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

Burch, Jessica and Bagdasarian, Alex L. and Hooshmand, Tanin and Nelson, Hosea M. (2020) Terpene Tail-to-Head Polycyclization Mediated by Small Molecule Catalysts: A Weakly-Coordinating Anion Approach. . (Unpublished)

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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 represent early examples of 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.

Item Type:Report or Paper (Discussion Paper)
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URLURL TypeDescription Paper
Bagdasarian, Alex L.0000-0003-2281-8068
Nelson, Hosea M.0000-0002-4666-2793
Additional Information:The content is available under CC BY NC ND 4.0 License. Financial support for this work was generously provided by the David and Lucile Packard Foundation (to H.M.N.), the Alfred P. Sloan Foundation (to H.M.N.), the Pew Charitable Trusts (to H.M.N), the NIH-NIGMS (R35 GM128936 to H.M.N.), and the National Science Foundation (DGE-1650604 to J.E.B.). A.L.B. thanks the Christopher S. Foote Fellowship for funding. The authors thank the UCLA Molecular Instrumentation Center for NMR and mass spectroscopy instrumentation. The authors would like to thank Prof. Dean Tantillo (University of California, Davis) and Dr. Johnny Gordon for useful discussions. Author Contributions: H.M.N. conceived the idea and supervised the project. J.E.B. and A.L.B. performed the described experiments and analysed the data. T. H. assisted in sample purification. H.M.N., J.E.B., and A.L.B. co-wrote the manuscript. The authors declare no competing financial interest.
Funding AgencyGrant Number
David and Lucile Packard FoundationUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
Pew Charitable TrustUNSPECIFIED
NIHR35 GM128936
NSF Graduate Research FellowshipDGE-1650604
Record Number:CaltechAUTHORS:20210811-225351281
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110210
Deposited By: George Porter
Deposited On:12 Aug 2021 22:09
Last Modified:16 Nov 2021 19:39

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