京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21796号 / 工博第4613号 / 新制||工||1718(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 松田 建児, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

No description available.

Transition metal catalysis is a necessary branch of organic synthesis. Both monometallic and bimetallic catalysts can reduce reaction times, improve regio- and enantioselectivity, and minimize byproducts. Additionally, bimetallic catalysts can cooperatively activate substrates, which can enable new reactions and mechanistic pathways. The first half of this work will describe the synthesis and catalytic ability of our novel Pd(I) and Pd(II) dimers. Both dimers use a 2-phosphinoimidazole ligand scaffold to bring the metal centers in close proximity. The Pd(II) dimer can catalyze the synthesis of 1,3-disubstituted naphthalene rings from commercially available aryl iodides and methyl ketones with high regioselectivity and yields. Mechanistic and theoretical studies suggest the mechanism undergoes a Pd(III)–Pd(III) like intermediate. Additionally, we studied the impact of precatalyst oxidation state on C–N bonding reactions. We found that our Pd(I) dimer performed better in Buchwald-Hartwig aminations, while our Pd(II) dimer was shown to be extremely active in aminocarbonylation reactions. Both reactions gave C–N bonding products in good to excellent yield. The second portion of this work describes our novel Pd N–H NHC complex and its application in Suzuki-Miyaura cross couplings. In the presence of methanol, a Pd(II) salt will insert into the C–P bond of a 2-phosphinoimidazole ligand to give a protic NHC complex. The acidic hydrogen can be deprotonated under reaction conditions to give an anionic complex, which further increases the electron density on palladium as shown in Tolman Electronic Parameter studies. Application of the catalyst in Suzuki-Miyaura and Sonogashira coupling reactions gave product in high yield. Since our Pd N–H NHC complex with a diphenylphosphine ligand could not activate aryl chlorides, we then applied 2-dialkylphopshinoimidazole ligands. When the dialkyl ligands were stirred with Pd(II) salts in methanol, an equilibrium was observed between N–H NHC and P–N coordination complexes. When the catalytic mixture was applied to Suzuki-Miyaura cross-couplings, (hetero)aryl chlorides gave high yields with low catalyst loadings.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24557号 / 薬科博第174号 / 新制||薬科||19(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 高須 清誠, 教授 大宮 寛久 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

No description available.

