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


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.


  1. Wender, P. A. et al. Toward the ideal synthesis. New transition metal-catalyzed reactions inspired by novel medicinal leads. Pure Appl. Chem. 74, 25–31 (2002).

    CAS  Article  Google Scholar 

  2. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    CAS  Article  Google Scholar 

  3. Wender, P. A. & Miller, B. L. in Organic Synthesis: Theory and Applications (ed. Hudlicky, T.) 27–66 (JAI Press, 1993).

    Google Scholar 

  4. Tietze, L. F. & Modi, A. Multicomponent domino reactions for the synthesis of biologically active natural products and drugs. Med. Res. Rev. 20, 304–322 (2000).

    CAS  Article  Google Scholar 

  5. Clavier, H. & Pellissier, H. Recent developments in enantioselective metal-catalyzed domino reactions. Adv. Synth. Catal. 354, 3347–3403 (2012).

    CAS  Article  Google Scholar 

  6. Slobbe, P., Ruijter, E. & Orru, R. V. A. Recent applications of multicomponent reactions in medicinal chemistry. Med. Chem. Commun. 3, 1189–1218 (2012).

    CAS  Article  Google Scholar 

  7. Kang, T., Kim, W-Y., Yoon, Y., Kim, B. G. & Lee, H-Y. Tandem cycloaddition reactions of allenyl diazo compounds forming triquinanes via trimethylenemethane diyls. J. Am. Chem. Soc. 133, 18050–18053 (2011).

    CAS  Article  Google Scholar 

  8. Van der Heijden, G., Ruijter, E. & Orru, R. V. A. Efficiency, diversity, and complexity with multicomponent reactions. Synlett 24, 666–685 (2013).

    CAS  Article  Google Scholar 

  9. Hopf, H. & Sherburn, M. S. Dendralenes branch out: cross-conjugated oligoenes allow the rapid generation of molecular complexity. Angew. Chem. Int. Ed. 51, 2298–2338 (2012).

    CAS  Article  Google Scholar 

  10. Souweha, M. S., Enright, G. D. & Fallis, A. G. Vinigrol: a compact, diene-transmissive Diels–Alder strategy to the tricyclic core. Org. Lett. 9, 5163–5166 (2007).

    CAS  Article  Google Scholar 

  11. Gani, O. A. B. S. M. & Engh, R. A. Protein kinase inhibition of clinically important staurosporine analogues. Nat. Prod. Rep. 27, 489–498 (2010).

    CAS  Article  Google Scholar 

  12. Awuah, E. & Capretta, A. Development of methods for the synthesis of libraries of substituted maleimides and α,β-unsaturated-γ-butyrolactams. J. Org. Chem. 76, 3122–3130 (2011).

    CAS  Article  Google Scholar 

  13. Tanramluk, D., Schreyer, A., Pitt, W. R. & Blundell, T. L. On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine. Chem. Biol. Drug Des. 74, 16–24 (2009).

    CAS  Article  Google Scholar 

  14. Chae, H. J. et al. Molecular mechanism of staurosporine-induced apoptosis in osteoblasts. Pharmacol. Res. Off. J. Ital. Pharmacol. Soc. 42, 373–381 (2000).

    CAS  Google Scholar 

  15. Omura, S. et al. A new alkaloid AM-2282 of Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. (Tokyo) 30, 275–282 (1977).

    CAS  Article  Google Scholar 

  16. Angus, R. O. Jr & Johnson, R. P. Butatriene cycloaddition equivalent approach to the multiple linear homologation of six-membered rings and the synthesis of benzocyclobutenes. J. Org. Chem. 48, 273–276 (1983).

    CAS  Article  Google Scholar 

  17. Hojo, M., Tomita, K., Hirohara, Y. & Hosomi, A. New access to di-exo-methylenecyclobutanes via [2+2] cycloaddition of 3-methylthio-4-trimethylsilyl-1,2-butadiene with alkenes mediated by a Lewis acid. Tetrahedron Lett. 34, 8123–8126 (1993).

    CAS  Article  Google Scholar 

  18. Hojo, M., Murakami, C., Nakamura, S. & Hosomi, A. Allenylmethylsilane derivative as a synthetic equivalent of 1,2,3-butatriene: synthesis and reactions of di-exo-methylenecyclobutanes and -cyclobutenes. Chem. Lett. 27, 331–332 (1998).

    Article  Google Scholar 

  19. Hojo, M., Tomita, K. & Hosomi, A. Synthesis and reactions of methyl (trimethylsilylmethyl)-acetylenecarboxylate. A general method for the generation of di-exo-methyleneisoxazolines and novel access to fused isoxazoles. Tetrahedron Lett. 34, 485–488 (1993).

