Efficient Hydroxylation Research Articles

Unveiling Alternate Electrode Electrolysis in Electro-Photochemical and Electro-Organic Syntheses.

Electro-photochemical organic synthesis is a rapidly growing field. Recently, technological advancement has contributed significantly to improve electro- and photolytic organic transformations in terms of energy efficiency and productivity. Herein, we have introduced alternating electrode electrolysis|alternate electrode electrolysis (AEE), a new technique in electrosynthesis which in combination with blue LED demonstrated an interesting three-component reaction with aryl diazoesters, 1,4-quinones, and acetone to synthesize ketal-functionalized 1,4-quinones. The AEE setup consists of two pairs of cathode-anode compared to the conventional setup of one pair. Each pair would be polarized or in a resting stage with a preset interval of choice. This would maintain a continuous potential resulting in maximum current and would facilitate the mass transport, thereby increasing the overall efficiency of the reaction. AEE offers the efficient utilization of photochemically generated carbenes. We extended AEE applications in paired photoelectrolysis reactions for the late-stage functionalization of bioactive molecules and pharmaceutical agents. As an application of AEE in electrosynthesis (without light), we demonstrated the efficient hydroxylation of fluorinated benzene and the reduction of benzonitrile to benzyl amine. The amalgamation of AEE with blue LED contributes to sustainability, and we believe that it holds great promise in the field of electro-photochemical organic synthesis.

Vanadium-Modified TS-1 Catalysts with Enhanced Lewis Acid and Charge Density for Efficient Hydroxylation of Benzene to Phenol

Vanadium-Modified TS-1 Catalysts with Enhanced Lewis Acid and Charge Density for Efficient Hydroxylation of Benzene to Phenol

On the engineering of reductase-based-monooxygenase activity in CYP450 peroxygenases.

Recent bioengineering of CYP450OleT shows that peroxide-based CYP450OleT can be converted to a reductase-based self-sufficient enzyme, which is capable of showing efficient hydroxylation and decarboxylation activity for a wide range of substrates. The so-generated enzyme creates several mechanistic puzzles: (A) as CYP450 peroxygenases lack the conventional acid-alcohol pair, what is the source of two protons that are required to create the ultimate oxidant Cpd I? (B) Why is it only CYP450OleT that shows the reductase-based activity but no other CYP members? The present study provides a mechanistic solution to these puzzles using comprehensive MD simulations and hybrid QM/MM calculations. We show that the fusion of the reductase domain to the heme-binding domain triggers significant conformational rearrangement, which is gated by the propionate side chain, which constitutes a new water aqueduct via the carboxylate end of the substrate that ultimately participates in Cpd I formation. Importantly, such well-synchronized choreographies are controlled by remotely located Tyr359, which senses the fusion of reductase and communicates to the heme domain via non-covalent interactions. These findings provide crucial insights and a broader perspective which enables us to make a verifiable prediction: thus, the catalytic activity is not only limited to the first or second catalytic shell of an enzyme. Furthermore, it is predicted that reinstatement of tyrosine at a similar position in other members of CYP450 peroxygenases can convert these enzymes to reductase-based monooxygenases.

Enhanced photocatalytic performance of Cr doped MgO/Bi2O3 nanocomposite for efficient hydroxylation of benzene to phenol under visible-light irradiation

A series of Cr-doped MgO/Bi2O3 (Cr-MgO/Bi2O3) nanocomposites were prepared for the photocatalytic benzene hydroxylation to produce phenol by the visible-light exposure, and the catalyst dosage, solvents and volume ratio of benzene to H2O2 were thoroughly examined. The well-characterized photocatalyst (10% Cr- MgO/Bi2O3) by various physico-chemical and spectroscopic techniques was found to be highly efficient with an optimal phenol selectivity of 98.5% and yield of 13.8%, which were much higher than those obtained from bare Bi2O3, MgO and MgO/Bi2O3. The remarkably improved photocatalytic activity was resulted from the conduction of heterojunction between Bi2O3 and MgO, as well as the generation of a new trapping level within Cr-MgO/Bi2O3 by Cr doping, which greatly accelerated the photogenerated charge carriers separation. This work combining heterojunction conduction and transition metal doping exhibits promising potential for future applications in organic transformation reactions.

