Synthetic and Biosynthetic Studies on Heterocycle Formation in Polyketide Biosynthesis

  • Joe M Barker

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Mupirocin, an antibiotic produced by Pseudomonas fluorescens, is a clinically important antibiotic which exhibits potent activity against a wide range of Gram positive bacteria including methicillin resistant Staphylococcus aureus (MRSA). Mupirocin is a mixture of pseudomonic acids, and extensive studies have led to a good understanding of their biosynthesis. However, the timing and mechanism of some key steps are unknown. The work described herein focuses on the mechanism of formation of the tetrahydropyran (THP) core of the pseudomonic acids which is essential for bioactivity.

Chapter two describes the synthesis of the linear substrate 59 incorporating a carbon-13 label required to investigate THP ring formation. 59 was prepared via a convergent route in 11 steps using a key Suzuki coupling/Mukaiyama aldol reaction to establish the stereocentres at C-5 and C-8. Bioassays with 59 in E. coli overexpressing MupW/MupZ revealed that alkene 60 is likely an intermediate in THP formation.

Chapter three describes the synthesis of triol 117 via a key Suzuki coupling and HWE olefination in 4.9% yield over 14 steps. This substrate 117 lacks the 5-OH required for THP formation and bioassays in E. coli overexpressing MupW provided the first NMR evidence that an epoxide intermediate is involved in THP formation.

Chapter four describes the studies towards the synthesis of 103, the proposed alkene intermediate in THP formation, as well as the synthesis of 146, which was confirmed not to be an intermediate in THP formation.

Chapter five concerns investigations into the biosynthesis of tenuipyrone (215), a spirocyclic polyketide isolated from Isaria tenuipes. The synthesis of 254 and 262, linear thioester analogues of cephalosporolide B (211) is described, and the key cyclisation with pyrone 210 to form tenuipyrone was investigated.
Date of Award24 Jun 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorChris L Willis (Supervisor)

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