N‐Halosuccinimide/BF<sub>3</sub>—H<sub>2</sub>O, Efficient Electrophilic Halogenating Systems for Aromatics.

Prakash, G. K. Surya; Mathew, Thomas; Hoole, Dushyanthi; Esteves, Pierre M.; Wang, Qi; Rasul, Golam; Oláh, George A.

doi:10.1002/chin.200515069

Cited by 22 publications

(24 citation statements)

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“…However, by traditional chemical synthesis, halogenations are generally not environmentally friendly reactions because most of these reactions need to be carried out under harsh conditions and often involve the use of toxic reagents, catalysts and solvents. Chemical halogenation reactions also lack regioselectivity, resulting in many byproducts (10)(11)(12)(13). The use of enzymes i.e.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the low catalytic capability of flavin-dependent halogenases

Phintha

Prakinee

Jaruwat

et al. 2021

Journal of Biological Chemistry

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Although flavin-dependent halogenases (FDHs) are attractive biocatalysts, their practical applications are limited because of their low catalytic efficiency. Here, we investigated the reaction mechanisms and structures of tryptophan 6-halogenase (Thal) from Streptomyces albogriseolususing stopped-flow, rapid-quench flow, QM/MM calculations, crystallography and detection of intermediate (hypohalous acid (HOX)) liberation. We found that the key flavin intermediate, C4a-hydroperoxyflavin (C4aOOH-FAD), formed by Thal and other FDHs(tryptophan 7-halogenase (PrnA) and tryptophan 5-halogenase (PyrH)), can react with I-, Br-, and Cl-but not F-, to form C4a-hydroxyflavin and HOX. Our experiments revealed that I-reacts with C4aOOH-FAD the fastest with the lowest energy barrier, and have shown for the first time that a significant amount of the HOX formed leaks out as free HOX. This leakage is probably a major cause of low product coupling ratios in all FDHs. Site-saturation mutagenesis of Lys79 showed that changing Lys79 to any other amino acid resulted in an inactive enzyme. However, the levels of liberated HOX of these variants are all similar, implying that Lys79 probably does not form a chloramine or bromamine intermediateas previously proposed. Computational calculations revealed that Lys79 has an abnormally lower pKa compared to other Lys residues, implying that the catalytic Lys may act as a proton donor in catalysis. Analysis of new X-ray structures of Thal also explains why pre-mixing of FDHs with FADH- generally results in abolishment of C4aOOH-FAD formation. These findings reveal the hidden factors restricting FDHs capability which should be useful for future development of FDHs applications.

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Section: Introductionmentioning

confidence: 99%

Dissecting the low catalytic capability of flavin-dependent halogenases

Phintha

Prakinee

Jaruwat

et al. 2021

Journal of Biological Chemistry

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“…Selective C-H activation is essential 1 for the synthesis of bioactive molecules [2][3][4] and natural products [5][6][7][8][9][10][11][12][13] , medicinal chemistry 3,[14][15][16][17] , the materials industry [18][19][20] , and agricultural industry [21][22][23] . Synthetic routes to activate unreactive C-H bonds require harsh conditions 24 and usually show poor selectivity 25 owing to the high C-H bond dissociation energy and its inertness due to low polarity 26 . Biological systems, such as non-heme iron enzymes, [27][28][29][30][31][32][33][34] carry out selective C-H activation of unreactive C-H bonds [35][36][37][38][39][40][41] efficiently at ambient conditions to catalyze a wide variety of reactions 37,[42][43][44] .…”

Section: Introductionmentioning

confidence: 99%

Are Vanadium Intermediates Suitable Mimics in Non-Heme Iron Enzymes? An Electronic Structure Analysis

Vennelakanti

Mehmood

Kulik

2022

Preprint

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Vanadyl intermediates are frequently used as mimics for the fleeting Fe(IV)=O intermediate in non-heme iron enzymes that catalyze C–H activation. Using density functional theory and correlated wavefunction theory, we investigate the degree to which vanadium mimic electronic structure is comparable to catalytic iron intermediates. Our calculations reveal crucial structural and energetic differences between vanadyl and ferryl intermediates primarily due to differences in ground spin states of low spin and high spin, respectively. This difference in spin state leads to differences in energetics for accessing isomers that confer activity in non-heme hydroxylase and halogenase enzymes. While interconversion between monodentate and bidentate succinate isomers of the key metal-oxo/hydroxo intermediates is energetically favorable for Fe, it is strongly unfavorable in V mimics. Additionally, isomerization of a terminal metal-oxo between an axial and equatorial position is energetically unfavorable for Fe but favorable for V. Electronic structure analyses to quantify differences in binding strength of Fe and V intermediates to –ketoglutarate and succinate cosubstrates reveal that both cosubstrates bind more strongly to V than Fe. Our work highlights the limits of using low- or intermediate-spin V-based intermediates as mimics in studies of fleeting high-spin Fe intermediates in non-heme iron enzymes.

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“…We could either brominate the final molecule PF‐622 or use 4‐bromophenyl isocyanate as a starting material to synthesize a halide precursor 7 of PF‐622 . There are several halogenation methods available in literatures . Some of the methods were tried and did not introduce halogen only into the phenyl ring A of the final molecule PF‐622 .…”

Section: Resultsmentioning

confidence: 99%

“…There are several halogenation methods available in literatures . Some of the methods were tried and did not introduce halogen only into the phenyl ring A of the final molecule PF‐622 . Krishna and her coworkers reported that an aniline and anisole can be brominated by the electrophilic substitution of bromine‐generated in situ from ammonium bromide as a bromine source and hydrogen peroxide as an oxidant.…”

Section: Resultsmentioning

confidence: 99%

Preparation of tritium‐labeled PF‐622, a novel fatty acid amide hydrolase inhibitor

Zhang

2017

Labelled Comp Radiopharmac

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To make a detailed characterization of the mechanism of inhibition and selectivity of a novel fatty acid amide hydrolase inhibitor PF-622, 3 tritium isotopomers were prepared. [ H]PF-622a labeled at the piperazine ring B and [ H]PF-622b labeled at both the ring B and phenyl ring A were synthesized via catalytic H(hydrogen)-T(tritium) exchange, utilizing 1 equiv and excess of Crabtree's catalyst, respectively. The preparation of [ H]PF-622c labeled only at the phenyl ring A was achieved via tritiodebromination of the bromide precursor, using Pd(PPh ) as a catalyst. The observations from these tritiation reactions might open a new perspective in the labeling for the targets having a similar moiety.

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N‐Halosuccinimide/BF₃—H₂O, Efficient Electrophilic Halogenating Systems for Aromatics.

Cited by 22 publications

References 1 publication

Dissecting the low catalytic capability of flavin-dependent halogenases

Dissecting the low catalytic capability of flavin-dependent halogenases

Are Vanadium Intermediates Suitable Mimics in Non-Heme Iron Enzymes? An Electronic Structure Analysis

Preparation of tritium‐labeled PF‐622, a novel fatty acid amide hydrolase inhibitor

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N‐Halosuccinimide/BF3—H2O, Efficient Electrophilic Halogenating Systems for Aromatics.

Cited by 22 publications

References 1 publication

Dissecting the low catalytic capability of flavin-dependent halogenases

Dissecting the low catalytic capability of flavin-dependent halogenases

Are Vanadium Intermediates Suitable Mimics in Non-Heme Iron Enzymes? An Electronic Structure Analysis

Preparation of tritium‐labeled PF‐622, a novel fatty acid amide hydrolase inhibitor

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N‐Halosuccinimide/BF₃—H₂O, Efficient Electrophilic Halogenating Systems for Aromatics.