Auswahl der wissenschaftlichen Literatur zum Thema „Hydroxylation reactions“

A series of racemic substituted cyclopentanones, with alkyl groups corresponding to the upper prostanoid side chain and (or) the lower prostanoid side chain without the C-15 alcohol, has been synthesized. Using a steroid template for the prostanoid molecule as a basis for selection, fungi capable of hydroxylating steroids have been used to biotransform the prostanoid substrates. The predominant products were hydroxylated at the prostanoid C-18 and C-19 positions. The hydroxylations were enantioselective, with excesses in the range 10–60%, and in most cases the predominant configuration corresponded to that of the natural prostanoids. The stereochemistry of the C-19 hydroxyl group was found to be R by degradation of products to methyl 6-acetoxyheptanoate and comparison of that material with a resolved sample, obtained via crystallization of the brucine salt of ethyl 6-phthaloxyheptanoate. Hydroxylation at C-18 gave the S configuration of alcohol. Hydroxylation at prostanoid C-15 was observed, but in all cases this was accompanied by other reactions. Hydroxylation of Rhizopusarrhizus has been used in a preparation of (−)-15-deoxy-19-(R)-hydroxy-PGE1 and (−)-15-deoxy-18-(S)-hydroxy-PGE1. Keywords: biotransformation, hydroxylation, prostaglandins, prostanoids.

Cytochrome P-450-dependent 6 beta-hydroxylation of bile acids in rat liver contributes to the synthesis of the quantitatively important pool of 6-hydroxylated bile acids, as well as to the detoxification of hydrophobic bile acids. The lithocholic acid 6 beta-hydroxylation reaction was investigated and compared with androstenedione 6 beta-hydroxylation. Differential responses of these two activities to inducers and inhibitors of microsomal P-450 enzymes, lack of mutual inhibition by the two substrates and differential inhibition by antibodies raised against several purified hepatic cytochromes P-450 were observed. From these results it was concluded that 6 beta-hydroxylation of lithocholic acid is catalysed by P-450 form(s) different from the subfamily IIIA cytochromes P-450 which are responsible for the bulk of microsomal androstenedione 6 beta-hydroxylation. Similar, but more tentative, results revealed that the 7 alpha-hydroxylation of lithocholic acid and of androstenedione may be also catalysed by distinct P-450 enzymes. The results indicate that cytochromes P-450 hydroxylating bile acids are distinct from analogous enzymes that carry out reactions of the same regio- and stereo-specificity on neutral steroids (steroid hormones). A comparison of pairs of cytochromes P-450 that catalyse the same reaction on closely related steroid molecules will help to define those structural elements in the proteins that determine the recognition of their respective substrates.

N’-nitrosonornicotine (NNN) is one of the tobacco-specific nitrosamines (TSNAs) that exists widely in smoke and smokeless tobacco products. NNN can induce tumors in various laboratory animal models and has been identified by International Agency for Research on Cancer (IARC) as a human carcinogen. Metabolic activation of NNN is primarily initiated by cytochrome P450 enzymes (CYP450s) via 2′-hydroxylation or 5′-hydroxylation. Subsequently, the hydroxylating intermediates undergo spontaneous decomposition to generate diazohydroxides, which can be further converted to alkyldiazonium ions, followed by attacking DNA to form various DNA damages, such as pyridyloxobutyl (POB)-DNA adducts and pyridyl-N-pyrrolidinyl (py-py)-DNA adducts. If not repaired correctly, these lesions would lead to tumor formation. In the present study, we performed density functional theory (DFT) computations and molecular docking studies to understand the mechanism of metabolic activation and carcinogenesis of NNN. DFT calculations were performed to explore the 2′- or 5′- hydroxylation reaction of (R)-NNN and (S)-NNN. The results indicated that NNN catalyzed by the ferric porphyrin (Compound I, Cpd I) at the active center of CYP450 included two steps, hydrogen abstraction and rebound reactions. The free energy barriers of the 2′- and 5′-hydroxylation of NNN are 9.82/8.44 kcal/mol (R/S) and 7.99/9.19 kcal/mol (R/S), respectively, suggesting that the 2′-(S) and 5′-(R) pathways have a slight advantage. The free energy barriers of the decomposition occurred at the 2′-position and 5′-position of NNN are 18.04/18.02 kcal/mol (R/S) and 18.33/19.53 kcal/mol (R/S), respectively. Moreover, we calculated the alkylation reactions occurred at ten DNA base sites induced by the 2′-hydroxylation product of NNN, generating the free energy barriers ranging from 0.86 to 4.72 kcal/mol, which indicated that these reactions occurred easily. The docking study showed that (S)-NNN had better affinity with CYP450s than that of (R)-NNN, which was consistent with the experimental results. Overall, the combined results of the DFT calculations and the docking obtained in this study provide an insight into the understanding of the carcinogenesis of NNN and other TSNAs.

