Dissertationen zum Thema „Carbonyl compounds“

New Zealand is the world’s third-largest honey exporter by value behind China and Argentina and honey accounts for up to 80 % of New Zealand’s exports. However, it is only the 16th biggest global supplier by volume. Manuka honey from New Zealand is sold for premium prices and merchandised for its health benefits. Because of its exceptional antibacterial effect, there is a strong market demand and the price for a kilogram of manuka honey has tripled in recent years (Ministry for Primary Industries 2015). When consumers are willing to pay prices up to 200 €/kg manuka honey, the risk of misleading advertisement and intended fraud increases. This thesis aims to further characterize manuka honey and contribute to the development of a manuka honey definition. The first part deals with the antibacterial activity of manuka honey. The effect of manuka honey is mainly due to methylglyoxal, whereas the effect of non-manuka honeys is primarily caused by hydrogen peroxide. The objective is to develop a method to quantify the effect solely due to one of the respective chemical compounds and compare their effectiveness. Finally, an evaluation of the contribution of methylglyoxal and hydrogen peroxide to the inhibitory effect of honey should be given. The second part deals with chemical reactions of carbonyl compounds in honey. Because of the reactive nature of carbonyl compounds, the formation of specific glycation compounds in honey is assumed. Since the carbonyl profile of manuka honey differs remarkably from non-manuka honeys, the reaction products are expected to vary widely. Specific compounds, solely present in manuka honey, could serve as quality control parameters to ensure manuka honey authenticity. The final part deals with the metabolism of food-derived carbonyl compounds. Carbonyl compounds, like methylglyoxal or 3-deoxyglucosone are discussed to be potentially toxic to human tissues. Until now, only little is known about the impact of the diet on the physiological carbonyl-load and the metabolism of carbonyl compounds. With the help of nutrition studies and the analysis of body fluids, the question of metabolic transit of carbonyl compounds shall be addressed. The antibacterial studies showed that bacterial species are affected differently by bioactive compounds present in honey. Methylglyoxal (MGO), which is solely present in manuka honeys and hydrogen peroxide, which is formed in most conventional honeys by glucose oxidase, are strong inhibitors of the growth of S. aureus and E. coli. The strain of P. aeruginosa used for this work was not inhibited by MGO, whereas B. subtilis was not inhibited by hydrogen peroxide. To compare and quantify the effect of MGO and hydrogen peroxide, a mathematic model was created. By comparing the slopes of the linearized dose-response curves, it was found that S. aureus, E. coli and P. aeruginosa were more sensitive to hydrogen peroxide than to MGO. However, the natural amounts of MGO in honey are higher than the formation of hydrogen peroxide. Although most bacteria are more sensitive to hydrogen peroxide, MGO is the predominantly antibacterial compound in honey, because of its higher concentrations compared to hydrogen peroxide formation. The inclusion of manuka honey in α-cyclodextrin had only minor consequences on bioavailability and antibacterial activity. The commercial product “Cyclopower” (α-cyclodextrin with manuka honey) does not enhance the antibacterial activity of manuka honey on S. aureus, E. coli and P. aeruginosa. With the help of the newly developed quantitative model, it was shown that the growth of B. subtilis is synergistically inhibited with cyclopower compared to manuka honey and α-cyclodextrin alone. The study of bacterial enzymes as possible targets for bacterial inhibition with manuka honey revealed that MGO and DHA inhibited jack bean urease, which was used as a model for Helicobacter pylori urease. The concentration of MGO and DHA in manuka honey positively correlated with its urease inhibition. Conventional honeys, which lack MGO and DHA, showed significantly less urease inhibition. Based on the unique presence of MGO, manuka honey has extraordinary effects on bacteria, which might lead to further application to fight the emerging crisis of antibacterial resistance to antibiotics. Until now, there