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:

Catalytic enantio- and diastereoselective domino halocyclization and spiroketalization

Nature Catalysis volume 3, pages 993–1001 (2020)Cite this article

Subjects

Abstract

Asymmetric domino electrophilic halocyclizations are highly useful in the synthesis of structurally complex and pharmaceutically important compounds. Although some studies aimed at catalytic and enantioselective polyene cyclizations are documented, the chiral products have been limited to fused rings. Here, we report an efficient and highly enantio- and diastereoselective halocyclization and spiroketalization of olefinic keto-acids. Instead of electron-deficient thiourea, in this study electron-rich thiourea catalysts are crucial for high enantioselectivity. The resulting spiro compounds are privileged cores of many drugs and natural products. Our experimental and computational studies revealed that the reaction proceeded via a double dynamic–kinetic resolution mechanism. We anticipate that this work will stimulate the synthesis of other multifunctional compounds via electrophilic halocyclization.

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

Fig. 1: Asymmetric domino halocyclization.
Fig. 2: Optimization of asymmetric halocyclization and spiroketalization of olefinic keto-acid.
Fig. 3: Substrate scope of stereoselective domino bromo- and iodocyclization–spiroketalization.
Fig. 4: Substrate scope of stereoselective domino chlorocyclization–spiroketalization.
Fig. 5: Enantio- and diastereoselective chlorocyclization–bis-spiroketalization of 5.
Fig. 6: Mechanistic study.
Fig. 7: DFT calculation for stereoselective domino bromocyclization–spiroketalization.

Similar content being viewed by others

Data availability

The findings of this study are available within the paper and its Supplementary Information. Crystallographic parameters for compounds 3a, 4a-Br, 5 and 6 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1978126 (3a), CCDC 1978123 (4a-Br), CCDC 1978125 (5) and 1978124 (6). All data are available from the authors upon reasonable request.

References

  1. Rodríguez, F. & Fañanás, F. J. in Handbook of Cyclization Reactions Vol. 2 (ed. Ma, S.) 951−990 (Wiley-VCH, 2010).

  2. Ranganathan, S., Muraleedharan, K. M., Vaish, N. K. & Jayaraman, N. Halo- and selenolactonisation: the two major strategies for cyclofunctionalisation. Tetrahedron 60, 5273–5308 (2004).

    CAS  Google Scholar 

  3. Chemler, S. R. & Bovino, M. T. Catalytic aminohalogenation of alkenes and alkynes. ACS Catal. 3, 1076–1091 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Neverov, A. A. & Brown, R. S. Br+ and I+ transfer from the halonium Ions of adamantylideneadamantane to acceptor olefins. Halocyclization of 1,ω-alkenols and alkenoic acids proceeds via reversibly formed intermediates. J. Org. Chem. 61, 962–968 (1996).

    CAS  Google Scholar 

  5. Denmark, S. E., Burk, M. T. & Hoover, A. J. On the absolute configurational stability of bromonium and chloronium ions. J. Am. Chem. Soc. 132, 1232–1233 (2010).

    CAS  PubMed  Google Scholar 

  6. Chen, G. & Ma, S. Enantioselective halocyclization reactions for the synthesis of chiral cyclic compounds. Angew. Chem. Int. Ed. 49, 8306–8308 (2010).

    CAS  Google Scholar 

  7. Castellanos, A. & Fletcher, S. P. Current methods for asymmetric halogenation of olefins. Chem. Eur. J. 17, 5766–5776 (2011).

    CAS  PubMed  Google Scholar 

  8. Snyder, S. A., Treitler, D. S. & Brucks, A. P. Halonium-induced cyclization reactions. Aldrichimica Acta 44, 27 (2011).

    CAS  Google Scholar 

  9. Hennecke, U. New catalytic approaches towards the enantioselective halogenation of alkenes. Chem. Asian J. 7, 456–465 (2012).

