Synthetic and biosynthetic studies on the ambruticins

Abstract

Antifungal resistance is an area of growing concern which poses a severe threat to public healthcare and global food supplies. Research into novel acting antimycotics is urgently required to address the issues associated with antifungal resistance. This thesis describes investigations into the synthesis and biosynthesis of the ambruticins, a family of polyketide natural products which exhibit potent antifungal activity. Chapter one introduces the current state of antimycotics, the development of antifungal resistance, and a summary of synthetic and biosynthetic studies on the ambruticins.

Chapter two discusses the selectivity of intramolecular epoxide ring opening of 4,5-epoxy alcohols and investigations into tetrahydropyran ring formation in ambruticin biosynthesis. Model epoxidation-cyclisation studies are outlined and indicate that the 5-hydroxyl and 8,9-alkene of ambruticin J may be responsible for controlling selectivity during AmbJ-catalysed epoxidation to form ambruticin F. A convergent total synthesis of the putative biosynthetic intermediate ambruticin J is also discussed, where four key fragments are united by a thallium-accelerated Suzuki-Miyaura cross-coupling and two olefinations.

Chapter three outlines investigations into dihydropyran ring formation in ambruticin biosynthesis. The first total synthesis of the proposed biosynthetic intermediate 20,21-dihydroambruticin F is reported, which employs a bioinspired epoxidation-cyclisation cascade and a Prins cyclisation to construct the two heterocyclic rings. The structure of 20,21-dihydroambruticin F was confirmed by comparison with an authentic sample obtained from gene-knockout experiments, providing definitive proof of its existence as a biosynthetic intermediate. Finally, the modular route was adapted to complete the first total synthesis of ambruticin F and a biomimetic total synthesis of ambruticin S.

Date of Award	3 Oct 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Matthew P Crump (Supervisor) & Chris L Willis (Supervisor)