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:

Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

Nature Chemistry volume 4, pages 130–133 (2012)Cite this article

Subjects

Abstract

The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.

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: Natural products and pharmaceuticals containing chiral N-heterocycles.
Figure 2: Solvent, N-substituent-group and ligand screen.
Figure 3: Scope of palladium-catalysed decarboxylative alkylation of lactams.
Figure 4: Utility of the lactam products.

Similar content being viewed by others

References

  1. Cordell, G. A. (ed.) in Alkaloids Vol. 69 (Academic Press, 2010).

  2. Joule, J. A. & Mills, K. in Heterocyclic Chemistry, 5th edn (Wiley, 2010).

    Google Scholar 

  3. Anton, A. & Baird, B. R. in Kirk–Othmer Encyclopedia of Chemical Technology Vol. 19, 5th edn, 739–772 (Wiley, 2006).

  4. Schlack, P. Polymerizable lactams. Pure Appl. Chem. 15, 507–523 (1967).

    Article  CAS  Google Scholar 

  5. Kohan, M. I. (ed.) in Plastics (Interscience, 1973).

    Google Scholar 

  6. Groaning, M. D. & Meyers, A. I. Chiral Non-racemic bicyclic lactams. Auxiliary-based asymmetric reactions. Tetrahedron 56, 9843–9873 (2000).

    Article  CAS  Google Scholar 

  7. Enders, D., Teschner, P., Raabe, G. & Runsink, J. Asymmetric electrophilic substitutions at the α-position of γ- and δ-lactams. Eur. J. Org. Chem. 4463–4477 (2001).

  8. Amat, M., Lozano, O., Escolano, C., Molins, E. & Bosch, J. Enantioselective synthesis of 3,3-disubstituted piperidine derivatives by enolate dialkylation of phenylglycinol-derived oxazolopiperidone lactams. J. Org. Chem. 72, 4431–4439 (2007).

    Article  CAS  Google Scholar 

  9. Trost, B. M. & Brennan, M. K. Asymmetric syntheses of oxindole and indole spirocyclic alkaloid natural products. Synthesis 3003–3025 (2009).

  10. Badillo, J. J., Hanhan, N. V. & Franz, A. K. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery. Curr. Opin. Drug Discov. Dev. 13, 758–776 (2010).

    CAS  Google Scholar 

  11. Zhou, F., Liu, Y.-L. & Zhou, J. Catalytic asymmetric synthesis of oxindoles bearing a tetrasubstituted stereocenter at the C-3 position. Adv. Synth. Catal. 352, 1381–1407 (2010).

    Article  CAS  Google Scholar 

  12. Ohmatsu, K., Kiyokawa, M. & Ooi, T. Chiral 1,2,3-triazoliums as new cationic organic catalysts with anion-recognition ability: application to asymmetric alkylation of oxindoles. J. Am. Chem. Soc. 133, 1307–1309 (2011).

    Article  CAS  Google Scholar 

  13. Franckevicius, V., Cuthbertson, J. D., Pickworth, M., Pugh, D. S. & Taylor, R. J. K. Asymmetric decarboxylative allylation of oxindoles. Org. Lett. 13, 4264–4267 (2011).

    Article  CAS  Google Scholar 

  14. Jakubec, P., Helliwell, M. & Dixon, D. J. Cyclic imine nitro-Mannich/lactamization cascades: a direct stereoselective synthesis of multicyclic piperidinone derivatives. Org. Lett. 10, 4267–4270 (2008).

    Article  CAS  Google Scholar 

  15. Moss, T. A., Alonso, B., Fenwick, D. R. & Dixon, D. J. Catalytic enantio- and diastereoselective alkylations with cyclic sulfamidates. Angew. Chem. Int. Ed. 49, 568–571 (2010).

    Article  CAS  Google Scholar 

  16. Trost, B. M. Asymmetric allylic alkylation, an enabling methodology. J. Org. Chem. 69, 5813–5837 (2004).

    Article  CAS  Google Scholar 

  17. Lu, Z. & Ma, S. Metal-catalyzed enantioselective allylation in asymmetric synthesis. Angew. Chem. Int. Ed. 47, 258–297 (2008).

