Thesis (M.S.)--Rochester Institute of Technology, 1994. / Typescript. Includes bibliographical references (leaves 62-65).

Thesis (doctoral)--University of Stockholm, 1983. / Bibliography: p. 36-39.

Chapter 1 gives an introduction on the physical and electronic properties of fluorine and the C-F bond. The application of fluorine in organic chemistry, which is mainly attributed to the electronic properties of fluorine is described. The role of fluorine in neuropsychiatric drug development and for influencing the conformational study of bioactive amines is also illustrated. Chapter 2 of the thesis describes the synthesis of the two fluorinated stereoisomers (2R, 3S) and (2S, 3S) 3-fluoro N-methyl–D-aspartate (NMDA). These were prepared as analogues to study the binding conformation of NMDA on the glutameric NMDA receptor. The (2S, 3S)-3-fluoro NMDA D-72 was successfully prepared from diethyl D-tartrate. The (2S,3R)- stereoisomer was prepared by separation of diastereoisomers generated by reaction of a meso- epoxide with an enantiomerically pure amine, followed by fluorination. Both the (2S,3R)- and (2R,3S)- enantiomers were prepared separately, however assignment of the absolute configuration to each enantiomer could not be unambiguously proven. The fluorinated 3F-NMDA stereoisomers were assessed by dose response analysis and TEVC analysis in the rat glutamate receptor. The biological results show that the (2S, 3S)-3F NMDA D-72 is a good agonist, whereas (2R, 3S)- and (2S, 3R)-3-fluoro NMDA are inactive stereoisomers. The result of this study indicates that (2S, 3S)-3F NMDA D-72 is the only relevant agonist that can access a conformation for binding to NMDA receptor. Chapter 3 describes the preparation of fluorinated analogues of the calcium receptor agonist Cinacalcet. The (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet diastereoisomers were prepared from 3’-(trifluoromethyl)cinnamic acid and 3’’-SF₅-137 Cinacalcet was synthesized from pentafluorosulfanyl benzyl alcohol. The biological assessment in the calcium receptor (CaR) revealed that both (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet is slightly lower in potency compared to the non-fluorinated Cinacalcet 117. This suggests that the Cinacalcet 117 adopts an extended conformation when bound to the receptor. The 3’’-SF₅-137 Cinacalcet possesses equipotent activity with Cinacalcet 117.

*Please refer to dissertation for diagrams. / Part I describes the silicon-hydrogen bond activation (SiHA) of silanes with both electron-deficient iridium porphyrin carbonyl chloride (Ir(ttp)Cl(CO)) and electron-rich iridium porphyrin methyl (Ir(ttp)Me) to give iridium(III) porphyrin silyls (Ir(ttp)SiR3). Firstly, Ir(ttp)SiR3 were synthesized in moderate to good yields conveniently from the reactions of Ir(ttp)Cl(CO) and Ir(ttp)Me with silanes, via SiHA in solvent-free conditions and non-polar solvents at 200°C. Base facilitated the SiHA reaction even at lower temperature of 140°C. Specifically, K3PO4 accelerated the SiHA with Ir(ttp)Cl(CO), while KOAc promoted the SiHA by Ir(ttp)Me. Mechanistic experiments suggest that Ir(ttp)Cl(CO) initially forms iridium porphyin cation (Ir(ttp)+), which then reacts with silanes likely via heterolysis to give iridium porphyrin hydride (Ir(ttp)H). Ir(ttp)H further reacts with silanes to yield Ir(ttp)SiR3. On the other hand, Ir(ttp)Me and Ir(ttp)SiR3 undergo either oxidative addition (OA) or sigma-bond metathesis (SBM) to form the products. In the presence of base, a penta-coordinated silicon hydride species likely forms and reacts with Ir(ttp)Me to form iridium porphyrin anion (Ir(ttp) -) that can further react with silane to yield Ir(ttp)H after protonation. Ir(ttp)H finally reacts with excess silane to give Ir(ttp)SiR 3.* / Part II describes successful base promoted aromatic carbon-fluorine (C-F) and carbon-hydrogen (C-H) bond activation of fluorobenzenes in neat conditions to give the corresponding iridium(III) porphyrin aryls (Ir(ttp)Ar) at 200°C in up to 95% yield. Mechanistic studies suggested that Ir(ttp)SiEt3 is firstly converted to Ir(ttp)- in the presence of KOH. Ir(ttp)- cleaves the aromatic C-F bond via an S NAr process. As the reaction proceeds, a hydroxide anion can coordinate to the iridium center of Ir(ttp)Ar to form an iridium porphyrin trans aryl hydroxyl anion (trans-[ArIr(ttp)OH]-). In the presence of water, trans-[ArIr(ttp)OH]- can give Ir(ttp)OH and ArH. Ir(ttp)OH then undergoes aromatic C-H bond activation reaction to give Ir(ttp)Ar'. Furthermore, the aromatic C-F bond activation products were found as the kinetic products, and aromatic C-H bond activation products were the thermodynamic ones.