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Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions

Nature Chemistry volume 4, pages 817–824 (2012)Cite this article

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Abstract

Small organic and metal-containing molecules (molecular mass <1,000) can catalyse synthetically useful reactions with the high levels of stereoselectivity typically associated with macromolecular enzymatic catalysts. Whereas enzymes are generally understood to accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions, enantioselectivity with chiral, small-molecule catalysts is rationalized typically by the steric destabilization of all but one dominant pathway. However, it is increasingly apparent that stabilizing effects also play an important role in small-molecule catalysis, although the mechanistic characterization of such systems is rare. Here, we show that arylpyrrolidino amido thiourea catalysts catalyse the enantioselective nucleophilic ring opening of episulfonium ions by indoles. Evidence is provided for the selective transition-state stabilization of the major pathway by the thiourea catalyst in the rate- and selectivity-determining step. Enantioselectivity is achieved through a network of attractive anion binding, cation-π and hydrogen-bond interactions between the catalyst and the reacting components in the transition-structure assembly.

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Figure 1
Figure 2: Proposed catalytic cycle for thiourea-catalysed ring-opening of episulfonium ions with indole.
Figure 3: Rate acceleration by 3e and acidity of the N–H motif of the 5-indole derivatives.
Figure 4: Enantio-induction with thiourea catalysts through a selective, attractive cation-π interaction between the extended aromatic residue on the catalyst and the acidic α-protons in the episulfonium ion.
Figure 5: Proposed transition-structure model.

References

  1. Zhang, Z. G. & Schreiner, P. R. (Thio)urea organocatalysis – what can be learnt from anion recognition? Chem. Soc. Rev. 38, 1187–1198 (2009).

    CAS  PubMed  Google Scholar 

  2. Reisman, S. E., Doyle, A. G. & Jacobsen, E. N. Enantioselective thiourea-catalyzed additions to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Brown, A. R., Kuo, W-H. & Jacobsen, E. N. Enantioselective catalytic α-alkylation of aldehydes via an SN1 pathway. J. Am. Chem. Soc. 132, 9286–9288 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. De, C. K., Klauber, E. G. & Seidel, D. Merging nucleophilic and hydrogen bonding catalysis: an anion binding approach to the kinetic resolution of amines. J. Am. Chem. Soc. 131, 17060–17061 (2009).

    CAS  PubMed  Google Scholar 

  5. Knowles, R. R. & Jacobsen, E. N. Attractive noncovalent interactions in asymmetric catalysis: links between enzymes and small molecule catalysts. Proc. Natl Acad. Sci. USA 107, 20678–20685 (2010).

    CAS  PubMed  Google Scholar 

  6. Knowles, R. R., Lin, S. & Jacobsen, E. N. Enantioselective thiourea-catalyzed cationic polycyclizations. J. Am. Chem. Soc. 132, 5030–5032 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zuend, S. J. & Jacobsen, E. N. Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions. J. Am. Chem. Soc. 131, 15358–15374 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fox, D. J., House, D. & Warren, S. Mechanisms of sulfanyl (RS) migrations: synthesis of heterocycles. Angew. Chem. Int. Ed. 41, 2462–2482 (2002).

    CAS  Google Scholar 

  9. Smit, W. A., Caple, R. & Smoliakova, I. P. Stepwise electrophilic addition. Some novel synthetic ramifications of an old concept. Chem. Rev. 94, 2359–2382 (1994).

    CAS  Google Scholar 

  10. Fachini, M., Lucchini, V., Modena, G., Pasi, M. & Pasquato, L. Nucleophilic reactions at the sulfur of thiiranium and thiirenium ions. New insight in the electrophilic additions to alkenes and alkynes. Evidence for an episulfurane intermediate. J. Am. Chem. Soc. 121, 3944–3950 (1999).

    CAS  Google Scholar 

  11. Toshimitsu, A., Hirosawa, C. & Tamao, K. Retention of configuration in the Ritter-type substitution reaction of chiral/3-arylthio alcohols through the anchimeric assistance of the arylthio group. Tetrahedron 50, 8997–9008 (1994).

    CAS  Google Scholar 

  12. Hamilton, G. L., Kanai, T. & Toste, F. D. Chiral anion-mediated asymmetric ring opening of meso-aziridinium and episulfonium ions. J. Am. Chem. Soc. 130, 14984–14986 (2008).

