Swerilactones and related natural products were isolated from the plant Swertia mileensis and related species from the Gentianacea family. All members have shown moderate bioactivity in a hepatitis B virus assay. Despite their appealing framework and bioactivity, to date no syntheses of these compounds have been reported in the literature. All members of the natural products family display a polycyclic framework, containing lactone-pyran fused bicyclic subunits, and are heavily oxygenated. En route to swerilactones A and B, featuring a complex pentacyclic (6/6/6/6) ring system, the successful syntheses of two key building blocks for studies of a biomimetic [4+2] cycloaddition have been accomplished. The challenges associated with the design of a novel synthesis of a 2H-pyran diene are presented and ultimately relied on a Saucy-Marbet rearrangement of a propargyl vinyl ether. Reactivity studies for the 2H-pyran have shown thermal normal demand and photoinduced, radical cation [4+2] cycloadditions are Diels-Alder modes of choice, whereas inverse demand pathways were unproductive. Synthetic routes to obtain carboxylate and various enol ether substituted dienophilic lactones are also outlined. They relied on a unified strategy, comprised of the rapid assembly of a β-brominated sorbate derivative via cross-couplings and final oxa-6π electrocyclization as an original ring closure strategy. Our attempts at coupling the 2H-pyran intermediate with the dienophilic lactones to access the core structure of swerilactones A and B, leveraging our preliminary reactivity studies are presented in detail. In addition, alternatives strategies to assemble the core structures of swerilactones A and B are described, along with our efforts (and potential routes) toward related members of this family of natural products.