteroatomsubstituted acetaldehydes [28,29] 8, 9 are promising substrates as the putative products 11, 12 of the reaction would open a wide range of further transformations towards more complex structures. The use of formaldehyde (7) [30] seemed attractive, because the elongated products are not easy to obtain selectively by chemical methods.…”

Section: Resultsmentioning

confidence: 99%

α,β‐Unsaturated Aldehydes as Substrates for Asymmetric CC Bond Forming Reactions with Thiamin Diphosphate (ThDP)‐Dependent Enzymes

et al. 2008

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The enzymes benzaldehyde lyase (BAL) from Pseudomonas fluorescens, benzoylformate decarboxylase (BFD) from Pseudomonas putida and pyruvate decarboxylase (PDC) from Saccharomyces cerevisiae provide different C À C bond forming possibilities of a,b-unsaturated aldehydes with aliphatic and aromatic aldehydes. Structure elucidation and determination of the absolute configuration of the products, which were obtained with high regio-and stereoselectivity were carried out. Selective 1,2-reactivity with yields of 75% and > 98% ee, for one single isomer (A) were obtained, by choosing the suitable enzyme in combination with the appropriate substrates. By varying enzymes or substrates the regioisomeric hydroxy ketones C, with up to > 99% ee, can be obtained. The application of these new chiral building blocks in the synthesis of natural products or biological active substances is considerably facilitated by applying the different ThDP-dependent enzymes as catalysts.Abbreviations: BAL, benzaldehyde lyase; BFD, benzoylformate decarboxylase; PDC, pyruvate decarboxylase; His, hexahistidine; 2-HPP, 2-hydroxy-1-phenylpropan-1-one; PAC, phenylacetylcarbinol; NTA, nitrilotriacetic acid; ThDP, thiamin diphosphate; wt, wild-type.Keywords: benzaldehyde lyase; benzoylformate decarboxylase; biocatalysts; pyruvate decarboxylase; stereochemistry IntroductionThiamin diphosphate (ThDP)-dependent enzymes are well-known to catalyse a broad range of asymmetric reactions.[1] Enzymes of this class like benzaldehyde lyase (BAL) from Pseudomonas fluorescens, [2] benzoylformate decarboxylase (BFD) from Pseudomonas putida [3] and pyruvate decarboxylase (PDC) from Saccharomyces cerevisiae [4] enable various modes of C À C bond forming reactions. Besides the physiological reactivity, several of these enzymes can catalyse, for example, the C À C bond formation between two aldehydes, giving chiral 2-hydroxy ketones with high enantioselectivity. The reactions of aromatic aldehydes as donor and aliphatic aldehydes as acceptor give rise to 2-hydroxy-1-phenyl-1-propanone derivatives with S absolute configuration in the case of BFD catalysis [5] and R for BAL.[6] If aromatic aldehydes are employed as donor and acceptor, (R)-benzoins are optained with both enzymes. [7,8] (R)-Phenylacetylcarbinol is formed in the PDC-catalysed reaction of decarboxylated pyruvate with benzaldehyde as acceptor aldehyde. [4,9] Here we describe the use of a,b-unsaturated aldehydes as substrates for C À C bond ligation in BAL-, BFD-and PDC-catalysed reactions. These substrates might act as donor and as acceptor for the 1,2-(A, C) and the 1,4-addition (B, D) (Scheme 1). Adv. Synth. Catal. 2008, 350, 759 -771 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 759 FULL PAPERSIn reactions according to Equation (1) the a,b-unsaturated aldehyde is bound to ThDP and reacts as donor resulting in the formation of hydroxy ketone A or hydroxy enone B. In reactions according to Equation (2) the a,b-unsaturated aldehyde is attacked by an "active aldehyde" and reacts as acceptor resulti...

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Section: Resultsmentioning

confidence: 99%

α,β‐Unsaturated Aldehydes as Substrates for Asymmetric CC Bond Forming Reactions with Thiamin Diphosphate (ThDP)‐Dependent Enzymes

et al. 2008

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“…Since the addition of either 20 % (v/v) DMSO or 15 % (v/v) PEG-400 has been successfully applied for BAL-and BFD-catalyzed carboligase reactions, [1,3,19,20] these organic solvents were tested with KdcA. The enzyme is completely stable in the presence of 20 % (v/v) DMSO (half-life: 150 h), whereas it is rapidly inactivated in the presence of 15 % (v/v) PEG-400 (half-life: 6 h) ( Figure 4).…”

Section: Organic Solventsmentioning

confidence: 99%

“…4.1.2.38) have been intensively studied with respect to their carboligation activity, offering an easy access to chiral 2-hydroxy ketones from aldehydes. [1][2][3][4][5][6][7][8] In order to enlarge the range of accessible 2-hydroxy ketones, we studied the carboligase properties of a recently described branchedchain keto acid decarboxylase (E.C. 4.1.1.72).…”

Section: Introductionmentioning

confidence: 99%

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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“…If incubated with an excess of benzaldehyde, BAL also catalyses the formation of the industrial pharmaceutical intermediate (R)-benzoin by enantioselective carbon-carbon bond ligation (Demir et al, 2002). A range of other aldehyde substrates for BAL have recently been identified (Sanchez-Gonzalez & Rosazza, 2003;Demir et al, 2003) and there is an increasing number of reports of the optimization of its activity for possible application of the enzyme in industrial processes (Stilger et al, 2006). As part of our continuing studies into the structural enzymology of unusual C-C bond lyases using X-ray crystallography (Leonard & Grogan, 2004;Leonard et al, 2006), we were interested in the molecular structural determinants of both catalysis and enantioselectivity in the reaction catalysed by BAL and we therefore crystallized the protein.…”

Section: Introductionmentioning

confidence: 99%

Structure of the ThDP-dependent enzyme benzaldehyde lyase refined to 1.65 Å resolution

et al. 2007

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Benzaldehyde lyase (BAL; EC 4.1.2.38) is a thiamine diphosphate (ThDP) dependent enzyme that catalyses the enantioselective carboligation of two molecules of benzaldehyde to form (R)-benzoin. BAL has hence aroused interest for its potential in the industrial synthesis of optically active benzoins and derivatives. The structure of BAL was previously solved to a resolution of 2.6 Å using MAD experiments on a selenomethionine derivative [Mosbacher et al. (2005), FEBS J. 272, 6067-6076]. In this communication of parallel studies, BAL was crystallized in an alternative space group (P2 1 2 1 2 1) and its structure refined to a resolution of 1.65 Å , allowing detailed observation of the water structure, active-site interactions with ThDP and also the electron density for the co-solvent 2-methyl-2,4-pentanediol (MPD) at hydrophobic patches of the enzyme surface.

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Benzaldehyde Lyase-Catalyzed Enantioselective Carboligation of Aromatic Aldehydes with Mono- and Dimethoxy Acetaldehyde

Cited by 78 publications

References 33 publications

α,β‐Unsaturated Aldehydes as Substrates for Asymmetric CC Bond Forming Reactions with Thiamin Diphosphate (ThDP)‐Dependent Enzymes

α,β‐Unsaturated Aldehydes as Substrates for Asymmetric CC Bond Forming Reactions with Thiamin Diphosphate (ThDP)‐Dependent Enzymes

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

Structure of the ThDP-dependent enzyme benzaldehyde lyase refined to 1.65 Å resolution

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