2D RGO nanosheets supported anti-spinel NiFe2O4 nanocubes for efficient hydroxylation of phenol

2D RGO nanosheets supported anti-spinel NiFe2O4 nanocubes for efficient hydroxylation of phenol

Efficient hydroxylation of flavonoids by using whole-cell P450 sca-2 biocatalyst in Escherichia coli.

The hydroxylation is an important way to generate the functionalized derivatives of flavonoids. However, the efficient hydroxylation of flavonoids by bacterial P450 enzymes is rarely reported. Here, a bacterial P450 sca-2mut whole-cell biocatalyst with an outstanding 3'-hydroxylation activity for the efficient hydroxylation of a variety of flavonoids was first reported. The whole-cell activity of sca-2mut was enhanced using a novel combination of flavodoxin Fld and flavodoxin reductase Fpr from Escherichia coli. In addition, the double mutant of sca-2mut (R88A/S96A) exhibited an improved hydroxylation performance for flavonoids through the enzymatic engineering. Moreover, the whole-cell activity of sca-2mut (R88A/S96A) was further enhanced by the optimization of whole-cell biocatalytic conditions. Finally, eriodictyol, dihydroquercetin, luteolin, and 7,3',4'-trihydroxyisoflavone, as examples of flavanone, flavanonol, flavone, and isoflavone, were produced by whole-cell biocatalysis using naringenin, dihydrokaempferol, apigenin, and daidzein as the substrates, with the conversion yield of 77%, 66%, 32%, and 75%, respectively. The strategy used in this study provided an effective method for the further hydroxylation of other high value-added compounds.

Enhanced biosynthesis of physiologically active vitamin D3 by constructing recombinant Escherichia coli BL21 with a multienzyme system

In this study, a recombinant E. coli strain with the multienzyme system of the vitamin D3 hydroxylase CYP105A1, the electron transport respiratory chain Fdx-FdR and the key enzymes (Glk-Zwf) in the cyclic regeneration of the coenzyme NADPH was constructed for the efficient hydroxylation of VD3 to prepare physiologically active 25(OH)VD3 and 1α, 25(OH)2VD3. The constructed recombinant E. coli strain with a multienzyme system was demonstrated to possess hydroxylation capability for VD3. The hydroxylation reaction of VD3 was carried out under optimal conditions. The highest concentration of the intermediate product 25(OH)VD3 was 58.92 mg/L with a yield of 11.31 %. The highest concentration of the final product 1α, 25(OH)2VD3 was 90.23 mg/L with a yield of 16.7 %. Ultimately, 395.92 mg/L 25(OH)VD3 and 272.21 mg/L 1α, 25(OH)2VD3 were produced by further substrate fed-batch experiments. This study contributes to the preparation of physiologically active 25(OH)VD3 and 1α, 25(OH)2VD3 by whole-cell biocatalysis of VD3 via the constructed recombinant strain.

Ni(I)-Catalyzed Hydroxylation of Aryl Halides with Water under Thermal Catalysis.

A highly efficient hydroxylation of (hetero)aryl halides using water as a hydroxyl source via Ni catalysis promoted by PhSiH3 under thermal catalysis is reported. This methodology provides a general procedure to obtain diverse multifunctional pharmaceutically phenols and polyphenols, some of which are proven challenging to be synthesized using literature methods. Mechanism studies demonstrated that the addition of PhSiH3 led to the generation of active Ni(I) species, which catalyze the hydroxylation via a Ni(I)-Ni(III) pathway.

Evolution-Guided Biosynthesis of Terpenoid Inhibitors.

Terpenoids, the largest and most structurally diverse group of natural products, include a striking variety of biologically active compounds, from flavors to medicines. Despite their well-documented biochemical versatility, the evolutionary processes that generate new functional terpenoids are poorly understood and difficult to recapitulate in engineered systems. This study uses a synthetic biochemical objective─a transcriptional system that links the inhibition of protein tyrosine phosphatase 1B (PTP1B), a human drug target, to the expression of a gene for antibiotic resistance in Escherichia coli (E. coli)─to evolve a terpene synthase to produce enzyme inhibitors. Site saturation mutagenesis of poorly conserved residues on γ-humulene synthase (GHS), a promicuous enzyme, yielded mutants that improved fitness (i.e., the antibiotic resistance of E. coli) by reducing GHS toxicity and/or by increasing inhibitor production. Intriguingly, a combination of two mutations enhanced the titer of a minority product─a terpene alcohol that inhibits PTP1B─by over 50-fold, and a comparison of similar mutants enabled the identification of a site where mutations permit efficient hydroxylation. Findings suggest that the plasticity of terpene synthases enables an efficient sampling of structurally distinct starting points for building new functional molecules and provide an experimental framework for exploiting this plasticity in activity-guided screens.