is no consistent definition for the term “genuine manuka honey”. In the present work, an approach based on unique chemical reactions in manuka honey was followed. It was shown that the exceptional high amounts of MGO induced the formation of 2-acetyl-1-pyrroline (2-AP). In manuka honey containing ≥ 250 mg/kg MGO, the 2-AP concentration was significantly increased compared to conventional honey. Moreover, honey proteins form MGO-derived reactions products, which were studied by measuring the molecular size of honey proteins. Manuka honey proteins significantly shifted to high molecular weights (HMW) with a size above 510 kDa. The amount of HMW protein in non-manuka honey was significantly lower. The cleavage of disulphide bonds led to a decrease of HMW fraction of conventional honeys but not of manuka honeys. It is hypothesized that MGO cross-linking of proteins is mainly responsible for the formation of HMW adducts in manuka honey. The formation of HMW adducts was also shown with fluorescence analysis, whereby manuka honey proteins had higher fluorescence intensities at λex=350 nm and λem=450 nm compared to non-manuka honeys. The artificial addition of MGO and its precursor dihydroxyacetone (DHA) to a non-manuka honey did not lead to an increased fluorescence up to the level of commercial manuka honeys. The MGO-derived modifications of proteins were further studied by quantifying the protein-bound Maillard reaction products N-ε-carboxyethyllysine (CEL) and methylglyoxal-derived hydroimidazolone 1 (MG-H1) after enzymatic hydrolysis of honey proteins and LC-MS/MS analysis. Their amount was significantly higher in manuka compared to conventional honeys and correlated with the MGO content of the honey. Most of the MGO-derived reactions could be simulated by spiking a conventional honey or a low MGO manuka honey with artificial MGO and subsequent storage at elevated temperatures. Higher storage temperatures were associated with a quick increase of 5-hydroxymethylfurfuraldehyd (HMF). The HMF level in honey is used as a quality parameter and should not exceed 40 mg/kg (Codex Alimentarius Commission, 2001). High concentrations of HMF may point to a fraudulent addition of MGO and the production of artificial high-price manuka honey products. Taken together, the Maillard reaction in honey could be used to control the natural origin of MGO and DHA. The consumption of honey and especially manuka honey exposes humans to high levels of dietary dicarbonyl compounds like MGO and 3-deoxyglucosone (3-DG). Both compounds were discussed as potential risk factors for the development of age-related diseases. The simulated digestion of manuka honey in the presence of gastric and ileal fluids showed that only 9 % of the initial concentration can be recovered after 8 h. The honey matrix had no stabilising effect on MGO compared to a synthetic MGO solution. In contrast to MGO, the manuka honey compound DHA was stable during all simulated digestion steps. The complexation of MGO with α-cyclodextrin did not enhance the stability of MGO. The metabolic transit of dietary MGO and 3-DG was further studied with an intervention study with healthy volunteers, who collected their daily urine. It was shown that urinary concentrations of 3-DG and its less reactive metabolites 3-deoxyfructose (3-DF) and 2-keto-3-deoxygluconic acid (3-DGA), but not MGO, were influenced by the diet. During the intervention studies, up to 40 % of dietary 3-DG was recovered as the sum of 3-DG, 3-DF and 3-DGA. The metabolite 3-DGA only played a minor role in the metabolism of dietary 3-DG in comparison to 3-DF. The concentrations 3-DF and 3-DGA in plasma only increased after the consumption of dietary 3-DG and not after the uptake of carbohydrate rich meals in general. This led to the conclusion that dietary 3-DG is effectively metabolized to 3-DF extracellularly on the apical site of the intestinal epithelium and is resorbed slowly into the circulation. In contrast, 3-DG, which is formed (intracellularly) postprandial from glucose, bypasses this metabolic system and cannot be metabolized as rapidly to 3-DF. Preliminary results obtained with saliva instead of urine as a bio fluid to study the dietary influence of dicarbonyl compounds, confirmed the hypothesis. Based on the present results, dietary dicarbonyl compounds are effectively metabolized during digestion.

