Techn. Hochsch., Diss., 2005--Aachen.

Th. 3e cycle--Chim. org. phys.--Lille 1, 1979. N°: 772.

The reactivity of perfluoroarenes and hetarenes towards SNAr reactions was studied as part of a synthetic programme to form an assembly of novel heterocyclic aromatic compounds for material and pharmaceutical applications. In chapter 1 the chemistry of perfluoroarenes is reviewed together with the use of conjugated compounds in organo-electronic applications. In chapter 2 the successful replacement of the remaining fluorine atoms in 6,12-difluorobenzo[1,2-b:4,5-b']bis[b]benzothiophene through SNAr reaction with long chain alkoxy and alkylthio nucleophiles is reported. An X-ray crystallographic investigation into their solid state packing was undertaken which would provide useful information for organoelectronic applications. Reactions with nitrogen and carbon based nucleophiles were also studied but met with little success. In chapter 3, alternative methods for the reductive cyclization of aryl and 2-bromoaryl perfluoroethers and sulfides to replace the currently used lithium-bromine exchange were explored, namely the use of radical cyclizations, palladium, magnesium, copper and Rieke metals. Some success was found using magnesium as a reagent although yields were low. Attempts to effect cyclisation reactions by ortho-lithiation and Ullmann coupling reaction with fluoroarenes is also reported. In chapter 4 attempts to generate alternative ring fusion in annulation reactions to form fused benzothiophenes by a dianion strategy are described. Development of methods to synthesise helicene or curved polycyclic structures from dibenzothiophene precursors is reported. In chapter 5 the synthesis of nitrogen containing fluorinated compounds with potential bioactivity is described. A series of novel amino substituted fluoroaromatics were successfully synthesised by adding different nitrogen based nucleophiles to pentafluoropyridine. Smiles rearrangement of a tetrafluoropyridyl sulphonamide was found to occur. A number of fluoropyridyl aniline derivatives were successfully synthesised some of which were submitted for biological screening. Substitution reactions of bis-nucleophiles bearing two heteroatom groups to form fused six membered rings were also studied. A Smiles rearrangement was identified in the reaction with an aminobenzenethiolate and confirmed by X-ray crystallography. Experimental procedures are given in chapter 6 as well as characterisation and crystallographic data of molecules synthesised during the research.

A new method for the synthesis of naphthalenes has been recently discovered. The Atom Transfer Radical Cyclisation (ATRC) of diverse 2-allylphenyl2',2',2'-trichloroacetates in the presence of a Cu complex afford schloronaphthalenes in good yields using either microwave or thermolytic methods of activation. A mechanism for the benzannulation reaction is proposed and experiments presented in order to validate this hypothesis. The use of 1,3-bis(2,6-diisopropylphenyl)imidazolium copper(I) chloride [(IPr)CuCl)] along with other metal carbenes is compared to the already reported CuCl/ligand system. Since the scope and synthetic utility of this new benzannulation reaction is restricted due to the use of the MW reactor, a solvent in which the thermal reaction can take place is reported, proving its efficiency in the synthesis of a range of substituted naphthalenes. The potential and versatility of the benzannulation reaction has been investigated. Studies towards the synthesis of gilvocarcin M which contains a tetracyclicaromatic core are presented. Gilvocarcins have potential use as anti-cancer agents and represent a member of the C-aryl glycosides found in natural products. Gilvocarcin M is a challenging target because there are a sparse number of total syntheses reported in the literature. The ATRC reaction of (vinyl)phenyl trichloroacetate has also been investigated, affording the synthesis of functionalised coumarins. The mechanism of this reaction has also been investigated, establishing that, in some cases, aretro-Kharasch reaction is observed.

The use of H2O as an additive in SmI2-mediated reductive processes provides access to new transformations and previously inaccessible chemical space. The cyclisation of radicals derived from the selective mono-reduction of Meldrum’s acid derivatives was further investigated and the scope of the methodology expanded to cyclisation cascades. The first general methodology for the reduction of amide-type carbonyls under single electron transfer conditions was developed and applied to the mono-reduction of barbituric acid derivatives, providing an unprecedented direct access to the corresponding hemiaminals with a good degree of stereocontrol. The intermediate acyl-type radicals were in addition successfully exploited in stereoselective radical cyclisations. The hemiaminals derived from mono-reduction and cyclisation of barbituric acid derivatives have been exploited as N-acyliminium equivalents, affording hydrouracils with an excellent degree of regio- and stereoselectivity. Efforts towards the synthesis of the azulene framework of pseudolaric acid B using a model substrate are also described.

Yes / t-BuOK-mediated rearrangement of 1,3-ketoesters with 2-(azidomethyl) aromatics in a two-step, one-pot telescoped sequence affords β-enaminoketoesters in moderate to good yields. A novel pathway is proposed in which the umpolung of the azide is achieved from electrophilicity to nucleophilicity via deprotonation and undergoes nucleophilic attack onto the 1,3-ketoester.

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.

Le premier chapitre de cette thèse porte sur l’étude modèle des différents partenaires nécessaires à la séquence de cyclisation de Vilsmeier-Haack et de cycloaddition dipolaire-1,3 intramoléculaire d’ylure d’azométhine utilisée pour réaliser la synthèse totale d’alcaloïdes Daphniphyllum de types daphilactone B et yuzurimine. L’étude du type de nucléophile permettant d’effectuer la première cyclisation, ainsi que les types d’ylures d’azométhine et de dipolarophiles nécessaires pour la cycloaddition finale est présentée. Le deuxième chapitre présente le développement d’une seconde synthèse du précurseur de la séquence de cyclisations étudiée au chapitre 1 permettant de résoudre les différents problèmes encourus au cours de ce même chapitre. Le type de dipolarophile utilisé lors de la cycloaddition dipolaire-1,3 d’ylure d’azométhine est à nouveau étudié. Enfin, les résultats obtenus pour la séquence de cyclisations étudiée ainsi que la fonctionnalisation du cycloadduit issu de cette dernière sont aussi exposés. Le troisième chapitre traite sur les efforts effectués vers la synthèse totale de la caldaphnidine C et de ses congénères. L’élaboration d’une stratégie permettant d’effectuer cette synthèse de façon non racémique ainsi que l’incorporation d’un centre quaternaire absent lors de l’étude modèle du précédent chapitre y sont abordés. Des travaux futurs sont finalement suggérés.

Une nouvelle synthèse d'isonitrile à partir de cyanure d'argent a été mise au point, et utilisée pour des réactions multicomposants en un seul pot. Parallèlement à ces travaux, une cascade de réarrangements de Smiles a été étudiée, permettant d'aboutir en deux étapes à des composés cycliques à haute valeur ajoutée.

Small molecule libraries have become essential for the development of drug discovery campaigns and chemical genetics. The studies towards the synthesis of a small molecule library, based upon the cis-ring fused phenanthridine core I, will be described. The first section of this thesis examines the development and application of a novel intramolecular Heck cyclisation to the synthesis of core phenanthridine structure II, via precursor III (Chapter 2).The second section (Chapter 3) describes the extension of this methodology towards the development of a library of phenanthridines IV. This includes methodology designed to incorporate the key principles of diversity-oriented synthesis, namely appendage, stereochemical and skeletal diversity. The final part of this thesis (Chapter 4) describes the merging of these various methodologies to generate a small library of novel phenanthridine analogues. Preliminary biological evaluation of the phenanthridine library using whole organism zebrafish phenotyping, will also be discussed.