New strategies for isoquinoline functionalisation with applications in total synthesis

Thesis

This thesis describes three techniques for the β-functionalisation of isoquinolines, with applications to the total synthesis of Crinane family natural products.

Chapter 1 is a general introduction to the chemistry of isoquinolines, covering background, synthesis and selected reactivity of this class of molecule.

Chapter 2 will detail a temporary dearomatisation strategy towards the direct β-functionalisation of isoquinolines, making use of nucleophilic activation by carboxylic acids. This reveals enamine functionality, which is then free to add into a conjugate acceptor. The scope of the reaction is explored, and a small scope of vinyl ketones is described.

Chapter 3 explores a different approach for achieving β-functionalised isoquinolines, building upon reductive functionalisation chemistry developed previously within the group to afford β functionalised THIQs. An oxidative approach is used to synthesise isoquinolines from THIQs, which furnishes a two-step sequence to β-functionalised isoquinolines from isoquinolinium salts. A scope is described, including both simple mono-functionalised THIQs and more complex systems including a quinoline example. The mechanism is investigated, and results indicate that a debenzylative retro-ene reaction is part of the oxidative sequence.

Expanding upon existing group methods focussing on reductive functionalisation, Chapter 4 describes the development and optimisation of a reductive annulation reaction. The design of an ambident electrophile is investigated to achieve a one-pot annulation reaction. Downstream-derivatisation of the tricyclic vinylogous amide product is subsequently investigated.

The methodology developed in Chapter 4 is then applied to an electron-rich isoquinoline system in Chapter 5, towards the synthesis of the Crinane family of natural products. The family’s parent compound Crinane is synthesised in 8 steps, with optimisation of several steps. A brief investigation towards route diversification strategies is attempted in order to synthesise further members of the natural product family.

Finally, Chapter 6 will explore the evolution of the reductive annulation reaction developed in Chapter 4 to render it enantioselective. A chiral auxiliary approach is adopted and explored through the development of further ambident chiral electrophiles incorporating auxiliaries as leaving groups. The reaction is then optimised and the mechanism briefly investigated through an alternative substrate that allows intermediate isolation.

Authors: Jenkins, T

• DOI: 10.5287/ora-dx56rmmv8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: temporary dearomatisation; reductive annulation; isoquinoline functionalisation; oxidative functionalisation
• Subjects: Organic compounds--Synthesis