Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach

28 July 2020, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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.


main group

Supplementary materials

Terpene SI


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.