Chapter 1: Intrinsic to the methodology developed within this thesis is the exploitation of a polyheteroatom 3,3-sigmatropic rearrangement. This chapter explores the chemistry of a selection of these rearrangements in order to highlight their utility in the creation of new carbon-carbon and carbon-heteroatom bonds. Chapter 2: In this chapter the most recent advances in the alpha-functionalisation of carbonyl compounds are discussed. This review focuses mainly on organocatalyzed methodologies as these represent the forefront of current research in the field. Chapter 3: In chapter 3 the principle underlying our methodology is further described along with our results for the alpha-oxybenzoylation of cyclic, heterocyclic and acyclic ketones. Our findings for the alpha-oxybenzoylation of acetals is also described. Chapter 4: Elaboration of our family of reagents to introduce alpha-oxycarbonate and carbamate functionalities is next described with our results for a variety of reactions with cyclic and acyclic ketones. Chapter 5: Continuing expansion of our reagent family is described in chapter 5. Within this chapter our results for the alpha-oxytosylation of cyclic, acyclic and di-carbonyl compounds are presented. Chapter 6: Chapter 6 describes our attempts at synthesising a thio analogue of our reagent for the creation of a C-S bond.

The findings to date have contributed to the development of a novel and useful class of synthetic protocol and have resulted in a greatly enhanced understanding of the fundamental workings of the &agr;-oxygenation.

The a-hydroxy carbonyl group represents a significant building block in organic synthesis, which is reflected by the extensive synthetic efforts directed towards introduction of this group in a chemo- regio-, stereo-, and enantioselective manner. Traditional methods for the a-oxygenation of carbonyl compounds involve the formation and reaction of air-sensitive intermediates. This thesis describes an alternative metal-free approach to the formation of C-O bonds a- to a carbonyl group, in an asymmetric manner. Chapter l provides an overview of the literature methods for the a-oxygenation of carbonyl compounds, incorporating recent advances in this field achieved previously within the group, following discovery of 63*HC1 to affect a one-pot a-oxygenation transformation. Chapter 2 outlines our objectives and describes methods for the preparation of chiral hydroxylamine reagents based on the generic structure 108. The focus of this chapter is on establishing asymmetric transformations and their optimisation. Chapter 3 examines varying the size and nature of the 0-acyl group (R2) in order to determine its effect on the asymmetric reaction. Chapter 4 studies the influence of relative electronic effects on the asymmetric reaction, by varying the electronic properties of R1 and R2. Chapter 5 explores the role of the TV-substituent (R1) on an asymmetric a-oxyacylation transformation. Application of our methodology to other carbonyl substrates is also examined. Chapter 6 investigates an alternative method for the synthesis of chiral a-oxygenated carbonyl compounds, involving formation and reaction of chiral nitrones. In recent years methods have been developed within the group for the a-oxycarbonoylation, oxycarbamoylation and oxytosylation of carbonyl compounds. Chapter 7 investigates application of the methodology developed within this thesis to each of these transformations. Following an interesting observation, a novel procedure for the conversion of primary amines into ketones was developed, which is discussed in Chapter 8.

Stereoselective alkylations are a very useful tool in synthetic chemistry and, specifically, natural product synthesis. One such reaction, named the Tsuji-Trost allylation, is a palladium-catalyzed substitution with the overall transformation being the replacement of an allylic leaving group with a nucleophile. First observed in 1965 with the allylation of diethyl malonate [1], and in 1973 made asymmetric with the use of chiral phosphine ligands by B. M. Trost [2], the reaction has been studied and utilized extensively over the years. While there have been many examples of this reaction in the literature, few explore functionalizing the allylic electrophile. Functionalizing the "2" position of an allylic acetate or carbonate could prove to be a useful synthetic tool. Allylic acetates, chlorides and carbonates bearing a methoxymethyl group at this middle position were synthesized. beta-carbonyl ketones which work well under the Tsuji-Trost conditions were also synthesized. Phosphine ligands that provided enantiomeric excess with a variety of nucleophiles in allylic alkylations were used. Upon reaction with a palladium (0) source, the pro-nucleophiles were successfully alkylated in a stereospecific manner. The work described herein investigates modification of the Tsuji-Trost allylation in which oxy-allylation is carried out with a high yield and high degree of enantioselectivity.

