Chemo‐Enzymatic Cascades

Slabu, Iustina; Bisagni, Serena; Hedley, Simon J.; Cherney, Alan H.; Pushpanath, Ahir; Bornadel, Amin; LePaih, Jacques; Mennen, Steven M.; Domı́nguez, Beatriz

doi:10.1002/9781119487043.ch12

Cited by 4 publications

(6 citation statements)

References 67 publications

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“…During optimization, only trace amounts of 3a were observed and very little 4a was encountered. This is likely due to the effectiveness of V 2 O 5 as a co-catalyst. ,, …”

Section: Resultsmentioning

confidence: 99%

“…This is likely due to the effectiveness of V 2 O 5 as a co-catalyst. 18,19,33 Enzyme Immobilization. The NR-55 and GDH-101 enzymes were not His-tagged, so use of affinity-based resins was not possible for immobilization.…”

Section: ■ Introductionmentioning

confidence: 99%

“… This presents a chemoenzymatic alternative to synthetic hydrogenation, running under atmospheric pressure, in aqueous media, and with perfect chemoselectivity. Several transition metal co-catalysts that can be used for hydroxylamine reduction in conjunction with NR mutants have been disclosed. − This permits the preparation of highly functionalized anilines using relatively mild and inexpensive conditions . There is therefore an opportunity for NR enzymes to be used within bioremediation of nitroaromatic compounds, with bacteria identified that use such compounds as energy sources. , Also, as stated, the significance of anilines in the development of bioactive molecules, coupled with the abundance of nitroaromatics as synthetic building blocks, offers new biosynthetic routes for NRs as replacements of synthetic hydrogenation catalysts in both discovery and process chemistry.…”

Section: Introductionmentioning

confidence: 99%

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Realizing the Continuous Chemoenzymatic Synthesis of Anilines Using an Immobilized Nitroreductase

Cosgrove

Miller

Bornadel

et al. 2023

ACS Sustainable Chem. Eng.

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The use of biocatalysis for classically synthetic transformations has seen an increase in recent years, driven by the sustainability credentials bio-based approaches can offer the chemical industry. Despite this, the biocatalytic reduction of aromatic nitro compounds using nitroreductase biocatalysts has not received significant attention in the context of synthetic chemistry. Herein, a nitroreductase (NR-55) is demonstrated to complete aromatic nitro reduction in a continuous packed-bed reactor for the first time. Immobilization on an amino-functionalized resin with a glucose dehydrogenase (GDH-101) permits extended reuse of the immobilized system, all operating at room temperature and pressure in aqueous buffer. By transferring into flow, a continuous extraction module is incorporated, allowing the reaction and workup to be continuously undertaken in a single operation. This is extended to showcase a closed-loop aqueous phase, permitting reuse of the contained cofactors, with a productivity of >10 gproduct gNR‑55 –1 and milligram isolated yields >50% for the product anilines. This facile method removes the need for high-pressure hydrogen gas and precious-metal catalysts and proceeds with high chemoselectivity in the presence of hydrogenation-labile halides. Application of this continuous biocatalytic methodology to panels of aryl nitro compounds could offer a sustainable approach to its energy and resource-intensive precious-metal-catalyzed counterpart.

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“…During optimization, only trace amounts of 3a were observed and very little 4a was encountered. This is likely due to the effectiveness of V 2 O 5 as a co-catalyst. ,, …”

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Realizing the Continuous Chemoenzymatic Synthesis of Anilines Using an Immobilized Nitroreductase

Cosgrove

Miller

Bornadel

et al. 2023

ACS Sustainable Chem. Eng.

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“…1 We recently developed an approach to the reduction of nitrobenzene derivatives that allows for robust chemoselectivity under mild conditions. 9,10 This methodology relies on the use of flavin mononucleotide (FMN)-dependent nitroreductases (NRs) in combination with a transition metal to catalyze the formation of the hydroxylamine intermediate and its subsequent disproportionation to form the corresponding aniline and the nitroso intermediate as a side product. The nitroso compound formed is efficiently recycled in the reaction by the NR catalysis.…”

mentioning

confidence: 99%

“…18 Herein, the reactor design and reaction parameters optimization were applied to increase the substrate concentration and minimize the accumulation of intermediates and side products, while enzyme engineering and high-throughput screening were employed to design and obtain improved enzymes for achieving higher productivities. Scale-up studies performed following the proof of concept 9,10 showed that increasing the substrate concentration in batch resulted in higher formation of the undesired side products, particularly 6. A batch reaction run at 200 mM (28 g/L) 2 catalyzed by 2.5 mg/mL NR-14 resulted in 89% 1, 1% 5, and 10% 6 after 4 h as measured by high-performance liquid chromatography (HPLC) (Table S4).…”

mentioning

confidence: 99%

Process Development and Protein Engineering Enhanced Nitroreductase-Catalyzed Reduction of 2-Methyl-5-nitro-pyridine

Bornadel

Bisagni

Pushpanath

et al. 2020

Org. Process Res. Dev.

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Reduction of aromatic nitro compounds to anilines is of great interest to the chemical industry. Biocatalytic reduction of nitroarenes has made it possible to effectively produce anilines by applying nitroreductase enzymes (NR) in combination with vanadium pentoxide. Herein, the NR-catalyzed reduction of 2-methyl-5-nitro-pyridine (2) to give the desired aniline (1) was studied as a model reaction. It demonstrates the importance of process development and enzyme engineering as key approaches to overcome scale-up issues and improve yield and productivity. Moving to fed-batch allowed controlling the feeding rate of 2 to prevent the accumulation of intermediates and formation of undesired side products. Starting with a substrate (2) concentration of 200 mM (28 g/L) and enzyme loading of 5 mg/mL (18% w/w), it was possible to achieve complete conversion and 1 in 95% yield by high-performance liquid chromatography (89.1% isolated yield) over 18 h, whereas, with 500 mM (69 g/L) 2 and an enzyme loading of 10 mg/mL (14.5% w/w), the same conversion and yield were achieved in 26 h. A rational engineering of NR-4 yielded faster variants, including NR-5, in only one round. The improved rate of the new variants allowed increasing the feeding rate of 2 to shorten the reaction time to less than a day as well as decreasing the enzyme loading to 3.6%.

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Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis

Holder,

Yuce,

Oriomah

et al. 2024

ChemBioChem

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Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR‐55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials. After screening on analytical scale, we show that sixteen substrates could be scaled to 1 mmol scale, with several poly‐functional anilines afforded with ease under the standard conditions. The aniline products were also screened for activity against several cell lines of interest, with modest activity observed for one compound. This study demonstrates the potential for nitroreductase biocatalysis to provide access to functional fragments under benign conditions.

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Chemo‐Enzymatic Cascades

Cited by 4 publications

References 67 publications

Realizing the Continuous Chemoenzymatic Synthesis of Anilines Using an Immobilized Nitroreductase

Realizing the Continuous Chemoenzymatic Synthesis of Anilines Using an Immobilized Nitroreductase

Process Development and Protein Engineering Enhanced Nitroreductase-Catalyzed Reduction of 2-Methyl-5-nitro-pyridine

Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis

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