Probing the Structures of Phomonol and Phomolide F by Total Synthesis

Abstract

Antimicrobial resistance is an emerging threat towards public health and agriculture, resulting in the urgent need for the development of novel antimicrobial agents. Natural products provide significant knowledge and insight for the discovery of new potent antimicrobials, since secondary metabolites produced by microorganisms can find remarkable applications in fighting antimicrobial infections. However, accurate elucidation of the structures of natural products is vital for achieving this goal. This thesis describes the investigation of the structure of the natural product phomonol (6) via its total synthesis, and the proposed total synthesis of the secondary metabolite phomolide F (3) which could assist in the assignment of the stereochemistry of the natural product.
Chapter one introduces the current threat posed to humans and the ecosystem by the rise of
antimicrobial resistance and describes the frequency and reasons for the erroneous structural elucidation of natural products.
Chapter two introduces the polyketide derived natural products phomonol (6) and phomolide F (3), tetrahydropyrans and decanolides, and gives a summary of the reported total syntheses of phomonol. Furthermore, it describes the total syntheses of the secondary metabolites phomolides G and H which are co-metabolites of phomonol (6) and phomolide F (3), which resulted in their structural revision.
Chapter Three reports my research leading to the total synthesis of phomonol (6) via Sharpless asymmetric epoxidation to construct the tetrahydropyran ring. The structure of the final compound synthesised was confirmed by comparison of the NMR spectroscopic data with the natural product. Modifications to the synthetic route were proposed leading to strategies for the total synthesis of 4-epi-phomonol and 6-epi-phomonol. Finally, a proposed strategy towards the total synthesis of phomolide F (3) is discussed.

Date of Award	23 Jan 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Chris L Willis (Supervisor)