    CAS  PubMed  Google Scholar 

  13. Wu, Y. J. in Heterocyclic Scaffolds II: Topics in Heterocyclic Chemistry Vol. 26 (ed. Gribble, G. W.) 1–29 (Springer, 2011).

    Google Scholar 

  14. Uyeda, C. & Jacobsen, E. N. Transition-state charge stabilization through multiple non-covalent interactions in the guanidinium-catalyzed enantioselective Claisen rearrangement. J. Am. Chem. Soc. 133, 5062–5075 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Denmark, S. E., Kornfilt, D. J. P. & Vogler, T. Catalytic asymmetric thiofunctionalization of unactivated alkenes. J. Am. Chem. Soc. 133, 15308–15311 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Denmark, S. E., Collins, W. R. & Cullen, M. D. Observation of direct sulfenium and selenenium group transfer from thiiranium and seleniranium ions to alkenes. J. Am. Chem. Soc. 131, 3490–3492 (2009).

    CAS  PubMed  Google Scholar 

  17. Denmark, S. E. & Vogler, T. Synthesis and reactivity of enantiomerically enriched thiiranium ions. Chem. Eur. J. 15, 11737–11745 (2009).

    CAS  PubMed  Google Scholar 

  18. Lucchini, V., Modena, G. & Pasquato, L. Enantiopure thiosulfonium salts in asymmetric synthesis. Face selectivity in electrophilic additions to unfunctionalised olefins. J. Chem. Soc. Chem. Commun. 1565–1566 (1994).

  19. Mayr, H., Kempf, B. & Ofial, A. R. π-nucleophilicity in carbon–carbon bond-forming reactions. Acc. Chem. Res. 36, 66–77 (2003).

    CAS  PubMed  Google Scholar 

  20. Birrell, J. A., Desrosiers, J-N. & Jacobsen, E. N. Enantioselective acylation of silyl ketene acetals through fluoride anion-binding catalysis. J. Am. Chem. Soc. 133, 13872–13875 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Blackmond, D. G. Reaction progress kinetic analysis: a powerful methodology for mechanistic studies of complex catalytic reactions. Angew. Chem. Int. Ed. 44, 4302–4320 (2005).

    CAS  Google Scholar 

  22. Blackmond, D. G., Ropic, M. & Stefinovic, M. Kinetic studies of the asymmetric transfer hydrogenation of imines with formic acid catalyzed by Rh-diamine catalysts. Org. Process Res. Dev. 10, 457–463 (2006).

    CAS  Google Scholar 

  23. Denmark, S. E. & Burk, M. T. Lewis base catalysis of bromo- and iodolactonization, and cycloetherification. Proc. Natl Acad. Sci. USA 107, 20655–20660 (2010).

    CAS  PubMed  Google Scholar 

  24. French, D. C. & Crumrine, D. S. Improved correlation of 33S chemical shifts with pKas of arenesulfonic acids: use of 33S NMR for pKa determination. J. Org. Chem. 55, 5494–5496 (1990).

    CAS  Google Scholar 

  25. Phan, T. B., Breugst, M. & Mayr, H. Towards a general scale of nucleophilicity? Angew. Chem. Int. Ed. 45, 3869–3874 (2006).

    CAS  Google Scholar 

  26. Maresh, J. J. et al. Strictosidine synthase mechanism of a Pictet–Spengler catalyzing enzyme. J. Am. Chem. Soc. 130, 710–723 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bosnich, B. Asymmetric Catalysis 14 (Marinus Nijhoff, 1986).

    Google Scholar 

  28. Kelly, T. R. & Kim, M. H. Relative binding affinity of carboxylate and its isosteres: nitro, phosphate, phosphonate, sulfonate, and δ-lactone. J. Am. Chem. Soc. 116, 7072–7080 (1994).

    CAS  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Scheerder, J., Engbersen, J. F. J., Casnati, A., Ungaro, R. & Reinhoudt, D. N. Complexation of halide anions and tricarboxylate anions by neutral urea-derivatized p-tert-butylcalix[6]arenes. J. Org. Chem. 60, 6448–6454 (1995).

