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Direct and highly regioselective and enantioselective allylation of β-diketones


The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem1,2,3,4,5,6,7,8, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Brønsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones.

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Figure 1: Origin and evolution of a proposal for a direct, enantioselective and regioselective allylation of β-diketones.
Figure 2: Reaction design and proof of concept.
Figure 3: Scope of the regio- and enantioselective allylation of β-diketones.
Figure 4: Regio-, diastereo- and enantioselective crotylation of β-diketones.
Figure 5: General mechanism and origin of regioselectivity.

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Data deposits

X-ray crystallographic data have been deposited in the Cambridge Crystallographic Data Centre database ( under accession code CCDC 874744.


  1. Nakamura, M., Hirai, A., Sogi, M. & Nakamura, E. Enantioselective addition of allylzinc reagent to alkynyl ketones. J. Am. Chem. Soc. 120, 5846–5847 (1998)

    Article  CAS  Google Scholar 

  2. Waltz, K. M., Gavenonis, J. & Walsh, P. J. A simple, reliable, catalytic asymmetric allylation of ketones. Angew. Chem. Int. Edn 41, 3697–3699 (2002)

    Article  CAS  Google Scholar 

  3. Wu, T. R., Shen, L. & Chong, J. M. Asymmetric allylboration of aldehydes and ketones using 3,3′-disubstitutedbinaphthol-modified boronates. Org. Lett. 6, 2701–2704 (2004)

    Article  CAS  Google Scholar 

  4. Canales, E., Prasad, K. G. & Soderquist, J. A. B-Allyl-10-Ph-9-borabicyclo[3.3.2]decanes: strategically designed for the asymmetric allylboration of ketones. J. Am. Chem. Soc. 127, 11572–11573 (2005)

    Article  CAS  Google Scholar 

  5. Wadamoto, M. & Yamamoto, H. Silver-catalyzed asymmetric Sakurai–Hosomi allylation of ketones. J. Am. Chem. Soc. 127, 14556–14557 (2005)

    Article  CAS  Google Scholar 

  6. Miller, J. J. & Sigman, M. S. Design and synthesis of modular oxazoline ligands for the enantioselective chromium-catalyzed addition of allyl bromide to ketones. J. Am. Chem. Soc. 129, 2752–2753 (2007)

    Article  CAS  Google Scholar 

  7. Barnett, D. S., Moquist, P. N. & Schaus, S. E. The mechanism and an improved asymmetric allylboration of ketones catalyzed by chiral biphenols. Angew. Chem. Int. Edn 48, 8679–8682 (2009)

    Article  CAS  Google Scholar 

  8. Shi, S.-L., Xu, L.-W., Oisaki, K., Kanai, M. & Shibasaki, M. Identification of modular chiral bisphosphines effective for Cu(I)-catalyzed asymmetric allylation and propargylation of ketones. J. Am. Chem. Soc. 132, 6638–6639 (2010)

    Article  CAS  Google Scholar 

  9. Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-butanesulfinimide. Chem. Rev. 110, 3600–3740 (2010)

    Article  CAS  Google Scholar 

  10. Pettit, G. R. et al. Isolation and structure of spongistatin 1. J. Org. Chem. 58, 1302–1304 (1993)

    Article  CAS  Google Scholar 

  11. Fusetani, N., Shinoda, K. & Matsunaga, S. Cinachyrolide A: a potent cytotoxic macrolide possessing two spiro ketals from marine sponge Cinachyra sp. J. Am. Chem. Soc. 115, 3977–3981 (1993)

    Article  CAS  Google Scholar 

  12. Kobayashi, M. et al. Altohyrtin A, a potent anti-tumor macrolide from the Okinawan marine sponge Hyrtios altum . Tetrahedr. Lett. 34, 2795–2798 (1993)

    Article  CAS  Google Scholar 

  13. Gaich, T. & Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673 (2010)

    Article  CAS  Google Scholar 

  14. Deng, D.-L. & Lu, Z.-H. Monoallylation of symmetric diketones in the presence of water by allylic bromide and metallic zinc. Chin. Chem. Lett. 5, 173–176 (1994)

    CAS  Google Scholar 

  15. Kira, M., Sato, K., Sekimoto, K., Gewald, R. & Sakurai, H. Stereoselective allylation of β-hydroxy- and β-amino-α,β-enones with allyltrifluorosilane/triethylamine systems. Chem. Lett. 1995, 281–282 (1995)

    Article  Google Scholar 

  16. Marton, D., Stivanello, D. & Tagliavini, G. Allylstannation of α-, β- and γ-diketones mediated by allylbutyltin halides: Bu2(CH2 = CHCH2)SnCl and Bu(CH2 = CHCH2)SnCl2 . J. Organomet. Chem. 540, 77–81 (1997)

