Developing environmentally sustainable processes are essential to improving the quality of life for future generations. In addition to reducing our impact on the environment, we must design processes to be both economical and safe. A large component of any chemical process is the solvents used to dissolve the reactants and extract the products. The research presented here focuses on coupling efficient homogeneous reactions with simple heterogeneous separations using propane-organic-aqueous tunable solvent systems. Our tunable solvents undergo a phase separation upon application of propane pressure to a fully miscible mixture of water and an organic solvent. The propane based tunable systems detailed here eliminate carbonic acid formation and reduce productphase contamination when compared with the equivalent CO2 based solvent systems previously studied. Additionally, we eliminate the need to use buffers and thus solids handling equipment is not needed.

Cyclic peroxides are abundant in Nature and synthetic manipulation of the peroxide linkage and alkene portion of 1,2-dioxines has established 1,2-dioxines as important compounds as both chemical building blocks and bioactive compounds. Much of the chemistry performed thus far utilizing 1,2-dioxines involves the initial rearrangement of 1,2-dioxines to γ-hydroxyenones allowing for the generation of structural motifs such as cyclopropanes, THF’s, THP’s, 1,4-diketones and natural sugars. Herein describes the synthesis of novel 1,2-dioxines with a variety of tethered functionalities and their transformations to afford novel cyclic compounds whilst maintaining the peroxide linkage intact. Chapter two outlines the intramolecular cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefin of 1,2- dioxines to generate both tetrahydrofurans and dihydrofuran-2(3H)-ones, whilst maintaining the peroxide linkage. This work presents the first examples of syn fused cyclic peroxide furans through intramolecular cyclisation of tethered hydroxyl groups. Improved methods for the oxidation of hydroxyl tethered 1,2-dioxines to carboxylic acid moieties are also reported. In addition, improved methods for intramolecular cyclisation of carboxylic acid moieties where developed to afford syn fused cyclic peroxide lactones. Furthermore, reduction of the peroxide bond enabled generation of functionalized tetrahydrofurans and dihydrofuran-2(3H)-ones which have previously been utilized as synthetic building blocks for several natural products. Chapter three reports the first examples of carbenoid insertion into the peroxide linkage of 1,2-dioxines allowing for the generation of novel bicyclic hemiacetals. Alternatively novel tricyclic cyclopropyl peroxides where generated through insertion into the olefin whilst maintaining the peroxide linage intact. Additionally, the attempted intramolecular cyclisation of diazoketone tethered bicyclic 1,2-dioxines was also probed. Furthermore, the attempted intermolecular insertion of diazoketones onto 1,2-dioxines are presented within this chapter. Finally, Chapter four outlines the intramolecular cyclisations of bromo-alkyl tethered 1,2-dioxines to furnish novel cyclic cyclopentyl peroxides whilst maintaining the peroxide linkage intact. The work presented in this chapter represents the first examples of the synthesis of syn fused cyclic cyclopentyl peroxides. In summary, this thesis outlines methodology towards the synthesis of novel cyclic peroxides from 1,2-dioxines containing tethered functional groups. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2009

Title from title page of PDF (University of Missouri--St. Louis, viewed March 22, 2010). Non-Latin script record Includes bibliographical references.

Techn. Hochsch., Diss., 2001--Aachen.

Techn. Universiẗat, Diss., 2005--Darmstadt.

Universiẗat, Diss., 2005--Karlsruhe.

