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Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents

Nature Chemistry volume 6, pages 448452 (2014) | Download Citation

Abstract

Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C≡CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to-diene transmissive reagent coupling two powerful and convergent cycloadditions—the homologous Diels–Alder and Diels–Alder cycloadditions—through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles.

  • Compound C8H14O2

    1-(2-Methoxyethoxy)-1-vinylcyclopropane

  • Compound C7H14OSi

    4-(Trimethylsily)but-2-yn-1-ol

  • Compound C9H12O

    4,5-Dimethylenecycloheptan-1-one

  • Compound C14H22OSi

    2-(Trimethylsilyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C15H22O3

    2,3-Bis(methoxymethyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C14H18O3

    Methyl 3-methyl-7-oxo-4,5,6,7,8,9-hexahydro-1H-benzo[7]annulene-2-carboxylate

  • Compound C15H18O5

    Dimethyl 7-oxo-4,5,6,7,8,9-hexahydro-1H-benzo[7]annulene-2,3-dicarboxylate

  • Compound C15H22O

    2-Butyl-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C18H20O

    2-Benzyl-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C19H23NO3S

    4-Methyl-N-((7-oxo-4,5,6,7,8,9-hexahydro-1H-benzo[7]annulen-2-yl)methyl)benzenesulfonamide

  • Compound C17H18O

    2-Phenyl-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C18H20O

    2-(o-Tolyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C17H17FO

    2-(3-Fluorophenyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C19H20O2

    2-(4-Acetylphenyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C17H17BrO

    2-(4-Bromophenyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C18H20O2

    2-(4-Methoxyphenyl)-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

  • Compound C24H27NO3

    tert-Butyl 5-(7-oxo-4,5,6,7,8,9-hexahydro-1H-benzo[7]annulen-2-yl)-1H-indole-1-carboxylate

  • Compound C13H14O4

    Cis-3a,4,5,6,8,9,10,10a-octahydro-1H-cyclohepta[f]isobenzofuran-1,3,7-trione

  • Compound C13H15NO3

    3a,4,5,6,8,9,10,10a-Octahydrocyclohepta[f]isoindole-1,3,7(2H)-trione

  • Compound C15H20O5

    Dimethyl 7-oxo-2,3,4,5,6,7,8,9-octahydro-1H-benzo[7]annulene-trans-2,3-dicarboxylate

  • Compound C15H20O5

    Dimethyl 7-oxo-2,3,4,5,6,7,8,9-octahydro-1H-benzo[7]annulene-cis-2,3-dicarboxylate

  • Compound C13H18O3

    Methyl 7-oxo-2,3,4,5,6,7,8,9-octahydro-1H-benzo[7]annulene-2-carboxylate

  • Compound C19H18O3

    Cis-5a,6,7,8,10,11,12,12a-octahydro-5H-cyclohepta[b]anthracene-5,9,13-trione

  • Compound C17H17N3O3

    2-Phenyl-5,6,7,9,10,11-hexahydro-1H,8H-cyclohepta[d][1,2,4]triazolo[1,2-a]pyridazine-1,3,8(2H)-trione

  • Compound C15H16O5

    Dimethyl 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2,3-dicarboxylate

  • Compound C19H14O3

    7,8,10,11-Tetrahydro-5H-cyclohepta[b]anthracene-5,9,13-trione

  • Compound C15H12O3

    6,7,9,10-Tetrahydro-1H-cyclohepta[b]naphthalene-1,4,8-trione

  • Compound C12H24OSi

    tert-Butyldimethyl(1-(prop-1-en-2-yl)cyclopropoxy)silane

  • Compound C14H17NO3

    6-Methyl-cis-3a,4,5,6,8,9,10,10a-octahydrocyclohepta[f]isoindole-1,3,7(2H)-trione

  • Compound C8H16OSi

    5-(Trimethylsilyl)pent-3-yn-2-ol

  • Compound C16H20O5

    Dimethyl 1-methyl-7-oxo-4,5,6,7,8,9-hexahydro-1H-benzo[7]annulene-2,3-dicarboxylate

  • Compound C19H22O

    3-Benzyl-1-methyl-1,4,5,6,8,9-hexahydro-7H-benzo[7]annulen-7-one

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Acknowledgements

This research was supported by the National Science Foundation (NSF, CHE1265956) and the National Institutes of Health (CA031841). Additional funding was provided by the NSF Graduate Research Fellowship (R.V.Q.), an Abbott Laboratories Stanford Graduate Fellowship (M.S.J.), Kanazawa University (F.I.) and the German Academic Exchange Service (M.P.).

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Author notes

    • Dennis N. Fournogerakis
    • , Matthew S. Jeffreys
    •  & Ryan V. Quiroz

    These authors contributed equally to this work

Affiliations

  1. Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080, USA

    • Paul A. Wender
    • , Dennis N. Fournogerakis
    • , Matthew S. Jeffreys
    • , Ryan V. Quiroz
    • , Fuyuhiko Inagaki
    •  & Magnus Pfaffenbach

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Contributions

P.A.W. conceived the study. F.I. and M.P. performed the initial syntheses of butynols and evaluated the initial viability of [5 + 2] and [5 + 2]/[4 + 2] reactions. D.N.F., M.S.J. and R.V.Q. determined the substrate profile and performed the synthesis and characterization of all reported compounds. M.S.J., R.V.Q. and P.A.W. wrote the paper. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul A. Wender.

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DOI

https://doi.org/10.1038/nchem.1917

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