Natural products and their derivatives account for 62% of all FDA-approved small molecules from 1981 to 2014. However, the use of natural products for pharmaceutical purposes is often limited by both the low natural abundance of such targets and general synthetic inefficiency in making complex molecules on scale. Herein, we hope to explore how we may surmount the latter limitation, as we discuss our efforts in the production of compounds with not only a high proportion of stereochemical information, but also stereochemically dense, heteroatom containing cores. These two attributes can be daunting on their own, however we believe they can be quite synergistic when approached as a cooperative problem, in which the presence of the heteroatoms throughout such scaffolds informs how best to tackle the overall targets. This dissertation will describe such synthetic efforts across three families of natural products: the Laurencia ethers, grayanotoxin diterpenoids, and cinncassiol diterpenoids.Chapter 1 will outline our efforts to complete the inaugural total synthesis of laurendecumallene B, a polyhalogenated and polycyclic Laurencia ether. The composition of this target consists of eight stereocenters within its 15-carbon skeleton, two bromines, and four oxygens. In this work, we will describe how we utilized the presence and placement of these heteroatoms, in concert with the various stereocenters throughout the system, to elucidate the first successful synthesis of this target. Furthermore, we also discuss the pivotal application of DFT to inform a critical route redesign alongside the unique reactivity of BDSB, a highly electrophilic bromonium source which introduces both bromines within laurendecumallene B. In Chapter 2, we outline initial efforts to potentially access several members of the grayanotoxin diterpenoids, a class of highly oxygenated tetracyclic compounds with a wide range of bioactivities. Herein, a general approach for the total synthesis of ten grayanane diterpenoids is proposed, all potentially stemming from a common intermediate. Of note, an intermolecular radical coupling cascade was planned to construct the common intermediate, the design of which was guided by the conserved placement of several oxygens across nearly the entire family of targets. Ultimately, these studies were ceased due to a recent publication sharing a similar approach to a related target. Finally, Chapter 3 will discuss current efforts focused on a second class of highly oxygenated natural products: the cinncassiol diterpenoids. These compounds are part of and/or related to the isoryanodane family and have shown a plethora of various biological activities accompanying their wide-ranging levels of oxidation. Our approach is centered on the total synthesis of cinncassiol F, differing from cinnamomol A by a single C-C bond proposed to be biosynthetically fashioned through an intramolecular aldol addition.