    CAS  Article  Google Scholar 

  20. Leroyer, L., Maraval, V. & Chauvin, R. Synthesis of the butatriene C4 function: methodology and applications. Chem. Rev. 112, 1310–1343 (2012).

    CAS  Article  Google Scholar 

  21. Schubert, W. M., Liddicoet, T. H. & Lanka, W. A. The synthesis of butatriene. J. Am. Chem. Soc. 74, 569–569 (1952).

    CAS  Article  Google Scholar 

  22. Chow, H-F., Cao, X-P. & Leung, M. Facile synthesis of alkyl and aryl substituted 1,2,3-butatrienes. J. Chem. Soc. Chem. Commun. 2121–2122 (1994).

  23. Wang, K. K., Liu, B. & Lu, Y. Facile synthesis of [3]cumulenes via 1,4-elimination of hydroxytrimethylsilane from 4-(trimethylsilyl)-2-butyn-1-ols. J. Org. Chem. 60, 1885–1887 (1995).

    CAS  Article  Google Scholar 

  24. Malkov, A. V. et al. A novel bifunctional allyldisilane as a triple allylation reagent in the stereoselective synthesis of trisubstituted tetrahydrofurans. Chem. Eur. J. 17, 7162–7166 (2011).

    CAS  Article  Google Scholar 

  25. Jervis, P. J., Kariuki, B. M. & Cox, L. R. Stereoselective synthesis of 2,4,5-trisubstituted tetrahydropyrans using an intramolecular allylation strategy. Org. Lett. 8, 4649–4652 (2006).

    CAS  Article  Google Scholar 

  26. Chiu, S. K. & Peterson, P. E. The preparation of propargyltrimethylsilanes. Tetrahedron Lett. 21, 4047–4050 (1980).

    CAS  Article  Google Scholar 

  27. Tong, R. et al. Total syntheses of durgamone, nakorone, and abudinol B via biomimetic oxa- and carbacyclizations. J. Am. Chem. Soc. 129, 1050–1051 (2007).

    CAS  Article  Google Scholar 

  28. Ambasht, S., Chiu, S. K., Peterson, P. E. & Queen, J. Preparation of trimethylsilylmethyl derivatives using phase transfer methods. Synthesis 1980, 318–320 (1980).

    Article  Google Scholar 

  29. Wein, A. N., Tong, R. & McDonald, F. E. An economical synthesis of 4-trimethylsilyl-2-butyn-1-ol. Org. Synth. 88, 296–308 (2011).

    CAS  Article  Google Scholar 

  30. Fleming, I., Morgan, I. T. & Sarkar, A. K. The stereochemistry of the vinylogous Peterson elimination. J. Chem. Soc. Perkin Trans. 1 2749–2764 (1998).

  31. Harmata, M. & Bohnert, G. J. A 4+3 cycloaddition approach to the synthesis of (±)-sterpurene. Org. Lett. 5, 59–61 (2003).

    CAS  Article  Google Scholar 

  32. Angell, R., Parsons, P. J., Naylor, A. & Tyrrell, E. An extremely mild method for the construction of E-1,3-dienes. Synlett 1992, 599–600 (1992).

    Article  Google Scholar 

  33. Takano, S., Otaki, S. & Ogasawara, K. A Facile synthesis of the substituted tetrahydronapthalenes by the benzo-Peterson reaction. Heterocycles 23, 2811–2814 (1985).

    CAS  Article  Google Scholar 

  34. Takano, S., Sato, N., Otaki, S. & Ogasawara, K. The total synthesis of (±)-sikkimotoxin via the benzo-Peterson reaction. Heterocycles 25, 69–73 (1987).

    CAS  Article  Google Scholar 

  35. Takano, S., Otaki, S. & Ogasawara, K. Stereocontrolled synthesis of (±)-deoxypodophyllotoxin via the benzyl equivalent of the Peterson reaction. J. Chem. Soc. Chem. Commun. 485–487 (1985).

  36. Angoh, A. G. & Clive, D. L. J. A synthetic equivalent for the butadienyl carbonium ion: use of 4-(trimethylsilyl)but-2-ynal for preparation of 1,3-dienes and macroexpansion of cyclic ketones. J. Chem. Soc. Chem. Commun. 534–536 (1984).

  37. Ahmed, M., Atkinson, C. E., Barrett, A. G. M., Malagu, K. & Procopiou, P. A. Synthesis of C-19-functionalized 1α-hydroxyvitamin D2 analogues via ring-closing metathesis. Org. Lett. 5, 669–672 (2003).

    CAS  Article  Google Scholar 

  38. Wender, P. A. & Williams, T. J. [(arene)Rh(cod)]+ complexes as catalysts for [5+2] cycloaddition reactions. Angew. Chem. Int. Ed. 41, 4550–4553 (2002).

    CAS  Article  Google Scholar 

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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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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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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).

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