Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres

Nature Chemistry volume 6, pages 47–51 (2014)Cite this article

Subjects

Abstract

The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables the single-step construction of three contiguous stereocentres, including vicinal all-carbon quaternary stereocentres, in a five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple bond-forming events, and provides a reliable catalytic process for the asymmetric synthesis of densely functionalized pyrrolidines.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of stereoselective construction of contiguous all-carbon quaternary stereocentres.
Figure 2: Examinations of individual absolute stereocontrol.
Figure 3: [3+2] cycloaddition of oxazolidinone and nitroacrylate.
Figure 4: Synthetic versatility of the present catalytic system.

Similar content being viewed by others

References

  1. Peterson, E. A. & Overman, L. E. Natural product synthesis special feature. Proc. Natl Acad. Sci. USA 101, 11943–11948 (2004).

    CAS  PubMed  Google Scholar 

  2. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon quaternary stereocenters. Synthesis 369–396 (2006).

  3. Hawner, C. & Alexakis, A. Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters. Chem. Commun. 46, 7295–7306 (2010).

    CAS  Google Scholar 

  4. Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).

    CAS  Google Scholar 

  5. Mitsunuma, H., Shibasaki, M., Kanai, M. & Matsunaga, S. Catalytic asymmetric total synthesis of chimonanthine, folicanthine, and calycanthine through double Michael reaction of bisoxindole. Angew. Chem. Int. Ed. 51, 5217–5221 (2012).

    CAS  Google Scholar 

  6. Trost, B. M. & Osipov, M. Palladium-catalysed asymmetric construction of vicinal all-carbon quaternary stereocenters and its application to the synthesis of cyclotryptamine alkaloids. Angew. Chem. Int. Ed. 52, 9176–9181 (2013).

    CAS  Google Scholar 

  7. Flynn, A. B. & Ogilvie, W. W. Stereocontrolled synthesis of tetrasubstituted olefins. Chem. Rev. 107, 4698–4745 (2007).

    CAS  Google Scholar 

  8. Fish, P. V. & Johnson, W. S. The first examples of nonenzymic, biomimetic polyene pentacyclizations. Total synthesis of the pentacyclic triterpenoid sophoradiol. J. Org. Chem. 59, 2324–2335 (1994).

    CAS  Google Scholar 

  9. Corey, E. J. & Lin, S. A short enantioselective total synthesis of dammarenediol II. J. Am. Chem. Soc. 118, 8765–8766 (1996).

    CAS  Google Scholar 

  10. Gilbert, J. C. & Selliah, R. D. Enantioselective synthesis of (−)-trichodiene. J. Org. Chem. 58, 6255–6265 (1993).

    CAS  Google Scholar 

  11. Lemieux, R. M. & Meyers, A. I. Asymmetric synthesis of (−)-trichodiene. Generation of vicinal stereogenic quaternary centers via the thio-Claisen rearrangement. J. Am. Chem. Soc. 120, 5453–5457 (1998).

    CAS  Google Scholar 

  12. Gu, Z., Herrmann, A. T., Stivala, C. E. & Zakarian, A. Stereoselective construction of adjacent quaternary chiral centers by the Ireland–Claisen rearrangement: stereoselection with esters of cyclic alcohols. Synlett. 1717–1722 (2010).

  13. Shimizu, Y., Shi, S-L., Usuda, H., Kanai, M. & Shibasaki, M. Catalytic asymmetric total synthesis of ent-hyperforin. Angew. Chem. Int. Ed. 49, 1103–1106 (2010).

    CAS  Google Scholar 

  14. Uyeda, C., Rötheli, A. R. & Jacobsen, E. N. Catalytic enantioselective Claisen rearrangements of O-allyl β-ketoesters. Angew. Chem. Int. Ed. 49, 9753–9756 (2010).

    CAS  Google Scholar 

  15. Stafford, J. A. & Heathcock, C. H. Daphniphyllum alkaloids. Part 8. Asymmetric total synthesis of (−)-secodaphniphylline. J. Org. Chem. 55, 5433–5434 (1990).

    CAS  Google Scholar 

  16. Doyle, M. P., Zhou, Q-L., Charnsangavej, C. & Longoria, M. A. Chiral catalysts for enantioselective intermolecular cyclopropanation reactions with methyl phenyldiazoacetate. Origin of the solvent effect in reactions catalyzed by homochiral dirhodium(II) prolinates. Tetrahedron Lett. 37, 4129–4132 (1996).