The acetylcholine (ACh) receptor system belongs to rhodopsin GPCR family and is an integral membrane protein divided into two types: muscarinic and nicotinic. The naturally occurring neurotransmitter acetylcholine binds to these two receptor systems non- selectively. The regulatory effects of the neurotransmitter acetylcholine are diverse ranging from autonomic nervous system and the central nervous system through different types of neurons innervated by cholinergic inputs. Muscarinic acetylcholine receptors (mAChRs) are divided into five receptor subtypes (M1-M5). In general, M1, M3 and M5 receptor subtypes are coupled via Gq like proteins; while M2 and M4 subtypes are coupled to Gi-proteins. Muscarinic receptors are widely distributed in the body where they mediate a variety of important physiological effects. mAChRs have been the target of drug development efforts for the treatment of various disorders including overactive bladder, Alzheimer's disease, pain, cognitive impairment, drug addiction, schizophrenia and Parkinson's disease. The development subtype selective ligands possess a challenge due to a high degree of homology among mAChR subtypes, however the recent availability of the X-ray crystal structure for the M2 and M3 receptor can be utilized for the design of new ligands. The pharmacophoric requirements for cholinergic ligands have been reported by numerous investigators based on structure-activity relationship (SAR) and/or molecular modeling data of known muscarinic ligands. These fundamental requirements are useful when designing muscarinic ligands but have provided little guidance in the design of subtype selective compounds. Our interest in developing novel muscarinic receptor ligands led to the design of lactone-based ligands using an approach similar to that reported by Kaiser et al. Preliminary binding studies of our previously synthesized lactone based compounds indicated that several were nonselective, low affinity (IC50 = µM range) muscarinic agonists (based on preliminary in vivo data). Hence based on the background information, we decided to utilize the previously synthesized lactone parent compound as lead molecule set out to investigate a new series of lactone based compounds in order improve the affinity and later the selectivity of ligands. Bioisosteric approach has been investigated for the metabolic lability of the lactone ring. Four probable bioisosteres have been evaluated: tetrahydrofuran, 1,3-benzodioxole, oxazolidinone and chromone. Thermal/microwave assisted synthesis has been utilized in the generation of intermediates as well as final compounds. Preliminary screening and further evaluation (IC50/ subtype selectivity) has resulted in the identification of promising fragments as bioisosteres for the lactone ring. / Pharmaceutical Sciences / Accompanied by one .pdf file.