    Article  CAS  Google Scholar 

  18. Mohr, J. T. & Stoltz, B. M. Enantioselective Tsuji allylations. Chem. Asian J. 2, 1476–1491 (2007).

    Article  CAS  Google Scholar 

  19. Weaver, J. D., Recio III, A., Grenning, A. J. & Tunge, J. A. Transition metal-catalyzed decarboxylative allylation and benzylation reactions. Chem. Rev. 111, 1846–1913 (2011).

    Article  CAS  Google Scholar 

  20. Behenna, D. C. & Stoltz, B. M. The enantioselective Tsuji allylation. J. Am. Chem. Soc. 126, 15044–15045 (2004).

    Article  CAS  Google Scholar 

  21. Mohr, J. T., Behenna, D. C., Harned, A. M. & Stoltz, B. M. Deracemization of quaternary stereocenters by Pd-catalyzed enantioconvergent decarboxylative allylation of racemic β-ketoesters. Angew. Chem. Int. Ed. 44, 6924–6927 (2005).

    Article  CAS  Google Scholar 

  22. Seto, M., Roizen, J. L. & Stoltz, B. M. Catalytic enantioselective alkylation of substituted dioxanone enol ethers: ready access to C(α)-tetrasubstituted hydroxyketones, acids, and esters. Angew. Chem. Int. Ed. 47, 6873–6876 (2008).

    Article  CAS  Google Scholar 

  23. Streuff, J., White, D. E., Virgil, S. C. & Stoltz, B. M. A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres. Nature Chem. 2, 192–196 (2010).

    Article  CAS  Google Scholar 

  24. McFadden, R. M. & Stoltz, B. M. The catalytic enantioselective, protecting group-free total synthesis of (+)-dichroanone. J. Am. Chem. Soc. 128, 7738–7739 (2006).

    Article  CAS  Google Scholar 

  25. White, D. E., Stewart, I. C., Grubbs, R. H. & Stoltz, B. M. The catalytic asymmetric total synthesis of elatol. J. Am. Chem. Soc. 130, 810–811 (2008).

    Article  CAS  Google Scholar 

  26. Enquist, J. A. Jr & Stoltz, B. M. The total synthesis of (–)-cyanthiwigin F via double catalytic enantioselective alkylation. Nature 453, 1228–1231 (2008).

    Article  CAS  Google Scholar 

  27. Day, J. J. et al. The catalytic enantioselective total synthesis of (+)-liphagal. Angew. Chem. Int. Ed. 50, 6814–6818 (2011).

    Article  CAS  Google Scholar 

  28. Trost, B. M. & Xu, J. Regio- and enantioselective Pd-catalyzed allylic alkylation of ketones through allyl enol carbonates. J. Am. Chem. Soc. 127, 2846–2847 (2005).

    Article  CAS  Google Scholar 

  29. Trost, B. M. & Xu, J. Palladium-catalyzed asymmetric allylic α-alkylation of acyclic ketones. J. Am. Chem. Soc. 127, 17180–17181 (2005).

    Article  CAS  Google Scholar 

  30. Trost, B. M., Bream, R. N. & Xu, J. Asymmetric allylic alkylation of cyclic vinylogous esters and thioesters by Pd-catalyzed decarboxylation of enol carbonate and β-ketoester substrates. Angew. Chem. Int. Ed. 45, 3109–3112 (2006).

    Article  CAS  Google Scholar 

  31. Trost, B. M., Xu, J. & Reichle, M. Enantioselective synthesis of α-tertiary hydroxyaldehydes by palladium-catalyzed asymmetric allylic alkylation of enolates. J. Am. Chem. Soc. 129, 282–283 (2007).

    Article  CAS  Google Scholar 

  32. Trost, B. M., Xu, J. & Schmidt, T. Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates. J. Am. Chem. Soc. 131, 18343–18357 (2009).