Correction: Efficient hydroxylation of benzene to phenol by H2O2 using Ni-doped CuWO4 on carbon nitride as a catalyst under solar irradiation and its structure–activity correlation

Correction for ‘Efficient hydroxylation of benzene to phenol by H2O2 using Ni-doped CuWO4 on carbon nitride as a catalyst under solar irradiation and its structure–activity correlation’ by Purashri Basyach et al., J. Mater. Chem. A, 2020, 8, 12774–12789, https://doi.org/10.1039/D0TA03729J.

A copper nitride catalyst for the efficient hydroxylation of aryl halides under ligand-free conditions.

Copper nitride (Cu3N) was used as a heterogeneous catalyst for the hydroxylation of aryl halides under ligand-free conditions. The cubic Cu3N nanoparticles showed high catalytic activity, comparable to those of conventional Cu catalysts with nitrogen ligands, demonstrating that the nitrogen atoms in Cu3N act as functional ligands that promote hydroxylation.

Selective hydroxylation of aryl iodides to produce phenols under mild conditions using a supported copper catalyst.

Owing to the high activity and low-cost, copper-based catalysts are promising candidates for transforming aromatic halides to yield phenols. In this work, we report the selective hydroxylation of aromatic iodides to produce phenols using an atomically dispersed copper catalyst (Cu–ZnO–ZrO2) under mild reaction conditions. The reactions were conducted without the use of additional organic ligands, and the protection of an inert atmosphere environment is not required. The catalyst can be easily prepared, scalable, and is very efficient for a wide range of substrates. The catalytic reactions can be carried out with only 1.24 mol% Cu loading, which shows great potential in mass production.

Development of Engineered Ferredoxin Reductase Systems for the Efficient Hydroxylation of Steroidal Substrates

9α-Hydroxy-4-androstene-3,17-dione (9OHAD), formed by the 9α-hydroxylation reaction catalyzed by 3-ketosteroid-9-hydroxylase (KSH), is an important precursor for the synthesis of adrenocortical hor...

Light‐Induced Efficient Hydroxylation of Benzene to Phenol by Quinolinium and Polyoxovanadate‐Based Supramolecular Catalysts

AbstractDirect Hydroxylation of benzene to phenol with high yield and selectivity has been the goal of phenol industrial production. Photocatalysis can serve as a competitive method to realize the hydroxylation of benzene to phenol owing to its cost‐effective and environmental friendliness, however it is still a forbidding challenge to obtain good yield, high selectivity and high atom availability meanwhile. Here we show a series of supramolecular catalysts based on alkoxohexavanadate anions and quinolinium ions for the photocatalytic hydroxylation of benzene to phenol under UV irradiation. We demonstrate that polyoxoalkoxovanadates can serve as efficient catalysts which can not only stabilize quinolinium radicals but also reuse H2O2 produced by quinolinium ions under light irradiation to obtain excellent synergistic effect, including competitive good yield (50.1 %), high selectivity (>99 %) and high atom availability.

Light-Induced Efficient Hydroxylation of Benzene to Phenol by Quinolinium and Polyoxovanadate-Based Supramolecular Catalysts.

Direct Hydroxylation of benzene to phenol with high yield and selectivity has been the goal of phenol industrial production. Photocatalysis can serve as a competitive method to realize the hydroxylation of benzene to phenol owing to its cost-effective and environmental friendliness, however it is still a forbidding challenge to obtain good yield, high selectivity and high atom availability meanwhile. Here we show a series of supramolecular catalysts based on alkoxohexavanadate anions and quinolinium ions for the photocatalytic hydroxylation of benzene to phenol under UV irradiation. We demonstrate that polyoxoalkoxovanadates can serve as efficient catalysts which can not only stabilize quinolinium radicals but also reuse H2 O2 produced by quinolinium ions under light irradiation to obtain excellent synergistic effect, including competitive good yield (50.1 %), high selectivity (>99 %) and high atom availability.