    Article  CAS  Google Scholar 

  17. Leighton, J. L. Powerful and versatile silicon Lewis acids for asymmetric chemical synthesis. Aldrichim. Acta 43, 3–12 (2010)

    CAS  Google Scholar 

  18. Kim, H., Ho, S. & Leighton, J. L. A more comprehensive and highly practical solution to enantioselective aldehyde crotylation. J. Am. Chem. Soc. 133, 6517–6520 (2011)

    Article  CAS  Google Scholar 

  19. Burns, N. Z., Hackman, B. M., Ng, P. Y., Powelson, I. A. & Leighton, J. L. The enantioselective allylation and crotylation of sterically hindered and functionalized aryl ketones: convenient access to unusual tertiary carbinol structures. Angew. Chem. Int. Edn 45, 3811–3813 (2006)

    Article  CAS  Google Scholar 

  20. Hackman, B. M., Lombardi, P. J. & Leighton, J. L. Highly diastereo- and enantioselective reagents for aldehyde crotylation. Org. Lett. 6, 4375–4377 (2004)

    Article  CAS  Google Scholar 

  21. Spletstoser, J. T., Zacuto, M. J. & Leighton, J. L. Tandem silylformylation–crotylsilylation/Tamao oxidation of internal alkynes: a remarkable example of generating complexity from simplicity. Org. Lett. 10, 5593–5596 (2008)

    Article  CAS  Google Scholar 

  22. Pinnavaia, T. J., Collins, W. T. & Howe, J. J. Triorganosilicon acetylacetonates. Enol ether isomerism and stereochemical lability. J. Am. Chem. Soc. 92, 4544–4550 (1970)

    Article  CAS  Google Scholar 

  23. Reich, H. J. & Murcia, D. A. Stereochemical studies of degenerate silyl rearrangements. Stereospecificity of the tropolone and acetylacetone trialkylsilyl ether rearrangements. J. Am. Chem. Soc. 95, 3418–3420 (1973)

    Article  CAS  Google Scholar 

  24. Pinnavaia, T. J. & McClarin, J. A. Rearrangements of 1-acetylacetonato-1-methyl-1-silacyclobutane via internal nucleophilic displacement. J. Am. Chem. Soc. 96, 3012–3013 (1974)

    Article  CAS  Google Scholar 

  25. McClarin, J. A., Schwartz, A. & Pinnavaia, T. J. 1,5-Migrations of silicon between oxygen centers in silyl β-diketones. J. Organomet. Chem. 188, 129–139 (1980)

    Article  CAS  Google Scholar 

  26. Seeman, J. I. Effect of conformational change on reactivity in organic chemistry. Evaluations, applications, and extensions of Curtin–Hammett Winstein–Holness kinetics. Chem. Rev. 83, 83–134 (1983)

    Article  CAS  Google Scholar 

  27. Mirarchi, D. & Ritchie, G. L. D. Solution-state conformations of 2-fluoro-, 2-chloro- and 2-bromo-acetophenone: a diploe moment and Kerr effect study. J. Mol. Struct. 118, 303–310 (1984)

    Article  ADS  CAS  Google Scholar 

  28. Kulhánek, J., Böhm, S., Palát, K., Jr & Exner, O. Steric inhibition of resonance: revision of the principle on the electronic spectra of methyl-substituted acetophenones. J. Phys. Org. Chem. 17, 686–693 (2004)

    Article  Google Scholar 

  29. Cheng, C. L. & Ritchie, G. L. D. Conformations of the formyl-, acetyl-, and benzoyl-pyridines. J. Chem. Soc. 2, 1461–1465 (1973)

    Google Scholar 

  30. Ramachandran, P. V., Gong, B., Brown, H. C. & Francisco, J. S. Relationship between the structure and enantioselectivity in the asymmetric reduction of 2’,6’-disubstituted acetophenones with DIP-chlorideTM. An ab initio study. Tetrahedr. Lett. 45, 2603–2605 (2004)

    Article  CAS  Google Scholar 

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This work was supported by a grant from the National Institute of General Medical Sciences (GM58133). W.A.C. was supported by a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship. We thank the US National Science Foundation (CRIF-0840451) for acquisition of a 400 MHz NMR spectrometer. We thank our colleagues G. Parkin and W. Sattler for an X-ray structure analysis (see the Supplementary Information), and the US National Science Foundation (CHE-0619638) for acquisition of an X-ray diffractometer.

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W.A.C. planned and did the vast majority of the experimental work. S.K.R. did the experiments that established the validity of the idea and optimized the allylation of acetylacetone. J.L.L. conceived and directed the project and wrote the manuscript.

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Correspondence to James L. Leighton.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-80, Supplementary Methods, Supplementary Table 1, and Supplementary References. (PDF 14180 kb)

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Chalifoux, W., Reznik, S. & Leighton, J. Direct and highly regioselective and enantioselective allylation of β-diketones. Nature 487, 86–89 (2012).

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