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.

Control of four stereocentres in a triple cascade organocatalytic reaction

Abstract

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centres continue to be important in both academic and industrial laboratories1. In particular, catalytic asymmetric multi-component ‘domino’ reactions, used during total syntheses of natural products and synthetic building blocks, are highly desirable2,3. These reactions avoid time-consuming and costly processes, including the purification of intermediates and steps involving the protection and deprotection of functional groups, and they are environmentally friendly and often proceed with excellent stereoselectivities4,5. Therefore, the design of new catalytic and stereoselective cascade reactions is a continuing challenge at the forefront of synthetic chemistry6. In addition, catalytic cascade reactions can be described as biomimetic, as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products7,8. Here we report the development of an asymmetric organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes. This three-component domino reaction proceeds by way of a catalysed Michael/Michael/aldol condensation sequence affording the products with good to moderate yields (25–58 per cent). During this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. In addition, variation of the starting materials can be used to obtain diverse polyfunctional cyclohexene derivatives, which can be used as building blocks in organic synthesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Asymmetric, organocatalytic three component multistep reaction cascade.
Figure 2: Proposed catalytic cycle of the triple cascade.
Figure 3: X-ray structure of 2b.

References

  1. 1

    Nicolaou, K. C., Montagnon, T. & Snyder, S. A. Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem. Commun. 551–564 (2003)

  2. 2

    Wasilke, J.-C., Obrey, S. J., Baker, R. T. & Bazan, G. C. Current tandem catalysis. Chem. Rev. 105, 1001–1020 (2005)

    CAS  Article  Google Scholar 

  3. 3

    Ramòn, D. J. & Yus, M. Asymmetric multicomponent reactions (AMCRs): the new frontier. Angew. Chem. Int. Edn Engl. 44, 1602–1634 (2005)

    Article  Google Scholar 

  4. 4

    Tietze, L. F. Domino reactions in organic synthesis. Chem. Rev. 96, 115–136 (1996)

    CAS  Article  Google Scholar 

  5. 5

    Tietze, L. F. & Haunert, F. in Stimulating Concepts in Chemistry (eds Vögtle, F., Stoddart, J. F. & Shibasaki, M.) 39–64 (Wiley-VCH, Weinheim, 2000)

    Google Scholar 

  6. 6

    Guo, H.-C. & Ma, J.-A. Catalytic asymmetric tandem transformations triggered by conjugate additions. Angew. Chem. Int. Edn Engl. 45, 354–366 (2006)

    CAS  Article  Google Scholar 

  7. 7

    Lehninger, A. L. Principles of Biochemistry (Worth, New York, 1993)

    Google Scholar 

  8. 8

    Mann, J. Chemical Aspects of Biosynthesis (Oxford Chemistry Primers, Oxford Univ. Press, Oxford, 1999)

    Google Scholar 

  9. 9

    Dalko, P. L. & Moisan, L. In the golden age of organocatalysis. Angew. Chem. Int. Edn Engl. 43, 5138–5175 (2004)

    CAS  Article  Google Scholar 

  10. 10

    Berkessel, A. & Gröger, H. Asymmetric Organocatalysis (Wiley VCH, Weinheim, 2005)

    Book  Google Scholar 

  11. 11

    Seayed, J. & List, B. Asymmetric organocatalysis. Org. Biomol. Chem. 3, 719–724 (2005)

    Article  Google Scholar 

  12. 12

    Ramachary, D. B. & Barbas, C. F. III Towards organo-click chemistry: Development of multicomponent reactions through combination of aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions. Chem. Eur. J. 10, 5323–5331 (2004)

    CAS  Article  Google Scholar 

  13. 13

    Yang, J. W., Hechavarria Fonseca, M. T. & List, B. Catalytic asymmetric reductive Michael cyclization. J. Am. Chem. Soc. 127, 15036–15037 (2005)

    CAS  Article  Google Scholar 

  14. 14

    Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Marigo, M., Schulte, T., Franzén, J. & Jørgensen, K. A. Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to α,β-unsaturated aldehydes. J. Am. Chem. Soc. 127, 15710–15711 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Hayashi, Y., Gotoh, H., Hayashi, T. & Shoji, M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Edn Engl. 44, 4212–4215 (2005)

    CAS  Article  Google Scholar 

  17. 17

    Prieto, A., Halland, N. & Jørgensen, K. A. Novel imidazolidine-tetrazole organocatalyst for asymmetric conjugate addition to nitroalkanes. Org. Lett. 7, 3897–3900 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Berner, O. M., Tedeschi, L. & Enders, D. Asymmetric Michael-additions to nitroalkenes. Eur. J. Org. Chem. 1877–1894 (2002)

  19. 19

    Enders, D., Kipphardt, H., Gerdes, P., Breña-Valle, L. J. & Bhushan, V. Large scale preparation of versatile chiral auxiliaries derived from (S)-proline. Bull. Soc. Chim. Belg. 97, 691–704 (1988)

    CAS  Article  Google Scholar 

  20. 20

    Franzén, J. et al. A general organocatalyst for direct α-functionalization of aldehydes: stereoselective C–C, C-N, C-F, C-Br, and C-S bond-forming reactions. Scope and mechanistic insights. J. Am. Chem. Soc. 127, 18296–18304 (2005)

    Article  Google Scholar 

  21. 21

    List, B., Pojarliev, P. & Martin, H. J. Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org. Lett. 3, 2423–2425 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Enders, D. & Seki, A. Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett, 26–28 (2002)

Download references

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SPP Organokatalyse) and the Fonds der Chemischen Industrie (thanked by C.G. for a Kekulé fellowship). We thank BASF AG, Degussa AG, Bayer AG and Wacker-Chemie for the donation of chemicals, and J. Runsink for the NOE measurements. Author Contributions M.R.M.H. and C.G. contributed equally to this work. The X-ray structure analysis was performed by G.R.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dieter Enders.

Ethics declarations

Competing interests

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 295450, and are available via www.ccdc.cam.ac.uk/data_request/cif. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains one figure summarizing the main finding of the manuscript, general information and general procedure of the chemical reactions, analytical data of all synthesized compounds, GC measurements of the reaction course, one figure and X-ray data, two figures. (PDF 256 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Enders, D., Hüttl, M., Grondal, C. et al. Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861–863 (2006). https://doi.org/10.1038/nature04820

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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