Flavones from Cyclopropanes: Development of Methodology and the Total Synthesis of Integrin and (±)-Oxyisocyclointegrin

Abstract

Cyclopropanes are important substrates in organic chemistry able to participate in many different classes of reactions which can be broadly classified as ring opening, cycloaddition and rearrangement reactions. The unique reactivity of cyclopropanes is a result of the unusual C-C bonding properties leading to a high degree of π-character, which allows the cyclopropane to be conjugated with unsaturated substituents. Electron withdrawing substituents activate the cyclopropane towards a variety of chemical reactions. Further activation is possible when an electron donating group is placed vicinal to an electron withdrawing group which creates a push-pull effect polarising the cyclopropane bond and resulting in a 1,3-dipole which renders the cyclopropane more reactive. It is this electronic character that makes donor-acceptor cyclopropanes especially useful tools for organic synthesis. As such, donor-acceptor cyclopropanes have attracted considerable research interest with hundreds of publications investigating the synthesis, reactions and properties of cyclopropanes, including their use in a significant number of natural product total syntheses. This thesis discloses new methodology to synthesise flavones and chromones from cyclopropanes, the application of this chemistry towards the construction of biologically relevant chemical scaffolds and the total synthesis of two flavone natural products, integrin (23k) and oxyisocyclointegrin (25f). Chapter 1 provides a general background on benzopyran natural products and more specific background on the natural products that were synthetic targets of this research. Literature methods to synthesise flavones are also discussed in detail as well as an introduction to the chemistry of cyclopropanes and some of the reaction types that they have been engaged in. Chapter 2 describes the development of synthetic methodology to access 2,3-functionalised chromones and flavones 302a-j with a unique allyl alcohol functional group at the 3-position from 1,1-diacylcyclopropanes. This study included exploration of substrate scope and presented evidence in support of a proposed reaction mechanism. Chapter 3 details the different synthetic approaches taken to achieve the total synthesis of the natural products integrin (23k) and oxyisocyclointegrin (25f), first isolated from Artocarpus integer. Key steps in the successful synthetic route included a novel Tsuji-Trost type allyl migration reaction and a photochemical oxidative cyclisation to form the oxepine scaffold. Chapter 4 discusses efforts taken towards the total synthesis of the natural product bromophycoic acid E (39), which further showcases the utility of the flavones prepared in Chapter 2 to provide rapid access to complex polycyclic scaffolds. Chapter 5 provides a brief summary of the results from Chapters 2-4 and outlines future directions of investigation.