Nimbolide (1, Figure ), contains an additional lactone ring formed by the C4 carboxylate and the C6 hydroxyl group. This added functionality further complicates the chemical synthesis of 1. In addition to an intricate and highly oxidized structure, 1 possesses potent biological activity. Specifically, nimbolide has been shown to prevent and reverse nearly all cancer hallmarks, particularly those associated with cancer metastasis, cancer-related inflammation, and angiogenesis. This unique activity profile has motivated decades of in vitro studies supporting further development towards an anti-cancer or anti-metastatic therapy. Despite the promising biological activity of nimbolide in vitro, poor pharmacokinetic properties and moderate toxicity in vivo have hampered preclinical studies. Identification of metabolic vulnerabilities and subsequent synthesis of analogs resistant to oxidative metabolism are necessary to improve the pharmacokinetic properties of nimbolide. Attempts to ameliorate metabolic liabilities through semisynthesis have been unsuccessful, and more deepseated modifications of this bioactive scaffold are likely required to improve the pharmacokinetic profile of nimbolide. To support these aims, we sought to design a rapid synthetic approach to nimbolide that would facilitate future structural modifications of this potent scaffold.