Author
Matej Oslaj
Bio: Matej Oslaj is an academic researcher. The author has contributed to research in topics: Pyran & Carboxylate. The author has an hindex of 4, co-authored 9 publications receiving 72 citations.
Topics: Pyran, Carboxylate, Lactol, Chemistry, Nitroso
Papers
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TL;DR: To the authors' knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme.
Abstract: Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L−1 h−1 (up to 50 g L−1 h−1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L−1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.
39 citations
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TL;DR: The combined overexpression of the endogenous DERA and the membrane-bound, PQQ-dependent glucose dehydrogenase, the latter being coupled to the respiratory chain, allows direct biosynthesis of 6-substituted lactones in a highly productive, high-yield, cost-effective and industrially scalable process.
19 citations
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20 Jan 2009
TL;DR: In this paper, the present invention relates to ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl carboxylates and a process for the production thereof.
Abstract: The present invention relates to ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl carboxylates and a process for the production thereof Furthermore, the present invention relates to a process for the production of statins and in particular of Rosuvastatin and derivates thereof, wherein the above mentioned compounds are used as intermediates
9 citations
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02 Apr 2008
TL;DR: The process for the synthesis of statins featuring the use of an early intermediate (4R,6S)-6-(dialkoxymethyl)tetrahydro-2H-pyran-2,4-diol which already possesses the desired stereochemistry corresponding to the final statin is described in this article.
Abstract: The process for the synthesis of statins featuring the use of an early intermediate (4R,6S)-6-(dialkoxymethyl)tetrahydro-2H-pyran-2,4-diol which already possesses the desired stereochemistry corresponding to the final statin.
8 citations
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02 Apr 2008
TL;DR: The process for the synthesis of statins featuring the use of an early intermediate (4R,6S)-6-(dialkoxymethyl)tetrahydro-2H-pyran-2,4-diol which already possesses the desired stereochemistry corresponding to the final statin is described in this article.
Abstract: The process for the synthesis of statins featuring the use of an early intermediate (4R,6S)-6-(dialkoxymethyl)tetrahydro-2H-pyran-2,4-diol which already possesses the desired stereochemistry corresponding to the final statin.
2 citations
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TL;DR: The scope and limitations of such dehydrogenase-mediated processes are overviewed, as are future possibilities for the evolution of enzymatic DYRKR.
Abstract: Over the past two decades, the domains of both frontline synthetic organic chemistry and process chemistry and have seen an increase in crosstalk between asymmetric organic/organometallic approaches and enzymatic approaches to stereocontrolled synthesis. This review highlights the particularly auspicious role for dehydrogenase enzymes in this endeavor, with a focus on dynamic reductive kinetic resolutions (DYRKR) to "deracemize" building blocks, often setting two stereocenters in so doing. The scope and limitations of such dehydrogenase-mediated processes are overviewed, as are future possibilities for the evolution of enzymatic DYRKR.
66 citations
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TL;DR: In this paper, a review of large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols.
Abstract: Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool for the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in the first half of the last century exploited whole-cell microorganisms where the specific enzyme at work was not known. In the meantime, novel molecular biology methods, such as efficient gene sequencing and synthesis, triggered breakthroughs in directed evolution for the rapid development of process-stable enzymes with broad substrate scope and good selectivities tailored for specific substrates. To date, enzymes are employed to enable shorter, more efficient, and more sustainable alternative routes toward (established) small molecule APIs, and are additionally used to perform standard reactions in API synthesis more efficiently. Herein, large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols (if available) regarding the steps, reaction conditions, and scale. The review is structured according to the functional group formed in the reaction.
60 citations
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TL;DR: This study implements a short, aldolase-based pathway in Escherichia coli to produce (R)-1,3-BDO from glucose, an essential component of pharmaceutical products and cosmetics and highlights the potential of the a Aldolase chemistry to synthesize diverse products directly from renewable resources in microbes.
50 citations
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TL;DR: To the authors' knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme.
Abstract: Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L−1 h−1 (up to 50 g L−1 h−1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L−1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.
39 citations
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TL;DR: The present review is aimed to provide a brief overview of DERA, its history, and progress made in understanding the functioning of the enzyme.
Abstract: 2-Deoxy-d-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective C–C bond formation between acetaldehyde and numerous other aldehydes. However, the practical application of DERA as a biocatalyst is limited by its poor tolerance towards industrially relevant concentrations of aldehydes, in particular acetaldehyde. Therefore, the development of proper experimental conditions, including protein engineering and/or immobilization on appropriate supports, is required. The present review is aimed to provide a brief overview of DERA, its history, and progress made in understanding the functioning of the enzyme. Furthermore, the current understanding regarding aldehyde resistance of DERA and the various optimizations carried out to modify this property are discussed.
37 citations