The reactions of carboline under various oxidative conditions are reported. The soft aerobic radiolysis, hydroxylation and rearrangement transformations are studied using isotopic labelling and GC–MS techniques.

The cytochromes P450 are a large family of oxidative haemoproteins that are responsible for a wide variety of oxidative transformations in a variety of organisms. This review focuses upon the reactions catalyzed specifically by bacterial enzymes, which includes aliphatic hydroxylation, alkene epoxidation, aromatic hydroxylation, oxidative phenolic coupling, heteroatom oxidation and dealkylation, and multiple oxidations including C–C bond cleavage. The potential for the practical application of the oxidizing power of these enzymes is briefly discussed.

The present paper is based on the combination of MAOI hydrazide moiety and tricyclic antidepressant moiety. This combination investigates new compounds as 1,3,4-oxadiazinoindole derivatives to find potent and safer antidepressants. Synthesis of 1,3,4-oxadiazinoindole derivatives are started from various animoacids. The sequence of synthesis reactions such as benzoylation reaction, Halo-De-hydroxylation (Nucleophilic substitution reaction), Schotten-Baumann reaction, Nucleophilic addition and finally cyclization reaction (Cyclo-De-Hydroxylation) are involved. Synthesized compounds are characterized via melting point, TLC, FT infrared spectroscopy, 1H-NMR, and mass spectroscopy techniques. All compound’s structures are confirmed.

AbstractInspired by the efficiency of natural enzymes in organic transformation reactions, the development of synthetic catalysts for oxygenation and oxidation reactions under mild conditions still remains challenging. Tyrosinases serve as archetype when it comes to hydroxylation reactions involving molecular oxygen. We herein present new copper(I) guanidine halide complexes, capable of the activation of molecular oxygen at room temperature. The formation of the reactive bis(µ-oxido) dicopper(III) species and the influence of the anion are investigated by UV/Vis spectroscopy, mass spectrometry, and density functional theory. We highlight the catalytic hydroxylation activity towards diverse polycyclic aromatic alcohols under mild reaction conditions. The selective formation of reactive quinones provides a promising tool to design phenazine derivatives for medical applications. Graphic abstract

The diploma thesis deals with post-polymerization hydroxylation of polypropylene in solid state. Regarding the literature review, polypropylene was hydroxylated by radical grafting in aqueous solution of potassium persulfate at 100 °C, under nitrogen atmosphere for 60 minutes. Hydroxylation of polypropylene was performed at different concentrations of potassium persulfate (1; 5; 10 mol. %) and two different water/potassium persulfate molar ratios. The effects of reaction system composition and reaction conditions on reaction efficiency, extent of side reactions, thermal and rheological properties of hydroxylated polypropylene were evaluated. The presence and concentration of hydroxyl groups on polypropylene surface was determined by structural analysis (FTIR, XPS), while the highest efficiency was achieved in the presence of nonionic wetting agents, using 10 mol. % potassium persulfate and at lower water/potassium persulfate molar ratio. Based on changes in polypropylene structure, the modification took place mainly in the amorphous phase of the polymer. In addition to hydroxylation, concurrent side reactions have been reported, in particular the oxidation of wetting agents and polypropylene, which has resulted in chain cleavage, reducing the average molecular weight of the polypropylene.

