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Biocatalytic access to betazole using a one-pot multienzymatic system in continuous flow.

ABSTRACT: As an alternative to classical synthetic approaches for the production of betazole drug, a one-pot biocatalytic system for this pharmaceutical molecule from its alcohol precursor has been developed. An ω-transaminase, an alcohol dehydrogenase and a water-forming NADH oxidase for in situ cofactor recycling have been combined to catalyse this reaction, yielding 75% molar conversion in batch reactions with soluble enzymes. This multienzyme system was then co-immobilised through a newly established protocol for sequential functionalization of a methacrylate-based porous carrier to enable tailored immobilisation chemistries for each enzyme. This pluri-catalytic system has been set up in a continuous flow packed-bed reactor, generating a space-time yield of up to 2.59 g L^-1 h^-1 with 15 min residence and a constant supply of oxygen for in situ cofactor recycling through a segmented air-liquid flow. The addition of an in-line catch-and-release column afforded >80% product recovery.

SUBMITTER: Romero-Fernandez M

PROVIDER: S-EPMC8215649 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades*.

Project description:A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross-reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine.

| S-EPMC8453870 | biostudies-literature

The Biocatalytic Synthesis of Syringaresinol from 2,6-Dimethoxy-4-allylphenol in One-Pot Using a Tailored Oxidase/Peroxidase System.

Project description:Syringaresinol was synthesized in a one-pot conversion containing eugenol oxidase (EUGO) and horseradish peroxidase (HRP) using the relatively cheap 2,6-dimethoxy-4-allylphenol as a substrate. This conversion is fully coupled as the hydrogen peroxide generated from the reaction of EUGO with the substrate is utilized by the HRP to convert the formed sinapyl alcohol into syringaresinol. To improve the performance of EUGO on 2,6-dimethoxy-4-allylphenol, structure-inspired enzyme engineering was performed. This yielded the I427A EUGO mutant that is significantly more efficient with 2,6-dimethoxy-4-allylphenol. The I427A EUGO mutant together with HRP were capable of efficiently producing syringaresinol as a major product. After optimization and upscaling the conversion to a semipreparative scale (1 gr), syringaresinol was obtained in 81% yield.

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Tandem One-Pot Biocatalytic Oxidation and Wittig Reaction in Water.

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One-Pot Synthesis of Diverse γ-Lactam Scaffolds Facilitated by a Nebulizer-Based Continuous Flow Photoreactor.

Project description:The use of a modified prototype continuous flow reactor (CFR) as a pivotal part of a number of versatile singlet oxygen-mediated reaction sequences is presented herein. These sequences target rapid access to structural complexity and diversity. The prototype reactor achieves high conversions and productivities by attaining large specific surface areas for these biphasic reactions. In the reactor, the reaction solution is nebulized (using either oxygen or air) and the resulting aerosol is irradiated by an LED jacket that surrounds the Pyrex reaction chamber. The one pot procedures developed herein are, according to many different criteria, both highly efficient and green. The key common intermediates and the source of both the complexity and variety of the final products are N-acyl imminium ions (NAI; protonated N-acyl enamines). The initial substrates are simple and readily accessible furans and the diverse array of products is composed of different complex γ-lactams. Many of the products are of particular interest due to their close relationships to known biologically active molecules.

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One-Pot Biocatalytic Synthesis of rac-Syringaresinol from a Lignin-Derived Phenol

Project description: Not available

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Continuous, One-pot Synthesis and Post-Synthetic Modification of NanoMOFs Using Droplet Nanoreactors.

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Biocatalytic Production of a Nylon 6 Precursor from Caprolactone in Continuous Flow.

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One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald-Hartwig N-Arylation.

Project description:The combination of biocatalysis and chemo-catalysis increasingly offers chemists access to more diverse chemical architectures. Here, we describe the combination of a toolbox of chiral-amine-producing biocatalysts with a Buchwald-Hartwig cross-coupling reaction, affording a variety of ?-chiral aniline derivatives. The use of a surfactant allowed reactions to be performed sequentially in the same flask, preventing the palladium catalyst from being inhibited by the high concentrations of ammonia, salts, or buffers present in the aqueous media in most cases. The methodology was further extended by combining with a dual-enzyme biocatalytic hydrogen-borrowing cascade in one pot to allow for the conversion of a racemic alcohol to a chiral aniline.

| S-EPMC7590080 | biostudies-literature

One-pot biocatalytic route from cycloalkanes to α,ω-dicarboxylic acids by designed Escherichia coli consortia.

Project description:Aliphatic α,ω-dicarboxylic acids (DCAs) are a class of useful chemicals that are currently produced by energy-intensive, multistage chemical oxidations that are hazardous to the environment. Therefore, the development of environmentally friendly, safe, neutral routes to DCAs is important. We report an in vivo artificially designed biocatalytic cascade process for biotransformation of cycloalkanes to DCAs. To reduce protein expression burden and redox constraints caused by multi-enzyme expression in a single microbe, the biocatalytic pathway is divided into three basic Escherichia coli cell modules. The modules possess either redox-neutral or redox-regeneration systems and are combined to form E. coli consortia for use in biotransformations. The designed consortia of E. coli containing the modules efficiently convert cycloalkanes or cycloalkanols to DCAs without addition of exogenous coenzymes. Thus, this developed biocatalytic process provides a promising alternative to the current industrial process for manufacturing DCAs.

| S-EPMC7542165 | biostudies-literature

Three-steps in one-pot: whole-cell biocatalytic synthesis of enantiopure (+)- and (-)-pinoresinol via kinetic resolution.

Project description:BackgroundPinoresinol is a high-value plant-derived lignan with multiple health supporting effects. Enantiomerically pure pinoresinol can be isolated from natural sources, but with low efficiency. Most chemical and biocatalytic approaches that have been described for the synthesis of pinoresinol furnish the racemic mixture. In this study we devised a three-step biocatalytic cascade for the production of enantiomerically pure pinoresinol from the cheap compound eugenol. Two consecutive oxidations of eugenol through vanillyl-alcohol oxidase and laccase are followed by kinetic resolution of racemic pinoresinol by enantiospecific pinoresinol reductases.ResultsThe addition of the enantiospecific pinoresinol reductase from Arabidopsis thaliana for kinetic resolution of (±)-pinoresinol to an in vitro cascade involving the vanillyl-alcohol oxidase from Penicillium simplicissimum and the bacterial laccase CgL1 from Corynebacterium glutamicum resulted in increasing ee values for (+)-pinoresinol; however, an ee value of 34% was achieved in the best case. The ee value could be increased up to ≥ 99% by applying Escherichia coli-based whole-cell biocatalysts. The optimized process operated in a one-pot "two-cell" sequential mode and yielded 876 µM (+)-pinoresinol with an ee value of 98%. Switching the reductase to the enantiospecific pinoresinol lariciresinol reductase from Forsythia intermedia enabled the production of 610 µM (-)-pinoresinol with an ee value of 97%.ConclusionA new approach for the synthesis of enantiomerically pure (+)- and (-)-pinoresinol is described that combines three biotransformation steps in one pot. By switching the reductase in the last step, the whole-cell biocatalysts can be directed to produce either (+)- or (-)-pinoresinol. The products of the reductases' activity, (-)-lariciresinol and (-)-secoisolariciresinol, are valuable precursors that can also be applied for the synthesis of further lignans.

| S-EPMC4862135 | biostudies-literature

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