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    Studies in Synthesis and Organocatalysis: (i) The Design and Synthesis of Novel Electron Deficient Dienes and their Application in the First Enamine Activated Organocatalytic 1,6-Conjugate Addition. (ii) The Development of a New Organocatalytic Methodology through the Combination of DNA-Based Catalysis and Organocatalysis


    Murphy, John J. (2012) Studies in Synthesis and Organocatalysis: (i) The Design and Synthesis of Novel Electron Deficient Dienes and their Application in the First Enamine Activated Organocatalytic 1,6-Conjugate Addition. (ii) The Development of a New Organocatalytic Methodology through the Combination of DNA-Based Catalysis and Organocatalysis. PhD thesis, National University of Ireland Maynooth.

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    Abstract

    A novel approach to substrate design led to the development of charge de-localized extended Michael acceptors. Using this methodology a family of both alkyl and aryl bis-phenylsulfonyl butadienes were synthesised and characterised. The first enamine activated organocatalytic 1,6- conjugate addition was performed on the sulfonyl acceptors, using aldehydic enamines, giving excellent yields and selectivities (up to 98% yield, uniformly 99% ee). The mechanism of this reaction was explored in detail. The products of these additions were fully characterised and were subsequently used as substrates for the conjugate addition of methyllithium (52% yield, 12 : 1 d.r.) and an organocatalysed inverse electron demand Diels-Alder reaction (DAINV) (76% yield, 3.1 : 1 : 1.5 d.r.). Combining the 1,6-addition and DAINV methodology let to the development of an enamine/iminium ion organocatalytic cascade reaction which delivered a product with 5 contiguous stereocenters (75% yield, 3.1 : 1 : 1.5 d.r.). We attempted to apply our 1,6-conjuagate addition methodology to the synthesis of Sildenafil analogues. Several steps of this challenging synthesis were completed. The step involving the oxidation of a homo-allylic alcohol remains to be solved. Interestingly a DMSO-based oxidation generated a sulfur ylide in high yield (90%), a possible explanation is provided. A second class of butadienes, bis-cyano butadienes, that are suitable substrates for 1,6-conjugate additions, were prepared and characterised. Addition of aldehydic enamines to these acceptors also yielded a regioselective 1,6-adduct in high yield and selectivity (up to 75% yield, up to 99% ee). An experimental investigation was performed into the synthesis of suitable trienes for 1,8-conugate additions. A 1,3-bis-phenylsulfonyl hexatriene was synthesised and characterised which did not undergo a selective 1,8-conjugate addition with aldehydic enamines. Upon heating, this triene was found to undergo an electrocyclisation reaction to give a biphenyl with a near zero twist angle. Synthesis of α,γ,ε-tris activated triene led to the isolation of a bis-phenylsulfonyl-cyano-arene and not the desired triene. A final experimental study was undertaken exploring the use of DNA and a suitable intercalating organocatalyst in asymmetric transformations. The design, synthesis and characterization of a novel achiral DNA-intercalating imidazolidinone was realized in high yield (40% yield over 4 steps). Several synthetic routes to the intercalating imidazolidinone were explored. The catalyst was found to still retain the ability to generate a reactive iminium ion and participate in a Diels-Alder reaction without DNA, albeit in reduced potency (24% yield). Future work will entail the application of the intercalating catalyst with salmon testes DNA.

    Item Type: Thesis (PhD)
    Keywords: Synthesis; Organocatalysis; Novel Electron Deficient Dienes; First Enamine Activated Organocatalytic 1,6-Conjugate Addition; Organocatalytic Methodology; DNA-Based Catalysis;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 4771
    Depositing User: IR eTheses
    Date Deposited: 18 Feb 2014 11:06
    URI:

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