RESUMO
Fluorinated pyrazoles play an important role in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Since the early 1990s, their popularity has grown exponentially. Moreover, more than 50% of all contributions on the topic have been published in the last 5 years. In this review, analysis of novel synthetic approaches to fluorinated pyrazoles that appeared in recent years is performed. A particular emphasis is devoted to a detailed consideration of reaction mechanisms. In addition, the reasons that have led to the ever-increasing popularity of fluorinated pyrazoles in various areas of science are discussed. At the end of the review, several potentially interesting but yet mostly unknown classes of fluorinated pyrazoles are outlined.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Pirazóis/química , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura MolecularRESUMO
The biocatalytic toolbox has recently been expanded to include enzyme-catalyzed carbene transfer reactions not occurring in Nature. Herein, we report the development of a biocatalytic strategy for the synthesis of enantioenriched α-trifluoromethyl amines through an asymmetric N-H carbene insertion reaction catalyzed by engineered variants of cytochrome c552 from Hydrogenobacter thermophilus. Using a combination of protein and substrate engineering, this metalloprotein scaffold was redesigned to enable the synthesis of chiral α-trifluoromethyl amino esters with up to >99% yield and 95:5 er using benzyl 2-diazotrifluoropropanoate as the carbene donor. When the diazo reagent was varied, the enantioselectivity of the enzyme could be inverted to produce the opposite enantiomers of these products with up to 99.5:0.5 er. This methodology is applicable to a broad range of aryl amine substrates, and it can be leveraged to obtain chemoenzymatic access to enantioenriched ß-trifluoromethyl-ß-amino alcohols and halides. Computational analyses provide insights into the interplay of protein- and reagent-mediated control on the enantioselectivity of this reaction. This work introduces the first example of a biocatalytic N-H carbenoid insertion with an acceptor-acceptor carbene donor, and it offers a biocatalytic solution for the enantioselective synthesis of α-trifluoromethylated amines as valuable synthons for medicinal chemistry and the synthesis of bioactive molecules.
Assuntos
Aminas/síntese química , Grupo dos Citocromos c/química , Hidrocarbonetos Fluorados/síntese química , Aminas/metabolismo , Compostos Azo/química , Bactérias/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biocatálise , Grupo dos Citocromos c/genética , Grupo dos Citocromos c/metabolismo , Evolução Molecular Direcionada , Heme/química , Mutação , Ligação Proteica , Engenharia de Proteínas , EstereoisomerismoRESUMO
Difluoromethyl amino acids (DFAA) exhibit intriguing biological properties, making them highly desirable motifs in agrochemical and pharmaceutical science. However, stereochemical control of direct difluoromethyl transformation via the difluorocarbene species has not been demonstrated. Here we describe an efficient copper-catalyzed asymmetric difluoromethylation reaction that systematically delivers chiral DFAA as rationally designed mechanism-based inhibitors of PLP-dependent amino acid decarboxylases. The reaction employs difluoromonochloromethane, an abundant raw material, as the direct precursor of difluorocarbene species, enabling the unprecedentedly direct conversion of amino esters into corresponding valuable DFAA products in good yields with excellent enantioselectivities. This de novo synthesis creates opportunities to integrate an asymmetric catalytic platform for the preparation of diverse libraries of biologically important DFAA derivatives and will support efforts in both drug discovery and development.
