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 diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

Nature Chemistry volume 9, pages 1269–1275 (2017)Cite this article

Subjects

Abstract

There are many biologically active organic molecules that contain one or more nitrogen-containing moieties, and broadly applicable and efficient catalytic transformations that deliver them diastereoselectively and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (for example, from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N–H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N–H ketimine, a monosubstituted allene and B2(pin)2, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. The utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models developed with the aid of density functional theory calculations, which account for the observed trends and levels of enantioselectivity, are presented.

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

Figure 1: State of the art in allyl additions to ketimines and goals of the study.
Figure 2: Further exploration of scope and illustration of utility.
Figure 3: Stereochemical models.

Similar content being viewed by others

References

  1. Riant, O. & Hannedouche, J. Asymmetric catalysis for the construction of quaternary carbon centres: nucleophilic addition on ketones and ketimines. Org. Biomol. Chem. 5, 873–888 (2007).

    Article  CAS  Google Scholar 

  2. Shibasaki, M. & Kanai, M. Asymmetric synthesis of tertiary alcohols and α-tertiary amines via Cu-catalyzed C–C bond formation to ketones and ketimines. Chem. Rev. 108, 2853–2873 (2008).

    Article  CAS  Google Scholar 

  3. Kobayashi, S., Mori, Y., Fossey, J. S. & Salter, M. M. Catalytic enantioselective formation of C–C bonds by addition to imines and hydrazones: a ten-year update. Chem. Rev. 111, 2626–2704 (2011).

    Article  CAS  Google Scholar 

  4. Clayden, J., Donnard, M., Lefranc, J. & Tetlow, D. J. Quaternary centres bearing nitrogen (α-tertiary amines) as products of molecular rearrangements. Chem. Commun. 47, 4624–4639 (2011).

    Article  CAS  Google Scholar 

  5. Yus, M., González-Gómez, J. C. & Foubelo, F. Catalytic enantioselective allylation of carbonyl compounds and imines. Chem. Rev. 111, 7774–7854 (2011).

    Article  CAS  Google Scholar 

  6. Wada, R. et al. Catalytic enantioselective allylation of ketoimines. J. Am. Chem. Soc. 128, 7687–7691 (2006).

    Article  CAS  Google Scholar 

  7. Trost, B. M. & Silverman, S. M. Enantioselective construction of highly substituted pyrrolidines by palladium-catalyzed asymmetric [3+2] cycloaddition of trimethylenemethane with ketoimines. J. Am. Chem. Soc. 132, 8238–8240 (2010).

    Article  CAS  Google Scholar 

  8. Luo, Y., Hepburn, H. B., Chotsaeng, N. & Lam, H. W. Enantioselective rhodium-catalyzed nucleophilic allylation of imines with allylboron reagents. Angew. Chem. Int. Ed. 51, 8309–8313 (2012).

    Article  CAS  Google Scholar 

  9. Hepburn, H. & Lam, H. W. The isomerization of allylrhodium intermediates in the rhodium-catalyzed nucleophilic allylation of cyclic imines. Angew. Chem. Int. Ed. 53, 11605–11610 (2014).

    Article  CAS  Google Scholar 

  10. Nakamura, S., Hyodo, K., Nakamura, M., Nakane, D. & Masuda, H. Catalytic enantioselective allylation of ketimines by using palladium pincer complexes with chiral bis(imidazoline)s. Chem. Eur. J. 19, 7304–7309 (2013).

    Article  CAS  Google Scholar 

  11. Tang, T. P. & Ellman, J. A. Asymmetric synthesis of β-amino acids derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines. J. Org. Chem. 67, 7819–7832 (2002).

    Article  CAS  Google Scholar 

  12. Zhao, Y.-S., Liu, Q., Tian, P., Tao, J.-C. & Lin, G.-Q. Copper-catalyzed asymmetric allylation of chiral N-tert-butanesulfinyl imines: dual stereocontrol with nearly perfect diastereoselectivity. Org. Biomol. Chem. 13, 4174–4178 (2015).

    Article  CAS  Google Scholar 

  13. Chen, J. L.-Y. & Aggarwal, V. K. Highly diastereoselective and enantiospecific allylation of ketones and imines using borinic esters: contiguous quaternary stereogenic centers. Angew. Chem. Int. Ed. 53, 10992–10996 (2014).

