Nosso grupo de pesquisa já vem há alguns anos estudando métodos para a síntese do núcleo estrutural dos furanoeliangolidos, mais especificamente do goiazensolido. A estrutura básica deste composto corresponde a um sistema 7-oxabiciclo [6.2.1] undecano, e ele possui atividades biológicas como esquistossomicida, citotóxica e antiinflamatória. Em nosso trabalho utilizamos como etapa chave a reação de Diels-Alder, que é geralmente eficiente e rápida para formação de sistemas policíclicos. Na ultima etapa da proposta sintética, propomos a clivagem da ligação interna do sistema policíclico para obtenção do macrociclo desejado. / Our research group has been studying, for some years, new methods for the synthesis of the core structure of the furanoheliangolides, more specifically of goyazensolide. The basic structure of this compound is a 7-oxabicyclo [6.2.1] undecane system, and it shows biological activities such as schistosomicidal, cytotoxic and anti-inflammatory. In this work, we have used the Diels-Alder reaction as a key step, since it is usually fast and efficient for the synthesis of polycyclic structures. As a last step, we proposed that the cleavage of the internal bond of the rings should furnish the desired macrocycle.

The Diels-Alder dimerization of trans-1-substituted butadienes is expected to yield a cyclohexene adduct with the substituents in the 3 and 4 positions cis to one another. This prediction is based on past observations of other Diels-Alder additions. The cis-isomer is the only one consistent with a two-stage mechanism proposed by Woodward and Katz. In the case of trans-phenylbutadiene, the expected adduct is cis-3-phenyl 1-4-(trans-styry1) cyclohexene. Alder, Haydn and Vogt, however, reported that the corresponding trans-isomer is the dimerization product. There is reason to believe that the observation of the trans-isomer may have been the result of product isomerization during purification. In view of the unexpected nature of the product and its implications with respect to the Diels-Alder mechanism, the dimerization reaction was reinvestigated. trans-Phenylbutadiene was heated at 1300 for six hours. Analysis by thin layer chromatography on silica gel impregnated with silver nitrate revealed two major components as well as several minor ones. The two major components were isolated by column chromatography on silica gel impregnated with silver nitrate. They were present in roughly equal proportions. One of them was purified and found to be identical with cis-3-pheny l~4-(trans-styry l) cyclohexene prepared by an independent method. The second major component, not yet isolated in pure form, is probably the corresponding trans-isomer on the basis of IR and NMR spectra as well as the fact that the trans-isomer was found by Alder et al. An evaluation of the significance of this reaction with respect to the Diels-Alder mechanism will have to await positive identification of the second component as well as a more careful determination of its relative proportion to the cis-isomer.

No description available.

Light as a “green” source of energy has become increasingly attractive throughout the past century and has shown versatility for the application of activating chemical reactions. Compared with traditional energy sources, it provides a more direct, selective and controllable method. My PhD study was focused on the study of photochemistry of organic materials in two different systems. The first system is regarding reversible photoacids which generate protons on irradiation. With the aim of systematically studying these novel types of long lived photoacids, a series of photoacids was designed, synthesized and whose chemical mechanism was thoroughly investigated. This type of photoacid changes from a weak acid to a strong acid with a pH change of several units, which achieves nearly complete proton dissociation upon visible light irradiation. The whole process is reversible and the half-life of the proton-dissociation state is long enough to be used in many applications. Besides fundamental studies, different applications based on this type of photoacids were also completed. An esterification reaction was catalyzed and the volume of a pH-sensitive polymer was altered due to the large amount of photo generated protons from this photoacid. A reversible electrical conductivity change of polyaniline (PANI) was also achieved by doping with this reversible photoacid. In order to induce a large conductivity increase, an irreversible photoacid generator (PAG) was embedded in a novel PANI/PAG/PVA novel composition. In this system, Poly (vinyl alcohol) (PVA) forms a hydrogen-bonding network to facilitate proton transfer between the PAG and PANI. A final electrical conductivity of 10-1 S cm-1 was successfully achieved after irradiation. The second system in which I explored photochemistry of organic molecules concerns Photoretro-Diels-Alder (PrDA) reactions and a variety of Diels-Alder (DA) adducts were designed for these studies. UV light was used to trigger the retro-Diels-Alder reactions. Quantum yield of iv each DA adducts was investigated. This revealed that the photo-reactivity of this process depends on the electron-donating ability of the diene and the electron-withdrawing ability of the dienophile component. Mechanistic studies of this PrDA reaction reveal that a charge-separated intermediate is generated from a singlet excited state. This was applied to an unsaturated cyclic α-diketones (DKs), which underwent PrDA reactions and generated anthracene derivatives and carbon monoxide (CO), which itself plays profound and important roles in biological systems. These unsaturated cyclic α-diketones (DKs) encapsulated in micelles are effective CO-releasing molecules (CORMs) and are capable of carrying and releasing CO in cellular systems. This novel type of organic CORMs has potentially low toxicity and generates fluorescence, which provides a useful tool for the study of the biological functions of CO.

