The Industrial Age of Biocatalytic Transamination Fuchs, Michael; Farnberger, Judith E.; Kroutil, Wolfgang
European journal of organic chemistry,
November 2015, Letnik:
2015, Številka:
32
Journal Article
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During the last decade the use of ω‐transaminases has been identified as a very powerful method for the preparation of optically pure amines from the corresponding ketones. Their immense potential ...for the preparation of chiral amines, together with their ease of use in combination with existing biocatalytic methods, have made these biocatalysts a competitor to any chemical methodology for (asymmetric) amination. An increasing number of examples, especially from industry, shows that this biocatalytic technology outmaneuvers existing chemical processes by its simple and flexible nature. In the last few years numerous publications and patents on synthetic routes, mainly to pharmaceuticals, involving ω‐transaminases have been published. The review gives an overview of the application of ω‐transaminases in organic synthesis with a focus on active pharmaceutical ingredients (APIs) and the developments during the last few years.
ω‐Transaminase‐catalyzed preparation of chiral amines has emerged as one of the most successful fields in biocatalysis over the past ten years. This review covers the development of the catalytic systems and points out the most important applications, especially with regard to industrial and commercial use of the technology.
We report a straightforward chemical strategy to tackle current challenges of irreversible deformation in low Tg vitrimers at operating temperature. In particular, vinylogous urethane (VU) vitrimers ...were prepared where reactive free amines, necessary for material flow, were temporarily shielded inside the network backbone, by adding a small amount of dibasic ester to the curing mixture. The amines could be released as reactive chain ends from the resulting dicarboxamide bonds via thermally reversible cyclisation to an imide moiety. Indeed, (re)generation of the required nucleophilic amines as network defects ensured reprocessing and rapid material flow at higher temperature, where exchange dynamics are (re)activated. As a result, VU vitrimers were obtained with limited creep at service temperature, yet with good reprocessability at elevated temperatures. Thus, by exerting strong control on the molecular level over the availability of exchangeable functional groups, a remarkable improvement of VU properties was obtained.
Viscous deformation in elastomeric vitrimers is suppressed by temporarily trapping a reactive side chain in the polymer backbone. Upon heating, the network defect is recovered allowing for fast exchange. This offers a versatile strategy to simultaneously achieve fast reprocessing, while maintaining the strong dimensional stability of vitrimers.
Lyophilized whole cells and the crude enzymatic extract from the fungus Stemphylium lycopersici were successfully immobilized in situ in rigid polyurethane foam, as an alternative biocatalyst for the ...kinetic resolution of rac-1-phenylethylamine, an interesting building block in the synthesis of pharmaceuticals. The enzymatic activity of immobilized whole cells and the crude enzymatic extract was 2.52 and 5.05 U/g, respectively. The immobilization yield in polyurethane of both forms was at least above 100%, and the process did not change the affinity of the biocatalyst for the substrate. The optima reaction conditions for the kinetic resolution of rac-1-phenylethylamine into acetophenone were: 32.5 °C, 120 rpm by 24 h containing 10 mL (20% m/v) of phosphate buffer (pH 7.5) and 20% biocatalyst mass, resulting in conversions of 45% and 34% using the immobilized lyophilized fungus and crude enzymatic extract, respectively. Stemphylium lycopersici was also subjected to high pressure using CO2. The best conditions provided conversions of 49 (99% ee) and 26.21 (without ee) using the immobilized lyophilized fungus and the immobilized lyophilized crude enzyme extract, respectively, with 20 cycles of reuse and recovery greater than 50% (fungus). Interestingly, the compounds were satisfactorily converted to the corresponding ketones with up to 90% ee for the R-enantiomer. The capacity for conversion of the immobilized lyophilized fungus to different amines: rac-1,2,3,4-tetrahydro-1-naphthylamine, rac-1-phenylpropylamine, and rac-phenylbutylamine was also evaluated. ω-transaminase activity changed significantly depending on the experimental conditions applied, allowing the selection of proper operating conditions for advantageous application of this biocatalyst in transamination reactions.
•Stemphylium lycopersici as biocatalyst for kinetic resolution of amines.•The efficiency of polyurethane for the immobilization of biocatalysts.•The fungal whole cell contributes positively for ω-transamination reactions.•The activation process in pressurized CO2 provided a better catalytic performance.
Compartmentalised flow reactors allow biocatalytic cascades that would be impossible using standard methods, as described by Sebastian C. Cosgrove, Sabine L. Flitsch, and co‐workers in their Research ...Article on page 18660. Carbonyl intermediates were continuously generated via biocatalytic oxidation, then converted into different amine products using immobilised aminating enzymes. The use of flow equipment allowed exquisite control of the paths and enabled a range of new biocatalytic cascades to be constructed, paving the way for fully automated continuous biocatalytic cascades.
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.
The use of continuous flow reactors enabled previously inaccessible enzyme combinations in multi‐enzyme cascade reactions. This included the combination of oxidases with aminating biocatalysts (transaminase/reductive aminase) and was extended to the continuous in situ biocatalytic generation of amino donors for the reductive aminase.
Electron‐deficient enamines such as enaminones and enaminoesters are moieties showing widespread application in organic synthesis. Among the various available electron‐deficient enamines, the ...N,N‐disubstituted amino‐functionalized ones (tertiary enamines) represent a class of special enamines with distinct properties and important applications. Based on our longstanding interest in exploring novel synthetic methods using electron‐deficient tertiary enamines, we present herein the research advances in organic synthesis via domino reactions making use of the combinatorial C–N, C=C, C–H, and other bond transformations of electron‐deficient tertiary enamines.
Electron‐deficient tertiary enamines such as N,N‐disubstituted enamines and enaminoesters are stable molecules containing multiple reaction sites, and are highly useful building blocks in organic synthesis. Recent advances in domino reactions designed by using combinatorial transformations on the chemical bonds of these enamines are summarized.
The acceptorless dehydrogenation of acyclic secondary amines is a highly desirable but still elusive catalytic process. Here we report the synthesis, characterization, and activity of Pd-doped ...hydrotalcites (Pd-HTs) for acceptorless dehydrogenation of both primary and secondary amines (cyclic and acyclic). These multifunctional catalysts comprise Brønsted basic and Lewis acidic surface sites that stabilize Pd in 0, 2+, and 4+ oxidation states. Pd speciation and corresponding catalytic performance is a strong function of metal loading. High activity is observed for the dehydrogenation of secondary aliphatic amines to imines, and N-heterocycles, such as indoline, 1,2,3,4-tetrahydroquinoline, and piperidine, to aromatic compounds. Oxidative transamination of primary amines is achieved using low Pd loading (0.5 mol %), without the need for oxidants. The relative yields of secondary imines afforded are consistent with trends for calculated free energy of reaction, while yields for transamination products correspond to the electrophilicity of primary imine intermediates. Reversible amine dehydrogenation and imine hydrogenation determine the relative selectivity for secondary imine/amine products. Poisoning tests evidence that Pd-HTs operate heterogeneously, with negligible metal leaching. Catalysts retain over 90% of activity over six reuse cycles, but do suffer some selectivity loss, attributed to changes of Pd phases.
The kinetic resolution of racemic amino acids mediated by dipeptides and pyridoxal provides a prebiotically plausible route to enantioenriched proteinogenic amino acids. The enzymatic transamination ...cycles that are key to modern biochemical formation of enantiopure amino acids may have evolved from this half of the reversible reaction couple. Kinetic resolution of racemic precursors emerges as a general route to enantioenrichment under prebiotic conditions.
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