Studies towards the total synthesis of (+)-lophotoxin and site-selective modification of the thiopeptide anticancer natural product Thiostrepton

Thesis

Chapter 1: Introduction

The isolation, biological activity and importance of the furanocembranoid family of natural products is outlined and a review of synthetic efforts towards their total synthesis provided. Both classical and catalytic methods for the synthesis of polysubstituted furan heterocycles are summarised, with an emphasis on olefin metathesis methods and their impact on the field.

Chapter 2: Methodology Development and Model Studies Towards (+)-Lophotoxin

The development of a temporary-silicon-tether ring-closing metathesis approach to trisubstituted furans is described. The discovery of Brønsted acid and photochemical cyclisation conditions is discussed and the scope of all procedures evaluated. The results of model studies towards to a total synthesis of (+)-lophotoxin are also reported.

Chapter 3: Progress Towards the Total Synthesis of (+)-Lophotoxin

The development of the retrosynthetic strategy and current progress towards a total synthesis of (+)-lophotoxin is discussed. Asymmetric routes to two key fragments are described, along with their union, and the application of the photochemical aromatisation procedure to the furan core of (+)-lophotoxin is disclosed.

Chapter 4: Site-selective Modification of the Thiopeptide Anticancer Agent Thiostrepton

This chapter focusses on a separate project, which aimed to provide synthetic tools to assist in structure-activity investigations of the natural product Thiostrepton. The natural product and its biological activity are introduced along with previous examples of its modification. The development of a general site-selective acylation reaction and the synthesis of a library of analogues is discussed. The results of their biological evaluation is also reported.

Authors: Walker, J

• DOI: 10.5287/ora-mnejzmvz8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Chemistry, Organic