The two projects described in this dissertation demonstrate the wide utility of noble metal N-heterocyclic carbene (NHC) complexes. The first project details the design of iridium NHC amino acid complexes for asymmetric transfer hydrogenation (ATH) of prochiral ketones. Iridium(I) bis-NHC complexes were found to undergo oxidative addition with a variety of alpha-amino acids, generating chiral iridium(III) complexes of the form Ir(NHC)2(aa)(H)(X) (aa = amino acid, X = halide). The complexes were screened for ATH of aryl and alkyl ketones, and optimization studies found enantioselectivity in this system was highly sensitive to the reaction temperature, NHC ligand, and amino acid. Incorporation of secondary amino acids was essential to enantioselectivity. Aryl ketones were reduced in high conversion and enantioselectivity when employing the Ir(IMe)2(L-Pro)(H)(I) catalyst in isopropyl alcohol, in some cases giving over 90% ee of the alcohol products. Density functional theory calculations were conducted in order to gain insight into the active catalytic species, and the results suggest that the high enantioselectivity of this system primarily arises from steric effects. The second project details the design of rhodium and iridium NHC piano-stool complexes featuring derivatized tetramethylcyclopentadienyl ligands (Cp*R, R = alkyl or aryl substituent) for antimicrobial applications. Complexes of the form (Cp*R)M(NHC)Cl2 (M = Rh or Ir) were synthesized by transmetallation of the NHC ligand using silver(I) oxide in the presence of the desired noble metal Cp*R dimer. The complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of these compounds were highly active against Mycobacterium smegmatis, displaying minimum inhibitory concentrations (MICs) as low at 0.25 microgram per mL. Analysis of structure-activity relationships found that incorporation of the NHC ligand greatly enhances the antimicrobial properties of rhodium and iridium piano-stool complexes, more so than previously investigated diamine, amino acid, or beta-diketonato ligands. Cytotoxicity studies on one of the rhodium NHC complexes showed this compound was nontoxic towards mammalian cells at low concentrations, which strengthens the potential of these types of compounds as viable drug candidates. / Doctor of Philosophy / This dissertation describes two practical applications of a series of complexes featuring the noble metals rhodium and iridium. In all of these complexes, the metal center is bonded to one or two groups known as N-heterocyclic carbenes (NHCs). The most common structural variant of NHCs are five-membered rings. The metal is usually bonded to a carbon atom on these rings, which is flanked by two nitrogen atoms. Noble metal complexes containing NHCs are widely investigated in contemporary chemical literature for a variety of reactions, primarily because noble metals form exceptionally strong bonds with NHCs, making these complexes very stable. N-Heterocyclic carbene compounds are also fairly easy to synthesize and structurally modify, which allows fine-tuning for specific applications. The first project in this dissertation employed iridium NHC amino acid complexes for the selective production of alcohols, meaning only one structure of the alcohol product is favorably generated. This is an important transformation in the chemical and pharmaceutical industries, which often require the synthesis of highly pure products. These complexes were found to be quite successful for this application on a range of model substrates, in some cases generating as high as 95% of one alcohol product over the other. Product selectivity was found to depend on the specific structure of the NHC compound. The second project investigated the antimicrobial properties of rhodium and iridium NHC complexes. In recent years, the growing threat of antimicrobial resistance against traditional pharmaceuticals has led to an interest in the development of metal-based drugs, which may allow for metal-specific mechanisms of drug action that are not possible for commonly employed antimicrobial agents. These NHC complexes were screened for biological activity against various bacteria, yeast, and fungi. Many of the complexes displayed high activity against Mycobacterium smegmatis, comparable to those displayed by other clinical drugs such as ampicillin or streptomycin. These results were highly encouraging, as Mycobacterium smegmatis often serves as a model to study other mycobacteria.

Yes / Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. / RMP and MS funded by Yorkshire Cancer Research (pump priming grant BPP 046). IJS and AL funded by NIHR Research & Innovation Division, Strategic Project Funding 2013 and Manchester Pharmacy School Fellowship.

Le développement de catalyseurs efficaces à base de ruthénium a contribué à l’essor de la métathèse des oléfines. Cette réaction catalysée par des complexes à base de tungstène, rhénium ou molybdène, était appliquée, jusqu’à présent, à des oléfines non fonctionnalisées. L’utilisation de précurseurs à base de ruthénium a permis d’élargir les domaines d’applications de la métathèse grâce à leur tolérance élevée à de nombreuses fonctions organiques. En effet, les esters méthyliques d’huiles végétales peuvent être valorisés en bases chimiques par la réaction de métathèse en présence de catalyseurs à base de ruthénium. Nous reportons, ici, l’étude de la réactivité des complexes de ruthénium en éthénolyse de l’oléate de méthyle ainsi que la conception et la caractérisation de nouveaux systèmes. Nous exposerons la synthèse de nouveaux catalyseurs de ruthénium contenant des ligands carbènes aminoalkyle cycliques et l’évaluation de leurs performances. Nous montrerons que ces précatalyseurs présentent des propriétés catalytiques intéressantes pour l’éthénolyse de l’oléate de méthyle. Ces ligands ont l’avantage d’être modulables, ce qui nous offrent de nombreuses possibilités en terme d’originalité, tout comme la fonctionnalisation du ligand isopropoxybenzylidène qui permet l’immobilisation des catalyseurs dans les liquides ioniques. Par ailleurs, des tentatives de coordination d’autres ligands, tels que le fluorénylidène et le silylène, susceptibles de conduire à des complexes de ruthénium efficaces seront abordées. / The development of efficient ruthenium based catalysts has contributed to the development of olefin metathesis. This reaction catalyzed by tungsten, rhenium or molybdenum complexes, was applied, until now, to non-fonctionalized olefins. The use of ruthenium precursors allowed to broaden range of applications of olefin metathesis owing to their high tolerance to various organic functions. Indeed, methyl esters of vegetable oils can be converted into chemical base by metathesis in the presence of ruthenium based catalysts. In this study, we report ruthenium complexes reactivities for ethenolysis of methyl oleate as well as the design and the characterization of new systems. We describe the synthesis of new ruthenium catalysts containing cyclic alkyl(amino)carbenes and the evaluation of their performances. We show that these precatalysts display interesting catalytic properties for the ethenolysis of methyl oleate. Modifications of the carbenes ligands architecture provide the possibility to create novel catalysts as the functionalization of the isopropoxybenzylidene ligand which allowed immobilization of catalysts in ionic liquid. Besides, attempts to coordinate other ligands, such as fluorenylidène and silylene, able to afford active complexes will be discuss.