* / Part III describes the successful C(C=O)-C(alpha) bond activation of acetophenones by high-valent iridium porphyrin complexes (Ir(ttp)X, X = Cl(CO), (BF4)(CO), Me) in solvent-free conditions at 200°C to give the corresponding iridium porphyrin benzoyls (Ir(ttp)COAr) in up to 92% yield. Mechanistic studies suggest that Ir(ttp)X reacts with acetophenones to give alpha-CHA product as the primary product, which can re-convert back to the active intermediate Ir(ttp)OH or Ir(ttp)H in the presence of water formed from the concurrent iridium-catalyzed aldol condensation of acetophenones. Then Ir(ttp)OH cleaves the aromatic C-H bonds to produce the aromatic CHA products, which are more thermally stable than the alpha-CHA product. Both Ir(ttp)H and Ir(ttp)OH were the possible intermediates to cleave the C(C=O)-C(alpha) bond to give thermodynamic products of Ir(ttp)COAr. On the other hand, only Ir(ttp)(BF 4)(CO) can react with the aliphatic ketones, likely due to the stronger Lewis acidity and the HBF4 generated in catalyzing the aldol condensation of aliphatic ketones to facilitate the formation of Ir(ttp)OH and Ir(ttp)H.* / The objectives of the research focus on the bond activation chemistry by iridium porphyrin complexes with three organic substrates, (1) hydrosilanes (HSiR3), (2) fluorobenzenes (C6HnF6-n , n = 0--6), and (3) aromatic or aliphatic ketones (RCOR, R = alkyl or aryl). / Li, Baozhu. / Adviser: Kin Shing Chan. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

The fluorinase enzyme, originally isolated from Streptomyces cattleya, has the unique ability to generate a C–F bond from aqueous fluoride ion and S-adenosylmethionine, making the fluorinase an attractive biochemical tool for radiolabelling biomolecules with fluorine-18 for application to positron emission tomography (PET). The inherent substrate specificity of the enzyme is, however, limiting, as only small modifications to the natural nucleoside substrate were known to be tolerated. This thesis describes an exploration and expansion of the substrate scope of the fluorinase enzyme, and its application to radiolabelling biomolecules for PET. The design and synthesis of a novel acetylene bearing substrate for the fluorinase, 5'-chloro-5'-deoxy-2-ethynyladenosine (ClDEA) is described. ClDEA proved an excellent substrate for the fluorinase, and the kinetics of the transformation and binding affinities of the new substrate and product were investigated. The fluorinated acetylenic product was demonstrated to undergo a copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction with an azide bearing RGD peptide, and this methodology was investigated for the synthesis of a novel fluorine-18-bearing prosthetic group for the synthesis of a radiolabelled RGD peptide, which was assessed in vivo in a rat. After the demonstration that the fluorinase can be used for “last step” radiolabelling of bioactive peptides, the synthesis of dimeric and tetrameric RGD-bearing substrates for the fluorinase was investigated. These large constructs underwent efficient enzymatic fluorination, and the fluorinated products showed increased binding affinity to their targets, compared to monomeric analogues. The challenges encountered during radiolabelling of these multimers with fluorine-18 using the fluorinase are discussed. A difluoromethyl-bearing nucleoside substrate (F₂DA) was synthesised as a potential substrate in the reverse direction for the fluorinase, to further probe the substrate specificity if the fluorinase. Upon incubation with the enzyme, F₂DA did not appear to undergo reaction, despite the demonstration that F₂DA binds to the enzyme. Finally, the optimisation of a fluorinase-based protocol for the synthesis of the PET radiotracer [¹⁸F]fluoroacetate is described. The enzymatic method proved unsuitable for a small animal study due to contamination of the final product, and a chemical method was investigated and optimised as an alternative approach. [¹⁸F]Fluoroacetate synthesised using the developed chemical method was employed in an in vivo evaluation of acetyl CoA synthetase (ACSS2) activity in healthy and tumour-bearing mouse models, in an study to assess the activity of ACSS2 in breast and colon cancer models in mice.

