Herein, I describe our synthetic studies toward the aphidicolin family of diterpenoid natural products and our synthesis of the isocyanosesquiterpene natural products 9-isocyanopupukeanane and 2-isocyanoallopupukeanane. Chapter 1 reviews the isolation, biosynthesis, biological activity, and previous syntheses of aphidicolin, as well as our proposal to synthesize aphidicolin and its more oxygenated congeners. This includes a detailed discussion of aphidicolin’s biological mode of action and our structural hypothesis for the development of aphidicolin-based therapeutics using the recently isolated congeners. Chapter 2 describes our various synthetic investigations toward constructing the aphidicolin scaffold. During these studies, we developed a pseudo-desymmetrization of a cyclobutyl pronucleophile using an allyl electrophile and subsequently established condition-dependant formation of linear or crossed intramolecular [2+2]-photocycloaddition adducts. This culminated in the formation of a late-stage pentacyclic intermediate containing the embedded aphidicolin scaffold. Chapter 3 reviews the isolation, biosynthesis, biological activity, and previous syntheses of various pupukeanane natural products—specifically, 9-isocyanopupukeanane and 2-isocyanoallopupukeanane. In addition, previous synthetic efforts performed in our group toward this family are described, culminating in a 10-step enantiospecific formal synthesis of 2-isocyanoallopupukeanane. This also includes computationally guided investigations into the “contra-biosynthetic” rearrangement of the allopupukeanane core to the pupukeanane core, which was achieved by the formation of a sultone. Chapter 4 details our subsequent synthetic investigations toward 9-isocyanopupukeanane, leveraging higher-order magnesiates to open the pupukeanyl sultone and introduce a functional handle to mediate desulfurization. This culminated in a 15-step enantiospecific formal synthesis of 9-isocyanopupukeanane, demonstrating the utility and feasibility of “contra-biosynthetic” strategies in total synthesis.