Total synthesis of plantazolicin A

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Wada, Hiroki (2017) Total synthesis of plantazolicin A. PhD thesis, University of Nottingham.

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Abstract

Chapter 1 is an introduction of this thesis highlighting the importance of natural products in drug discovery utilising chemical modification of the original motif, especially together with an application of various bioisosteric approaches. Then, it gives an overview of a natural product, plantazolicin A which contains multiazoles with peptide bioisosteric properties. Other azole containing natural products including Thiazole/Oxazole Modified Microcins (TOMMs) are also introduced here. The current practical synthetic methods of the azoles such as thiazole and oxazole are discussed, especially with newly developed rhodium(II)-catalysed oxazole formation reaction via rhodium carbenoids derived from -diazocarbonyl compounds.

Chapter 2 describes the total synthesis of plantazolicin A with the retrosynthetic plan by using the carbene chemistry, mainly starting from two precursors to prepare the key intermediate I and II. Each synthetic method is detailed including the choice of the optimum protecting groups and their development. The multi-oxazoles are formed via rhodium(II)-catalysed oxazole formation reactions with -diazocarbonyl compounds and the detailed procedures are explained. The two key intermediates I and II are combined together to give the main plantazolicin A scaffold and the detailed investigation to remove the protecting groups are also discussed here. A conformational study was carried out with extensive NMR nOe study together with molecular modelling to find the most stable conformational energy. A hairpin-like 3D structure of plantazolicin A is revealed here.

In Chapter 3, the design of analogues of plantazolicin A is discussed and the synthesis is detailed using rhodium(II) catalysed oxazole formation reaction, following the success of the total synthesis of plantazolicin A. The analogues are tested against the growth of bacteria, especially methicillin-resistant Straphylococcus aureus (MRSA). The detailed structure-activity relationship (SAR) is also discussed here.

Chapter 4 summarises the results of chapter 2 and 3, and chapter 5 contains full experimental details for all the work carried out.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Moody, Christopher J.
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 37595
Depositing User: Wada, Hiroki
Date Deposited: 18 Jul 2017 04:40
Last Modified: 07 May 2020 12:16
URI: https://eprints.nottingham.ac.uk/id/eprint/37595

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