    CAS  Google Scholar 

  17. Gao, L., Hwang, G-S. & Ryu, D. H. Oxazaborolidinium ion-catalysed cyclopropanation of α-substituted acroleins: enantioselective synthesis of cyclopropanes bearing two chiral quaternary centers. J. Am. Chem. Soc. 133, 20708–20711 (2011).

    CAS  PubMed  Google Scholar 

  18. Cao, Z-Y. et al. Highly stereoselective olefin cyclopropanation of diazooxindoles catalyzed by a C2-symmetric spiroketal bisphosphine/Au(I) complex. J. Am. Chem. Soc. 135, 8197–8200 (2013).

    CAS  PubMed  Google Scholar 

  19. Payette, J. N. & Yamamoto, H. Regioselective and asymmetric Diels–Alder reaction of 1- and 2-substituted cyclopentadienes catalysed by a Brønsted acid activated chiral oxazaborolidine. J. Am. Chem. Soc. 129, 9536–9537 (2007).

    CAS  PubMed  Google Scholar 

  20. Trost, B. M., Cramer, N. & Silverman, S. M. Enantioselective construction of spirocyclic oxindolic cyclopentanes by palladium-catalyzed trimethylenemethane-[3+2]-cycloaddition. J. Am. Chem. Soc. 129, 12396–12397 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, H., Hong, L., Kang, H. & Wang, R. Construction of vicinal all-carbon quaternary stereocenters by catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles: total synthesis of (+)-perophoramidine. J. Am. Chem. Soc. 135, 14098–14101 (2013).

    CAS  PubMed  Google Scholar 

  22. Lautens, M., Klute, W. & Tam, W. Transition metal-mediated cycloaddition reactions. Chem. Rev. 96, 49–92 (1996).

    CAS  PubMed  Google Scholar 

  23. Frühauf, H-W. Metal-assisted cycloaddition reactions in organotransition metal chemistry. Chem. Rev. 97, 523–596 (1997).

    PubMed  Google Scholar 

  24. Kobayashi, S. & Jorgensen, K. A. (eds) Cycloaddition Reactions in Organic Synthesis (Wiley, 2002).

    Google Scholar 

  25. Wang, C. & Tunge, J. A. Asymmetric cycloadditions of palladium-polarized aza-o-xylylenes. J. Am. Chem. Soc. 130, 8118–8119 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Trost, B. M. & Silverman, S. M. Enantioselective construction of pyrrolidines by palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethane with imines. J. Am. Chem. Soc. 134, 4941–4954 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Shintani, R., Park, S., Shirozu, F., Murakami M. & Hayashi, T. Palladium-catalyzed asymmetric decarboxylative lactamization of γ-methylidene-δ-valerolactones with isocyanates: conversion of racemic lactones to enantioenriched lactams. J. Am. Chem. Soc. 130, 16174–16175 (2008).

    CAS  PubMed  Google Scholar 

  28. Trost, B. M., Lam, T. M. & Herbage, M. A. Regio- and enantioselective synthesis of pyrrolidines bearing a quaternary center by palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethanes. J. Am. Chem. Soc. 135, 2459–2461 (2013).

    CAS  PubMed  Google Scholar 

  29. Trost, B. M., Morris, P. J. & Sprague, S. J. Palladium-catalyzed diastereo- and enantioselective formal [3+2]-cycloadditions of substituted vinylcyclopropanes. J. Am. Chem. Soc. 134, 17823–17831 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Du, C., Li, L., Li, Y. & Xie, Z. Construction of two vicinal quaternary carbons by asymmetric allylic alkylation: total synthesis of hyperolactone C and (−)-biyouyanagin A. Angew. Chem. Int. Ed. 48, 7853–7856 (2009).

    CAS  Google Scholar 

  31. Trost, B. M. & Fandrick, D. R. Palladium-catalyzed dynamic kinetic asymmetric allylic alkylation with the DPPBA ligands. Aldrichimica Acta 40, 59–72 (2007).

    CAS  Google Scholar 

  32. Ohmatsu, K., Ito, M., Kunieda, T. & Ooi, T. Ion-paired chiral ligands for asymmetric palladium catalysis. Nature Chem. 4, 473–477 (2012).