No description available.

This dissertation describes a new platform for the synthesis of thermally reversible polymers, based on Diels-Alder reactions of bis-cyclopentadienes (bis-CPDs) and bis-maleimides (bis-MIs), that meets two main objectives. First, the bis-CPD must resist characteristic self-coupling. Second, the CPD-MI adducts should undergo the retro-Diels-Alder (rDA) reaction (i.e., thermal depolymerization) in a temperature regime that is comparable or slightly higher than that of the freely reversible bis-furan/bis-MI polymers (rDA between 80 °C and 130 °C) but much lower than that of bis-CPD homopolymers (rDA above 160 °C). Structure-reactivity relationships gleaned from the literature and from related but as yet unpublished work in our own laboratories led to our main hypothesis that a CPD moiety bearing one sterically encumbering substituent such as isopropyl (𝑖Pr) or tert-butyl (𝑡Bu) and one electronwithdrawing substituent such as perfluoroaryl would have the desired reactivity and adduct stability in combination with an 𝑁-substituted maleimide. Synthetic considerations led to a bisCPD monomer design in which two alkylcyclopentadiene groups (alkyl = 𝑖Pr or 𝑡Bu) are connected by an octafluorobiphenylene linker. As an initial fundamental step (Chapter 3), 1-(nonafluorobiphenyl-4’-yl)-4-tertbutylcyclopentadiene (1) was synthesized to provide a monofunctional model for the proposed difunctional CPD monomer. Reactions of 1 and 𝑁-(4-fluorophenyl)maleimide (FMI) afforded up to five regio- and stereo-isomeric adducts (of fourteen possible). Variable-temperature reactivity studies combined with NMR spectroscopic analysis, X-ray crystallography, and computational modeling enabled product distributions to be understood according to a conventional kinetic-vs- iii thermodynamic framework. These studies also predicted the microstructure of polymers derived from the proposed bis-CPD monomer, which is structurally analogous to 1, and bis-MIs. Moreover, 1 does not undergo DA self-coupling under ordinary conditions (T < 180 °C). Thermolysis studies of the major adducts revealed that the rDA becomes observable on a laboratory timescale (hours) at about 140 °C, which is at the upper end of the temperature range reported for furan+MI adducts but well below that of CPD+CPD adducts. In contrast, adducts formed from either of the analogous monosubstituted cyclopentadienes (𝑡BuC₅H₅ and C₆F₅C₅H₅) do not undergo rDA below 180 °C. These results strongly support the proposed bis-CPD monomer design. In a second fundamental step (Chapter 4), the hypothesis that an electron-withdrawing CPD substituent would destabilize a CPD-MI adduct was further tested by reacting 𝑁-(4- fluorophenyl)maleimide with a series of triarylated cyclopentadienes (1,2,3-Ar₃C₅H₃ and 1,2,4- Ar₃C₅H₃, Ar = C₆F₅, C₆F₄CF₃, and Ar = C₅F₄N). The perfluorophenyl- and perfluorotolylsubstituted compounds were previously reported, but the perfluoropyridyl-substituted cyclopentadienes were prepared for this study using SNAr reactions of pentafluoropyridine and sodium cyclopentadienide. The least electron deficient cyclopentadiene in each series (Ar = C₆F₅) reacted the most quickly and with the highest ultimate equilibrium binding constant, confirming the electron-effects hypothesis as well as the underlying presumption that DA reactions of even relatively electron-poor CPDs with MI would behave according to normal-electron-demand principles. In the main section of this dissertation (Chapter 5) the proposed bis(cyclopentadiene)s reacted with a series of previously reported bis(maleimides) to form linear polymers having molecular weights (Mn) up to 40 kDa. Relationships among the length and flexibility of the bis-MI linker (C₆H₁₂, C₁₂H₂₄, C₆H₄OC₆H₄, and (C₂H₄O)₂), the identity of the CPD alkyl substitutent (CHMe₂, CMe₃ and CMe₂Ph) and the glass transition temperature (Tg) as measured by differential scanning calorimetry (DSC) were understood in terms of a general model of local segmental mobility and free volume. Solution thermolysis of a model polymer system (bis-MI linker = C₆H₁₂ (7), CPD alkyl substituent = 𝑡Bu) showed a rapid decrease in molecular weight at 160 °C as determined by size exclusion chromatography (SEC). Solution thermolysis in the presence of excess FMI (as a trap for free CPD moieties) revealed that the onset temperature for rDA on a laboratory time scale (hours) was as low as 120 °C. In the bulk, thermolysis above 250 °C under vacuum led to recovery of a small portion of the bis-CPD monomer, but bulk thermolysis at 200 °C did not reveal a change in molecular weight as determined by SEC. The current interpretation of these observations is that limited mobility in these glassy polymers prohibits retro-DA decoupling. These findings largely validate the main hypothesis of this dissertation. / Ph. D.