A Doença de Chagas é causada pelo Trypanosoma cruzi, e possui duas fases clínicas, sendo o tratamento com o fármaco benznidazol eficaz somente na fase aguda, porém com diversos efeitos adversos ao longo do período do tratamento. Desta forma, consórcios vêm sendo estabelecidos entre \"governo - universidade - indústria\", com auxilio de capital nacional e estrangeiro para o desenvolvimento de novos fármacos. Apesar de diversas ferramentas disponíveis para o planejamento de novos compostos, a busca por produtos naturais ainda desperta interesse de muitos pesquisadores. Diversos trabalhos vêm descrevendo estudos de síntese e atividade tripanocida de lignanas, as quais merecem destaque, veraguensina (17) e grandisina (18). Devido à falta de tratamento e a alta toxicidade dos agentes disponíveis, este trabalho tem como objetivo sintetizar análogos dessas lignanas, relacionados a derivados de tetraidrofurânicos, furânicos, pirrólicos e de seus intermediários e testa-lasfrente à atividade tripanocida e citotóxica. O planejamento sintético envolveu a geração de derivados 1,4-diaril-2-butino-1,4-diol (28a-t) a partir da reação de condensação entre fenil carbinol (26) e aldeídos arílicos (27a-t) com diferentes padrões de substituiçõescom diversos grupos funcionais. Estes intermediários, obtidos em rendimentos moderados, foram convertidos aos correspondentes 1,4-diaril-1,4-diidroxílicos (30a-g), pela reação de redução em dióxido de platina e, posteriormente, oxidados a 1,4-diaril-1,4-dicetonas (29a-g). A partir da formação dos intermediários 29 e 30, os produtos de interesse, 2,5-diaril-furano (32a-g) e 2,5-diaril-tetraidrofurano (31a-g) foram preparados empregando reações de ciclização na presença de ácidos tríflico e trifluoroacético, respectivamente. Os intermediários e produtos obtidos em rendimentos de moderado a bom, totalizando 48 compostos, foram avaliados em ensaios de atividade tripanocida, envolvendo a cepa Tulahuen de T. cruzi, bem como ensaios de citotoxicidade. Considerando as cinco séries sintetizadas (28, 29, 30, 31 e 32), vale destacar que a maioria apresentou compostos com potente atividade tripanocida, a partir de 1,4 ?M, superior ao fármaco disponível benznidazol (7,9 ?M) e, adicionalmente, não apresentaram citotoxicidade em ensaios realizados por citometria de fluxo. / Chagas\' disease is caused by the Trypanosoma cruzi, whichhas two clinical stages. The treatment with the benznidazole is effective only in the acute stage, although with several side effects throughout the treatment period. Therefore, consortia are being established between \"government - university - industry\", with national and foreign financial support for drug discovery development. In spite of many available tools to design new compounds, the search for natural products still arouse interestfor a great number of researchers. Several papers have described studies of synthesis and trypanocidal activity of lignans, being veraguensin (17) and grandisin (18) worth to mention. Due to the lack of treatment and the high toxicity of the available drugs, this research has the aimto synthesize analogues from the above lignans, such astetrahydrofuran, furanic, pyrrolic derivatives and their intermediates,and test their trypanocidal activity and cytotoxicities. The synthetic strategy was based on the synthesis of 1,4-diarylacetylene-1,4-glycols (28a-t) via condensation reaction between phenyl carbinol (26) and substituted aryl aldehydes (27a-t) with several functional groups at different positionsof the aromatic ring. These intermediates, obtained in moderate yields, were converted to their corresponding 1,4-diaryl-1,4-dihydroxyl derivatives (30a-g) by the reduction reaction using platinum dioxide and, subsequently, oxidized to 1,4-diaryl-1,4-diketones (29a-g). From the synthesis of the intermediates 29 and 30, products of interest, 2,5-diaryl-furan (32a-g) and 2,5-diaryl-tetrahydrofuran (31a-g) were prepared from the cyclization reaction in the presence of the triflic and trifluoracetic acids, respectively. The intermediates and products, obtained in moderate to good yields, in a total of 48 compounds, were assessed in trypanocidal assays, using T. cruzi Tulahuen strain,as well as cytotoxicity assays. Considering the five synthesized series (28, 29, 30, 31 e 32), it is worth noting that the majority of the compounds showed potent trypanocidal activity from 1.4 ?M, higher than the available benznidazole (7,9 ?M) and, additionally, they were not cytotoxicin Flow Cytometry assays.