    CAS  PubMed  Google Scholar 

  10. Denmark, S. E., Kuester, W. E. & Burk, M. T. Catalytic, asymmetric halofunctionalization of alkenes—a critical perspective. Angew. Chem. Int. Ed. 51, 10938–10935 (2012).

    CAS  Google Scholar 

  11. Cheng, Y. A., Yu, W. Z. & Yeung, Y.-Y. Recent advances in asymmetric intra- and intermolecular halofunctionalizations of alkenes. Org. Biomol. Chem. 12, 2333–2343 (2014).

    CAS  PubMed  Google Scholar 

  12. Cochrane, N. A., Nguyen, H. & Gagne, M. R. Catalytic enantioselective cyclization and C3-fluorination of polyenes. J. Am. Chem. Soc. 135, 628–631 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Snyder, S. A., Treitler, D. S. & Schall, A. A two-step mimic for direct, asymmetric bromonium- and chloronium-induced polyene cyclizations. Tetrahedron 66, 4796–4804 (2010).

    CAS  Google Scholar 

  14. Grayfer, T. D., Retailleau, P., Dodd, R. H., Dubois, J. & Cariou, K. Chemodivergent, tunable, and selective iodine(iii)-mediated bromo-functionalizations of polyprenoids. Org. Lett. 19, 4766–4769 (2017).

    CAS  PubMed  Google Scholar 

  15. Sawamura, Y., Nakatsuji, H., Sakakura, A. & Ishihara, K. “Phosphite–urea” cooperative high-turnover catalysts for the highly selective bromocyclization of homogeranylarenes. Chem. Sci. 4, 4181–4186 (2013).

    CAS  Google Scholar 

  16. Snyder, S. A., Treitler, D. S. & Brucks, A. P. Simple reagents for direct halonium-induced polyene cyclizations. J. Am. Chem. Soc. 132, 14303–14314 (2010).

    CAS  PubMed  Google Scholar 

  17. Snyder, S. A. & Treitler, D. S. Et2SBr·SbCl5Br: an effective reagent for direct bromonium-induced polyene cyclizations. Angew. Chem. Int. Ed. 48, 7899–7903 (2009).

    CAS  Google Scholar 

  18. Arnold, A. M., Pöthig, A., Drees, M. & Gulder, T. NXS, morpholine, and HFIP: the ideal combination for biomimetic haliranium-induced polyene cyclizations. J. Am. Chem. Soc. 140, 4344–4353 (2018).

    CAS  PubMed  Google Scholar 

  19. Sakakura, A., Ukai, A. & Ishihara, K. Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites. Nature 445, 900–903 (2007).

    CAS  PubMed  Google Scholar 

  20. Sawamura, Y., Ogura, Y., Nakatsuji, H., Sakakura, A. & Ishihara, K. Enantioselective bromocyclization of 2-geranylphenols induced by chiral phosphite–urea bifunctional catalysts. Chem. Commun. 52, 6068–6071 (2016).

    CAS  Google Scholar 

  21. Samanta, R. C. & Yamamoto, H. Catalytic asymmetric bromocyclization of polyenes. J. Am. Chem. Soc. 139, 1460–1463 (2017).

    CAS  PubMed  Google Scholar 

  22. Kotke, M. & Schreiner, P. R. Acid-free, organocatalytic acetalization. Tetrahedron 62, 434–439 (2006).

    CAS  Google Scholar 

  23. Yousefi, R. et al. Catalytic, enantioselective synthesis of cyclic carbamates from dialkyl amines by CO2-capture: discovery, development, and mechanism. J. Am. Chem. Soc. 141, 618–625 (2019).

    CAS  PubMed  Google Scholar 

  24. Vara, B. A., Struble, T. J., Wang, W., Dobish, M. C. & Johnston, J. N. Enantioselective small molecule synthesis by carbon dioxide fixation using a dual Brønsted acid/base organocatalyst. J. Am. Chem. Soc. 137, 7302–7305 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, F., Zhang, S. & Tu, Y. Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketals. Nat. Prod. Rep. 35, 75 (2018).

