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Development of the conjugate addition/nitro-Mannich reaction

This thesis describes the development of the conjugate addition/nitro-Mannich reaction and its use in the synthesis of useful molecules like pyrrolidin-2-ones and piperazin-2-ones. The introductory chapter of this thesis outlines the literature related to the nitro-Mannich reaction, describing the different existing methodologies for performing the reaction in diastereo- and enantioselective manner. The synthetic applications of the reaction are also described, especially its uses in the synthesis of biologically active natural products. Moreover, the syntheses and uses of two classes of compounds, pyrrolidin-2-ones and piperazin-2-ones are briefly discussed. The results and discussion chapter starts by presenting the use of a one-pot conjugate addition/nitro-Mannich/lactamisation reaction in the synthesis of densely functionalised pyrrolidin-2-ones. The development of an asymmetric protocol, as well as some functionalisations of the pyrrolidinone core are also described. Our efforts to synthesise human neutrophil elastase inhibitor GW311616A using the developed methodology are then detailed. The next part of the results and discussion chapter portrays the development of a conjugate addition/nitro-Mannich reaction of non-zinc nucleophiles to ethyl 3-nitroacrylate and β-nitrostyrene. The scope and limitations of the reaction were investigated using a variety of different nucleophiles including amines, thiols, phosphines, alcohols, enolates and nitriles. Finally, our work towards synthesising the biologically active piperazin-2-one piperazirum, using the nitro-Mannich methodology is described. The diastereoselective synthesis and characterisation of a densely functionalised piperazin-2-one was accomplished. A detailed description of the experimental details and analytical data for all novel compounds is described in the experimental section. Tables of coupling constants and X-ray crystallographic data are presented in the appendices section, followed by a list of literature references.
Date January 2013
CreatorsKalogirou, A.
PublisherUniversity College London (University of London)
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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