PROJECT SUMMARY Natural products continue to play an important role in pharmacology by serving as potent medicines and new lead compounds for drug discovery. A particularly important class of bioactive natural products are the polycyclic polyprenylated acylphloroglucinols (PPAPs), which are known for their diverse bioactivities including anticancer, antiviral, anti-inflammatory, antidepressant, antimicrobial, antioxidant, and neuroprotective activities. The most well-known PPAP, hyperforin, is the active constituent of St. John’s wort, an herbal antidepressant approved for clinical use in the UK and available over-the-counter worldwide. PPAPs are characterized by a highly oxygenated, polycyclic core decorated by prenyl-derived substituents. Because the range of bioactivities offered by these compounds is controlled by the precise identity, position, and configuration of these substituents, modular syntheses of PPAPs that enable the rapid synthesis of numerous natural and unnatural PPAPs have been highly sought after. Although PPAPs have attracted significant attention from the synthetic community, nearly all efforts have been devoted to the synthesis of PPAPs containing a bicyclo[3.3.1]nonane-2,4,9-trione core. This proposal discloses the first modular route to tricyclic PPAPs and the first route to PPAPs containing a bicyclo[3.3.1]nonane-2,8-dione core. The tricyclic PPAPs are more complex than bicyclic PPAPs and consequently have not been prepared in a modular fashion. Several natural products with impressive bioactivities lie within the class of molecules we will target, including garcixanthochymones A and B, which exhibit antiproliferative activities comparable to the FDA-approved chemotherapeutic doxorubicin, and plukenetione A, which exhibits antitumor activity by inhibiting DNA polymerase and topoisomerase I. To achieve these syntheses, we have outlined a plan that defers the installation of each of the substituents to the end of the synthesis, thereby harnessing the hidden symmetry of adamantane-type PPAPs and bicyclo[3.3.1]nonane-2,8-dione-type PPAPs. In the context of this synthesis, we will develop new desymmetrizations that set quaternary stereocenters, directed asymmetric conjugate additions, and bridgehead metalations. These methods will have broad applications in organic synthesis beyond the field of natural product synthesis. The proposed research will positively affect human health by expanding the availability of complex, bioactive PPAPs, ultimately accelerating the discovery of new treatments based on these privileged scaffolds.