Systematic Evolution of Decoy Molecules for the Highly Efficient Hydroxylation of Benzene and Small Alkanes Catalyzed by Wild-Type Cytochrome P450BM3

Highly effective dipeptidic decoy molecules, which stimulate the direct hydroxylation of benzene by wild-type cytochrome P450BM3, were successfully developed through a rationally designed screening...

Efficient hydroxylation of benzene to phenol by H2O2 using Ni-doped CuWO4 on carbon nitride as a catalyst under solar irradiation and its structure–activity correlation

A series of environmentally benign and highly efficient Z-scheme Ni-doped CuWO4 nanoparticles on graphitic carbon nitride (g-C3N4) were synthesized.

Tuning the oxidation state of copper in CuMgAl hydrotalcite using partially oxidized MoS2 for efficient hydroxylation of phenol

The CuMgAl ternary hydrotalcite (CuMgAl) has been reported to achieve the decomposition of H2O2 to OH for hydroxylation of phenol, and the key active site is Cu+. The Cu2+ must be converted to Cu+, which is a slow step that lowers the total reaction efficiency. Herein, the partially oxidized MoS2 loaded CuMgAl (PO-MoS2/CuMgAl-1.12) sample was designed to overcome this issue. As a variable valence metal the Mo can partly tune the Cu2+ to Cu+ by forming MoOCu electron transport system which enhances the catalytic performance of our catalyst.

Directed Evolution of P450 BM3 towards Functionalization of Aromatic O-Heterocycles.

The O-heterocycles, benzo-1,4-dioxane, phthalan, isochroman, 2,3-dihydrobenzofuran, benzofuran, and dibenzofuran are important building blocks with considerable medical application for the production of pharmaceuticals. Cytochrome P450 monooxygenase (P450) Bacillus megaterium 3 (BM3) wild type (WT) from Bacillus megaterium has low to no conversion of the six O-heterocycles. Screening of in-house libraries for active variants yielded P450 BM3 CM1 (R255P/P329H), which was subjected to directed evolution and site saturation mutagenesis of four positions. The latter led to the identification of position R255, which when introduced in the P450 BM3 WT, outperformed all other variants. The initial oxidation rate of nicotinamide adenine dinucleotide phosphate (NADPH) consumption increased ≈140-fold (WT: 8.3 ± 1.3 min−1; R255L: 1168 ± 163 min−1), total turnover number (TTN) increased ≈21-fold (WT: 40 ± 3; R255L: 860 ± 15), and coupling efficiency, ≈2.9-fold (WT: 8.8 ± 0.1%; R255L: 25.7 ± 1.0%). Computational analysis showed that substitution R255L (distant from the heme-cofactor) does not have the salt bridge formed with D217 in WT, which introduces flexibility into the I-helix and leads to a heme rearrangement allowing for efficient hydroxylation.

Highly Regioselective and Stereoselective Hydroxylation of Free Amino Acids by a 2-Oxoglutarate-Dependent Dioxygenase from Kutzneria albida.

Hydroxyl amino acids have tremendous potential applications in food and pharmaceutical industries. However, available dioxygenases are limited for selective and efficient hydroxylation of free amino acids. Here, we identified a 2-oxoglutarate-dependent dioxygenase from Kutzneria albida by gene mining and characterized the encoded protein (KaPH1). KaPH1 was estimated to have a molecular weight of 29 kDa. The optimal pH and temperature for its l-proline hydroxylation activity were 6.5 and 30 °C, respectively. The Km and kcat values of KaPH1 were 1.07 mM and 0.54 s–1, respectively, for this reaction by which 120 mM l-proline was converted to trans-4-hydroxy-l-proline with 92.8% yield (3.93 g·L–1·h–1). EDTA, [1,10-phenanthroline], Cu2+, Zn2+, Co2+, and Ni2+ inhibited this reaction. KaPH1 was also active toward l-isoleucine for 4-hydroxyisoleucine synthesis. Additionally, the unique biophysical features of KaPH1 were predicted by molecular modeling whereby this study also contributes to our understanding of the catalytic mechanisms of 2-oxoglutarate-dependent dioxygenases.