Cascade reactions are among the most powerful and elegant tools available to chemists allowing for the quick and efficient construction of complex molecules form simple starting materials. This class of reactions has shown its worth time and time again in the arena of natural product synthesis, which has and continues to serve as the proving ground for chemical methods. Over the last century, a vast number of challenging targets have succumbed to syntheses enabled by both biomimetic and rationally designed cascades. However, despite the plethora of work done, much still remains to be done with even the most well studied methodologies still have largely unexplored areas. This dissertation herein reports the study of transition metal mediated cascades particularly Mizoroki-Heck cascades for the construction of complex polycyclic frameworks. Chapter 1 describes the inspiration for the initial work towards the total synthesis of the pentacyclic sesterterpene retigeranic acid A as part of our group’s interest in the synthesis of unfunctionalized terpenes via Pd-Mediated Heck cascade. The lessons learned over the course of our initial attempts with the cascade ultimately proved to be the impetus that led us to begin our studies on Ni mediated Heck cascades, of which only a handful of examples have been reported in contrast to the veritable ocean of Pd literature. Chapter 2 begins with a brief introduction into the unique properties of Ni in the context of the Heck reaction and a overview of the state of the Ni Heck reaction. Next, we report our development of mild base-mediated conditions for aryl and vinyl triflates. Our conditions have proved quite general and give comparable, and in some cases superior, yields and selectivities to the corresponding Pd reaction. We are able to access a wide variety of spirocyclic and fused ring systems and applications with systems taken from the total synthesis literature are discussed. Chapter 3 focuses on an intriguing intermolecular variant of the Heck reaction in which Ni exhibits divergent reactivity to Pd leading to the formation of 1,2-dihydronapthalenes. Following our initial discovery of the novel selectivity using our base mediated conditions, we chose instead to focus on the development of racemic and enantioselective conditions using a reducing metal mediated approach, which allowed us to access a wide variety of 1,2-dihydronapthlenes in good yield and ee. The application of this new strategy in the total syntheses of furomollugin and norcardione B as well a discussion of the origin of the observed [6-endo-trig] selectivity are also found within this chapter. Chapter 4 concludes the dissertation by returning to our studies towards retigeranic acid A now via a new Pd-enolate in the hopes of overcoming the β-hydride elimination and [3-exo-trig] pathways that hampered our original approach. Following the synthesis of enoate and enone based cascades substrates, we found the formation of the vinyl cyclopropane motif via the [3-exo-trig] pathway was unavoidable leading us to investigate both radical and Rh catalyzed [3+2] cyclizations in order to access the target. Future work towards retigeranic acid A is also discussed.