Due to their interesting biological properties and complex molecular architectures, the rubromycin family of natural products, have attracted the attention of a number research groups over the last sixty years. Despite this significant interest, there is still a requirement for a short, robust, and modular synthetic route towards these intriguing secondary metabolites. This thesis presents an investigation into the application and development of Bray’s recent [4+2] cycloaddition methodology, towards achieving this goal (Scheme I). Scheme I. Retrosynthetic analysis of the rubromycin scaffold The initial introductory chapter outlines the structural relationships and biological properties of the rubromycins, in addition to providing details of the current understanding of their biochemical synthesis. This is followed by a comprehensive review of the five synthetic strategies used to construct the challenging [5,6]-bisbenzannulated spiroketal rubromycin core outlined in turn. In the third and final introductory chapter, the application and relative merits of these strategies towards the synthesis of fully elaborated rubromycin scaffolds is discussed. The results of this investigation towards a flexible and modular synthesis of γ-rubromycin are then presented and discussed in chapter four. The three main topics covered are; exploration of synthetic routes towards the napthazarin (II), exploration of synthetic routes towards the ortho-quinone methide (III), and utility of the orthoquinone methide in ‘inverse’ electron-demand [4+2] cycloaddition reactions. The experimental details of this investigation and selected 1H and 13C are also reported in chapters 5 and 6 respectively.