    CAS  PubMed  Google Scholar 

  26. Aho, J. E., Pihko, P. M. & Rissa, T. K. Nonanomeric spiroketals in natural products: structures, sources, and synthetic strategies. Chem. Rev. 105, 4406–4440 (2005).

    CAS  PubMed  Google Scholar 

  27. Galloway, W. R. J. D., Isidro-Llobet, A. & Spring, D. R. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 80 (2010).

    PubMed  Google Scholar 

  28. Singh, G. S. & Desta, Z. Y. Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks. Chem. Rev. 112, 6104–6155 (2012).

    CAS  PubMed  Google Scholar 

  29. Painter, T. O. et al. Skeletal diversification via heteroatom linkage control: preparation of bicyclic and spirocyclic scaffolds from N-substituted homopropargyl alcohols. J. Org. Chem. 78, 3720–3730 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Guérot, C., Tchitchanov, B. H., Knust, H. & Carreira, E. M. Synthesis of novel angular spirocyclic azetidines. Org. Lett. 13, 780–783 (2011).

    PubMed  Google Scholar 

  31. Burkhard, J. A. et al. Synthesis of azaspirocycles and their evaluation in drug discovery. Angew. Chem. Int. Ed. 49, 3524–3527 (2010).

    CAS  Google Scholar 

  32. Burkhard, J. A., Guérot, C., Knust, H., Rogers-Evans, M. & Carreira, E. M. Synthesis and structural analysis of a new class of azaspiro[3.3]heptanes as building blocks for medicinal chemistry. Org. Lett. 12, 1944–1947 (2010).

    CAS  PubMed  Google Scholar 

  33. Wuitschik, G. et al. Spirocyclic oxetanes: synthesis and properties. Angew. Chem. Int. Ed. 47, 4512–4515 (2008).

    CAS  Google Scholar 

  34. Čorić, I. & List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature 483, 315–319 (2012).

    PubMed  Google Scholar 

  35. Zinzalla, G., Milroy, L.-G. & Ley, S. V. Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives. Org. Biomol. Chem. 4, 1977–2002 (2006).

    CAS  PubMed  Google Scholar 

  36. Kalyani, D., Kornfilt, D. J.-P., Burk, M. T. & Denmark, S. E. in Lewis Base Catalysis in Organic Synthesis (eds Vedejs, E. & Denmark, S. E.) Ch. 24 (Wiley-VCH, 2016).

  37. Zhou, L., Tan, C. K., Jiang, X. & Yeung, Y.-Y. Asymmetric bromolactonization using amino-thiocarbamate catalyst. J. Am. Chem. Soc. 132, 15474–15476 (2010).

    CAS  PubMed  Google Scholar 

  38. Schreiner, P. R. & Wittkopp, A. H-bonding additives act like Lewis acid catalysts. Org. Lett. 4, 217–220 (2002).

    CAS  PubMed  Google Scholar 

  39. Banik, S. M., Levina, A., Hyde, A. M. & Jacobsen, E. N. Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 358, 761–764 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    CAS  PubMed  Google Scholar 

  41. Takemoto, Y. Recognition and activation by ureas and thioureas: stereoselective reactions using ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 3, 4299–4306 (2005).

    CAS  PubMed  Google Scholar 

  42. Zhang, D.-W. et al. Two new diterpenoids from cell cultures of Salvia miltiorrhiza. Chem. Pharm. Bull. 61, 576–580 (2013).

    CAS  Google Scholar 

  43. Ashtekar, K. D. et al. A new tool to guide halofunctionalization reactions: the halenium affinity (HalA) scale. J. Am. Chem. Soc. 136, 13355–13362 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Park, Y., Schindler, C. S. & Jacobsen, E. N. Enantioselective aza-Sakurai cyclizations: dual role of thiourea as H‑bond donor and Lewis base. J. Am. Chem. Soc. 138, 14848–14851 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Boyle, P. D. & Godfrey, S. M. The reactions of sulfur and selenium donor molecules with dihalogens and interhalogens. Coord. Chem. Rev. 223, 265–299 (2001).

