Highly stereoselective biocatalytic reduction of alpha-halo ketones

Alanvert, Emmanuelle; Doherty, Claire; Moody, Thomas S.; Nesbit, Nicholena; Rowan, Andrew S.; Taylor, Stephen J.; Vaughan, Fatima; Vaughan, Tony; Wiffen, Jonathan; Wilson, Ian F.

doi:10.1016/j.tetasy.2009.10.008

Cited by 16 publications

(6 citation statements)

References 26 publications

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“…[51-54, 57, 58] This strategy was employed successfully in the bioreduction of b-cyanoacrylates catalyzed by ene reductase to provide access to both enantiomers of chiral pregabalin precursors. [57] For the reduction of chloroketones 5, single keteoreductases with complementary stereoselectivity for substrates that bear different protecting groups were reported during biocatalyst screening, [31,32] but the reactions were not further optimized to develop a process that is able to furnish both diastereomers with acceptable conversions and diastereomeric excess through reduction catalyzed by a single biocatalyst.…”

Section: Resultsmentioning

confidence: 99%

“…Most importantly, enzymes usually present high chemo-, regio-, and stereoselectivity, so that they can shorten synthetic routes and are especially suitable for asymmetric transformations. [17,[25][26][27][28][29][30] Biocatalytic methods for the reduction of N-protected chloroketones such as 5 have been reported and include reductions catalyzed by isolated engineered ketoreductases, [31][32][33] wildtype, [34][35][36] and mutagenized micro-organisms. [37] However, these methods possess drawbacks, such as long reaction times, the requirement of a second enzyme for cofactor regeneration, or the use of biocatalysts that are not available easily or the preparation of which requires elaborate and intricate methods, which limits their applicability and reproducibility.…”

Section: Introductionmentioning

confidence: 99%

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Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

et al. 2015

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E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a–d, the corresponding halohydrins 6 a–d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin (R,S)‐6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through “substrate‐based” stereocontrol. The RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % diastereomeric excess (de) and (S,S)‐6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an “inverted” mode in comparison to tert‐butyloxycarbonyl‐ and methyloxycarbonyl‐protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % de and (S,S)‐6 b with 95 % conversion and 86 % de.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

et al. 2015

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“…It is considered as a potent once‐daily drug with proven efficacy in both treatment‐experienced and treatment‐naive patients 2 . The synthetic route of atazanavir includes the synthesis of the key intermediate chlorohydrin (2 R ,3 S )‐N‐tert‐Butoxycarbonyl‐3‐amino‐1‐chloro‐2‐hydroxy‐4‐phenylbutane 1b 3,4 . In various chemical synthetic routes for atazanavir, the introduction of the chiral hydroxyl of 1b is realized by the stereoselective reduction of the N ‐protected chloroketone (3 S )‐3‐( N ‐Boc‐amino)‐1‐chloro‐4‐phenyl‐butanone 1a.…”

Section: Introductionmentioning

confidence: 99%

Efficient synthesis of an antiviral drug intermediate using overexpressed short‐chain dehydrogenase and cross‐linked enzyme aggregates stabilization

Yang

et al. 2020

J of Chemical Tech & Biotech

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BACKGROUND (2R,3S)‐N‐tert‐Butoxycarbonyl‐3‐amino‐1‐chloro‐2‐hydroxy‐4‐phenylbutane (1b) is key for the synthesis of the antiviral drug atazanavir. It can be obtained via the stereoselective bioreduction of (3S)‐3‐(N‐Boc‐amino)‐1‐chloro‐4‐phenyl‐butanone (1a) with short‐chain dehydrogenase/reductase (SDR) (EC 1.1.1.1). To develop a practical and cost‐effective biocatalytic approach with high stability and reusability, an SDR mutant (muSDR) from Novosphingobium aromaticivorans was overexpressed in Escherichia coli cell and immobilized by cross‐linked enzyme aggregates with enhanced stability and high efficiency. RESULTS muSDR gene was successfully cloned and overexpressed in Escherichia coli and reduced 1a to 1b with high stereoselectivity. Four resin‐bound muSDR and cross‐linked muSDR aggregates (muSDR‐CLEAs) were prepared and compared. With addition of Tween‐80, the muSDR‐CLEAs demonstrated much higher activity recovery than resin‐bound muSDR. Compared with free enzyme, muSDR‐CLEAs demonstrated enhanced thermal, pH, and storage stabilities and could obtain 1b with high substrate concentration, high de, and complete conversion. The reusability of CLEAs was also determined as no significant activity loss was observed after seven batches of reactions. The space time yield of the bioreduction using muSDR‐CLEAs was 226.6 g∙L−1∙day−1. CONCLUSION Overexpressed muSDR was efficiently immobilized, and it demonstrated superior stability and reusability. The recombinant muSDR and muSDR‐CLEAs are practical potential biocatalysts for industrial production of the atazanavir precursor. © 2020 Society of Chemical Industry (SCI)

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“…In addition, whole cells are often easy to produce and are relatively inexpensive. However, one disadvantage of using whole cells is that the volume efficiency of the reaction may be low and the reactions also frequently produce low yields (Alanvert et al 2009;Kroutil et al 2004). The use of whole cells from microorganisms has shown to be an important source of the new enzymes for the reduction of carbonylated compounds (Kratzer et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Bioreduction of 1-(4-Methoxyphenyl)ethanone by Whole Cells of Marine-Derived Fungi

et al. 2011

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Nine strains of marine-derived fungi (Aspergillus sydowii Ce15, A. sydowii Ce19, Aspergillus sclerotiorum CBMAI 849, Bionectria sp. Ce5, Beauveria felina CBMAI 738, Cladosporium cladosporioides CBMAI 857, Mucor racemosus CBMAI 847, Penicillium citrinum CBMAI 1186, and Penicillium miczynskii Gc5) were screened, catalyzing the asymmetric bioreduction of 1-(4-methoxyphenyl)ethanone 1 to its corresponding 1-(4-methoxyphenyl)ethanol 2. A. sydowii Ce15 and Bionectria sp. Ce5 produced the enantiopure (R)-alcohol 2 (>99% ee) in accordance with the anti-Prelog rule and, the fungi B. felina CBMAI 738 (>99% ee) and P. citrinum CBMAI 1186 (69% ee) in accordance with the Prelog rule. Stereoselective bioreduction by whole cells of marine-derived fungi described by us is important for the production of new reductases from marine-derived fungi.

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Highly stereoselective biocatalytic reduction of alpha-halo ketones

Cited by 16 publications

References 26 publications

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

Efficient synthesis of an antiviral drug intermediate using overexpressed short‐chain dehydrogenase and cross‐linked enzyme aggregates stabilization

Stereoselective Bioreduction of 1-(4-Methoxyphenyl)ethanone by Whole Cells of Marine-Derived Fungi

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