Thesis
Emerging synthetic methods for routes towards molecules of biological relevance
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2013
- Thesis identifier
- T13734
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Investigations into the application of catalysts, of the type [Ir(COD)(PR₃)(NHC)]PF₆, within the realm of alkyne dimerization have been undertaken. These novel catalysts, previously synthesised within our research group, feature both a bulky phosphine ligand and a sterically-encumbered N-heterocyclic carbene ligand. The use of these iridium complexes in alkyne dimerization has been examined, with particular emphasis being placed upon tuning the selectivity of the dimerization whilst maintaining high yields. The relative paucity of iridium-mediated (Z)-selective dimerization procedures detailed in the literature rendered this transformation an appealing process to investigate. Subsequent studies led to a broadly employable system being developed which was applied to a range of aryl alkynes, resulting in the formation of the analogous (Z)-enynes in good yield. Following this, a programme of research in collaboration with the Beatson Institute for Cancer Research, Glasgow, describes contributions towards the construction of specific '3D libraries' for potential application in fragment-based drug discovery. The chemistry investigated during this time forms the basis of the Beatson's contribution to the recently formed '3D libraries consortium' concerned with the fragment-based drug discovery. The ultimate goal was the preparation of an array of compounds featuring a non-planar conformation. It is hypothesised that the fragments will play key roles in inhibiting protein-protein interactions in key oncological processes. Further, it is envisaged that the conformational complexity imparted to the compounds will provide an advantage in overcoming difficulties associated with protein specificity. The aim of the project was to design a synthetic route to a novel pyridyl cyclopropane scaffold. The goal was that the preparative approach would allow for rapid access to a key late-stage intermediate, which in turn would then be able to undergo a series of transformations to allow for a range of fragments, based around a common scaffold, to be synthesised. The isolated compounds will form the basis of biophysical and biochemical based screening assays examining the compound's anti-cancer profile, with particular focus on identifying inhibitors of proteinprotein interactions. The final section of research centred on efforts towards the total synthesis of Agariblazeispirol C. As a result, significant steps towards the synthesis of the natural product have been achieved and a functionalised advanced intermediate has been reached. In this regard, a robust and efficient preparative pathway to the advanced intermediate has been designed. In addition, the key oxygenated sidechain has been installed in a late-stage species and represents an auspicious step towards the synthesis of the target molecule. The introduction of this key moiety was achieved following sustained synthetic efforts focusing on olefination and organometallic addition chemistry. The stereochemistry of the resulting intermediate has been deduced based on NMR studies. Subsequent synthetic investigations facilitated the formation of a suitable precursor for the ultimate synthetic transformation, a Pauson-Khand reaction. Preliminary attempts to promote the annulation protocol are discussed and it is likely that this work will significantly enhance the likelihood of accessing the natural product for the first time.
- Resource Type
- DOI
- Date Created
- 2013
- Former identifier
- 1032527
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