Les catalyseurs chimiques sont utilisés dans différents procédés de synthèse. Cependant, la pollution qu'ils causent sur l'environnement n’est pas prise en considération. Les procédés de synthèse chimique nécessitent généralement un grand volume de solvants organiques, produisant d’énormes quantités de déchets chimiques, souvent toxiques et non dégradables. Le remplacement des catalyseurs chimiques par des biocatalyseurs (enzymes) pourrait donc bénéficier de leur nature écologique et de leur grande sélectivité envers les produits désirés. Néanmoins, la faible activité et stabilité des enzymes ainsi que leurs coûts élevés sont des obstacles majeurs au développement des systèmes enzymatiques. Par conséquent, des études axées sur le développement de systèmes biocatalytiques plus actifs, stables et rentables, pouvant ouvrir les portes vers un environnement plus vert, sont très souhaitables. Parmi les enzymes qui catalysent des réactions d’importance dans de nombreux procédés de synthèse, le cytochrome P450 BM3 issu de Bacillus megaterium fait l'objet de cette thèse. L'enzyme est capable d’hydroxyler les liaisons C–H des acides gras (C₁₂-C₂) à température ambiante et pH physiologique. Pour cette réaction, BM3 n'a besoin que d’oxygène et de deux électrons habituellement obtenus de son cofacteur naturel, le NADPH. Cependant, pour engager cette enzyme dans les réactions d'hydroxylation, quelques obstacles importants doivent être surmontés : (i) le cofacteur coûteux (NADPH), devrait être remplacé par une source d'électrons moins chère ou régénérée, (ii) la stabilité enzymatique devrait être améliorée et (iii) l'enzyme devrait être facilement récupérable du milieu de réaction pour être réutilisée. Dans ce contexte, cette étude propose pour la première fois l'immobilisation d'un BM3 sur des nanoparticules magnétiques (NMP) d’oxyde de fer. Ce système enzymatique bénéficie (i) de la préférence de l'enzyme pour les cofacteurs NADH et BNAH (moins chers que le NADPH), (ii) de la réutilisation facile du biocatalyseur et (iii) d’une stabilité significative de l’enzyme lors du stockage. Les NMP synthétisées ont été fonctionnalisées pour permettre l’immobilisation de l'enzyme par adsorption ou liaison covalente. Par conséquent, les BM3-NMP adsorbées / réticulées ou liées de façon covalente ont été obtenues en immobilisant P450 BM3 (R966D / W1046S) sur Ni²⁺-PMIDA-NMP ou sur des NMP activés par glutaraldéhyde, respectivement.
L'activité de l’enzyme immobilisée a été comparée avec celle de l’enzyme libre dans la réaction d'hydroxylation du 10-pNCA comme substrat modèle. L'acide myristique a également été utilisé comme substrat modèle pour confirmer la capacité d’hydroxylation sélective de l’enzyme sur les atomes de carbone ω-1, -2 ou -3. Pour les mêmes conditions opératoires, le BM3 adsorbé / réticulé a montré plus de 85% de l'activité de l’enzyme libre, alors que pour les BM3-NMP liées de manière covalente cela représente 60%. La séparation facile des NMP du milieu réactionnel à l’aide d’un aimant a permis de réutiliser le système enzymatique cinq fois consécutives. Après 5 cycles de réaction, l'enzyme réticulée a conservé 100% de son activité initiale. Compte tenu que le recyclage de l’enzyme libre n’est pas faisable, ce résultat est d’une importance considérable dans les applications pratiques. De plus, la stabilité de l’enzyme pendant un mois de stockage à 4 ºC a été évaluée pour chaque système de BM3. Les résultats ont montré que l’enzyme libre n’était plus active après seulement une semaine de stockage dans ces conditions. L'enzyme réticulée n'a montré qu'une activité relative de 41% après un mois de stockage, mais pour le BM3 fixée de façon covalente, la valeur correspondante a été de 80%. La cinétique de l'hydroxylation du 10-pNCA en présence de l’enzyme libre ou immobilisée a été également étudiée. Sur la base des données expérimentales, un modèle de Hill (coefficient de Hill égal à 2) a été obtenu pour l'enzyme libre. Il a été démontré que les mêmes paramètres cinétiques sont capables de prédire le comportement du système BM3-adsorbé et BM3-réticulé dans la réaction d’hydroxylation, étant donné sa similarité avec celui de l’enzyme libre. En conclusion, les résultats de cette thèse ont montré qu'un système enzymatique actif, stable et rentable peut être obtenu en immobilisant le BM3 sur des NMP fonctionnalisées. Il bénéficie autant des avantages de l'enzyme que du support. Ainsi, l'immobilisation sur des NMP d’une enzyme spécialement conçue pour remplacer le couteux NADPH par des cofacteurs moins chers mais efficaces (NADH et BNAH) offre en même temps une amélioration significative de sa stabilité et facilite son recyclage.