    CAS  Google Scholar 

  33. Ohmatsu, K., Ito, M., Kunieda, T. & Ooi, T. Exploiting the modularity of ion-paired chiral ligands for palladium-catalyzed enantioselective allylation of benzofuran-2(3H)-ones. J. Am. Chem. Soc. 135, 590–593 (2013).

    CAS  PubMed  Google Scholar 

  34. Aoyagi, K., Nakamura, H. & Yamamoto, Y. Palladium-catalyzed aminoallylation of activated olefins with allylic halides and phthalimide. J. Org. Chem. 67, 5977–5980 (2002).

    CAS  PubMed  Google Scholar 

  35. Knight, J. G., Stoker, P. A., Tchabanenko, K., Harwood, S. J. & Lawrie, K. W. M. Synthesis of highly substituted pyrrolidines via palladium-catalyzed cyclization of 5-vinyloxazolidinones and activated alkenes. Tetrahedron 64, 3744–3750 (2008).

    CAS  Google Scholar 

  36. Lowe, M. A. et al. Palladium-mediated annulation of vinyl aziridines with Michael acceptors: stereocontrolled synthesis of substituted pyrrolidines and its application in a formal synthesis of (−)-α-kainic acid. Angew. Chem. Int. Ed. 50, 6370–6374 (2011).

    CAS  Google Scholar 

  37. O'Hagan, D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nat. Prod. Rep. 17, 435–446 (2000).

    CAS  PubMed  Google Scholar 

  38. Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 22, 603–626 (2005).

    CAS  PubMed  Google Scholar 

  39. Blanco-Ania, D. et al. Synthesis of dihydrouracils spiro-fused to pyrrolidines: druglike molecules based on the 2-arylethyl amine scaffold. Molecules 15, 2269–2301 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fagnou, K. & Lautens, M. Halide effects in transition metal catalysis. Angew. Chem. Int. Ed. 41, 26–47 (2002).

    CAS  Google Scholar 

  41. Ooi, T., Kameda, M. & Maruoka, K. Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts: synthesis and application to practical asymmetric synthesis of α-amino acids. J. Am. Chem. Soc. 125, 5139–5151 (2003).

    CAS  PubMed  Google Scholar 

  42. Kan, T. & Fukuyama, T. Ns strategies: a highly versatile synthetic method for amines. Chem. Commun. 353–359 (2004).

  43. Schärer, K., Morgenthaler, M., Seiler, P. & Diederich, F. Enantiomerically pure thrombin inhibitors for exploring the molecular-recognition features of the oxyanion hole. Helv. Chim. Acta 87, 2517–2538 (2004).

    Google Scholar 

  44. Fokkens, J. & Klebe, G. A simple protocol to estimate differences in protein binding affinity for enantiomers without prior resolution of racemates. Angew. Chem. Int. Ed. 45, 985–989 (2006).

    CAS  Google Scholar 

  45. Nicolotti, O. et al. Screening of benzamidine-based thrombin inhibitors via a linear interaction energy in continuum electrostatics model. J. Comput. Aided Mol. Des. 24, 117–129 (2010).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to Professor Keiji Maruoka on the occasion of his 60th birthday. Financial support was provided by NEXT program, the Program for Leading Graduate Schools ‘Integrative Graduate Education and Research Program in Green Natural Sciences’ in Nagoya University, and the Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, 464-8602, Japan

    Kohsuke Ohmatsu & Takashi Ooi

  2. Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan

    Kohsuke Ohmatsu, Naomichi Imagawa & Takashi Ooi

Authors
  1. Kohsuke Ohmatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naomichi Imagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Ooi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.O. and T.O. conceived and designed the study, and co-wrote the paper. K.O. and N.I. performed the experiments, and analysed the data. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Takashi Ooi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2819 kb)

Supplementary information

Crystallographic data for compound 11a (CIF 30 kb)

Supplementary information

Crystallographic data for compound 11j (CIF 15 kb)

Supplementary information

Crystallographic data for compound 13 (CIF 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohmatsu, K., Imagawa, N. & Ooi, T. Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres. Nature Chem 6, 47–51 (2014). https://doi.org/10.1038/nchem.1796

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1796

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing