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Organocatalysed conjugate addition reactions of aldehydes to nitroolefins with anti selectivity

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Abstract

Catalytic reactions that enable access to different diastereoisomers are important but often difficult to achieve. One long-standing unsolved challenge is the anti-selective conjugate addition reaction between aldehydes and nitroolefins. This organocatalytic transformation is a versatile method for the synthesis of γ-nitroaldehydes and downstream compounds such as pyrrolidines and γ-butyrolactams, which are key moieties in bioactive molecules. Numerous amine catalysts have been developed for this transformation, but all provide syn-configured products. Here, we present a tripeptide as a general catalyst for the synthesis of anti-configured γ-nitroaldehydes. Key to the anti selectivity is the installation of substituents at Cδ of the reactive pyrrolidine of proline to enable the formation of s-cis enamine intermediates. The peptidic catalyst converts different aldehyde and nitroolefin combinations into the products in high yields and stereoselectivities. Conformational and mechanistic studies revealed a Curtin–Hammett scenario for the catalytic system. The strategy provides long-sought-after access to anti-configured γ-nitroaldehydes and a guide for reversing the diastereoselectivity of amine-based organocatalysts.

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Fig. 1: Concept for anti selectivity in conjugate addition reactions.
Fig. 2: Catalytic performance of peptidic catalyst 2 with substituents at Cδ.
Fig. 3: Substrate scope.
Fig. 4: Conformational and mechanistic insights.

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Data availability

The authors declare that all data supporting the findings of this study are available within the manuscript and its Supplementary information.

References

  1. Mukherjee, S., Yang, J. W., Hoffmann, S. & List, B. Asymmetric enamine catalysis. Chem. Rev. 107, 5471–5569 (2007).

    CAS  PubMed  Google Scholar 

  2. Alonso, D. A. et al. Recent advances in asymmetric organocatalyzed conjugate additions to nitroalkenes. Molecules 22, 895–945 (2017).

    PubMed Central  Google Scholar 

  3. van der Helm, M. P., Klemm, B. & Eelkema, R. Organocatalysis in aqueous media. Nat. Rev. Chem. 3, 491–508 (2019).

  4. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  PubMed  Google Scholar 

  5. 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. Ed. 44, 4212–4215 (2005).

    CAS  Google Scholar 

  6. Lalonde, M. P., Chen, Y. & Jacobsen, E. N. A chiral primary amine thiourea catalyst for the highly enantioselective direct conjugate addition of α,α-disubstituted aldehydes to nitroalkenes. Angew. Chem. Int. Ed. 45, 6366–6370 (2006).

    CAS  Google Scholar 

  7. Palomo, C., Vera, S., Mielgo, A. & Gómez-Bengoa, E. Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes catalyzed by a simple trans-4-hydroxyprolylamide. Angew. Chem. Int. Ed. 45, 5984–5987 (2006).

    CAS  Google Scholar 

  8. García-García, P., Ladépêche, A., Halder, R. & List, B. Catalytic asymmetric Michael reactions of acetaldehyde. Angew. Chem. Int. Ed. 47, 4719–4721 (2008).

    Google Scholar 

  9. Zhu, S., Yu, S. & Ma, D. Highly efficient catalytic system for enantioselective Michael addition of aldehydes to nitroalkenes in water. Angew. Chem. Int. Ed. 47, 545–548 (2008).

    CAS  Google Scholar 

  10. Wiesner, M., Revell, J. D. & Wennemers, H. Tripeptides as efficient asymmetric catalysts for 1,4-addition reactions of aldehydes to nitroolefins–a rational approach. Angew. Chem. Int. Ed. 47, 1871–1874 (2008).

    CAS  Google Scholar 

  11. Wiesner, M., Neuburger, M. & Wennemers, H. Tripeptides of the type H-D-Pro-Pro-Xaa-NH2 as catalysts for asymmetric 1,4-addition reactions: structural requirements for high catalytic efficiency. Chem. Eur. J. 15, 10103–10109 (2009).

    CAS  PubMed  Google Scholar 

  12. Seebach, D. & Goliński, J. Synthesis of open-chain 2,3-disubstituted 4-nitroketones by diastereoselective Michael-addition of (E)-enamines to (E)-nitroolefins. A topological rule for C,C-bond forming processes between prochiral centres. Preliminary communication. Helv. Chim. Acta 64, 1413–1423 (1981).