MNPs have been synthesized and surface functionalized to attach the enzyme via two different methods, adsorption and covalent binding. Moreover, glutaraldehyde was used to treat the adsorbed enzyme molecules on MNPs (crosslinking-adsorption). Therefore, adsorbed, crosslinked-adsorbed, or covalently bound BM3-MNPs were obtained by immobilizing P450 BM3 on synthesized Ni²⁺-functionalized MNPs or glutaraldehyde pre-activated MNPs, respectively. The immobilized enzyme activity was compared to its free counterpart in hydroxylation reaction of 10-pNCA (10-(4-Nitrophenoxy) decanoic acid) as a substrate model. Myristic acid was also used as a substrate model to confirm the enzyme selective hydroxylation at ω-1, -2, or -3 carbon positions. The effect of cofactor (NADH and its analogue, BNAH) on the enzyme activity was also investigated. The adsorbed/crosslinked-adsorbed BM3 showed more than 85% of the free enzyme activity while the covalently bound BM3-MNPs presented 60% of the free enzyme activity under the same reaction conditions. An important feature of BM3-MNPs system is the possibility of recycling the biocatalyst. Facile separation of the magnetic nanoparticles from the reaction medium by applying a magnet provided the opportunity of reusing the enzymatic system for five times. After 5 cycles of reaction, the crosslinked-adsorbed enzyme retained 100% of its initial activity. Although the covalently bound enzyme showed, only half of the crosslinked-adsorbed enzyme activity, its storage stability was more significant. Taking into account that the enzyme reuse is an essential concern in many large-scale applications and the free BM3 cannot be recovered and reused, this result is noteworthy. Storage stability tests revealed that the free enzyme became inactive after one-week while the crosslinked-adsorbed enzyme and the covalently attached BM3 on MNPs showed 41% and 80% relative activity after one month, respectively. Finally, the steady-state kinetics of 10-pNCA hydroxylation by free and immobilized BM3 was investigated. Based on the experimental data, a non-Michaelis-Menten, Hill model (Hill coefficient of 2) was obtained for the free enzyme which could also predict the adsorbed and crosslinked-adsorbed BM3-MNPs system performance. This sigmoidal behavior was found to be independent of enzyme concentration and type of cofactor. However, since the enzyme activity was only 60% of the free enzyme for covalently bound BM3, further studies are necessary for a better understanding of this system. In summary, the results of this thesis show that an active, stable, and cost-effective BM3-MNPs system can be obtained by immobilizing an engineered BM3 on functionalized MNPs. Such systems benefit from the advantages of both enzyme and support. An engineered enzyme can fulfill the desired targets including the replacement of costly NADPH by less-expensive, yet effective cofactors namely NADH and BNAH. Furthermore, immobilization of this enzyme on MNPs improves its stability and facilitates the recycling process.
Chemical catalysts are used in different synthetic processes from lab to industrial scales. High reaction yields usually achieved by this type of processes favor their application in many industries without considering the pollution they cause to the environment. Chemical synthesis processes usually require a high volume of organic solvents and produce tons of chemical wastes which are often toxic and not degradable. Replacing conventional catalysts by biocatalysts (enzymes) can benefit from their environmentally friendly nature and high selectivity toward the desired products. Although the advantages of biocatalysts over chemical catalysts have been proven, the application of enzymes in an industrial level is still not considerable. The enzyme low activity, stability, and high cost are the main concerns in developing large-scale enzymatic systems. Therefore, in the context of a greener environment, studies focusing on the development of more active, stable, and cost-effective enzymatic systems are in great demand. Among several enzymes that can catalyze essential synthesis reactions, cytochrome P450 BM3 from Bacillus megaterium is the subject of this thesis. This enzyme hydroxylates the saturated and unsaturated C–H bonds of medium to long chain fatty acids at room temperature and physiological pH. For this reaction, BM3 only needs molecular oxygen and two electrons usually obtained from its natural cofactor, NADPH. However, to engage this enzyme in hydroxylation reactions, some important obstacles should be overcome: (i) the costly cofactor (NADPH) should be replaced by a cheaper source of electrons or regenerated, (ii) the enzyme stability should be improved, and (iii) the enzyme should be easily recovered from the reaction medium to be reused. In this context, this study proposes for the first time the immobilization of an optimized BM3 mutant on functionalized iron oxide magnetic nanoparticles (MNPs). This enzymatic system benefits from (i) the enzyme preference towards cofactors like the reasonably priced NADH and the very cheap BNAH, (ii) facile recovery and reuse of the biocatalyst (enzyme-MNPs), and (iii) the enzyme significant storage stability.