    CAS  Google Scholar 

  46. Jakab, G., Hosseini, A., Hausmann, H. & Schreiner, P. R. Mild and selective organocatalytic iodination of activated aromatic compounds. Synthesis 45, 1635–1640 (2013).

    CAS  Google Scholar 

  47. Piers, E., Britton, R. W., Beraghty, M. B., Keziere, R. J. & Smillie, R. D. Stereoselective total synthesis of copa and ylango sesquiterpenoids: preparation of (–)-(1S,4S,5R,7R)-1,7-dimethyl-4-isopropylbicyclo[3.2.1.]octa-6,8-dione and (+)-(1R,4S,5S,7S)-1,7-dimethyl-4-isopropylbicyclo[3.2.1]octa-6,8-dione. Can. J. Chem. 53, 2827–2837 (1975).

    CAS  Google Scholar 

  48. Newberry, R. W. & Raines, R. T. The n→π* interaction. Acc. Chem. Res. 50, 1838–1846 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sahariah, B. & Sarma, B. K. Relative orientation of the carbonyls groups determines the nature of orbital interactions in carbonyl–carbonyl short contacts. Chem. Sci. 10, 909–917 (2019).

    CAS  PubMed  Google Scholar 

  50. Glendening, E. D. et al. NBO 7.0 (University of Wisconsin, 2018); https://nbo7.chem.wisc.edu/biblio_css.htm

  51. Becke, A. The Quantum Theory of Atoms in Molecules: From Solid State to DNA and Drug Design (John Wiley, 2007).

  52. Frisch, M. J. et al. Gaussian 09 Revision D.01 (Gaussian Inc., 2009).

  53. Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215–241 (2008).

    CAS  Google Scholar 

  54. Grimme, S., Ehrlich, S. & Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 32, 1456–1465 (2011).

    CAS  PubMed  Google Scholar 

  55. Neese, F. Software update: the ORCA program system, version 4.0. WIREs Comput. Mol. Sci. 8, e1327 (2018).

    Google Scholar 

  56. Kozuch, S. & Martin, J. M. Spin‐component‐scaled double hybrids: an extensive search for the best fifth‐rung functionals blending DFT and perturbation theory. J. Comput. Chem. 34, 2327–2344 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Hong Kong Special Administrative Region General Research Funding (grant number CUHK14304918), the Chinese University of Hong Kong Direct Grant (grant number 4053329) and Innovation and Technology Commission to the State Key Laboratory of Synthetic Chemistry (GHP/004/16GD). We thank Professor B. List (Max-Planck-Institut für Kohlenforschung) for a helpful discussion.

Author information

Authors and Affiliations

  1. Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Hong Kong, China

    Tianyu Zheng, Xinyan Wang, Wing-Hin Ng, Ying-Lung Steve Tse & Ying-Yeung Yeung

Authors
  1. Tianyu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wing-Hin Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying-Lung Steve Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying-Yeung Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.-Y.Y. conceived of and directed the project. T.Z. performed the experimental works. W.-H.N. assisted the preparation of some starting materials. Y.-L.S.T. directed the DFT calculations and mechanism analysis. X.W. performed the DFT calculations. T.Z., X.W., Y.-L.S.T. and Y.-Y.Y. co-wrote the manuscript.

Corresponding authors

Correspondence to Ying-Lung Steve Tse or Ying-Yeung Yeung.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–16, Tables 1–4, Methods, References

Supplementary Data

Supplementary Data for DFT

Supplementary Data 1

CIF file for the crystallographic data of compound 3a.

Supplementary Data 2

CIF file for the crystallographic data of compound 4a-Br.

Supplementary Data 3

CIF file for the crystallographic data of compound 5.

Supplementary Data 4

CIF file for the crystallographic data of compound 6.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, T., Wang, X., Ng, WH. et al. Catalytic enantio- and diastereoselective domino halocyclization and spiroketalization. Nat Catal 3, 993–1001 (2020). https://doi.org/10.1038/s41929-020-00530-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-020-00530-9

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