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Approaches to the synthesis of streptonigrin

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dc.contributor.advisor Prof. C.W. Holzapfel en_US
dc.contributor.author Dwyer, Catherine Lynn
dc.date.accessioned 2012-08-13T06:33:50Z
dc.date.available 2012-08-13T06:33:50Z
dc.date.issued 2012-08-13
dc.date.submitted 1999-03
dc.identifier.uri http://hdl.handle.net/10210/5463
dc.description D.Sc. en_US
dc.description.abstract The objective of the research described in this thesis was to develop a general synthetic method which could be applied to the synthesis of the potent anti-cancer compound, streptonigrin, and analogues thereof. The approach was based on retrosynthetic analysis as well as a critical appraisal of previous approaches to the synthesis or partial synthesis of such compounds, and relied heavily on palladium-catalysed carbon-carbon bond forming reactions. The research was, therefore, carried out against the background of a detailed literature study, which is summarised in the first chapter of this thesis. The first problem that received attention was the development of a general route to synthetic equivalents of the streptonigrin AB quinoline system, with potential for coupling to the CD moiety. This route centres on the use of appropriately substituted o-nitrophenyltriflates (readily prepared via ortho nitration and triflation of the corresponding phenols) as key intermediates. A palladium-catalysed Heck reaction of various o-nitrophenyl triflates, followed by reduction of the ortho nitro group and cyclisation of the resultant aminocinnamate, provided access to a variety of substituted 2-hydroxyquinolines. These could be converted to the corresponding 2-halo derivatives using known methodology. The instability of highly electron-deficient triflates under basic Heck conditions led to the development of this reaction under neutral conditions using epichlorohydrin as a neutral proton scavenger. The preparation of two streptonigrin AB equivalents was achieved using this route, but was initially complicated by competitive oxidation reactions encountered upon nitration of the electron-rich starting material, 3,5- dimethoxyphenol. The use of nitronium tetrafluoroborate or claycop as the nitrating agent was shown to largely overcome these problems. The successful nitration of a selection of other electron-rich aromatics was also achieved using these reagents. The significance of these results is evident: The direct nitration of several of these substrates has not been reported previously. The o-nitrophenyl triflates employed as intermediates in 2-hydroxyquinoline synthesis were also shown to be versatile intermediates for the synthesis of a variety of other heterocyclic compounds. The o-nitrocinnamate products obtained from the Heck reaction of o-nitrophenyl triflates with methyl acrylate furnished the corresponding indole-2-carboxylates via reductive cyclisation. o-Nitrophenyl triflates were also shown to be excellent substrates for palladiumcatalysed cross-coupling reactions. The resulting 2-nitrobiphenyl products provided ready access to substituted carbazoles, and can also be used in the synthesis of fluorenones, phenanthridinones and phenanthridines. en_US
dc.language.iso en en_US
dc.subject Organic compounds - Synthesis. en_US
dc.subject Streptonigrin en_US
dc.title Approaches to the synthesis of streptonigrin en_US
dc.type Thesis en_US

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