The development of new unconventional routes to small functionalized fluorocarbons (FCs) continues to be an attractive target due to the high utility of FCs in a broad range of applications, including their use as refrigerants, solvents, and surfactants. With the phasing out of hydrofluoroalkanes as refrigerants, there is a growing interest in the synthesis of new hydrofluoroolefins (HFOs), which are known to have significantly reduced global warming potential relative to hydrofluoroalkanes. Currently, energy-intensive conditions and toxic starting materials are typically necessary for their syntheses, making these processes environmentally problematic. The approach we have proposed for alternative ‘greener’ methods for functionalized FC production targets a transition metal-catalyzed synthesis involving the formation of metallacyclic intermediates through the oxidative cycloaddition of simple fluorinated alkenes, e.g., tetrafluoroethylene (TFE) and trifluoroethylene (TrFE), at low-valent nickel centres. There is precedent for the generation of short fluoroalkyl chain (C4-C6) compounds through homogeneous catalysis. For example, Baker et al. showed that you could catalytically hydrodimerize two molecules of tetrafluoroethylene (TFE) or one molecule of TFE with one molecule of ethylene using low valent Ni catalysts and π-acidic monodentate ancillary ligands, affording octafluorobutane and 1,1,2,2-tetrafluorobutane respectively. The objective of this Thesis is to further the state-of-the-art in fluoroorganometallic chemistry by gaining a deeper understanding of transition metal fluoroalkyl complexes as a function of metal-fluoroalkyl and carbon-fluorine bond reactivity. The over-arching goal is to harness said reactivity for the synthesis of new value-added fluorocarbons. Due to the robust nature of carbon-fluorine and metal-fluoroalkyl bonds in transition metal fluoroalkyl complexes, intensive conditions are often necessary to achieve any reactivity. Recently, bifunctional ligands have proven to be useful at effecting challenging transformations through unconventional ligand-assisted substrate activation pathways. Chapters 2 and 3 herein explore the use of a bidentate phosphinothiol ligand in the context of perfluoronickelacyclopentane reactivity. Synthetic approaches for the formation of phosphinothioether- and phosphinothiolate-supported perfluorometallacycles are outlined along with ensuing reactivity studies, including examples of Cα-F, Cβ-F, and Ni-Cα bond activation. Furthermore, a metal-mediated synthesis of functionalized FC, (E)-1,2,3,3,4,4-hexafluoro-1-butene, is provided. Chapter 4 sheds light on the comparatively underdeveloped chemistry of fluorinated nickelacycles generated from TrFE. A systematic study of monodentate phophine and phosphite ligand effects on metallacyclopentane regio-/stereochemistry is presented. The behaviour of the generated hydrofluoronickelacyclopentanes in the presence of acidic additives allows for a direct analogy to be made regarding the effects of the extent of metallacycle fluorination on C-F and Ni-C activation. In search of new approaches to novel functionalized FC synthesis, Chapter 5 will re-visit the use of bifunctional ligands, investigating the formation and reactivity of new perfluoronickelacycles featuring [P,NH] and [P,Nˉ] bidentate ligands. Finally, Chapter 6 summarizes the findings of this Thesis and discusses some of the future opportunities that will build on this work. The increased understanding of the stoichiometric systems presented herein will be directly important to the development of nickel-catalyzed routes to HFOs. As the demand for new “greener” refrigerants and propellants increases, the synthesis of small-molecule functionalized FCs using transition metal catalysis and waste fluorinated feedstocks can offer a mild, atom economical approach to new, unique candidates that will be appealing to industrial partners.

