A Four-Step Synthesis of (±)-Nanolobatolide via Site-Specific Olefin Functionalization

Abstract: Natural product synthesis continues to inspire innovative approaches for constructing structurally intricate and biologically significant molecules. In this study, we present a paradigm shift from late-stage modifications to early-stage structural recognition, enabling a more streamlined and efficient synthetic strategy. For the first time, guaiazulene has been utilized as a starting material, employing a novel dearomative approach to construct the guaiane core. This strategy facilitated the concise, four-step total synthesis of (±)-nanolobatolide, a complex tetracyclic diterpenoid (5/5/5/7 system). The synthesis highlights a selective Diels-Alder reaction targeting a specific diene within a polyene framework, followed by site-specific epoxidation coupled with an in-situ lactonization. Additionally, a late-stage face- and site-selective hydrogenation, mediated by cooperative hydrogen atom transfer (cHAT) catalysis, underscores the importance of precise olefin functionalization in achieving structural complexity. In addition to this, we have also synthesized a novel cyclopropyl-bearing pentacyclic diterpenoid through proximity-driven cascade cyclizations, showcasing the critical role of functional group orientation in constructing strained molecular architectures. This work redefines strategies for building complex terpenoid frameworks, demonstrating how site-selective olefin functionalization can overcome synthetic challenges with remarkable precision and efficiency.