The use of ionic liquids (ILs) as both reagents and solvents is widely recognised. ILs offer a number of advantages compared to regular molecular solvents. These advantages include: chemical and thermal stability, no measurable vapour pressure, no or lower toxicity, non-flammability, catalytic ability, high polarity and they can be recycled. There are a number of research groups investigating the various applications of this reaction medium and most studies have focused on solvents derived from the imidazolium cation. The use of the imidazolium-based ILs in the Diels-Alder reaction has been studied in detail and higher yields compared to conventional methods have been reported. The IL affects the rate and interesting selectivities have been observed. However, not much attention has been paid to the scope and limitations of phosphonium ILs (PILs). Therefore the focus of this thesis is the synthesis and application of novel chiral PILs as environmentally benign, task-specific solvents for the Diels-Alder reaction. In addition, this research seeks alternative ways to eliminate the use of toxic heavy metal catalysts and to exploit methodologies which reduce the energy consumption of the Diels-Alder reaction. A series of CILs were synthesised from the chiral pool and they were characterised by thermogravimetric analysis, differential scanning calorimetry and spectroscopy. They were then investigated as solvents and catalysts in the Diels-Alder reactions of a series of dienes (cyclopentadiene, isoprene, 2,3-dimethylbuta-1,3-diene, furan, pyrrole, N-methyl pyrrole) and dienophiles (methyl acrylate, methyl vinyl ketone, acrylonitrile, dimethyl maleate, acrolein, dimethylacetylene dicarboxylate, maleic anhydride and maleimide). Investigation of the effect of PILs in the presence of three heterogeneous catalysts Al2O3, SiO2 and K-10 montmorillonite were studied. Ultrasound and microwave-assisted Diels-Alder reactions in the PILs, in the absence and presence of the catalysts, were also studied. The reactions of these prototypical substrates illustrated that the solvents are indeed task-specific.