Assuntos
Aminoácidos/química , Cobre/química , Hidrocarbonetos Fluorados/síntese química , Aminoácidos/síntese química , Catálise , Hidrocarbonetos Fluorados/química , Metilação , EstereoisomerismoRESUMO
Density functional calculations have provided evidence that a Ag(I)-mediated deconstructive fluorination of N-benzoylated cyclic amines (LH) with Selectfluor [(F-TEDA)(BF4)2] begins with an association of the reactants to form a singlet state adduct {[(LH)-Ag]-[F-TEDA]2+}. The subsequent formation of an iminium ion intermediate, [L+-Ag]-HF-[TEDA]+, is, formally, a Ag(I)-mediated hydride abstraction event that occurs in two steps: (a) a formal oxidative addition (OA) of [F-TEDA]2+ to the Ag(I) center that is attended by an electron transfer (ET) from the substrate (LH) to the Ag center (i.e., OA + ET, this process can also be referred to as a F-atom coupled electron transfer), followed by (b) H-atom abstraction from LH by the Ag-coordinated F atom. The overall process involves lower-lying singlet and triplet electronic states of several intermediates. Therefore, we formally refer to this reaction as a two-state reactivity (TSR) event. The C-C bond cleavage/fluorination of the resulting hemiaminal intermediate via a ring-opening pathway has also been determined to be a TSR event. A competing deformylative fluorination initiated by hemiaminal to aldehyde equilibration involving formyl H-atom abstraction by a TEDA2+ radical dication, decarbonylation, and fluorination of the resulting alkyl radical by another equivalent of Selectfluor may also be operative in the latter step.
Assuntos
Aminas/química , Prata/química , Catálise , Ciclização , Transporte de Elétrons , Elétrons , Halogenação , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Conformação Molecular , Oxirredução , Teoria QuânticaRESUMO
Plant parasitic nematodes have always been a pressing problem in the field of plant protection. Well-established chemical nematicides, especially organophosphorus and carbamates are the most used products for nematode control worldwide. Due to long-term overuse, they have developed serious resistance and new innovative solutions are urgently required. In this study, thirty-one novel trifluorobutene amide derivatives were designed and synthesized, and their nematicidal activities were determined. Three different synthetic methods have been developed for the final amidation reaction enabling the successfully syntheses of the target compounds independently from the nucleophilicities of the substrate amino group. Most target compounds showed good nematicidal activity in our in vitro test. Among all the compounds, compounds A8 and A23 exhibited excellent nematicidal activity against Meloidogyne incognita, their LC50 values are 2.02 mg L-1 and 0.76 mg L-1, respectively. In particular, compound A23 has found to be almost as active as the commercial nematicide fluensulfone. Furthermore, most compounds gave full control (100% inhibition) of M. incognita at 40 mg L-1 in the in vivo tests in sandy soil, the best compounds were further investigated for in vivo activity in matrix soil. Among the compound tested, compound A8 showed excellent in vivo nematicidal activity. At a concentration of 5 mg L-1 still 56% inhibition was observed. The results of our study indicate that compound A8 possesses excellent in vitro and in vivo nematicidal activity, and can be considered as promising lead molecule for further modification.
Assuntos
Amidas/síntese química , Antinematódeos/síntese química , Hidrocarbonetos Fluorados/síntese química , Doenças das Plantas/prevenção & controle , Tylenchoidea/efeitos dos fármacos , Amidas/farmacologia , Animais , Antinematódeos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Controle de Pragas , Doenças das Plantas/parasitologia , Relação Estrutura-Atividade , Sulfonas/farmacologia , Sulfonas/normas , Tiazóis/farmacologia , Tiazóis/normasRESUMO
An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.
Assuntos
Hidrocarbonetos Fluorados/farmacologia , Janus Quinase 3/antagonistas & inibidores , Cetonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Janus Quinase 3/metabolismo , Cetonas/síntese química , Cetonas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min-1), the strongest phototoxicity (IC50 = 1.24 µM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.
Assuntos
Antineoplásicos/uso terapêutico , Éteres/uso terapêutico , Hematoporfirinas/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Teoria da Densidade Funcional , Éteres/síntese química , Éteres/efeitos da radiação , Feminino , Hematoporfirinas/síntese química , Hematoporfirinas/efeitos da radiação , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/efeitos da radiação , Luz , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Químicos , Neoplasias/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (PPY). Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.
Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/química , Hidrocarbonetos Fluorados/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Receptor A2A de Adenosina/metabolismo , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Animais , Autorradiografia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Hidrocarbonetos Fluorados/síntese química , Imageamento por Ressonância Magnética , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases/química , Hidrocarbonetos Fluorados , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Relação Estrutura-AtividadeRESUMO
Strategic replacement of protons with fluorine atoms or functional groups with fluorine-containing fragments has proven a powerful strategy to optimize the activity of therapeutic compounds. For this reason, the synthetic chemistry of organofluorides has been the subject of intense development and innovation for many years. By comparison, the literature on fluorine biocatalysis still makes for a slim chapter. Herein we introduce S-adenosylmethionine (SAM) dependent methyltransferases as a new tool for the production of fluorinated compounds. We demonstrate the ability of halide methyltransferases to form fluorinated SAM (S-adenosyl-S-(fluoromethyl)-L-homocysteine) from S-adenosylhomocysteine and fluoromethyliodide. Fluorinated SAM (F-SAM) is too unstable for isolation, but is accepted as a substrate by C-, N- and O-specific methyltransferases for enzyme-catalyzed fluoromethylation of small molecules.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Indicadores e Reagentes/química , Metiltransferases/química , S-Adenosilmetionina/análogos & derivados , Bactérias/enzimologia , Proteínas de Bactérias/química , Halogenação , MetilaçãoRESUMO
Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.
Assuntos
Descoberta de Drogas , Hidrocarbonetos Fluorados/síntese química , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Oxirredução , Processos FotoquímicosRESUMO
The first example of free amine γ-C(sp3)-H fluorination is realized using 2-hydroxynicotinaldehyde as the transient directing group. A wide range of cyclohexyl and linear aliphatic amines could be fluorinated selectively at the γ-methyl and methylene positions. Electron withdrawing 3,5-disubstituted pyridone ligands were identified to facilitate this reaction. Computational studies suggest that the turnover determining step is likely the oxidative addition step for methylene fluorination, while it is likely the C-H activation step for methyl fluorination. The explicit participation of Ag results in a lower energetic span for methylene fluorination and a higher energetic span for methyl fluorination, which is consistent with the experimental observation that the addition of silver salt is desirable for methylene but not for methyl fluorination. Kinetic studies on methyl fluorination suggest that the substrate and PdL are involved in the rate-determining step, indicating that the C-H activation step may be partially rate-determining. Importantly, an energetically preferred pathway has identified an interesting pyridone-assisted bimetallic transition state for the oxidative addition step in methylene fluorination, thus uncovering a potential new role of the pyridone ligand.
Assuntos
Aminas/química , Hidrocarbonetos Fluorados/síntese química , Paládio/química , Catálise , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura MolecularRESUMO
The hydrodefluorination of CF3-substituted alkenes can be catalyzed by a nickel(II) hydride bearing a pincer ligand. The catalyst loading can be as low as 1 mol%. gem-Difluoroalkenes containing a number of functional groups can be formed in good to excellent yields by a radical mechanism initiated by H⢠transfer from the nickel hydride. The relative reactivity of various substrates supports the proposed mechanism, as does a TEMPO trapping experiment.
Assuntos
Alcenos/síntese química , Complexos de Coordenação/química , Hidrocarbonetos Fluorados/síntese química , Níquel/química , Silanos/química , Catálise , Modelos Químicos , Estrutura MolecularRESUMO
Difluoromethylene-containing compounds have attracted substantial research interest over the past decades for their ability to mimic biological functions of traditional functional groups while providing a wide variety of pharmacological benefits bestowed by the C-F bond. We report a novel strategy to access RCF2Br-containing heterocycles by regio- and enantioselective bromocyclization of difluoroalkenes enabled by chiral anion phase-transfer catalysis. The utility of this methodology was highlighted through a synthesis of an analogue of efavirenz, a drug used for treating HIV. Additionally, the synthetic versatility of the CF2Br intermediates was showcased through functionalization to a variety of enantioenriched α,α-difluoromethylene-containing products.