Chapter 1 gives an overview of the fluorine chemistry field, from its early developments to recent applications in medicinal chemistry. The development of asymmetric electrophilic or nucleophilic installation of fluorine in organic molecules is highlighten. Chapter 2 of this thesis discusses the enantioselective synthesis of α-fluoroamides. The study is applied to the synthesis of fluoroenantiomers of the bioactive molecule capsaicin and short-chain analogues. The biological activity of these compounds is assayed with the TRPV1 receptor. Results show that enantioselective α-fluoroamides (R)-97, (R)-99 and (S)-99 can generate differentiated biological responses, from TRPV1 agonists to TRPV1 antagonists. Chapter 3 focuses on the optimisation and development of 2-(aminomethyl)piperidine (R)-251 dihydrochloride. The development of 2-(aminomethyl)piperidine (R)-251 as its ditetrafluoroborate salt proved to offer excellent reactivity and solubility for the preparation of derivatives. This tetrafluoroborate salt was used to improve the syntheses of organocatalysts 2,2,2-trifluoro-N-(piperidin-2-ylmethyl)acetamide 363 and 4-methyl-N-(piperidin-2-ylmethyl)benzenesulfonamide 364.The catalytic properties of these latter two molecules for asymmetric Mannich reaction is demonstrated. Both (R)-363 and (R)-364 show up to 86% ee, in a typical 20 mol% loading, but loading of (R)-363 as low as 5 mol% still induces the catalysis.

This thesis is divided into three main results chapters that reflect the path my research took. In the first results chapter, the first organocatalyst for the carbonyl-ene reaction was discovered and found to give high conversion using 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea. Various carbonyl and alkene precursors were examined in the ene reaction in both catalysed and uncatalysed reactions. It was found that ene reactions using fluoral and ethyl trifluoropyruvate give higher rates of reaction when compared to other carbonyl compounds. A novel enantiopure thiourea was synthesised and the ene reaction was catalysed enantioselectively to 33% e.e. In an attempt to catalyse the reaction to a further extent a new thiourea bonded to a P(=S)R2 group was developed. However, the intramolecular hydrogen bonding of this catalyst was thought to be so strong that this it did not catalyse the reaction. The synthesis of a chiral phosphoric acid was achieved but this was an unsuccessful catalyst in the ene reaction. Two component achiral thiourea and chiral acids were also examined in the ene and Mannich-type reaction. The new easily synthesised thiourea for this reaction has an interesting intermolecular hydrogen bonding coordination in the solid state. Asymmetric fluorination of ketoesters using palladium is a dynamic kinetic resolution. In the 2nd chapter cationic palladium complexes were synthesised and used to determine the optimum parameters for bidentate ligands in this reaction. Four carbon chain phosphines were found to give the highest conversion for this reaction among those ligands tested such as 1,4-bisdiphenylphosphinobutane (bite angle 99º). A new bis-phosphinous amide chiral ligand was developed with a bite angle of 96.7º. The dichloropalladium complex of this phosphine was isolated and structurally characterised. The use of the palladium complex in asymmetric fluorination was attempted however this was found to be unsuccessful. Mechanistic studies reveal that the formation of the desired cationic catalyst did not occur under conditions shown to work well for other palladium phosphine complexes. The ligand was investigated further in hydrogenation reactions. The phosphinous amide was protected as its borane and was used in the rhodium catalysed hydrogenation of alkenes to give high conversion and up to 93% e.e. The borane protected phosphinous amide was also found to catalyse the hydrogenation of acetophenone using copper complexes with up to 84% e.e for the hydrogenation of acetophenone, although conversion was quite low.

