Towards the synthesis of yuzurimine-type Daphniphyllum alkaloids

Thesis

Chapter 1 provides an introduction to the total synthesis of natural products, with a particular focus on the Daphniphyllum alkaloids. Following a discussion of seminal and more recent total syntheses of these natural products, the yuzurimine-type Daphniphyllum subfamily is introduced. Prior synthetic campaigns towards these alkaloids conducted within the Dixon group are then highlighted, and yunnandaphnine D is identified as the primary synthetic target of this work.

In Chapter 2, a novel synthetic route towards yunnandaphnine D is proposed. An expeditious synthesis of a key bis-enone cyclisation precursor is developed in seven steps, and the crucial seven-membered ring is constructed using a SmI2-mediated ketyl radical cyclisation.

Chapter 3 describes a complementary synthetic strategy towards the core of the target natural products, featuring a diastereoselective radical cyclisation to construct a key tricyclic intermediate. The introduction of an allyl group at the 6,7-ring junction is then investigated, utilising interesting and unexpected transannular cyclisation reactions to bias the conformation of the allylation substrate.

In Chapter 4, the development of a ring-closing metathesis strategy towards the tricyclic core of yunnandaphnine D is detailed. Within this overarching theme, two different strategies are described, varying in the order that key C–C bonds are constructed. The second-generation asymmetric approach enabled the construction of the contiguous all-carbon quaternary stereocentres at the heart of the target natural products with the desired stereochemical configuration.

Lastly, Chapter 5 discusses a third-generation ring-closing metathesis strategy, developed in response to key findings in the previous chapter. Using this highly-convergent synthetic route, the successful synthesis of the tricyclic core of yunnandaphnine D is achieved, incorporating vital functional handles for continuation of the synthesis.

Authors: Davidson, TA

• DOI: 10.5287/ora-xo8g7mz8z
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: total synthesis
• Subjects: Chemistry, Organic