The thesis gives an account of the application of two methodologies, "Side Chain Incorporation" and "Cleavage of the Zero Bridge in Bicycles," to the ring expansion, by one, three, and four carbons, of five-, six-, and seven-membered ring benzocyclic carbonyl compounds.

Formaldehyde is a chemical used widely in the manufacture of building materials. A remarkable example is represented by the Lucite two-step Alpha technology for the large scale production of methyl methacrylate (MMA), the essential building block of all acrylic-based products. Esters and ketones are important intermediates in the manufacture of acrylate esters therefore α-hydroxymethylenation of carbonyl compounds using formaldehyde as a one carbon alkylating agent and subsequent dehydration to the corresponding methylenated derivatives has been explored in the current work. We report a novel catalytic approach for the synthesis of methyl methacrylate (MMA) via one-pot α-methylenation of methyl propanoate (a chemical intermediate of the ALPHA process) with formaldehyde, generated in situ by Ru-catalysed dehydrogenation of methanol. Elucidation of the mechanism involved in the catalytic dehydrogenation of methanol along with the collateral alcohol decarbonylation reaction was gained through a combined experimental and DFT study. The development of an alternative process where anhydrous formaldehyde is produced in situ would provide a simplification over the current second step of the ALPHA technology where the formaldehyde is initially produced as formalin, subsequently dehydrated to afford anhydrous formaldehyde in order to ensure high selectivity to MMA. As an alternative approach, ketones, in particular 3-pentanone and 2-butanone, were targeted as potential substrates in order to overcome some of the problems related to competing reactions that occur at the ester group. Hydroxymethylenation, followed by dehydration and Baeyer-Villager oxidation, possibly catalysed by enzymes to reverse the normal selectivity, leads to the formation of acrylate esters. The catalytic reaction is enabled by a gold carbene hydroxide complex in such a way that the substrate undergoes C-H activation and the nascent metal alkyl acts as a nucleophile towards the electrophilic formaldehyde, supplied in the form of alcoform* (solution of paraformaldehyde in methanol).

The chemistry of homogeneous transition metal systems offer parallels to the reactions on the surfaces of industrial hydrodesulphurization catalysts. The reactions of several ruthenium complexes with sulphur-containing reagents are described, with an emphasis on the kinetics and mechanisms thereof. The complex Ru(CO)₂(PPh₃)₃ (2), for example, reacts quickly with thiols and disulphides, producing cct-RuH(SR)(CO)₂(PPh₃)₂ (9) and cct-Ru(SR)₂(CO)₂(PPh₃)₂ (14), respectively, although 2 fails to react with unstrained thioethers. Reactions of the related complex Ru(CO)₂(PPh₃)(dpm) (dpm=Ph₂PCH₂PPh₂) are complicated by the lability of all of the three different ligands. The two dihydrides cct-RuH₂(CO)₂(PPh₃)₂ (3) and RuH₂(dpm)₂, as a cis/trans mixture (7), react with thiols to produce the hydrido-thiolato complexes 9 and RuH(SR)(dpm)₂ (13). respectively. The mechanisms appear to depend on the basicity of the hydride ligands; the more basic dihydride, 7, is probably protonated by the thiol, giving an unobserved molecular hydrogen intermediate, while 3 reacts by slow reductive elimination of H₂. The same rate constant, rate law, and activation parameters are found for the reaction of 3 with thiols, CO or PPh₃. The reaction of 3 with RSSR produces mostly 9, with small amounts of 14. The complete characterization of several members of the series 9 and 14 is described, including the crystal structure of the p-thiocresolate example of each. The reactions of 9 with other thiols, P(C₆H₄pCH₃)₃, CO, RSSR, HCl, PPh₃, and H₂, are also reported. The first three of these reactions share the same rate law and rate constant, the common rate determining step probably being initial loss of