Made available in DSpace on 2014-06-11T19:31:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-05-16Bitstream added on 2014-06-13T20:22:04Z : No. of bitstreams: 1 zuanaze_rcc_dr_botfmvz.pdf: 2365698 bytes, checksum: 5ed70ccdd25955ad8f5b2e015a21dec7 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação para o Desenvolvimento da UNESP (FUNDUNESP) / O monofluoroacetato de sodio (MFAS) ou composto 1080 e um rodenticida que foi amplamente utilizado para o controle de roedores e predadores domesticos, apos sua descoberta em 1945. Este potente rodenticida age bloqueando o ciclo de Krebs por acao do seu metabolito toxico, o fluorocitrato, e como consequencia, inibe a resposta celular e a producao de ATP. O MFAS foi proibido por lei no Brasil e em diversos paises, mas seu uso indiscriminado continua causando diversos casos de intoxicacoes potencialmente fatais no homem e animais domesticos, principalmente em caes e gatos, representadas por alteracoes neurologicas e cardiacas. Pretendeu-se com este estudo caracterizar o perfil hematologico e bioquimico, as alteracoes histopatologicas e toxicologicas de gatos intoxicados experimentalmente com MFAS, com o objetivo de determinar metodos diagnosticos eficazes. Para tanto, foram utilizadas amostras de sangue de 16 gatos intoxicados experimentalmente com 0,45mg/kg de MFAS, por via oral. Estas amostras foram colhidas por puncao jugular e analisadas quanto ao perfil hematologico, bioquimica serica e analises toxicologicas em cromatografia liquida de alta eficiencia (CLAE), para deteccao e quantificacao do MFAS no soro dos animais. Avaliaram-se tambem as lesoes macro e microscopicas dos animais intoxicados que vieram a obito. Observaram-se leucopenia e trombocitopenia transitorias; hiperglicemia, aumento das enzimas musculares creatinoquinase (CK) e creatinoquinase fracao cardiaca (CK-MB); observaram-se tambem hipocalemia, hipofosfatemia e hipomagnesemia. Os achados macroscopicos e histopatologicos demonstraram lesoes caracteristicas de processos isquemicos e as analises toxicologicas demonstraram um metodo diagnostico simples e eficiente... / Sodium monofluoroacetate (SMFAC) or 1080 compound is a potent rodenticide, largely used since 1945 for rodent and domestic pest control. The toxic effects of SMFAC are caused by fluorocitrato, a toxic metabolite, which has a competitive action with aconitase enzyme, leading to citrate accumulation and interferes in energy production by Krebs cycle blockade. In Brazil, although prohibited by law, there is illegal use, keep causing intoxication in children and domestic animals, specially dogs and cats. The most common intoxication clinical signs are from the cardiac and neurological alterations. In the present study, 16 domestic cats were intoxicated with oral doses of monofluoroacetate (0.45mg/kg). The hematologic and biochemical profiles, and histophatological and blood serum toxicological analysis by high performance liquid chromatography (HPLC) were made to looking for a efficient diagnosis methods. The hematologic profile showed transitory leucopenia and trombocitopenia; the biochemical profile presented hiperglycemia, increase of creatinoquinase enzyme (CK) and creatinoquinase cardiac fraction (CK-MB), hypokalemia and hypophosfatemia were observed. The macrocospic and histopathological findings showed lesions characteristic of degenerative and ischemic processes. The toxicological analysis was shown to be a simple and efficient diagnostic method. SMFAC was detected in 75% of the serum samples analysed, and it was verified an average concentration of 0.32 ìg/mL in them; 4.81% of the serum samples did not show metabolized SMFAC six hours after the induced intoxication of the animals used in this study.