    CAS  Google Scholar 

  13. Seebach, D., Beck, A. K., Goliński, J., Hay, J. N. & Laube, T. Über den sterischen verlauf der umsetzung von enaminen aus offenkettigen aldehyden und ketonen mit nitroolefinen zu 2,3-disubstituierten 4-nitroketonen. Helv. Chim. Acta 68, 162–172 (1985).

    CAS  Google Scholar 

  14. Husch, T., Seebach, D., Beck, A. K. & Reiher, M. Rigorous conformational analysis of pyrrolidine enamines with relevance to organocatalysis. Helv. Chim. Acta 100, e1700182 (2017).

    Google Scholar 

  15. Földes, T. et al. Stereocontrol in diphenylprolinol silyl ether catalyzed Michael additions: steric shielding or Curtin–Hammett scenario? J. Am. Chem. Soc. 139, 17052–17063 (2017).

    PubMed  Google Scholar 

  16. Zhu, S., Yu, S., Wang, Y. & Ma, D. Organocatalytic Michael addition of aldehydes to protected 2-amino-1-nitroethenes: the practical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidines. Angew. Chem. Int. Ed. 49, 4656–4660 (2010).

    CAS  Google Scholar 

  17. Uehara, H. & Barbas, C. anti-Selective asymmetric Michael reactions of aldehydes and nitroolefins catalyzed by a primary amine/thiourea. Angew. Chem. Int. Ed. 48, 9848–9852 (2009).

    CAS  Google Scholar 

  18. Kano, T., Sugimoto, H., Tokuda, O. & Maruoka, K. Unusual anti-selective asymmetric conjugate addition of aldehydes to nitroalkenes catalyzed by a biphenyl-based chiral secondary amine. Chem. Commun. 49, 7028–7030 (2013).

    CAS  Google Scholar 

  19. Macharia, J. et al. A designed approach to enantiodivergent enamine catalysis. Angew. Chem. Int. Ed. 56, 8756–8760 (2017).

    CAS  Google Scholar 

  20. Duschmalé, J. & Wennemers, H. Adapting to substrate challenges: peptides as catalysts for conjugate addition reactions of aldehydes to α,β-disubstituted nitroolefins. Chem. Eur. J. 18, 1111–1120 (2012).

    PubMed  Google Scholar 

  21. Kastl, R. & Wennemers, H. Peptide-catalyzed stereoselective conjugate addition reactions generating all-carbon quaternary stereogenic centers. Angew. Chem. Int. Ed. 52, 7228–7232 (2013).

    CAS  Google Scholar 

  22. Krattiger, P., Kovasy, R., Revell, J. D., Ivan, S. & Wennemers, H. Increased structural complexity leads to higher activity: peptides as efficient and versatile catalysts for asymmetric aldol reactions. Org. Lett. 7, 1101–1103 (2005).

    CAS  PubMed  Google Scholar 

  23. Grünenfelder, C. E., Kisunzu, J. K. & Wennemers, H. Peptide-catalyzed stereoselective conjugate addition reactions of aldehydes to maleimide. Angew. Chem. Int. Ed. 55, 8571–8574 (2016).

    Google Scholar 

  24. Schnitzer, T. & Wennemers, H. Influence of the trans/cis conformer ratio on the stereoselectivity of peptidic catalysts. J. Am. Chem. Soc. 139, 15356–15362 (2017).

    CAS  PubMed  Google Scholar 

  25. Wiesner, M., Upert, G., Angelici, G. & Wennemers, H. Enamine catalysis with low catalyst loadings - high efficiency via kinetic studies. J. Am. Chem. Soc. 132, 6–7 (2010).

    CAS  PubMed  Google Scholar 

  26. Bächle, F., Duschmalé, J., Ebner, C., Pfaltz, A. & Wennemers, H. Organocatalytic asymmetric conjugate addition of aldehydes to nitroolefins: identification of catalytic intermediates and the stereoselectivity-determining step by ESI-MS. Angew. Chem. Int. Ed. 52, 12619–12623 (2013).

    Google Scholar 

  27. Duschmalé, J., Wiest, J., Wiesner, M. & Wennemers, H. Effects of internal and external carboxylic acids on the reaction pathway of organocatalytic 1,4-addition reactions between aldehydes and nitroolefins. Chem. Sci. 4, 1312–1318 (2013).