PPh₃. Some equilibrium constants for the exchange reactions of 9d (R=CH₂CH₃) with other thiols were tetermined, the Keq values increasing with the acidity of the incoming thiol. The mercapto hydrogens of 9a and 14a (R=H) exchange with the acidic deuterons of added CD₃OD. The hydridic and ortho-phenyl hydrogens exchange more slowly, presumably by intramolecular processes. Complex 14b (R=C₆H₄pCH₃) is unstable in the presence of light, exchanges phosphines rapidly with added P(C₆H₄pCH₃)₃, exchanges thiolate groups with added thiols, and is converted by high pressures of H₂ to a mixture of 9b and 3. Intermediates proposed for the mechanism of the thiol exchange reactions of 9 and 14 contain two or three thiolate groups sharing a proton. A related complex, [Ru(CO)₂(PPh₃)(μSEt)₂(μ₃SEt)Na(THF)]₂, which contains three thiolate groups on a ruthenium centre sharing a sodium cation, was isolated from the reaction of cct-RuCl₂(CO)₂(PPh₃)₂ with sodium ethanethiolate. In acetone, 9b and 14b can be formed cleanly from cct-RuHCl(CO)₂(PPh₃)₂ and cct-RuCl₂(CO)₂(PPh₃)₂, respectively, by reaction with p-thiocresolate. Complex 3 or cheaper analogues could be used as catalysts for the reduction of disulphides by H₂, or as recyclable reagents for the non-oxidative extraction of thiols from thiol-containing mixtures such as oil fractions. The chemistry described above will help to guide future researchers to systems that more closely parallel the processes occurring on the surfaces of industrial hydrodesulphurization catalysts.
Science, Faculty of
Chemistry, Department of
Graduate

Includes abstract.
Includes bibliographical references (leaves 26-29).
Ligand-bridged dinuc1ear carbonyl compounds of ruthenium and osmium have been successfully prepared and characterised by various analytical and spectroscopic techniques. X-ray crystal structures have been determined for the osmium complexes [OS2(CO)4(p-02CCsH4FeCsHs)2L2] {L = PPh3 (102), py (103)}. Some of the complexes were then investigated for their catalytic activity in the oxidation of cyc10hexane and octane. In this work, hydrogen peroxide was used as an oxidant and acetonitrile as the solvent. A higher selectivity for the alcohol products over the ketones was observed. The average ratio of alcohols to ketones was found to be 4.56 and 1.76 for cyc10hexane and octane respectively. The complexes [OS2(CO)6(p-02CMeh] (4) [Ru(CO)2(p-02CMe)2]n (86), [Ru2( CO )4(p-02CMe )(p-dppm h] [PF 6] (117) and [Ru2( CO)4(p -( 02CMe h(MeCN)2] (118), were tested as homogeneous catalysts for the isomerisation of terminal alkenes. Complex 4 was inactive while the complex 118 gave a 100 % conversion. It is proposed that the catalysis proceeded via the displacement of one acetonitrile ligand from the metal centre providing a vacant site onto which the substrate coordinated. The redox behaviour of the four complexes [Ru2(CO)2(p-COh(

[ES] El espectro de la luz solar está compuesto por una amplia gama de radiaciones electromagnéticas las cuales tienen diferentes impactos sobre la vida en la tierra. Entre ellas, las pertenecientes a la región ultravioleta toman un papel principal cuando nos referimos a la fotobiología, ya que pueden interactuar con las biomoléculas por medio de procesos tanto directos como fotosensibilizados. Como resultado, estas biomoléculas pueden sufrir modificaciones que no siempre tienen efectos beneficiosos. En este contexto, los daños fotoinducidos al ADN son de gran relevancia ya que están estrechamente relacionados con la creciente incidencia de cáncer de piel. Por ello, es necesario investigar tanto los mecanismos involucrados en dichos procesos como el desarrollo de nuevas estrategias para combatirlos. En la presente tesis se da respuesta a estas necesidades mediante el desarrollo y empleo de grupos protectores fotolábiles (PPG). En una primera parte se avanza en el desarrollo de nuevos PPG basados en filtros solares. Estos ofrecen la ventaja de actuar, una vez liberados, como un escudo protector frente a la radiación ultravioleta. En este contexto, en