Since the rediscovery of carbon nanotubes (CNTs) due to the publication of Sumio Iijima's article Helical microtubules of graphitic carbon in the magazine Nature in 1991 the interest in carbon nanotubes has rapidly increased. This bachelor thesis also deals with this popular material with the aim to functionalize CNTs for further uses in the microelectronic industry. A promising approach is the functionalization of the CNTs with metal nanoparticles or metal films. To achieve this, one can perform an atomic layer deposition (ALD) on CNTs. In the present work the Trimethylaluminum (TMA) ALD is the chosen process for the functionalization of the CNTs, which will be studied here. Since the available knowledge on the CNT-functionalization by gas phase reactions is very limited, a theoretical study of possible reaction pathways is necessary. Those studies are carried out with two modern quantumchemical programs, Turbomole and DMol³, which are described together with an introduction into Density Functional Theory, as well as an introduction of CNTs and the ALD process. A basic model of a CNT with a Single Vacancy defect, which had been selected according to the demands of the studies, is introduced. Because the TMA ALD process requires hydroxyl groups as its starting point, not only is the performance of a TMA ALD cycle on a CNT studied, but also reactions which result in the CNTs owning of hydroxyl groups. Consequently, this bachelor thesis will focus on two di erent aspects: The performance of one TMA ALD cycle and the study of possible educts for the TMA ALD process. This study of the educts includes possible structures which can be formed when a CNT comes into contact with air.

