The increasing emergence of multi-drug-resistant microorganisms has led the World Health Organisation to plead for action to be taken against antimicrobial resistance. The fungal secondary metabolite (+)-pleuromutilin displays antibacterial activity with a novel mode of action: pleuromutilin derivatives bind to functionally important nucleotides within the peptidyl transfer centre of the prokaryotic ribosome and inhibit bacterial protein synthesis. The first non-racemic total synthesis of the antibiotic natural product pleuromutilin has been developed. A chiral pool strategy has been employed to gain access to the cyclisation substrate, which underwent a SmI2-mediated cyclisation cascade to give the 5,6,8 tricyclic core in a single step. The reaction proceeded with excellent diastereocontrol at the four contiguous stereocentres generated during the cascade. Elaboration of the cyclisation product to (+)-pleuromutilin was achieved by electron transfer reduction of the hindered ester at C5, stereoselective introduction of the hydroxyl at C11 and installation of the quaternary stereocentre at C12. Finally the first efficient conversion of (+)-mutilin to the target was developed. This strategy is now being used for the synthesis of simplified novel analogues of pleuromutilin: access to a range of simplified cores has been demonstrated in 5 steps.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:618049 |
| Date | January 2014 |
| Creators | Fazakerley, Neal James |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-total-synthesis-of-pleuromutilin-and-novel-analogues(b665d0f5-9231-4c2d-a803-c88f56e50202).html |
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