el Capítulo 3 se profundiza en las propiedades fotofísicas y fotoquímicas de los sistemas formados por la avobenzona como PPG de ácidos carboxílicos, más concretamente del ketoprofeno (KP) y del naproxeno (NPX). En este estudio se analiza por medio de modelado molecular y técnicas espectroscópicas la influencia que tiene la energía relativa del triplete de la avobenzona en su forma dicetónica, 3AB(K)*, respecto a la de los compuestos protegidos en el proceso de liberación. Siguiendo en esta misma línea de trabajo, en el Capítulo 4 se ha desarrollado un nuevo PPG capaz de liberar el filtro solar oxibenzona (OB) junto con compuestos carbonílicos. En una segunda parte, el foco de atención se ha puesto en el concepto de "Caballo de Troya", el cual establece que ciertas lesiones del ADN pueden actuar a su vez como fotosensibilizadores endógenos generando así nuevas lesiones en su entorno. En este contexto, en el Capítulo 5 se han estudiado, mediante métodos tanto experimentales como teóricos, las propiedades fotosensibilizantes de dos de los daños oxidativos del ADN, el 5-formiluracilo (ForU) y la 5-formilcitosina (ForC), poniendo especial énfasis en la capacidad de estos para poblar sus estados tripletes, así como de inducir la formación fotosensibilizada de dímeros ciclobutánicos de pirimidina (CPD). Por último, en el Capítulo 6 se ha desarrollado una nueva alternativa sintética para la incorporación del ForU en oligonucleótidos. Debido a la inestabilidad del grupo aldehído, esta síntesis se lleva a cabo generalmente mediante la incorporación de un precursor el cual es posteriormente convertido en el ForU mediante la acción de un agente oxidante. Por el contrario, en la nueva alternativa planteada el aldehído es protegido con un PPG, de manera que una vez insertado en el ODN, el aldehído es liberado de forma selectiva mediante el empleo de luz. Este trabajo supone un avance en el estudio de las propiedades fotosensibilizantes del ForU ofreciendo una nueva herramienta para la evaluación de las mismas en un entorno más cercano al del ADN.
[CA] L'espectre de la llum solar està compost per una àmplia gamma de radiacions electromagnètiques les quals tenen diferents impactes sobre la vida en la terra. Entre elles, les pertanyents a la regió ultraviolada prenen un paper principal quan ens referim a la fotobiologia, ja que poden interactuar amb les biomolècules per mitjà de processos tant directes com fotosensibilitzats. Com a resultat, aquestes biomolècules poden patir modificacions que no sempre tenen efectes beneficiosos. En este context, els danys fotoinduits a l'ADN són de gran rellevància ja que estan estretament relacionats amb la creixent incidència de càncer de pell. Per això, és necessari tant d'investigar els mecanismes involucrats en els processos com el desenvolupament de noves estratègies per a combatre'ls. En la present tesi es dóna resposta a aquestes necessitats per mitjà del desenvolupament i ús de grups protectors fotolàbils (PPG). En una primera part s'avança en el desenvolupament de nous PPG basats en filtres solars. Estos ofereixen l'avantatge d'actuar, una vegada alliberats, com un escut protector enfront de la radiació ultraviolada. En este context, en el capítol 3 s'aprofundeix en les propietats fotofísiques i fotoquímiques dels sistemes formats per l'avobenzona com PPG d'àcids carboxílics, més concretament del ketoprofé (KP) i del naproxé (NPX). En este estudi s'analitza per mitjà de modelatge molecular i tècniques espectroscòpiques la influència que té en el procés d'alliberament l'energia relativa del triplet de l'avobenzona en la seua forma dicetònica, 3AB(K)*, respecte a la dels compostos protegits. En esta mateixa línia de treball, en el capítol 4 s'ha desenvolupat un nou PPG capaç d'alliberar el filtre solar oxibenzona (OB) junt amb compostos carbonílics. En una segona part, el focus d'atenció s'ha posat en el concepte de "Cavall de Troia", el qual estableix que certes lesions de l'ADN poden actuar al seu torn com fotosensibilitzadors endògens generant