Biomimetic total synthesis has played a pivotal role in the development of synthetic organic chemistry. In particular, efforts aimed at mimicking the head-to-tail (HT) cation–π cyclization cascades invoked in terpene biosynthesis, such as those catalyzed by type-II cyclases, have led to a multitude of new synthetic methods, chemical concepts, and total syntheses over the past century. Conversely, synthetic methodology that mimics tail-to-head (TH) cation–π cyclization cascades, mediated by Mg²⁺ type-I terpene cyclases, remains elusive in organic synthesis, despite key roles in the biosynthesis of privileged therapeutic molecules such as taxol and artemesinin. Here we report that Li⁺/weakly-coordinating anion (WCA) salts catalyze the TH polycyclization of linaloyl fluoride, leading to high-yielding mixtures of polycyclic terpene natural products including cedrenes, cadinadiene, epizonarene, and 𝛿-selinene. The examples reported herein are the first small molecule-catalyzed TH polycyclization reactions enabling the shortest (formal) total synthesis of (±)-artemisinin. Moreover we apply this strategy to the diterpene geranyllinaloyl fluoride, resulting in a two-step total synthesis of the tricyclic core of the gersemiols (named here as α-gersemiene), a recently discovered class of marine diterpenoid natural products.

仿生全合成在合成有机化学的发展中起着关键作用。特别是，旨在模仿萜烯生物合成中所调用的头尾（HT）阳离子-π环化级联反应的努力，例如II型环化酶催化的级联反应，已经导致了许多新的合成方法，化学概念和过去一个世纪的总合成。相反，由Mg ²⁺ I型萜烯环化酶介导的模仿尾对头（TH）阳离子-π环化级联反应的合成方法，尽管在特权治疗分子（如紫杉醇）的生物合成中起着关键作用，仍无法有机合成。和青蒿素。在这里，我们报告说，李⁺/弱配位阴离子（WCA）盐催化芳酰氟的TH多环化反应，从而导致多环萜烯天然产物（包括雪松烯，卡丁二烯，表二芳烃和se-selinene）的高产混合物。本文报道的实例是第一个小分子催化的TH多环化反应，可实现（±）-青蒿素的最短（正式）全合成。此外，我们将此策略应用于二萜类香叶基壬二酰氟，导致了两步全合成的葛根三醇（此处称为α- gersemiene）的三环核心，这是最近发现的海洋二萜类天然产物。