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|Title: ||Studies towards the total synthesis of non-ribosomal peptide natural products|
|Authors: ||Santhakumar, Gajan|
|Issue Date: ||Feb-2015|
|Publisher: ||University of Sydney|
School of Chemistry
|Abstract: ||Non-ribosomal peptides (NRPs) are a fascinating class of natural products. Unlike their ribosomal counterparts, these compounds are built enzymatically and the constituent monomers are not restricted to the 20 proteinogenic amino acids. In addition, the enzymatic machinery that assembles these peptide natural products can introduce structural changes to the side chains and the peptide backbone. Examples include epimerisation of the -centre, installation of building blocks derived from polyketides, addition of heterocycles and cyclisation of the linear peptide chain. In addition to the inherent structural complexity within NRPs, members of this family often display interesting and potent biological activity.
There have been efforts into understanding how these peptides are built by nature and additionally studies into their mode of action when they have been demonstrated to possess in vitro biological activity. However, efforts into synthesising these molecules in a laboratory setting are not as prevalent because assembly of these heavily functionalised, complex asymmetric molecules is challenging, requiring often lengthy and often synthetic routes with numerous stereocontrolled steps. The total synthesis of NRPs is an important endeavour as it facilitates the confirmation of the chemical structure of the natural products. In addition, an efficient synthesis of NRPs enables rapid generation of analogues that may possess superior biological activity than the original NRP.
This thesis presents the synthetic studies towards the total synthesis of a number of NRPs, namely, polydiscamide B, polydiscamide C, polydiscamide D, microspinosamide and the Burkholdine family. The successful total synthesis of polydiscamides B-D showcased a unique native chemical ligation-oxidation approach towards these natural products, streamlining the chemical synthesis that is amenable to analogue generation. This novel approach was used to interrogate the structure of the anti-HIV molecule microspinosamide, of which the absolute stereochemistry has not been assigned. Finally, efforts were focussed on the synthetic studies towards the burkholdine natural products, an intriguing family of structurally complex cyclic glycolipopeptides with potent anti-fungal activity.|
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|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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