    Article  CAS  Google Scholar 

  33. Nakamura, M., Hajra, A., Endo, K. & Nakamura, E. Synthesis of chiral α-fluoroketones through catalytic enantioselective decarboxylation. Angew. Chem. Int. Ed. 44, 7248–7251 (2005).

    Article  CAS  Google Scholar 

  34. Burger, E. C., Barron, B. R. & Tunge, J. A. Catalytic asymmetric synthesis of cyclic α-allylated α-fluoroketones. Synlett. 2824–2826 (2006).

  35. Bélanger, É., Cantin, K., Messe, O., Tremblay, M. & Paquin, J-F. Enantioselective Pd-catalyzed allylation reaction of fluorinated silyl enol ethers. J. Am. Chem. Soc. 129, 1034–1035 (2007).

    Article  Google Scholar 

  36. Schulz, S. R. & Blechert, S. Palladium-catalyzed synthesis of substituted cycloheptane-1,4-diones by an asymmetric ring-expanding allylation (AREA). Angew. Chem. Int. Ed. 46, 3966–3970 (2007).

    Article  CAS  Google Scholar 

  37. McDougal, N. T., Virgil, S. C. & Stoltz, B. M. High-throughput screening of the asymmetric decarboxylative alkylation reaction of enolate-stabilized enol carbonates. Synlett. 1712–1716 (2010).

  38. Helmchen, G. & Pfaltz, A. Phosphinooxazolines—a new class of versatile, modular P,N-ligands for asymmetric catalysis. Acc. Chem. Res. 33, 336–345 (2000).

    Article  CAS  Google Scholar 

  39. Tani, K., Behenna, D. C., McFadden, R. M. & Stoltz, B. M. A facile and modular synthesis of phosphinooxazoline ligands. Org. Lett. 9, 2529–2531 (2007).

    Article  CAS  Google Scholar 

  40. McDougal, N. T., Streuff, J., Mukherjee, H., Virgil, S. C. & Stoltz, B. M. Rapid synthesis of an electron-deficient t-BuPHOX ligand: cross-coupling of aryl bromides with secondary phosphine oxides. Tetrahedron Lett. 51, 5550–5554 (2010).

    Article  CAS  Google Scholar 

  41. Edler, M. C. et al. Demonstration of microtubule-like structures formed with (–)-rhazinilam from purified tubulin outside of cells and a simple tubulin-based assay for evaluation of analog activity. Arch. Biochem. Biophys. 487, 98–104 (2009).

    Article  CAS  Google Scholar 

  42. Magnus, P. & Rainey, T. Concise synthesis of (±)-rhazinilam. Tetrahedron 57, 8647–8651 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This publication is based on work supported by award from the King Abdullah University of Science and Technology (KAUST; no. KUS-11-006-02). The authors thank NIH-NIGMS (R01GM080269-01 and a postdoctoral fellowship to D.E.W.), the Gordon and Betty Moore Foundation, Amgen, Abbott, Boehringer Ingelheim and Caltech for financial support. T.Y. acknowledges the Japan Society for the Promotion of Science for a predoctoral fellowship.

Author information

Authors and Affiliations

  1. Division of Chemistry and Chemical Engineering and The Caltech Center for Catalysis and Chemical Synthesis, The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, 91125, California, USA

    Douglas C. Behenna, Yiyang Liu, Taiga Yurino, Jimin Kim, David E. White, Scott C. Virgil & Brian M. Stoltz

Authors
  1. Douglas C. Behenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiyang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taiga Yurino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jimin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David E. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Scott C. Virgil
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Brian M. Stoltz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.C.B., Y.L., T.Y. and J.K. planned and carried out the experimental work. D.C.B., T.Y., D.E.W. and S.C.V. took part in the initial reaction development and screening experiments. B.M.S. conceived, initiated and directed the project and wrote the manuscript. All authors commented on the manuscript.

Corresponding author

Correspondence to Brian M. Stoltz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 11489 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Behenna, D., Liu, Y., Yurino, T. et al. Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams. Nature Chem 4, 130–133 (2012). https://doi.org/10.1038/nchem.1222

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1222

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