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Chiral sulfinamidourea and strong Brønsted acid–cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines

Nature Protocols volume 9, pages 1860–1866 (2014)Cite this article

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Abstract

This protocol describes a method for the laboratory synthesis of enantiomerically enriched, chiral tetrahydroisoquinolines through the application of a chiral sulfinamido urea catalyst for the Povarov reaction. Tetrahydroisoquinolines are bicyclic organic frameworks present in a wide assortment of natural and synthetic biologically important compounds including martinelline, scoulerine and tubocurarine. The methodology involves the [4+2] cycloaddition of a N-arylimines with electron-rich olefins such as vinyl lactams and dihydropyrroles in the presence of a two-catalyst system consisting of an achiral strong Brønsted acid (o-nitrobenzenesulfonic acid), together with the chiral sulfinamido urea derivative 1. The anion-binding properties of the urea lead to the association of the ion pair that results from protonation of the imine substrate. Cycloaddition is followed by spontaneous proton loss with re-aromatization to provide the tetrahydroisoquinoline products in highly enantio-enriched form.

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Figure 1: Asymmetric catalysis by strong Brønsted acids.
Figure 2: Generalized Povarov reaction cocatalyzed by o-nitrobenzenesulfonic acid and chiral urea 1 (R1, R2, R3 and X are organic substuents).
Figure 3
Figure 4
Figure 5
Figure 6: Applications of the enantioselective Povarov reaction catalyzed by 1.
Figure 7
Figure 8: Synthesis of sulfinamidourea catalyst 1.

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References

  1. Eigen, M. Proton transfer acid-base catalysis: enzymatic hydrolysis. Part 1. Elementary processes. Angew. Chem. Int. Ed. 3, 1–19 (1964).

    Article  Google Scholar 

  2. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  3. Uraguchi, D., Sorimachi, K. & Terada, M. Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. J. Am. Chem. Soc. 126, 11804–11805 (2004).

    Article  CAS  Google Scholar 

  4. Nakashima, D. & Yamamoto, H. Design of chiral N-triflyl phosphoramide as a strong chiral Brønsted acid and its application to asymmetric Diels-Alder reaction. J. Am. Chem. Soc. 128, 9626–9627 (2006).

    Article  CAS  Google Scholar 

  5. Hatano, M., Maki, T., Moriyama, K., Arinobe, M. & Ishihara, K. Pyridinium 1,1′-binaphthyl-2,2′-disulfonates as highly effective chiral Brønsted acid-base combined salt catalysts for enantioselective Mannich-type reaction. J. Am. Chem. Soc. 130, 16858–16860 (2008).

    Article  CAS  Google Scholar 

  6. Ishihara, K., Kaneeda, M. & Yamamoto, H. Lewis-acid assisted chiral Brønsted acid for enantioselective protonation of silyl enol ethers and ketene bis(trialkyl silyl) acetals. J. Am. Chem. Soc. 116, 11179–11180 (1994).

    Article  CAS  Google Scholar 

  7. Yamamoto, H. & Futatsugi, K. 'Designer acids': combined acid catalysis for asymmetric synthesis. Angew. Chem. Int. Ed. 44, 1924–1942 (2005).

    Article  CAS  Google Scholar 

  8. Raheem, I.T., Thiara, P.S., Peterson, E.A. & Jacobsen, E.N. Enantioselective Pictet-Spengler-type cyclizations of hydroxylactams: H-bond donor catalysis by anion binding. J. Am. Chem. Soc. 129, 13404–13405 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Kouznetsov, V.V. Recent synthetic developments in a powerful imino Diels-Alder reaction (Povarov reaction): application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron 65, 2721–2750 (2009).

    Article  CAS  Google Scholar 

  12. Xu, H., Zuend, S.J., Woll, M.G., Tao, Y. & Jacobsen, E.N. Asymmetric cooperative catalysis of strong Brønsted acid-promoted reactions using chiral ureas. Science 327, 986–990 (2010).