Assuntos
Alcinos/síntese química , Benzoxazinas/síntese química , Ciclopropanos/síntese química , Hidrocarbonetos Fluorados/síntese química , Alcinos/química , Benzoxazinas/química , Ciclopropanos/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , EstereoisomerismoRESUMO
Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of hOAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1R,3S,4S)-3-amino-4-fluoro cyclopentane-1-carboxylic acid (1), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective hOAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of hOAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.
Assuntos
Ácidos Cicloexanocarboxílicos/química , Cicloexilaminas/química , Inibidores Enzimáticos/química , Hidrocarbonetos Fluorados/química , Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores , Ácidos Cicloexanocarboxílicos/síntese química , Ácidos Cicloexanocarboxílicos/metabolismo , Cicloexilaminas/síntese química , Cicloexilaminas/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ornitina-Oxo-Ácido Transaminase/química , Ornitina-Oxo-Ácido Transaminase/metabolismo , Ligação Proteica , Fosfato de Piridoxal/química , Ácido gama-Aminobutírico/análogos & derivadosRESUMO
The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.
Assuntos
Alcenos/farmacologia , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Alcenos/síntese química , Alcenos/química , Amidas/síntese química , Amidas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In spite of only a few naturally occurring products having one or more fluorine atoms, organofluorine compounds have been widely utilized in pharmaceutical, agrochemical, and functional material science fields due to the characteristic properties of the fluorine atom. Therefore, the development of new methods for the introduction of fluorine-containing functional groups has been a long-standing research topic. This article discusses our contributions to this area. The first topic is on the trifluoromethylations of C-C multiple bonds using Togni reagent based on our working hypothesis that hypervalent iodine could be activated by coordination of the carbonyl moiety to the Lewis acid catalyst. The second topic relates to asymmetric fluorofunctionalization of alkenes. A newly designed phase-transfer catalyst consisting of a carboxylate anion functioning as a phase-transfer agent and a primary hydroxyl group as a site that captures the anionic substrate was revealed to be an effective catalyst for asymmetric fluorolactonization. Inspired by the mechanistic studies of fluorolactonization, we produced a linked binaphthyl dicarboxylate catalyst, which catalyzes the 6-endo-fluorocyclization and the deprotonative fluorination of allylic amides in a highly enantioselective manner. The third topic is on C-H fluorofunctionalizations using either catalysis or photoactivation. Benzylic trifluoromethylation, which is still a rare reaction, using Togni reagent and aromatic C-H trifluoromethylation using Umemoto reagent under simple photoirradiation conditions were achieved. In addition, the Csp3-H fluorination of alkyl phthalimide derivatives is demonstrated.
Assuntos
Hidrocarbonetos Fluorados/síntese química , Halogenação , Hidrocarbonetos Fluorados/química , Estrutura MolecularRESUMO
New fluorinated 3,6-dihydropyridines were obtained by the electrophilic fluorination of 1,2-dihydropyridines with Selectfluor®. These 3-fluoro-3,6-dihydropyridines were easily converted to corresponding pyridines by the elimination of hydrogen fluoride under mild conditions. A new approach to the synthesis of methyl 2-(fluoromethyl)-5-nitro-6-arylnicotinates by the fluorination of 3-fluoro-2-methyl-5-nitro-3,6-dihydropyridines or 1,2-dihydropyridines with Selectfluor® has been developed.
Assuntos
Di-Hidropiridinas/química , Flúor/química , Halogenação , Hidrocarbonetos Fluorados , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/químicaRESUMO
Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by the photochemical activity of an electron donor-acceptor (EDA) complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences.
Assuntos
Alcenos/química , Hidrocarbonetos Fluorados/síntese química , Iodetos/química , Catálise , Hidrocarbonetos Fluorados/química , Processos FotoquímicosRESUMO
Applications of TEMPO. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO. -catalyzed, redox-neutral C-H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO. /TEMPO+ redox catalytic cycle. Mechanistic studies also suggest that Li2 CO3 plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO. catalysis.