Towards the total synthesis of (+)-lophotoxin

Thesis

Chapter 1: Introduction

This chapter gives an overview of the furanocembranoid family of natural products, and its most prominent member (+)-lophotoxin. Biosynthetic, biological, and structural properties, as well as interconversion and synthetic studies are discussed. The chapter ends with a research proposal and lays out the synthetic strategy which was developed to approach this project.

Chapter 2: Synthesis of the right-hand furan fragment and model furans

This chapter describes the retrosynthesis and forward synthesis of several furan fragments used in our approach to lophotoxin. The organocatalytic Baylis–Hillman reaction to introduce the secondary alcohol alcohol at position C-13 stereoselectively, as well as the RCM-based furan methodology to introduce the core furan heterocycle, are described as key steps.

Chapter 3: Cross-coupling approaches for fragment linkage

This chapter discusses the synthesis of literature-known vinyl iodide, intended as the lefthand fragment, and attempts to couple it with various furan fragments via cross-coupling methods. The biggest challenge was a competing intramolecular Heck reaction.

Chapter 4: Synthesis of aldehyde left-hand fragments

This chapter details the restrosynthesis and forward synthesis of several aldehyde fragments, intended for an alternative fragment coupling strategy. The crucial Sharpless dihydroxylation of a 1,1-disubstituted olefin to introduce the tertiaty alcohol at position C-8 stereoselectively is discussed. The stereochemical assignment of C-8 and different protecting group strategies are summarised.

Chapter 5: Fragment coupling and synthesis of the carbon skeleton

This chapter depicts coupling reactions of furan and aldehyde fragments. Shiina macrolactonisation and RCM-mediated butenolide synthesis are reported as key steps to provide the carbon skeleton of (+)-lophotoxin. Different protecting group strategies are evaluated for their efficiency.

Chapter 6: Experimental procedures and supporting Information

This chapter lists all procedures for experiments described in this thesis. Additionally, all spectral data for the characterisation of synthesised compounds are given.

Authors: Hoff, O

• DOI: 10.5287/ora-kekrxxkz9
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: ring-closing metathesis; natural product; lophotoxin; total synthesis; furanocembranoid
• Subjects: Synthesis; Chemistry, Organic