així noves lesions en el seu entorn. En este context, en el capítol 5 s'han estudiat, per mitjà de mètodes tant experimentals com teòrics, les propietats fotosensibilitzants de dos dels danys oxidatius de l'ADN, el 5-formiluracil (ForU) i la 5-formilcitosina (ForC), posant especial èmfasi tant en la capacitat d'estos per a poblar els seus estats triplet, com d'induir la formació fotosensibilitzada de dímers ciclobutànics de pirimidina (CPD). Finalment, en el capítol 6 s'ha desenvolupat una nova alternativa sintètica per a la incorporació del ForU en oligonucleòtids. A causa de la inestabilitat del grup aldehid, esta síntesi es duu a terme generalment per mitjà de la incorporació d'un precursor el qual és posteriorment convertit en el ForU per mitjà de l'acció d'un agent oxidant. Al contrari, en la nova alternativa plantejada l'aldehid és protegit amb un PPG, de manera que una vegada inserit en l'oligonucleòtid, l'aldehid és alliberat de forma selectiva per mitjà de l'ús de llum. Este treball suposa un avanç en l'estudi de les propietats fotosensibilitzants del ForU i ofereix una nova ferramenta per a l'avaluació de les mateixes en un entorn més pròxim al de l'ADN.
[EN] The solar spectrum is composed of a wide range of electromagnetic radiations which have different impacts on life on earth. Among them, those belonging to the ultraviolet region are of utmost importance when we refer to photobiology, since they can interact with biomolecules through both direct and photosensitized processes. As a result, these biomolecules can undergo modifications that do not always have beneficial effects. In this context, photoinduced DNA damage is of great relevance as it is closely related to the increasing incidence of skin cancer. Therefore, it is necessary both to investigate the mechanisms involved in these processes and to develop new strategies to avoid them. In this Thesis these issues have been addressed through the development and use of photolabile protecting groups (PPG). The first part of this Thesis involves the development of new PPG based on solar filters. Once released, these PPG offer the advantage of acting as ultraviolet shields. In this context, Chapter 3 looks into the photophysical and photochemical properties of those systems formed by avobenzone as PPG of carboxylic acids, more specifically ketoprofen (KP) and naproxen (NPX). In this study, the influence on the photorelease process of the relative energetic location of the avobenzone triplet manifold in its diketo form, 3AB(K)*, with respect to that of its caged compound, is duly analyzed by means of molecular modeling and spectroscopic techniques. Following this same line of work, a new PPG capable of releasing oxybenzone (OB) solar filter along with carbonyl compounds has been developed in Chapter 4. The second part of this Thesis focuses on the "Trojan Horse" concept, which establishes that certain DNA lesions can act as endogenous photosensitizers, thus generating new lesions in their neighborhood. In this context, in Chapter 5 the photosensitizing properties of two oxidatively generated DNA damages, namely 5-formyluracil (ForU) and 5-formylcytosine (ForC), have been studied by means of experimental and theoretical approaches. Here, special emphasis has been placed on unraveling their capacity to photoinduce the formation of cyclobutane pyrimidine dimers (CPD). Finally, in Chapter 6 a new synthetic alternative for the incorporation of ForU into oligodeoxynucleotides (ODN) has been developed. Due to the instability of the aldehyde group, this synthesis is generally carried out by incorporating a precursor which is subsequently converted into ForU by the action of an oxidative agent. On the contrary, in the new approach, the aldehyde is protected with a PPG, so that once inserted into the ODN, the aldehyde is selectively released through the use of light. This work entails a step forward in the study of the photosensitizing properties of ForU, offering a new tool for their evaluation within the DNA environment.
