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. 2023 Mar 29;145(12):7021-7029.
doi: 10.1021/jacs.3c01262. Epub 2023 Mar 16.

Asymmetric Total Synthesis of Illisimonin A

Christoph Etling  1 , Giada Tedesco  1 , Anna Di Marco  1 , Markus Kalesse  1
Affiliations

Asymmetric Total Synthesis of Illisimonin A

Christoph Etling et al. J Am Chem Soc. .

Abstract

The discovery of illisimonin A in 2017 extended the structural repertoire of the Illicium sesquiterpenoids─a class of natural products known for their high oxidation levels and neurotrophic properties─with a new carbon backbone combining the strained trans-pentalene and norbornane substructures. We report an asymmetric total synthesis of (-)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.2.1.01,5]decanes via radical cyclization was explored. This approach was applied in a two-stage strategy consisting of Ti(III)-mediated cyclization and semipinacol rearrangement to access the natural product's carbon backbone. These key steps were combined with carefully orchestrated C-H oxidations to establish the dense oxidation pattern.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Structure of (−)-Illisimonin A (1) and Approaches to Enantioenriched Tricyclo[5.2.1.01,5]decane 2
BOM = benzyloxymethyl.
Scheme 2
Scheme 2. (a) Access to Spirocyclic Ketones via the Tandem-Nazarov/Ene Cyclization, (b) C5–C6 Bond Formation Strategy, and (c) Retrosynthetic Analysis
FGI = functional group interconversion, PG = protecting group.
Scheme 3
Scheme 3. (a) Asymmetric Synthesis of Spirocyclic Key Intermediate 15 and Further Derivatization via a Silicon-Based One-Carbon Homologation and C7 Oxidation and (b) Divergent Opening Behavior of Oxasilolane 19
acac = acetylacetonate, brsm = based on recovered starting material, DIBAL-H = diisobutylaluminum hydride, 4-DMAP = 4-dimethylaminopyridine, DMSO = dimethyl sulfoxide, IBX = 2-iodoxybenzoic acid, KHMDS = potassium bis(trimethylsilyl)amide, LDA = lithium diisopropylamide, MTBE = methyl tert-butyl ether, r.t. = room temperature, TBAF = tetra-n-butylammonium fluoride, TES = triethylsilyl, Tf = trifluoromethanesulfonyl, THF = tetrahydrofuran.
Scheme 4
Scheme 4. Evolution of the Tricyclo[5.2.1.01,5]decane Synthesis—Studies on the C5 Stereocontrol for Radical-Based C5–C7 Cyclizations
Cp = cyclopentadienyl, dpm = 2,2,6,6-tetramethyl-3,5-heptanedionate, TBS = tert-butyldimethylsilyl.
Scheme 5
Scheme 5. (a) Access to the Carbon Framework of Illisimonin A via Our Cyclization/Rearrangement Strategy, (b) Completion of the Total Synthesis via Rychnovsky and Burns’ Route, and (c) Exploration of an Alternative Endgame
mCPBA = meta-chloroperoxybenzoic acid, HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol, PDP = [N,N′-bis(2-pyridylmethyl)]-2,2′-bipyrrolidine.
See this image and copyright information in PMC

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