In this thesis further developments on the thermal cascade reaction discovered in the Parsons group have been made. The substrate scope has been increased to include the ketone linked 1,6-diynes, which had failed to cyclise in previous studies. Furthermore, variations on the precursor molecule have led to the cyclisation of nitrogen and sulphur analogues to provide the respective annulated pyrrole and thiophene products. The synthesis of these compounds using the Parsons-Board-Waters cyclisation had not been explored during earlier studies within the group. The increased scope of the Parsons-Board-Waters cyclisation was applied to the total synthesis of the natural product (+)-aphidicolin. The development of model systems are described, with the importance of the ketone functionality being highlighted by the unsuccessful cyclisation of dioxolane protected precursors. Furthermore, the enantioselective synthesis of a key intermediate containing the required 1,3-diol functionality present in the natural product is reported. This will provide a route to future research on the application of the Parsons-Board-Waters cyclisation to (+)-aphidicolin.