    Article  CAS  Google Scholar 

  14. Rabbat, P. M. A., Valdez, S. C. & Leighton, J. L. Phenol-directed enantioselective allylation of aldimines and ketimines. Org. Lett. 8, 6119–6121 (2006).

    Article  CAS  Google Scholar 

  15. Perl, N. R. & Leighton, J. L. Enantioselective imidazole-directed allylation of aldimines and ketimines. Org. Lett. 9, 3699–3701 (2007).

    Article  CAS  Google Scholar 

  16. Dhudshia, B., Tiburcio, J. & Thadani, A. N. Diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones. Chem. Commun. 5551–5553 (2005).

  17. Meng, F., Jang, H., Jung, B. & Hoveyda, A. H. Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their in situ site-, diastereo-, and enantioselective additions to aldehydes and ketones. Angew. Chem. Int. Ed. 52, 5046–5051 (2013).

    Article  CAS  Google Scholar 

  18. Meng, F., Haeffner, F. & Hoveyda, A. H. Diastereo- and enantioselective reactions of bis(pinacolato)diboron, 1,3-enynes, and aldehydes catalyzed by an easily accessible bisphosphine–Cu complex. J. Am. Chem. Soc. 136, 11304–11307 (2014).

    Article  CAS  Google Scholar 

  19. Meng, F., McGrath, K. P. & Hoveyda, A. H. Multifunctional organoboron compounds for scalable natural product synthesis. Nature 513, 367–374 (2014).

    Article  CAS  Google Scholar 

  20. Yeung, K., Ruscoe, R. E., Rae, J., Pulis, A. P. & Procter, D. J. Enantioselective generation of adjacent stereocenters in copper-catalyzed three-component coupling of imines, allenes and diboranes. Angew. Chem. Int. Ed. 55, 11912–11916 (2016).

    Article  CAS  Google Scholar 

  21. Liu, R. Y., Yang, Y. & Buchwald, S. L. Regiodivergent and diastereoselective CuH-catalyzed allylation of imines with terminal alkenes. Angew. Chem. Int. Ed. 55, 14077–14080 (2016).

    Article  CAS  Google Scholar 

  22. Hou, G. et al. Enantioselective hydrogenation of N–H imines. J. Am. Chem. Soc. 131, 9882–9883 (2009).

    Article  CAS  Google Scholar 

  23. Tran, D. N. & Cramer, N. syn-Selective rhodium(I)-catalyzed allylation of ketimines proceeding through a directed C–H activation/allene addition sequence. Angew. Chem. Int. Ed. 49, 8181–8184 (2010).

    Article  CAS  Google Scholar 

  24. Thompson, L. A. et al. Compounds for the reduction of beta-amyloid production. US patent 2013/0131051 A1 (2012).

  25. Butler, C. R. et al. Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design. J. Med. Chem. 58, 2678–2702 (2015).

    Article  CAS  Google Scholar 

  26. Gao, F., Carr, J. L. & Hoveyda, A. H. A broadly applicable NHC–Cu-catalyzed approach for efficient, site- and enantioselective coupling of readily accessible (pinacolato)alkenylboron compounds to allylic phosphates and applications to natural product synthesis. J. Am. Chem. Soc. 136, 2149–2161 (2014).

    Article  CAS  Google Scholar 

  27. Shi, Y., Jung, B., Torker, S. & Hoveyda, A. H. N-Heterocyclic carbene–copper-catalyzed group-, site-, and enantioselective allylic substitution with a readily accessible propargyl(pinacolato)boron reagent: utility in stereoselective synthesis and mechanistic attributes. J. Am. Chem. Soc. 137, 8948–8964 (2015).

    Article  CAS  Google Scholar 

  28. Brown, K. M., May, T. L., Baxter, C. A. & Hoveyda, A. H. All-carbon quaternary stereogenic centers by enantioselective Cu-catalyzed conjugate additions promoted by a chiral N-heterocyclic carbene. Angew. Chem. Int. Ed. 46, 1097–1100 (2007).

    Article  CAS  Google Scholar 

  29. Dabrowski, J. A., Villaume, M. T. & Hoveyda, A. H. Enantioselective synthesis of quaternary carbon stereogenic centers through copper-catalyzed conjugate additions of aryl- and alkylaluminum reagents to acyclic trisubstituted enones. Angew. Chem. Int. Ed. 52, 8156–8159 (2013).

