The penostatins are a family of polycyclic natural products isolated from marine bacteria. They exhibit unique biological activity and have garnered interest from synthetic organic chemists due to their complex structure. In particular, the complex oxidation pattern combined with either a fused tricyclic or bridged bicyclic core presents significant challenges to synthesis. The lack of a completed total synthesis of the bridged bicyclic congener penostatin F has motivated the pursuit of a strategy for its synthesis based on a Diels-Alder reaction /Claisen rearrangement sequence. In this work, progress and limitations of this approach are presented. A hydroxy-directed Diels-Alder/Claisen Rearrangement cascade was envisioned and explored however a series of roadblocks prevented the elaboration of bridged bicycle intermediates. Through this process, a novel degradation of hydroxy-dienes was uncovered as well as the isolation of a bridged bicycle containing a cyclic anti-Bredt alkene. The challenges uncovered led to a pivot away from this strategy and ultimately to a new approach for the synthesis of penostatin natural products. In this strategy, a hydroxyl group is used as a tether for an intramolecular Michael addition. Following the optimization of this reaction, an unexpected retro-Dieckman rearrangement of the product forced the development of an alternative route to an initially envisioned decarboxylation. This approach was employed to yield 5-deoxypenostatin B. Finally, progress towards integrating the cyclopentanol ring of penostatin B as part of this strategy via a Tamao-Fleming reaction is described.