    CAS  Google Scholar 

  31. Lan, T. & McLaughlin, L. W. The energetic contribution of a bifurcated hydrogen bond to the binding of DAPI to dA-dT rich sequences of DNA. J. Am. Chem. Soc. 123, 2064–2065 (2001).

    CAS  PubMed  Google Scholar 

  32. Braun, J., Neusser, H. J. & Hobza, P. N–H···π interactions in indole···benzene-h6,d6 and indole···benzene-h6,d6 radical cation complexes. Mass analyzed threshold ionization experiments and correlated ab initio quantum chemical calculations. J. Phys. Chem. A 107, 3918–3924 (2003).

    CAS  Google Scholar 

  33. Biswal, H. S. & Wategaonkar, S. Nature of the N–H···S hydrogen bond. J. Phys. Chem. A 113, 12763–12773 (2009).

    CAS  PubMed  Google Scholar 

  34. Herrera, R. P., Sgarzani, V., Bernardi, L. & Ricci, A. Catalytic enantioselective Friedel–Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst. Angew. Chem. Int. Ed. 44, 6576–6579 (2005).

    CAS  Google Scholar 

  35. James, W. H. III et. al. Evolution of amide stacking in larger γ-peptides: triamide H-bonded cycles. J. Phys. Chem. A 115, 13783–13798 (2011).

    CAS  PubMed  Google Scholar 

  36. Gustafson, J., Lim, D. & Miller, S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 328, 1251–1255 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Shepodd, T. J., Petti, M. A. & Dougherty, D. A. Tight, oriented binding of an aliphatic guest by a new class of water-soluble molecules with hydrophobic binding sites. J. Am. Chem. Soc. 108, 6085–6087 (1986).

    CAS  PubMed  Google Scholar 

  38. Kearney, P. C. et al. Molecular recognition in aqueous media. New binding studies provide further insights into the cation-π interaction and related phenomena. J. Am. Chem. Soc. 115, 9907–9919 (1993).

    CAS  Google Scholar 

  39. Ma, J. C. & Dougherty, D. A. The cation-π interaction. Chem. Rev. 97, 1303–1324 (1997).

    CAS  PubMed  Google Scholar 

  40. Dougherty, D. A. Cation-π interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271, 163–168 (1996).

    CAS  PubMed  Google Scholar 

  41. Raju, R. K., Bloom, J. W. G., An, Y. & Wheeler, S. E. Substituent effects on non-covalent interactions with aromatic rings: insights from computational chemistry. ChemPhysChem 12, 3116–3130 (2011).

    CAS  PubMed  Google Scholar 

  42. Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A. & Dougherty, D. A. Nicotine binding to brain receptors requires a strong cation-π interaction. Nature 458, 534–538 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Vijay, D. & Sastry, G. N. Exploring the size dependence of cyclic and acyclic π-systems on cation-π binding. Phys. Chem. Chem. Phys. 10, 582–590 (2008).

    CAS  PubMed  Google Scholar 

  44. Gal, J-F. et al. Lithium-cation/π complexes of aromatic systems. The effect of increasing the number of fused rings. J. Am. Chem. Soc. 125, 10394–10401 (2003).

    CAS  PubMed  Google Scholar 

  45. Li, X., Liu, P., Houk, K. N. & Birman, V. B. Origin of enantioselectivity in CF3–PIP-catalyzed kinetic resolution of secondary benzylic alcohols. J. Am. Chem. Soc. 130, 13836–13837 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ngola, S. M. & Dougherty, D. A. Evidence for the importance of polarizability in biomimetic catalysis involving cyclophane receptors. J. Org. Chem. 61, 4355–4360 (1996).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institute of General Medical Sciences (NIGMS) (P50 GM-69721 and RO1 GM-43214) and by a predoctoral fellowship to S.L. from Eli Lilly. We thank R. Knowles, K. Brak and H. Mayr for helpful discussions, A. Brown, D. Lehnherr and A. Hyde for the use of catalysts, and S-L. Zheng for crystal structure determinations.

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  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Song Lin & Eric N. Jacobsen

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  1. Song Lin
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S.L. conducted the experiments, S.L. and E.N.J. co-wrote the manuscript and E.N.J. guided the research.

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Correspondence to Eric N. Jacobsen.

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Lin, S., Jacobsen, E. Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions. Nature Chem 4, 817–824 (2012). https://doi.org/10.1038/nchem.1450

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