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.

中文翻译：

---

通过位点特异性烯烃官能化合成 （±）-nanolobatolide 的四步法


摘要：天然产物合成继续激发构建结构复杂且具有生物学意义的分子的创新方法。在这项研究中，我们提出了从晚期修饰到早期结构识别的范式转变，从而实现了更简化和高效的合成策略。愈创木酚首次被用作起始材料，采用一种新颖的脱氢方法来构建愈创木酚核心。这种策略促进了 （±）-nanolobatolide 的简洁、四步全合成，这是一种复杂的四环二萜类化合物 （5/5/5/7 系统）。该合成突出了针对多烯框架内特定二烯的选择性 Diels-Alder 反应，然后是位点特异性环氧化与原位内酯化。此外，由协同氢原子转移 （cHAT） 催化介导的后期面和位点选择性氢化强调了烯烃精确官能化在实现结构复杂性方面的重要性。除此之外，我们还通过邻近驱动的级联环化合成了一种新型的含环丙基的五环二萜类化合物，展示了官能团定向在构建应变分子结构中的关键作用。这项工作重新定义了构建复杂萜类化合物框架的策略，展示了位点选择性烯烃功能化如何以卓越的精度和效率克服合成挑战。