O objetivo deste trabalho foi iniciar o estudo de uma nova metodologia sintética para a obtenção do sistema 11-oxabiciclo[6.2.1]undecano, o esqueleto estrutural básico de uma classe de produtos naturais conhecidos como furanoeliangolidos. A abordagem sintética proposta envolveria a formação de um composto bicíclico através da reação de Diels-Alder com derivados de furano, seguida pela formação de um hexanel e, finalmente, ruptura de uma ligação central para formação do sistema macrocíclico. Além disso, a reação de Diels-Alder entre derivados de furano e acetileno dará origem a compostos que apresentam como esqueleto estrutural o sistema 7-oxabiciclo[2.2.1]heptano, que podem ser utilizados como material de partida para a síntese de diversos produtos naturais. Iniciamos este estudo com a reação de Diels-Alder entre o 3,4-dimetoxi-2-metil furano e o bromopropiolato de metila, onde foi obtido o produto 85, que após algumas modificações deu origem ao composto 92. Entretanto, após inúmeras tentativas não conseguimos transformar o composto 92 no triciclo desejado. Para evitar essas transformações que se mostraram problemáticas, resolvemos estudar a reação de Diels-Alder entre derivados de furano e benzoquinonas 2,5-dissubstituídas, que dará origem aos adutos devidamente funcionalizados para serem transformados no derivado do sistema 11-oxabiciclo [6.2.1]undecano. No entanto, após o estudo dessas reações de cicloadição, observamos que elas têm o equilíbrio fortemente deslocado no sentido dos materiais de partida. Por esse motivo, a continuidade desta metodologia sintética mostrou ser inviável. Iniciamos então, um estudo da reação de Diels-Alder entre os diverso derivados de furanos e acetilenos. Após o estudo dessas reações de Diels-Alder foi possível verificar que a maioria dos adutos derivados dos furanos é instável no meio reacional. Os melhores resultados obtidos nessas reações de Diels-Alder foram usando o acetilenodicarboxilato de dimetila como dienófilo. Os adutos obtidos são intermediários importantes e bem funcionalizados, que podem ser utilizados na continuidade do estudo de desenvolvimento de nova metodologia sintética para a obtenção do sistema 11-oxabiciclo[6.2.1]undecano / The aim of this work was to start the study of a new methodology to synthesize the 11-oxabicycle[6.2.1]undecane system, the main carbon skeleton of the furanoheliangolides. The proposed synthetic approach involves the preparation of a bicyclic compound through a Diels-Alder reaction with furan derivatives, followed by formation of a six membered ring and, finally, cleavage of the central bond to obtain of the macrocyclic system. The Diels-Alder reaction between furan and acetylene derivatives gives a compound with the 7-oxabicyclico[2.2.1]heptane system, that is a potential starting material for the synthesis of several natural products. We started this study with the Diels-Alder reaction between the 3,4-dimethoxy-2-methylfuran and methyl bromopropiolate, and obtained the product 85 that after some modifications furnished the compound 92. However, after various attempts we were unable to convert the compound 92 into the desired tricycle. We have then decided to study the Diels-Alder reaction between furan and 2,5-disubstituted benzoquinone derivatives, that could furnish the adducts properly functionalized to be transformed in the 11-oxabicyclico[6.2.1]undecane system. However, we observed that the equilibrium is strongly shifted towards the starting materials in these cycloaddition reactions. This methodology has thus showed to be impracticable. As a third alternative, we affected the study the Diels-Alder reaction between the furans derivatives and the acetylenes. The adducts obtained present 7-oxabicyclico[2.2.1]heptane system that could be used to synthesizes of structural skeleton of furanoheliangolide.