    Article  CAS  Google Scholar 

  30. Peese, K. M. & Gin, D. Y. Asymmetric synthetic access to the hetisine alkaloids: total synthesis of (+)-nominine. Chem. Eur. J. 14, 1654–1665 (2008).

    Article  CAS  Google Scholar 

  31. Takemura, H. et al. A study of C–F···M+ interaction: metal complexes of fluorine containing cage compounds. J. Am. Chem. Soc. 123, 9293–9298 (2001).

    Article  CAS  Google Scholar 

  32. Yamazaki, T., Kawashita, S., Kitazume, T. & Kubota, T. Diastereoselective alkylation of glycinates by assistance of intramolecular potassium···fluorine interactions. Chem. Eur. J. 15, 11461–11464 (1999).

    Article  Google Scholar 

  33. Sazarin, Y., Liu, B., Maron, L. & Carpentier, J.-F. Discrete, solvent-free alkaline-earth metal cations: metal···fluorine interactions and ROP catalytic activity. J. Am. Chem. Soc. 133, 9069–9087 (2011).

    Article  Google Scholar 

  34. Julian, L. D. & Hartwig, J. F. Intramolecular hydroamination of unbiased and functionalized primary aminoalkenes catalyzed by a rhodium aminophosphine complex. J. Am. Chem. Soc. 132, 13813–13822 (2010).

    Article  CAS  Google Scholar 

  35. Musacchio, A. J., Nguyen, L. Q., Beard, G. H. & Knowles, R. R. Catalytic olefin hydroamination with aminium radical cations: a photoredox method for direct C–N bond formation. J. Am. Chem. Soc. 136, 12217–12220 (2014).

    Article  CAS  Google Scholar 

  36. Du, Y. et al. Asymmetric reductive Mannich reactions to ketimines by a C(I) complex. J. Am. Chem. Soc. 130, 16146–16147 (2008).

    Article  CAS  Google Scholar 

  37. Hayashi, M. et al. Direct asymmetric Mannich-type reaction of α-isocyanoacetates with ketimines using cinchona alkaloid/copper(II) catalysts. Angew. Chem. Int. Ed. 53, 8411–8415 (2014).

    Article  CAS  Google Scholar 

  38. Wieland, L. C., Vieira, E. M., Snapper, M. L. & Hoveyda, A. H. Ag-catalyzed diastereo- and enantioselective vinylogous Mannich reactions of α-ketoimine esters. Development of a method and investigation of its mechanism. J. Am. Chem. Soc. 131, 570–576 (2009).

    Article  CAS  Google Scholar 

  39. Kano, T., Song, S., Kubota, Y. & Maruoka, K. Highly diastereo- and enantioselective Mannich reactions of synthetically flexible ketimines with secondary amine organocatalysts. Angew. Chem. Int. Ed. 51, 1191–1194 (2012).

    Article  CAS  Google Scholar 

  40. Lipshutz, B. H. & Shimizu, H. Copper(I)-catalyzed asymmetric hydrosilylations of imines at ambient temperature. Angew. Chem. Int. Ed. 43, 2228–2230 (2004).

    Article  CAS  Google Scholar 

  41. Niu, J. et al. Copper(I)-catalyzed aryl bromides to form intermolecular and intramolecular carbon–oxygen bonds. J. Org. Chem. 74, 5075–5078 (2009).

    Article  CAS  Google Scholar 

  42. Wang, J. L. et al. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life. Bioorg. Med. Chem. Lett. 20, 7159–7163 (2010).

    Article  CAS  Google Scholar 

  43. Shavnya, A., Coffey, S. B., Smith, A. C. & Mascitti, V. Palladium-catalyzed sulfination of aryl and heteroaryl halides: direct access to sulfones and sulfonamides. Org. Lett. 15, 6226–6229 (2013).

    Article  CAS  Google Scholar 

  44. Ye, X.-Y. et al. Synthesis and structure–activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists. Bioorg. Med. Chem. Lett. 24, 2539–2545 (2014).

    Article  CAS  Google Scholar 

  45. Wagner, J. P. & Schreiner, P. R. London dispersion in molecular chemistry—reconsidering steric effects. Angew. Chem. Int. Ed. 54, 12274–12296 (2015).

    Article  CAS  Google Scholar 

  46. Chen, L., Ren, P. & Carrow, B. P. Tri(1-adamantyl)phosphine: expanding the boundary of electron-releasing character available to organophosphorus compounds. J. Am. Chem. Soc. 138, 6392–6395 (2016).

