Considerations for the Scale‐up of <i>in vitro</i> Transaminase‐Catalyzed Asymmetric Synthesis of Chiral Amines

Madsen, Jørgen Steen; Woodley, John M.

doi:10.1002/cctc.202300560

Cited by 7 publications

(2 citation statements)

References 195 publications

(115 reference statements)

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“…was present in 35% of the top 200 small-molecule drugs sold in 2018, making them a key building block in the pharmaceutical sector. [15][16][17][18] The model system is shown in Scheme 1, and consists of the ω-transaminase-catalyzed synthesis of a model pyridine methylamine ((S)-1-(6-methoxypyridin-3-yl)ethanamine) of pharmaceutical relevance as intermediate for positive allosteric modulators of nicotinic acetylcholine receptor as used for various mental disorders. 19 2 | MATERIALS AND METHODS…”

Section: Convolutional Neural Network Model Development For Real-time...mentioning

confidence: 99%

“…This scenario is shown in Figure 9, in which the equilibrium shift toward conversion was managed due to evaporation of the acetone either by a not properly sealed lid (E) or by constant nitrogen sweeping (F). 15 It is noted that there are only Raman data for F up until approximately 8 h. This was due to the high evaporation rate of the reaction media itself, leading to the liquid level decreasing to beneath the immersion probe.…”

Section: Model Developmentmentioning

confidence: 99%

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Raman spectroscopy and one‐dimensional convolutional neural network modeling as a real‐time monitoring tool for in vitro transaminase‐catalyzed synthesis of a pharmaceutically relevant amine precursor

Madsen,

Topalian,

Jacobsen

et al. 2024

Biotechnology Progress

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Raman spectroscopy has been used to measure the concentration of a pharmaceutically relevant model amine intermediate for positive allosteric modulators of nicotinic acetylcholine receptor in a ω‐transaminase‐catalyzed conversion. A model based on a one‐dimensional convolutional neural network was developed to translate raw data augmented Raman spectra directly into substrate concentrations, with which the conversion from ketone to amine by ω‐transaminase could be determined over time. The model showed very good predictive capabilities, with R2 values higher than 0.99 for the spectra included in the modeling and 0.964 for an independent dataset. However, the model could not extrapolate outside the concentrations specified by the model. The presented work shows the potential of Raman spectroscopy as a real‐time monitoring tool for biocatalytic reactions.

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Section: Convolutional Neural Network Model Development For Real-time...mentioning

confidence: 99%

Section: Model Developmentmentioning

confidence: 99%

Raman spectroscopy and one‐dimensional convolutional neural network modeling as a real‐time monitoring tool for in vitro transaminase‐catalyzed synthesis of a pharmaceutically relevant amine precursor

Madsen,

Topalian,

Jacobsen

et al. 2024

Biotechnology Progress

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Two‐Step Biocatalytic Synthesis of (1S)‐Nor(pseudo)ephedrine Catalyzed by Immobilized Enzymes

Patti,

Magrini Alunno,

Semproli

et al. 2024

ChemCatChem

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Nor(pseudo)ephedrines [N(P)Es] are naturally occurring compounds showing sympathomimetic activity that have many applications especially in the chemical industry and in the pharmaceutical field. Recently a two‐step biocatalytic cascade for the preparation of (1S)‐N(P)E was designed, consisting of a benzoin‐type condensation catalyzed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) followed by a transamination mediated by either a (S)‐ or (R)‐selective amine transaminase (ATA). In this study, we successfully immobilized both Ao:DCPIP OR and two ATAs of opposite enantioselectivity and used them in the biosynthetic cascade to N(P)Es. Immobilization yield, activity recovery, and stability of the immobilized enzymes, both after use (enzyme recycling) and storage (shelf‐life), were assessed. Ao:DCPIP OR immobilized on glyoxyl‐agarose exhibited remarkable stability under storage conditions throughout the 30‐days monitoring period. Moreover, it was successfully reused in the synthesis of (S)‐phenylacetylcarbinol [(S)‐PAC] yielding high conversion (>94%) and enantiomeric excess (>99%). The (R)‐selective At‐ATA from Aspergillus terreus, immobilized on Eupergit® C, demonstrated a slightly higher storage stability when compared to the (S)‐selective Sbv333‐ATA from Streptomyces sp. Bv333 immobilized on the same carrier. Remarkably, both enzymes were effectively reused for ten reaction cycles in the synthesis of N(P)Es, starting from the enzymatically synthesized (S)‐PAC, achieving complete conversions and excellent diastereoselectivity (>99%).

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Moving Horizon Parameter Estimation for an Enzyme‐Catalyzed Transamination Reaction with Integrated Product Removal

Behrens,

Tiedemann,

Kunde

et al. 2024

Chemie Ingenieur Technik

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Chiral amines are key building blocks in producing active pharmaceutical ingredients and can be synthesized via the amine transaminase pathway under mild conditions with eco‐friendly solvents. For model‐based design and control, mathematical models can be utilized. This requires reliable parameterization of the model. In this study, a model for the production of (S)‐(3 methoxyphenyl)‐ethylamine is presented. Parameter identifiability is analyzed using the method of profile likelihoods. The parameter identifiability is then tested in two different batch operation scenarios by using moving horizon estimation, which can be applied for on‐line model adaption and control purposes. In a batch process, identifiability decreases over time. A repetitive batch strategy improves parameter identifiability.

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Considerations for the Scale‐up of in vitro Transaminase‐Catalyzed Asymmetric Synthesis of Chiral Amines

Cited by 7 publications

References 195 publications

Raman spectroscopy and one‐dimensional convolutional neural network modeling as a real‐time monitoring tool for in vitro transaminase‐catalyzed synthesis of a pharmaceutically relevant amine precursor

Raman spectroscopy and one‐dimensional convolutional neural network modeling as a real‐time monitoring tool for in vitro transaminase‐catalyzed synthesis of a pharmaceutically relevant amine precursor

Two‐Step Biocatalytic Synthesis of (1S)‐Nor(pseudo)ephedrine Catalyzed by Immobilized Enzymes

Moving Horizon Parameter Estimation for an Enzyme‐Catalyzed Transamination Reaction with Integrated Product Removal

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