L'électrochimie est apparue comme un puissant outil de synthèse durable en chimie organique, qui évite l'utilisation d'un oxydant stoechiométrique externe et permet le développement de méthodes de difonctionnalisation très efficaces et sélectives des indoles dans des conditions douces. L'utilisation de médiateurs redox pour réaliser l'électrolyse indirecte a gagné en importance ces dernières année, ce qui offre de nombreux avantages par rapport à l'électrolyse directe. Les réactions de désaromatisation des hétéroarènes achiraux, et en particulier des indoles, donnent des structures tridimensionnelles d’un grand intérêt pour la synthèse totale ou la découverte de médicaments, via la génération de deux centres stéréogéniques contigus. Ainsi des efforts de synthèse intensifs ont été consacrés à la difonctionnalisation désaromatisante d’indoles. Dans ce contexte, le développement de réactions de désaromatisation des indoles a été étudié au cours de cette thèse. Dans la première partie de la thèse, une diallylation désaromatisante de N-acylindoles médiée par FeCl₃ a été développée pour obtenir des indolines tridimensionnelles sélectives possédant deux centres stéréogéniques contigus. Dans ce procédé, deux groupes allyle ont été introduits sur des N-acylindoles avec de l'allyltriméthylsilane en présence de FeCl₃, conduisant à la formation de deux liaisons carbone-carbone et de deux centres stéréogéniques contigus. La stéréosélectivité de cette transformation est contrôlée par la substitution du noyau indole. Des applications synthétiques ont permis d'obtenir des squelettes trans-tétrahydrocarbazoles et aza[4.4.3]propellanes par RCM. L'hydratation sélective de l'un des groupes allyliques a également été réalisée. Dans la deuxième partie de la thèse, une désomatisation oxydante directe des indoles a été réalisée par électrochimie, conduisant à des 2,3-dialcoxy ou des 2,3-diazido indolines avec une cellule non divisée à courant constant. Cette difonctionnalisation électrochimique des indoles évite l'utilisation d'un oxydant externe et présente une excellente compatibilité de groupes fonctionnels, ce qui devrait inspirer le développement d'autres réactions de désaromatisation afin d'accéder à des architectures à haute valeur ajoutée à partir de matériaux de départ facilement disponibles. Sur la base de l'étude mécanistique, nous pensons que la formation des deux liaisons C-O ou C-N résulte de l'oxydation des indoles en un intermédiaire radical cation. Dans la troisième partie de la thèse, une désaromatisation oxydante par électrolyse indirecte des indoles a été conçue en utilisant MgBr₂ comme médiateur redox pour éviter l'oxydation directe du noyau indole à l'anode. L’oxydation de l’indole en un ion bromonium induite par la génération d’un réactif électrophile bromé à partir de MgBr₂, conduit à des réactions de dihydroxylation, d’hydroxycyclisation et de bromocyclisation d’indoles. Aucun sous-produit organique n'est généré avec ce protocole qui ne nécessite aucun électrolyte supplémentaire. L’intérêt de cette transformation est démontré par les applications synthétiques
Electrochemistry emerged as a powerful sustainable synthetic tool in organic chemistry, which avoids the use of an external stoichiometric oxidant and enables the development of methods for the highly efficient and selective difunctionalization of indoles in mild conditions. The use of redox mediators to achieve indirect electrolysis is attaining increased significance, which offers many advantages compared to direct electrolysis. Dearomatization reactions of achiral heteroarenes and in particular of indoles, afford three-dimensional structures of high interest for total synthesis or drug discovery, through the generation of two contiguous stereogenic centers. Intensive synthetic efforts have been devoted to dearomative difunctionalization of indoles. In this context, the development of dearomatization reactions of indoles has been studied in this thesis. In the first part of the thesis, a dearomative diallylation of N-acylindoles mediated by FeCl₃ was developed to obtain selectively three-dimensional indolines possessing two contiguous-stereogenic centers. In this process, two allyl groups were introduced to N-acylindoles with allyltrimethylsilane in the presence of FeCl₃, leading to the formation of two carbon-carbon bonds and two contiguous-stereogenic centers. The stereoselectivity of this transformation is controlled by the substitution of the indole nucleus. Synthetic application allowed to obtain trans-tetrahydrocarbazoles and aza[4.4.3]propellane scaffolds by RCM. Selective hydration of one of the allyl group was achieved. In the second part of the thesis, a direct oxidative dearomatization of indoles was performed with electrochemistry, leading to 2,3-dialkoxy or 2,3-diazido indolines under undivided cell conditions at a constant current. This general difunctionalization of indoles avoids the use of an external oxidant and displays excellent functional group compatibility, which should inspire the development of other dearomatization reactions to access high added-value architectures from readily available starting materials. Based on the mechanistic study, the formation of the two C-O or C-N bonds is believed to arise from the oxidation of the indoles into radical cation intermediates. In the third part of the thesis, an indirect oxidative dearomatization of indoles was devised by using MgBr₂ as the redox mediator to avoid the direct oxidation of the indole nucleus at the anode. The oxidation of the indole into a bromonium ion induced by the generation of an electrophilic bromine reagent from MgBr₂, and lead to dihydroxylation, hydroxycyclization and bromocyclization reactions of indoles. No organic byproducts are generated with this protocol which requires no additional electrolyte. The potential of this transformation is demonstrated by synthetic applications