    Google Scholar 

  28. Rigling, C. et al. Conformational properties of a peptidic catalyst: insights from NMR spectroscopic studies. J. Am. Chem. Soc. 140, 10829–10838 (2018).

    CAS  PubMed  Google Scholar 

  29. Schnitzer, T., Wiesner, M., Krattiger, P., Revell, J. D. & Wennemers, H. Is more better? A comparison of tri- and tetrapeptidic catalysts. Org. Biomol. Chem. 15, 5877–5881 (2017).

    CAS  PubMed  Google Scholar 

  30. Schnitzer, T. & Wennemers, H. Effect of γ-substituted proline derivatives on the performance of the peptidic catalyst H-dPro-Pro-Glu-NH2. Synthesis 50, 4377–4382 (2018).

    CAS  Google Scholar 

  31. Harder, E. et al. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J. Chem. Theory Comput. 12, 281–296 (2016).

    CAS  PubMed  Google Scholar 

  32. Still, W. C., Tempczyk, A., Hawley, R. C. & Hendrickson, T. Semianalytical treatment of solvation for molecular mechanics and dynamics. J. Am. Chem. Soc. 112, 6127–6129 (1990).

    CAS  Google Scholar 

  33. Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 132, 154104 (2010).

    PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. Krishnan, R., Binkley, J. S., Seeger, R. & Pople, J. A. Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 72, 650–654 (1980).

    CAS  Google Scholar 

  37. McLean, A. D. & Chandler, G. S. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z=11–18. J. Chem. Phys. 72, 5639–5648 (1980).

    CAS  Google Scholar 

  38. Schmid, M. B., Zeitler, K. & Gschwind, R. M. Distinct conformational preferences of prolinol and prolinol ether enamines in solution revealed by NMR. Chem. Sci. 2, 1793–1803 (2011).

    CAS  Google Scholar 

  39. Haindl, M. H., Hioe, J. & Gschwind, R. M. The proline enamine formation pathway revisited in dimethyl sulfoxide: rate constants determined via NMR. J. Am. Chem. Soc. 137, 12835–12842 (2015).

    CAS  PubMed  Google Scholar 

  40. Schmid, M. B., Zeitler, K. & Gschwind, R. M. Formation and stability of prolinol and prolinol ether enamines by NMR: delicate selectivity and reactivity balances and parasitic equilibria. J. Am. Chem. Soc. 133, 7065–7074 (2011).

    CAS  PubMed  Google Scholar 

  41. Metrano, A. J. & Miller, S. J. Peptide-based catalysts reach the outer sphere through remote desymmetrization and atroposelectivity. Acc. Chem. Res. 52, 199–215 (2019).

    CAS  PubMed  Google Scholar 

  42. Colby Davie, E. A., Mennen, S. M., Xu, Y. & Miller, S. J. Asymmetric catalysis mediated by synthetic peptides. Chem. Rev. 107, 5759–5812 (2007).

    CAS  Google Scholar 

  43. Lewandowski, B. & Wennemers, H. Asymmetric catalysis with short-chain peptides. Curr. Opin. Chem. Biol. 22, 40–46 (2014).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Fonds der Chemischen Industrie (Germany) for a Kekulé Fellowship for T.S., the Alfred Werner Fund of the Swiss Chemical Society Foundation for an MSc scholarship for A.B. and the Swiss National Science Foundation (grant no. 200020_169423).

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Authors and Affiliations

  1. Laboratory of Organic Chemistry, ETH Zurich, Zurich, Switzerland

    Tobias Schnitzer, Alena Budinská & Helma Wennemers

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  1. Tobias Schnitzer
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  2. Alena Budinská
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Contributions

T.S. and A.B. conducted the experiments. T.S. and H.W. conceived and designed the project, analysed the data and prepared this manuscript.

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Correspondence to Helma Wennemers.

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Supplementary information

Supplementary Information

Supplementary methods, Tables 1–5, Figs. 1 and 2 and references.

Supplementary Data 1

Coordinates of the calculated lowest-energy structures.

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Schnitzer, T., Budinská, A. & Wennemers, H. Organocatalysed conjugate addition reactions of aldehydes to nitroolefins with anti selectivity. Nat Catal 3, 143–147 (2020). https://doi.org/10.1038/s41929-019-0406-4

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