    Article  CAS  Google Scholar 

  13. Gerard, B. et al. Application of a catalytic asymmetric Povarov reaction using chiral ureas to the synthesis of a tetrahydroquinoline library. ACS Combi. Sci. 14, 621–630 (2012).

    Article  CAS  Google Scholar 

  14. Tan, K.L. & Jacobsen, E.N. Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angew. Chem. Int. Ed. 46, 1315–1317 (2007).

    Article  CAS  Google Scholar 

  15. Ishitani, H. & Kobayashi, S. Catalytic asymmetric aza Diels-Alder reactions using a chiral lanthanide Lewis acid. Enantioselective synthesis of tetrahydroquinoline derivatives using a catalytic amount of a chiral source. Tetrahedron Lett. 37, 7357–7360 (1996).

    Article  CAS  Google Scholar 

  16. Akiyama, T., Morita, H. & Fuchibe, K. Chiral Brønsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction. J. Am. Chem. Soc. 128, 13070–13071 (2006).

    Article  CAS  Google Scholar 

  17. Liu, H., Dagousset, G., Masson, G., Retailleau, P. & Zhu, J.P. Chiral Brønsted acid-catalyzed enantioselective three-component Povarov reaction. J. Am. Chem. Soc. 131, 4598–4599 (2009).

    Article  CAS  Google Scholar 

  18. Witherup, K.M. et al. Martinelline and martinellic acid, novel G-protein linked receptor antagonists from the tropical plant Martinella iquitosensis (Bignoniaceae). J. Am. Chem. Soc. 117, 6682–6685 (1995).

    Article  CAS  Google Scholar 

  19. Xia, C.F., Heng, L.S. & Ma, D.W. Total synthesis of (±)-martinelline. Tetrahedron Lett. 43, 9405–9409 (2002).

    Article  CAS  Google Scholar 

  20. Batey, R.A. et al. A three-component coupling protocol for the synthesis of substituted hexahydropyrrolo[3,2-c]quinolines. Chem. Commun. 651–652 (1999).

  21. Keinicke, L., Fristrup, P., Norrby, P.-O. & Madsen, R. Nonradical zinc-Barbier reaction for diastereoselective synthesis of vicinal amino alcohols. J. Am. Chem. Soc. 127, 15756–15761 (2005).

    Article  CAS  Google Scholar 

  22. Kraus, G.A. & Neuenschwander, K. Facile synthesis of N-acyl-2-pyrrolines. J. Org. Chem. 46, 4791–4792 (1981).

    Article  CAS  Google Scholar 

  23. Trost, B.M. & Marrs, C.M. A [3+2] cycloaddition and [4+3] cycloaddition approach to N-heterocycles via palladium-catalyzed TMM reactions with imines. J. Am. Chem. Soc. 115, 6636–6645 (1993).

    Article  CAS  Google Scholar 

  24. Larrow, J.F. & Jacobsen, E.N. (R,R)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino manganese(III) chloride, a highly enantioselective epoxidation catalyst. Org. Syn. 75, 1 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was carried out with support from the US National Institutes of Health (grants no. GM-43214 and P50 GM-69721), and by fellowship support from the Dreyfus Foundation (to H.X.).

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA

    Hao Xu, Hu Zhang & Eric N Jacobsen

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  1. Hao Xu
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  2. Hu Zhang
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  3. Eric N Jacobsen
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Contributions

H.X. designed and performed the experiments, and co-wrote the paper. H.Z. performed the synthesis of catalyst 1. E.N.J. designed and supervised the experiments, analyzed data and co-wrote the paper.

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Correspondence to Eric N Jacobsen.

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Xu, H., Zhang, H. & Jacobsen, E. Chiral sulfinamidourea and strong Brønsted acid–cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines. Nat Protoc 9, 1860–1866 (2014). https://doi.org/10.1038/nprot.2014.125

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