A Doença de Chagas é causada pelo Trypanosoma cruzi, e possui duas fases clínicas, sendo o tratamento com o fármaco benznidazol eficaz somente na fase aguda, porém com diversos efeitos adversos ao longo do período do tratamento. Desta forma, consórcios vêm sendo estabelecidos entre \"governo - universidade - indústria\", com auxilio de capital nacional e estrangeiro para o desenvolvimento de novos fármacos. Apesar de diversas ferramentas disponíveis para o planejamento de novos compostos, a busca por produtos naturais ainda desperta interesse de muitos pesquisadores. Diversos trabalhos vêm descrevendo estudos de síntese e atividade tripanocida de lignanas, as quais merecem destaque, veraguensina (17) e grandisina (18). Devido à falta de tratamento e a alta toxicidade dos agentes disponíveis, este trabalho tem como objetivo sintetizar análogos dessas lignanas, relacionados a derivados de tetraidrofurânicos, furânicos, pirrólicos e de seus intermediários e testa-lasfrente à atividade tripanocida e citotóxica. O planejamento sintético envolveu a geração de derivados 1,4-diaril-2-butino-1,4-diol (28a-t) a partir da reação de condensação entre fenil carbinol (26) e aldeídos arílicos (27a-t) com diferentes padrões de substituiçõescom diversos grupos funcionais. Estes intermediários, obtidos em rendimentos moderados, foram convertidos aos correspondentes 1,4-diaril-1,4-diidroxílicos (30a-g), pela reação de redução em dióxido de platina e, posteriormente, oxidados a 1,4-diaril-1,4-dicetonas (29a-g). A partir da formação dos intermediários 29 e 30, os produtos de interesse, 2,5-diaril-furano (32a-g) e 2,5-diaril-tetraidrofurano (31a-g) foram preparados empregando reações de ciclização na presença de ácidos tríflico e trifluoroacético, respectivamente. Os intermediários e produtos obtidos em rendimentos de moderado a bom, totalizando 48 compostos, foram avaliados em ensaios de atividade tripanocida, envolvendo a cepa Tulahuen de T. cruzi, bem como ensaios de citotoxicidade. Considerando as cinco séries sintetizadas (28, 29, 30, 31 e 32), vale destacar que a maioria apresentou compostos com potente atividade tripanocida, a partir de 1,4 ?M, superior ao fármaco disponível benznidazol (7,9 ?M) e, adicionalmente, não apresentaram citotoxicidade em ensaios realizados por citometria de fluxo. / Chagas\' disease is caused by the Trypanosoma cruzi, whichhas two clinical stages. The treatment with the benznidazole is effective only in the acute stage, although with several side effects throughout the treatment period. Therefore, consortia are being established between \"government - university - industry\", with national and foreign financial support for drug discovery development. In spite of many available tools to design new compounds, the search for natural products still arouse interestfor a great number of researchers. Several papers have described studies of synthesis and trypanocidal activity of lignans, being veraguensin (17) and grandisin (18) worth to mention. Due to the lack of treatment and the high toxicity of the available drugs, this research has the aimto synthesize analogues from the above lignans, such astetrahydrofuran, furanic, pyrrolic derivatives and their intermediates,and test their trypanocidal activity and cytotoxicities. The synthetic strategy was based on the synthesis of 1,4-diarylacetylene-1,4-glycols (28a-t) via condensation reaction between phenyl carbinol (26) and substituted aryl aldehydes (27a-t) with several functional groups at different positionsof the aromatic ring. These intermediates, obtained in moderate yields, were converted to their corresponding 1,4-diaryl-1,4-dihydroxyl derivatives (30a-g) by the reduction reaction using platinum dioxide and, subsequently, oxidized to 1,4-diaryl-1,4-diketones (29a-g). From the synthesis of the intermediates 29 and 30, products of interest, 2,5-diaryl-furan (32a-g) and 2,5-diaryl-tetrahydrofuran (31a-g) were prepared from the cyclization reaction in the presence of the triflic and trifluoracetic acids, respectively. The intermediates and products, obtained in moderate to good yields, in a total of 48 compounds, were assessed in trypanocidal assays, using T. cruzi Tulahuen strain,as well as cytotoxicity assays. Considering the five synthesized series (28, 29, 30, 31 e 32), it is worth noting that the majority of the compounds showed potent trypanocidal activity from 1.4 ?M, higher than the available benznidazole (7,9 ?M) and, additionally, they were not cytotoxicin Flow Cytometry assays.

The acid-mediated osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendent alkene has been shown to be a powerful method for the formation of cis-2,5-disubstituted tetrahydrofurans. This thesis describes the development of this methodology to broaden the scope of the general reaction, followed by applying the oxidative cyclisation to the synthesis of tetrahydrofuran containing natural products. Introduction: This section reports a range of ractions that osmium oxo-species will facilitate, namely the formation of carbon-oxygen and carbon-nitrogen bonds in a selective manner. In addition to this a variety of similar metal-mediated oxidative cyclisations are discussed. Results and Discussion: The process for optimising the oxidative cyclisation is documented, along with examples which directly compare newly developed methodology with existing methodology. The incorporation of a catalytic amount of a Lewis acid is shown to be more effective than using an excess of a Brønsted acid, with osmium catalyst loading being reduced to 0.2 mol%. Subsequently, this methodology is shown to facilitate the successful oxidative cyclisation of vinyl silanes to form silyl-substituted tetrahydrofurans, along with methodology to “unmask” the silane, as a potential route to lactols. Finally, the application of this methodology to synthesis is demonstrated, with the successful synthesis of neodysiherbaine A being achieved in 7 steps and the C21-30 fragment of pectenotoxin-4 in 12 steps.