Les carbènes N-hétérocycliques (NHC) sont très utilisés pour complexer les métaux de transition. Ils quittent rarement ce rôle de ligand ancillaire et trouvent, depuis une vingtaine d’années, des applications en catalyse ou, plus récemment, en chimie médicinale. Dans ce travail, nous discuterons d’une méthode de synthèse douce conduisant à la formation de complexes AgI – NHC via une source d’argent soluble. Cette méthode nous a permis d’obtenir des complexes bien connus mais également d’accéder à une nouvelle série de complexes NHC-Ag-phosphine. Nous présenterons également une nouvelle réaction où des NHC portant une fonction azoture à proximité du carbone du carbène quittent leur rôle de ligand ancillaire et conduisent à la formation d’hétérocycles azotés par cyclisation carbène-nitrène. Cette réaction sera présentée en détail, ainsi que la caractérisation spectroscopique concernant une sous-série de composés fluorescents obtenus par cette méthode. Enfin, nous présenterons une stratégie de post-fonctionnalisation de complexes développée dans notre équipe. Des complexes argent(I)-NHC portant un azoture proches du centre carbénique catalysent leur propre fonctionnalisation. De plus, des complexes de cuivre(I) portant des azotures en position éloignée du centre métallique seront greffés sur des nanoparticules magnétiques pour servir de catalyseur recyclables. / N-heterocyclic carbenes (NHC) are widely used to complex transition metals. They rarely leave their role as ancillary ligand and find, since 20 years, applications in catalysis or, more recently, in medicinal chemistry. In this work, we will discuss a mild synthetic method leading to the formation of AgI – NHC complexes via a soluble silver species. This method allowed us to obtain well known complexes but also to access a new series of NHC-Ag-phosphine complexes. We will also present a new reaction where NHC ligands bearing an azide function close to the carbenic center leave their role as ancillary ligand and lead to the formation of nitrogen rich heterocycles by a carbene-nitrene cyclization. This reaction will be presented in detail, along with the spectroscopic characterization regarding a sub-series of fluorescent compounds obtained by this method. Finally, we will present a post-functionalization strategy of complexes developed in our team. Silver(I)-NHC complexes tagged by an azide close to the carbenic center catalysed their own functionalization. Moreover, copper(I) complexes tagged by an azide function in a distant position from the metallic centre will be grafted on magnetic nanoparticles to act as recyclable catalysts.