    Article  CAS  Google Scholar 

  47. Albers, L., Rathjen, S., Baumgartner, J., Marschner, C. & Müller, T. Dispersion-energy-driven Wagner–Meerwein rearrangements in oligosilanes. J. Am. Chem. Soc. 138, 6886–6892 (2016).

    Article  CAS  Google Scholar 

  48. Slutskyy, Y. et al. Short enantioselective total syntheses of trans-clerodane diterpenoids: convergent fragment coupling using a trans-decalin tertiary radical generated from a tertiary alcohol precursor. J. Org. Chem. 81, 7029–7035 (2016).

    Article  CAS  Google Scholar 

  49. Lee, Y. & Hoveyda, A. H. Efficient boron–copper additions to aryl-substituted alkenes promoted by NHC-based catalysts. Enantioselective Cu-catalyzed hydroboration reaction. J. Am. Chem. Soc. 131, 3160–3161 (2009).

    Article  CAS  Google Scholar 

  50. Lee, Y., Jang, H. & Hoveyda, A. H. Vicinal diboronates in high enantiomeric purity through tandem site-selective NHC–Cu-catalyzed boron–copper additions to terminal alkynes. J. Am. Chem. Soc. 131, 18234–18235 (2009).

    Article  CAS  Google Scholar 

  51. Corberán, R., Mszar, N. W. & Hoveyda, A. H. NHC-Cu-catalyzed enantioselective hydroboration of acyclic and exocyclic 1,1-disubstituted aryl alkenes. Angew. Chem. Int. Ed. 50, 7079–7082 (2011).

    Article  Google Scholar 

  52. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of allylboronates bearing a tertiary or a quaternary B-substituted stereogenic carbon by NHC-Cu-catalyzed substitution reactions. J. Am. Chem. Soc. 132, 10634–10647 (2010).

    Article  CAS  Google Scholar 

  53. Meng, F., Jang, H. & Hoveyda, A. H. Exceptionally E- and β-selective NHC–Cu-catalyzed proto-silyl additions to terminal alkynes and site- and enantioselective proto-boryl additions to the resultine vinylsilanes: synthesis of enantiomerically enriched vicinal and geminal borosilanes. Chem. Eur. J. 19, 3204–3214 (2013).

    Article  CAS  Google Scholar 

  54. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of allylboronates bearing a tertiary or a quaternary B-substituted stereogenic carbon by NHC-Cu-catalyzed substitution reactions. J. Am. Chem. Soc. 132, 10634–10647 (2010).

    Article  CAS  Google Scholar 

  55. Jang, H., Jung, B. & Hoveyda, A. H. Catalytic enantioselective protoboration of disubstituted allenes. Access to alkenylboron compounds in high enantiomeric purity. Org. Lett. 16, 4658–4661 (2014).

    Article  CAS  Google Scholar 

  56. Lee, J., Torker, S. & Hoveyda, A. H. Versatile homoallylic boronates by chemo-, SN2′-, diastereo- and enantioselective catalytic sequence of Cu–H addition to vinyl-B(pin)/allylic substitution. Angew. Chem. Int. Ed. 56, 821–826 (2017).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant from the National Institutes of Health (GM-57212). H.J. was supported as a LaMattina Graduate Fellow in Chemical Synthesis. The authors thank F. Meng and J. Lee for discussions. We thank M.S. Mikus and B. Li for their assistance regarding X-ray structure determinations.

Author information

Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts, 02467, USA

    Hwanjong Jang, Filippo Romiti, Sebastian Torker & Amir H. Hoveyda

Authors
  1. Hwanjong Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Filippo Romiti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastian Torker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amir H. Hoveyda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.J. and F.R. developed the catalytic method and its various applications. S.T. designed and performed the DFT calculations. A.H.H. directed the investigations and composed the manuscript, with revisions provided by the other authors.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 14726 kb)

Supplementary information

Crystallographic data for compound 3y. (CIF 1345 kb)

Supplementary information

Crystallographic data for compound 9b. (CIF 269 kb)

Supplementary information

Crystallographic data for compound rac-3a. (CIF 1798 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jang, H., Romiti, F., Torker, S. et al. Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines. Nature Chem 9, 1269–1275 (2017). https://doi.org/10.1038/nchem.2816

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2816

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