Orientador: Michiko Sakate / Banca: Noeme Sousa Rocha / Banca: Manoel Lima de Menezes / Banca: Mara Regina Stipp Balarin / Banca: Silvana Lima Gorniak / Resumo: O monofluoroacetato de sodio (MFAS) ou composto 1080 e um rodenticida que foi amplamente utilizado para o controle de roedores e predadores domesticos, apos sua descoberta em 1945. Este potente rodenticida age bloqueando o ciclo de Krebs por acao do seu metabolito toxico, o fluorocitrato, e como consequencia, inibe a resposta celular e a producao de ATP. O MFAS foi proibido por lei no Brasil e em diversos paises, mas seu uso indiscriminado continua causando diversos casos de intoxicacoes potencialmente fatais no homem e animais domesticos, principalmente em caes e gatos, representadas por alteracoes neurologicas e cardiacas. Pretendeu-se com este estudo caracterizar o perfil hematologico e bioquimico, as alteracoes histopatologicas e toxicologicas de gatos intoxicados experimentalmente com MFAS, com o objetivo de determinar metodos diagnosticos eficazes. Para tanto, foram utilizadas amostras de sangue de 16 gatos intoxicados experimentalmente com 0,45mg/kg de MFAS, por via oral. Estas amostras foram colhidas por puncao jugular e analisadas quanto ao perfil hematologico, bioquimica serica e analises toxicologicas em cromatografia liquida de alta eficiencia (CLAE), para deteccao e quantificacao do MFAS no soro dos animais. Avaliaram-se tambem as lesoes macro e microscopicas dos animais intoxicados que vieram a obito. Observaram-se leucopenia e trombocitopenia transitorias; hiperglicemia, aumento das enzimas musculares creatinoquinase (CK) e creatinoquinase fracao cardiaca (CK-MB); observaram-se tambem hipocalemia, hipofosfatemia e hipomagnesemia. Os achados macroscopicos e histopatologicos demonstraram lesoes caracteristicas de processos isquemicos e as analises toxicologicas demonstraram um metodo diagnostico simples e eficiente...(Resumo completo, clicar acesso eletrõnico abaixo) / Abstract: Sodium monofluoroacetate (SMFAC) or 1080 compound is a potent rodenticide, largely used since 1945 for rodent and domestic pest control. The toxic effects of SMFAC are caused by fluorocitrato, a toxic metabolite, which has a competitive action with aconitase enzyme, leading to citrate accumulation and interferes in energy production by Krebs cycle blockade. In Brazil, although prohibited by law, there is illegal use, keep causing intoxication in children and domestic animals, specially dogs and cats. The most common intoxication clinical signs are from the cardiac and neurological alterations. In the present study, 16 domestic cats were intoxicated with oral doses of monofluoroacetate (0.45mg/kg). The hematologic and biochemical profiles, and histophatological and blood serum toxicological analysis by high performance liquid chromatography (HPLC) were made to looking for a efficient diagnosis methods. The hematologic profile showed transitory leucopenia and trombocitopenia; the biochemical profile presented hiperglycemia, increase of creatinoquinase enzyme (CK) and creatinoquinase cardiac fraction (CK-MB), hypokalemia and hypophosfatemia were observed. The macrocospic and histopathological findings showed lesions characteristic of degenerative and ischemic processes. The toxicological analysis was shown to be a simple and efficient diagnostic method. SMFAC was detected in 75% of the serum samples analysed, and it was verified an average concentration of 0.32 ìg/mL in them; 4.81% of the serum samples did not show metabolized SMFAC six hours after the induced intoxication of the animals used in this study. / Doutor