Thesis (PhD (Chemistry and Polymer Science))--Stellenbosch University, 2008. / Novel gold(I) trithiophosphite complexes were synthesised by utilising the ligands P(SR)3 (R = Me, Ph) and 1,2-bis(1,3,2-dithiaphospholan-2-ylthio)ethane (2L). Reaction with (tht)AuCl or (tht)AuC6F5 readily yielded the corresponding complexes (RS)3PAuX and 2L(AuX)2 (X = Cl, C6F5) as well as {Au[P(SMe)3]2}CF3SO3. Structural characterisation by X-ray diffraction revealed linear complexes in part associating by Au…Au and/or Au…S contacts, two polymorphs of one compound associating by either Au…S interactions or p-stacking was also obtained. (MeS)3PAuCl and (MeO)3PAuCl were found to be isostructural in the solid state. The complex chloro[tris(4-methylthiazol-2-yl)phosphane]gold, A, was used to probe the electronic influence tris(azol-2-yl)phosphanes exert upon gold(I) by substituting the chloride with various thiolates. In contrast to Ph3PAuCl, only NCS– and PhC(O)S– afforded stable compounds which could be attributed to a weaker donating capability of the tris- (azolyl)phosphane ligand class. The compounds A and chloro[tris(thiazol-2-yl)phosphane]- gold, B, were shown to crystallise in 4 new polymorphs and solvates bringing the total to an exceptional seven. Among the solid-state structures of A the rare instance of a polymorph and a thf solvate not exhibiting aurophilic interactions as opposed to the original structure were observed. Complex B was shown to crystallise in polymorphs where dimers are associated either by Au…Au or Au…Cl interactions but otherwise exhibit similar arrangements of the ligand, this set of polymorphs is unprecedented amongst gold complexes. An NMR experiment proved that tris(thiazolyl)phosphane complexes are subject to hydrolysis under alkaline conditions. A trimeric gold(I) heterometallacycle, obtained by reacting (tht)AuCl with 4,4-dimethyl-2-(2- thienyl)oxazoline deprotonated at C-5 of the thiophene ring, was structurally characterised. Intramolecular Au…S interactions were found to be present which precluded interaction of the gold atoms with other metal centres such as Me3CNCAuCl or AgNO3. A second solvate obtained additionally exhibits Au…Au interactions. The scope of uncommon bis-imine coordination to AuI was expanded by utilising 1,2-bis(1-imidazolylmethyl)-2,4,6-trimethylbenzene (2L) to synthesise the [Au2(μ-2L)2]2+ cation. The triflate salt forms the first porous crystal structure of gold and the co-crystallised solvent could be partially removed by evacuation at elevated temperatures. Utilising a ditopic phosphite ligand instead of the commonly used ditopic phosphane ligands, a new cationic species of the type [Au2(μ-2L)3]2+ was characterised in the solid state for the first time. Finally, employing 2-phenylthiazole and 1-(thiazol-2-yl)piperidine which can be deprotonated at C-5 of the thiazole ring, Fischer-type pentacarbonyltungsten carbeniate complexes were prepared and structurally characterised. Starting from these complexes, the analogous Fischertype methoxycarbene as well as carbyne complexes could be obtained by alkylation and formal oxide abstraction, respectively. The latter products readily formed dinuclear adducts with AuCl. A Fischer-type methoxycarbene could be transferred to AuI affording the first such gold(I) complex exhibiting Au…Au interactions in the solid state as well as a rare agostic Au…H interaction which was examined by low-temperature 1H NMR measurements. Transfer of the carbeniate ligand derived from 1-(thiazol-2-yl)piperidine to Ph3PAu+ afforded an aurated thiazole product (by an unprecedented loss of CO) which may be represented as a pseudoabnormal azolylidene complex owing to W(CO)5-coordination at a distant nitrogen. The carbeniate originating from 2-phenylthiazole, on the other hand, afforded, by rare W(CO)5- trapping and without CO-loss, a pseudo Fischer-type carbene complex. Carbene transfer to gold was complemented by the first transfers of rNHC ligands from chromium and tungsten to gold(I) affording a novel class of complexes, all of which were structurally characterised. This work bridges the unnatural divide created between Fischer and N-heterocyclic carbene complexes.