Lineros Rosa, M. (2021). Photoremovable protecting groups for carbonyl compounds of biological interest [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/167764
TESIS

Thermal reactions and flash photolysis are used to study the olefin bond-migration promoted by tungsten carbonyls. Substitution of piperidine (pip) by 2- allylphenyldiphenylphosphine (adpp) in the cis-(pip)(η^1- adpp)W(CO)-4 complex was investigated, and no olefin bond-migration was observed. This suggests that a vacant coordinated site adjacent to the coordinated olefin is an essential requirement for olefin bond rearrangement. The rates of olefin attack on the photogenerated coordinatively unsaturated species, cis-[(CB)(η^1-ol- P)W(CO)-4] (CB = chlorobenzene, p-ol = Ph-2P(CH-2)-3CH=CH-2; n = 1-4) were measured. Kinetics data obtained both in pure CB and in CB/cyclohexane mixtures support a dissociative mechanism in which the W-CB bond is broken in the transition state. In contrast to results observed in studies of other related systems, no olefin bond-migration is noted. This observation is attributed to P-W coordination at all stages of the reaction, which precludes formation of a reactive intermediate containing a vacant coordination site adjacent to a P-ol bond.

A facile method for the direct conversion of oximes into carbonyl compounds by treatment with manganese triacetate is described. Manganese triacetate can be used for an effective and mild oxidizing agent for the regeneration of carbonyl compounds in good yield. Many functional groups are tolerated under reaction conditions.

Hydrosilation of $ alpha, beta$-unsaturated carbonyl compounds catalyzed by hydridotetrakis(triphenylphosphine)rhodium(I) (2.20) was found to be highly regioselective, depending on the type of silicon hydrides used. Diphenylsilane was found to give 1,2-hydrosilation (100%), whereas dimethylphenylsilane and other monohydrosilanes gave 1,4-addition (100%).
The kinetic isotope effect of the hydrosilation reaction was examined. A kinetic isotope effect of $k sb{H}/k sb{D}=2$ was observed in the hydrosilation of acetophenone (2.78) by dihydrosilane, $ rm H sb2SiPh sb2$ (2.21) and $ rm D sb2SiPh sb2$ (2.83), catalyzed by the complex 2.20. While a mixture of 1:1 labeled and unlabeled sec-phenethyl alcohols was obtained for the same reaction with monohydrosilane, $ rm HSiMe sb2Ph$ (2.14) and DSiMe$ sb2$Ph (2.86).
A mechanism was proposed to account for the regioselection and the kinetic isotope effect. With the proposed intermediate O in Chart 2.5,$ sp*$ when R $ ne$ H, the hydrosilation proceeds at the rhodium center to give the 1,4-selection product; when R = H, the reaction occurs at the silicon center to generate the 1,2-reduction product.
The reaction catalyzed by 2.20 was also diastereoselective, in both 1,2-hydrosilation (up to 100% de) and 1,4-hydrosilation (84% de) of $ alpha, beta$-unsaturated ketones.
A moderate enantiomeric excess was achieved in the asymmetric hydrosilation of prochiral ketones with chiral complexes derived from complex 2.20 with chiral phosphine ligands (up to 78% ee), and with chiral oxazolinyl compound 2.139 (up to 46% ee). Two C$ sb3$ symmetric ligands have been designed and synthesized, which were found to be too unstable to form C$ sb3$-metal complexes. ftn$ sp*$Please refer to the dissertation for diagram.

Kyoto University (京都大学)
0048
新制・課程博士
博士(人間・環境学)
甲第10308号
人博第195号
14||159(吉田南総合図書館)
新制||人||48(附属図書館)
UT51-2003-H729
京都大学大学院人間・環境学研究科人間・環境学専攻
(主査)教授 松本 澄, 教授 山内 淳, 教授 山口 良平
学位規則第4条第1項該当