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. 2021 Jun 25;27(36):9257-9262.
doi: 10.1002/chem.202101041. Epub 2021 May 27.

A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds

Christoph Etling  1 , Giada Tedesco  1 , Markus Kalesse  1   2   3
Affiliations

A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds

Christoph Etling et al. Chemistry. .

Abstract

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3+2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.

Keywords: Nazarov cyclization; cyclization; domino reactions; ene reaction; spiro compounds.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Nazarov key steps in the total syntheses of (±)‐merrilactone A, (±)‐rocaglamide, (−)‐calychiphylline N, (−)‐farnesin and (−)‐oridonin. Bn=benzyl, mCPBA=m‐chloroperoxybenzoic acid, DMF=N,N‐dimethylformamide, Phth=phthaloyl, PMB=p‐methoxybenzyl, PMP=p‐methoxyphenyl, TBS=tert‐butyldimethylsilyl, TIPS=triisopropylsilyl, TMS=trimethylsilyl.
Scheme 2
Scheme 2
Supporting literature to the retrosynthetic approach towards illisimonin A (1), and the novel interrupted Nazarov cyclization. Ms=methanesulfonyl, TFE=2,2,2‐Trifluoroethanol.
Scheme 3
Scheme 3
Interrupted Nazarov cyclization approach to the core of illisimonin A (1).
Scheme 4
Scheme 4
Proposed reaction pathways for the formation of products 4 to 7. LA=Lewis acid.
Scheme 5
Scheme 5
First mechanistic hypothesis for the formation of spirocycle 8 from 3. An ene reaction is favored over the envisioned [3+2] cyclization.
Scheme 6
Scheme 6
Cyclization behavior of further functionalized precursors 10 and 12. (a) B(C6F5)3⋅H2O (1.1 equiv.), Et2O, r.t., 1 h; (b) B(C6F5)3 (7.5 mol%), toluene, r.t., 8.5 h.
Scheme 7
Scheme 7
Mechanistic proposal for the observed interrupted Nazarov cyclization leading to spiro compounds, and deuterium labelling studies in support of the proposal.
See this image and copyright information in PMC

References

    1. He W., Huang J., Sun X., Frontier A. J., J. Am. Chem. Soc. 2007, 129, 498–499. - PubMed
    1. Malona J. A., Cariou K., Frontier A. J., J. Am. Chem. Soc. 2009, 131, 7560–7561. - PMC - PubMed
    1. Shvartsbart A., Smith A. B., J. Am. Chem. Soc. 2014, 136, 870–873. - PMC - PubMed
    1. Que Y., Shao H., He H., Gao S., Angew. Chem. Int. Ed. 2020, 59, 7444–7449; - PubMed
    2. Angew. Chem. 2020, 132, 7514–7519;
    3. Angew. Chem. 2020, 132, 7514–7519;
    4. Angew. Chem. Int. Ed. 2020, 59, 7444–7449. - PubMed
    1. None

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