Stereoselective synthesis of bulky 1,2-diols with alcohol dehydrogenases

Kulig, Justyna; Simon, Robert C.; Rose, Christopher A.; Husain, Syed Masood; Häckh, Matthias; Lüdeke, Steffen; Zeitler, Kirsten; Kroutil, Wolfgang; Pohl, Martina; Rother, Dörte

doi:10.1039/c2cy20120h

Cited by 57 publications

(66 citation statements)

References 30 publications

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“…To gain access to a broad product platform, we focused on the establishment of enzyme toolboxes. These toolboxes comprise numerous enzymes that catalyze one kind of reaction, but the catalysts differ in their substrate spectrum and stereoselectivity . As an example, by an enzymatic two‐step reaction, vicinal 1,2‐diols can be generated.…”

Section: Introductionmentioning

confidence: 99%

“…These compounds are versatile building blocks for active pharmaceutical ingredients but their chemical synthesis often suffers from low stereoselectivity, toxic reactants, or low yields . Biocatalytically, we are able to access a platform of differently substituted diols selectively by the reduction of the corresponding 2‐hydroxy ketones using a diverse toolbox of alcohol dehydrogenases . The 2‐hydroxy ketones can also be produced biocatalytically by the carboligation of aldehydes using another toolbox of enzymes that depend on thiamine diphosphate (ThDP) (Scheme ) …”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…2 To date all chemical approaches [3][4][5] and most of the biochemical approaches [6][7][8] only allow the formation of one of the two chiral products: either the α-hydroxy ketones or vicinal diols. A particular challenge is the development of methodologies allowing for the targeted selective synthesis of both α-hydroxy ketones and vicinal diols, in particular with aliphatic side chains (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Assessing the stereoselectivity of Serratia marcescens CECT 977 2,3-butanediol dehydrogenase

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Kwakernaak

et al. 2017

Catal. Sci. Technol.

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α-Hydroxy ketones and vicinal diols constitute well-known building blocks in organic synthesis. Here we describe one enzyme that enables the enantioselective synthesis of both building blocks starting from diketones. The enzyme 2,3-butanediol dehydrogenase (BudC) from S. marcescens CECT 977 belongs to the NADH-dependent metal-independent short-chain dehydrogenases/reductases family (SDR) and catalyses the selective asymmetric reductions of prochiral α-diketones to the corresponding α-hydroxy ketones and diols. BudC is highly active towards structurally diverse diketones in combination with nicotinamide cofactor regeneration systems. Aliphatic diketones, cyclic diketones and alkyl phenyl diketones are well accepted, whereas their derivatives possessing two bulky groups are not converted. In the reverse reaction vicinal diols are preferred over other substrates with hydroxy/keto groups in non-vicinal positions.

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“…The stability of the enzyme could be augmented by the addition of calcium ions. RasADH was subsequently also applied to the reduction of -hydroxy ketones [10] and in the dynamic kinetic resolution (DKR) of -alkyl--keto esters such as 3 ( Figure 1) to give (2S, 3S)-products of type 4 [11].…”

Section: Introductionmentioning

confidence: 99%

Structures of Alcohol Dehydrogenases from Ralstonia and Sphingobium spp. Reveal the Molecular Basis for Their Recognition of ‘Bulky–Bulky’ Ketones

et al. 2013

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Alcohol dehydrogenases (ADHs) are applied in industrial synthetic chemistry for the production of optically active secondary alcohols. However, the substrate spectrum of many ADHs is narrow, and few, for example, are suitable for the reduction of prochiral ketones in which the carbonyl group is bounded by two bulky and/or hydrophobic groups; so-called 'bulky-bulky' ketones. Recently two ADHs, RasADH from Ralstonia sp. DSM 6428, and SyADH from Sphingobium yanoikuyae DSM 6900, have been described, which are distinguished by their ability to accept bulky-bulky ketones as substrates. In order to examine the molecular basis of the recognition of these substrates the structures of the native and NADPH complex of RasADH, and the NADPH complex of SyADH have been determined and refined to resolutions of 1.5, 2.9 and 2.5 Å respectively. The structures reveal hydrophobic active site tunnels near the surface of the enzymes that are well-suited to the recognition of large hydrophobic substrates, as determined by modelling of the bulkybulky substrate n-pentyl phenyl ketone. The structures also reveal the bases for NADPH specificity and (S)-stereoselectivity in each of the biocatalysts for n-pentyl phenyl ketone and related substrates.

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Stereoselective synthesis of bulky 1,2-diols with alcohol dehydrogenases

Cited by 57 publications

References 30 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

Assessing the stereoselectivity of Serratia marcescens CECT 977 2,3-butanediol dehydrogenase

Structures of Alcohol Dehydrogenases from Ralstonia and Sphingobium spp. Reveal the Molecular Basis for Their Recognition of ‘Bulky–Bulky’ Ketones

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