The Total Synthesis of Pseudonocardia sp. Quinolone Natural Products and Studies Towards the Total Synthesis of 1β-Hydroxyalantolactone

Natural products have long been known for their broad range of useful therapeutic properties, and have been widely utilised in the field of medicine. This dissertation describes work towards the total synthesis of natural products possessing biological activity in two important areas. The first section concerns the total synthesis of six 4-quinolone natural products, four of which had never been synthesised before. These compounds were originally isolated from a soil bacterium of the genus Pseudonocardia, and bear intriguing structural resemblance to the Pseudomonas Quinolone Signal. This signalling molecule is vital to the quorum sensing activity of the human pathogen Pseudomonas aeruginosa, which is a phenomenon by which it regulates many of its virulence factors. These natural products possess the potential to disrupt this system, hence attenuating the pathogenicity of the bacteria. The routes that were developed are highly divergent, efficiently giving access to multiple natural products from mutual late stage intermediates. Key steps included regioselective epoxidation, palladium-catalysed heterocylisation and acid catalysed 1,3-transposition of an allylic alcohol. In the second section, attention turns towards the total synthesis of the complex sesquiterpene lactone 1β-Hydroxyalantolactone. The compound possesses five stereogenic centres, one of which is quaternary, alongside a challenging tricyclic core scaffold. Previous biological studies have revealed a range of intriguing properties, including anti-inflammatory and anti-tumour activity. The chosen route utilises as its key step the catalytic desymmetrisation of a diene which was itself accessed by Birch reduction chemistry. Whilst the synthesis is as yet incomplete, access was granted to a key intermediate encompassing around half of the stereocentres present in the natural product.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Geddis, Stephen Michael

Advisor dc:contributor.advisor

• Spring, David

• Total Synthesis
• Antimicrobial
• Quorum Sensing
• Anti-inflammatory
• Anti-tumour
• Terpenes
• 4-quinolones
• Natural Products

Statement dc:rights

• P. 19, Figure of Bacterial Growth Curves, copyright holder is John Wiley & Sons, Inc.

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8157fa38-252f-4b5d-9485-56ca987f3af7/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.24866

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/277551