Transition metal mediated [2 + 2 + 2] cyclizations have been well researched over the past several years. As a well-developed methodology, [2 + 2 + 2] chemistry has been employed as a major pathway to various carbo- and heterocyclic synthetic targets. Numerous transition metals have been applied as catalysts for these cyclizations. Previous work in our group developed cobalt(I) catalyzed inter- and intramolecular [2 + 2 + 2] cyclizations of two alkynes and a nitrile, leading to the preparation of tetrahydro-naphthyridines. Pyridazines could be generated if the cyclization could be accomplished with two nitriles and an alkyne, which would be a novel way to synthesize 1,2-diazines through the formation of the N-N bond. To this end, metal-catalyzed intramolecular [2 + 2 + 2] cyclizations between an alkyne and two nitriles were investigated. The intramolecular nature of the reaction provided the entropic advantage to successfully assist the formation of the critical N-N bond. Optimal conditions were achieved with cobalt(I) catalysts under microwave irradiation in chlorobenzene, producing the desired pyridazines in moderate to good yields. This success led to the preparation of a series of annulated pyridazines. The use of two tethering nitrogens in the preparation of the cyclization precursors incorporated points for further diversification, the next step in the development of this chemistry. This ring closure through N,N-bond formation allowed the construction of annulated pyridazine scaffolds that were utilized further in a small molecule library synthesis. Using this methodology, sixteen new annulated pyridazines were prepared. Inverse electron demand Diels-Alder (IEDDA) reactions of arynes and 1,2,4-triazines were also investigated for the generation of isoquinoline core structures. The results showed that only triazines with electron withdrawing groups participated in the IEDDA reactions with benzyne as a partner after screening of several different arynes, which limited the scope of the reaction. Liebeskind–Srogl reactions of 3-methylthiotriazines and boronic acids were investigated during the diversification of triazines, and microwave irradiation with palladium and copper catalysts were found to be the optimal conditions for the coupling. The chemistry allowed for further triazine diversification.

This thesis describes the total synthesis of the polyketide derived marine natural product (-)-maurenone (14) and synthetic studies of a model system for the marine polyketides, the spiculoic acids (20, 22-24). A biomimetic approach involving cyclisation of linear polyketide precursors to install the complex chemical frameworks was employed. Maurenone is a polypropionate derived metabolite isolated from pulmonate molluscs collected off the coast of Costa Rica. While structural assignment following isolation revealed a relatively uncommon tetra-substituted dihydropyrone moiety the only stereochemical information deduced was the trans-relative relationship between the C8 and C9 protons. The total synthesis of a series of eight stereoisomeric putative structures was achieved in order to assign the stereochemistry of (-)-maurenone (14), as that depicted above. A time and cost efficient strategy was developed utilising common intermediates providing access to the eight stereoisomeric structures in a convergent manner. Six key fragments, four aldehydes (109) and two ketones (110), were synthesised using highly diastereoselective syn- and anti-boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclisation/dehydration enabled installation the ƒ×-dihydropyrone ring. All eight isomers of one enantiomeric series were synthesised by coupling two ketones with each of four aldehydes. By comparison of the NMR data for the eight isomers with that reported for the natural product, the relative stereochemistry was established as shown. The (-)-enantiomer of maurenone was synthesised in nine linear steps (13 % overall yield) from (R)-2-benzylpentan-3-one ((R)-40) and (R)-2-benzoyloxypentan-3-one ((R)-39). The spiculoic acid family of polyketide derived natural products, isolated from plakortis sponges, possess a unique [4.3.0]-bicyclic core which is proposed to be formed via an enzyme catalysed Intramolecular Diels-Alder (IMDA) cycloaddition reaction of linear polyene precursors 25. Model linear precursors (114), possessing various olefin geometries at C2 and both stereochemical orientations of the C5 stereocentre, were synthesised in order to examine stereoselectivity of the thermally induced IMDA cycloaddition reaction. The two alternative C4-C6 stereotriads of the linear precursors 114 were achieved by employing highly diastereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the facial preference of (R)-2-benzoyloxypentan-3-one ((R)-39), and a syn-titanium aldol reaction, under the control of chiral N-acylthiazolidinethione ((R)-43a). The diene and dienophile moieties were installed using either standard Wittig, H.W.E. or ¡§modified¡¨ Julia olefination reactions. A thorough stereochemical assignment of the cycloadducts of the thermally induced IMDA reaction of each linear precursor was accomplished employing 2D NMR techniques. Comparison of the stereochemistry of each of the cycloadducts with the spiculoic acids revealed that the linear precursor (2E,5S)-114 produced a cycloadduct 232 with stereochemistry analogous to the natural products in 94 % diastereoselectivity. Thus, a synthetic approach to the spiculoic acids via synthesis of a linear precursor 285 possessing a TBS ether at C5 in the S configuration was proposed. Unfortunately, problems encountered in the synthesis of the proposed linear precursors to the spiculoic acids ultimately prevented the total synthesis from being achieved.