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Title: Towards a biomimetic synthesis of the lomaiviticin agylcone and related studies
Author: Burnley, James
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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This thesis describes studies towards the biomimetic synthesis of the lomaiviticin aglycone. Also described in this thesis are studies towards the reductive dimerisation of ahaloketones with the aim of applying this strategy to the synthesis of the lomaiviticin aglycone. The introduction comprises of an overview of the natural products lomaiviticins A and Band their parent family of natural products, the kinamycins. A brief overview of biomimetic synthesis is given, along with a proposed biomimetic hypothesis for the formation of lomaiviticins A and B. Also presented in the introduction is the previous work conducted by others with regards to the total synthesis of the lomaiviticin aglycone. The results and discussion begins with a brief over view of the photochemistry of epoxyketones and quinones. Next, the synthesis of several models of the proposed monomer of the lomaiviticin aglycone is presented. The attempted dimerisation of these models by photochemical and metal-based reductive means is discussed. A discussion of the reductive dimerisation of haloketones with regards to natural product synthesis is followed by the synthesis and attempted dimerisation of a model a-bromoketone. The final part of the results and discussion describes the synthetic efforts towards the proposed monomer. The monomer was synthesised up to the penultimate step, namely deprotection of an acetonide and epoxide formation. An attempted dimerisation was made on an advanced bromoketone, however, no dimer could be isolated. Several efforts were made in light of the failed final step, however, all efforts to install an epoxide motif earlier on in the synthesis also failed. l The next section of this thesis begins with a discussion of the dimeric natural product kingianin A, and then moves on to cover a proposed biosynthesis of the molecule. Next, a possible biomimetic synthesis is discussed, followed by a section regarding the synthesis of a proposed monomer. The final part of this section includes a brief discussion concerning the attempts to dimerise a proposed monomer. The penultimate chapter of prose in this thesis regards novel studies conducted on radical azide chemistry. The first part of the chapter discusses a novel method for the reduction of nitroaromatic azides. The serendipitous discovery of this reaction is discussed followed by an optimisation of conditions to promote effective reduction of a model system. The preferred conditions are then applied to a series of substrates. The mechanism is probed though radical quenching experiments and the synthesis and evaluation of a likely intermediate is discussed. The section then ends with a proposed mechanism, followed by a conclusion . The second part of this chapter is an extension of the methodology whereby a proposed intermediate of the reduction is trapped by an aldehyde rather than a proton, leading to a novel synthesis of electron poor amides. The section begins with a brief overview of amide synthesis and the discussion of two relevant recent a~vances in the field. The reaction is optimised for a model substrate and the reaction is shown to be amenable to a one-pot diazotisation-azidation-amidation sequence leading to high yields of amides. The methodology is then extended to several substrates. The mechanism of the reaction is probed by radical quenching experiments, nitrogen 15 labelling studies and the evaluation of a likely intermediate. The chapter ends with a plausible mechanism followed by a conclusions section. The final chapter of prose in this thesis relates to the development of a novel aryne sigma bond insertion reaction. The chapter begins with a brief overview of aryne chemistry followed by a summary of the common methods for the stannylation of aromatic molecules. The development of the reaction using a model is then discussed, followed by the application of the methodology to several substrates. The final part of the thesis contains an experimental section, which gives detailed procedures for the synthesis and characterisation of the compounds discussed throughout this thesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available