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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 448–452 (2014)Cite this article

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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.

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Figure 1: Retrosynthetic analysis of staurosporine analogues based on butatriene-enabled cycloadditions.
Figure 2: General depiction of the [5 + 2] cycloaddition/vinylogous Peterson elimination/[4 + 2] cycloaddition cascade and mechanistic possibilities.

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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

  1. Dennis N. Fournogerakis, Matthew S. Jeffreys and Ryan V. Quiroz: These authors contributed equally to this work

Authors and Affiliations

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

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Correspondence to Paul A. Wender.

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The authors declare no competing financial interests.

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Wender, P., Fournogerakis, D., Jeffreys, M. et al. Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents. Nature Chem 6, 448–452 (2014). https://doi.org/10.1038/nchem.1917

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