7. Project Summary/Abstract The class of prenylated indole alkaloids known as the ambiguines represents a structurally intriguing class of compounds with interesting biological activity including promising antibiotic and anti-fungal properties. Ambiguine E is arguably the most potent of these natural products with a minimum inhibitory concentration (MIC) against Staphylococcus aureus comparable to that of the FDA approved antibiotic gentamicin (1.5 and 1.4 ?g/mL respectively). Perhaps a more fascinating feature of these natural products is their biosynthesis, which is suggested to involve the class of non-heme C?H functionalizing enzymes known as the Rieske-oxygenases. It has been proposed that these enzymes are responsible for the final oxidative diversification among the ambiguines including cyclization, epoxidation, and dihydroxylation. In addition, a novel class of non-heme C?H chlorinating enzymes have been identified as responsible for a late-stage stereoselective sp3 chlorination leading to the chlorine-containing ambiguine natural products. While a synthesis of tetracyclic (+)-ambiguine H was recently reported by Baran and coworkers, a synthesis of any of the pentacyclic ambiguines has not yet been accomplished. We envision that a divergent total synthesis of these densely functionalized indole alkaloids will help elucidate mechanisms for the final Rieske mediated oxidations in addition to exploring the promiscuity of the C?H chlorinating enzymes. In light of this goal, we have completed a synthesis of the pentacyclic core of the ambiguines utilizing a novel strategy in a four-step sequence. The completion of the natural products and subsequent biosynthetic studies are proposed here.