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

preprint
revised on 27.07.2020 and posted on 28.07.2020 by Jessica Burch, Alex L. Bagdasarian, Tanin Hooshmand, Hosea Nelson

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.

Funding

R35 DGE-1650604

History

Email Address of Submitting Author

jessburch@g.ucla.edu

Institution

University of California, Los Angeles

Country

USA

ORCID For Submitting Author

0000-0002-3578-1770

Declaration of Conflict of Interest

no conflict of interest

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