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Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds

Nature Chemistry volume 3, pages 377–381 (2011)Cite this article

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Abstract

Carbon–carbon bond formation is the basis for the biogenesis of nature's essential molecules. Consequently, it lies at the heart of the chemical sciences. Chiral catalysts have been developed for asymmetric C–C bond formation to yield single enantiomers from several organometallic reagents. Remarkably, for extremely reactive organolithium compounds, which are among the most broadly used reagents in chemical synthesis, a general catalytic methodology for enantioselective C–C formation has proven elusive, until now. Here, we report a copper-based chiral catalytic system that allows carbon–carbon bond formation via allylic alkylation with alkyllithium reagents, with extremely high enantioselectivities and able to tolerate several functional groups. We have found that both the solvent used and the structure of the active chiral catalyst are the most critical factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active form of the chiral catalyst has been identified through spectroscopic studies as a diphosphine copper monoalkyl species.

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Figure 1
Figure 2: Mechanistic study of chiral catalyst formation and the effect of copper salt and co-solvents present in the alkyllithium reagent.

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  • 15 March 2011

    In the version of this Article originally published, the Acknowledgements section was incorrect. This error has now been corrected in all versions of the Article.

References

  1. Tidwell, T. T. Wilhelm Schlenk: the man behind the flask. Angew. Chem. Int. Ed. 40, 331–337 (2001).

    Article  CAS  Google Scholar 

  2. Schlenk, W. & Holtz, J. The simplest organometallic alkali compounds. Ber. Dtsch. Chem. Ges. 50, 262–274 (1917).

    Article  CAS  Google Scholar 

  3. Rappoport, Z. & Marek, I. (eds) The Chemistry of Organolithium Compounds. (Wiley-VCH, 2004).

    Book  Google Scholar 

  4. Nájera, C. & Yus, M. Functionalized organolithium compounds: new synthetic adventures. Curr. Org. Chem. 7, 867–926 (2003).

    Article  Google Scholar 

  5. Hodgson, D. M. (eds) Organolithiums in Enantioselective Synthesis. (Springer-Verlag, 2003).

    Book  Google Scholar 

  6. Majewski, M. & Snieckus, V. (eds) Organometallics: Compounds of Group 1 (Li…Cs). (Thieme, 2006).

    Google Scholar 

  7. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis: Suppl. 2. (Springer-Verlag, 2004).

    Google Scholar 

  8. Noyori, R. (eds) Asymmetric Catalysis in Organic Synthesis. (John Wiley & Sons, 1994).

    Google Scholar 

  9. Teichert, J. F. & Feringa, B. L. Phosphoramidites: privileged ligands in asymmetric catalysis. Angew. Chem. Int. Ed. 49, 2486–2528 (2010).

    Article  CAS  Google Scholar 

  10. Feringa, B. L., Naasz, R., Imbos, R. & Arnold, L. A. Copper-catalyzed enantioselective conjugate addition reactions of organozinc reagents, in Modern Organocopper Chemistry (ed. Krause, N.) 224–258 (Wiley-VCH, 2002).

    Chapter  Google Scholar 

  11. Hird, A. W. & Hoveyda, A. H. Catalytic enantioselective alkylations of tetrasubstituted olefins. Synthesis of all-carbon quaternary stereogenic centers through Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to enones. J. Am. Chem. Soc. 127, 14988–14989 (2005).

    Article  CAS  Google Scholar 

  12. Alexakis, A., Bäckvall, J. E., Krause, N., Pàmies, O. & Diéguez, M. Enantioselective copper-catalyzed conjugate addition and allylic substitution reactions. Chem. Rev. 108, 2796–2823 (2008).

    Article  CAS  Google Scholar 

  13. Gao, F., McGrath, K. P., Lee, Y., Mandai, K., Hoveyda, A. H. Synthesis of quaternary carbon stereogenic centers through enantioselective Cu-catalyzed allylic substitutions with vinyaluminum reagents. J. Am. Chem. Soc. 132, 14315–14320 (2010).

    Article  CAS  Google Scholar 

  14. Hawner, C., Cirriez, V., Li, K. & Alexakis, A. Copper-catalyzed asymmetric conjugate addition of aryl aluminum reagents to trisubstituted enones: construction of aryl-substituted quaternary centers. Angew. Chem. Int. Ed. 47, 8211–8214 (2008).

    Article  CAS  Google Scholar 

  15. Gao, F., Lee, Y., Mandai, K. & Hoveyda, A. H. Quaternary carbon stereogenic centers through copper-catalyzed enantioselective allylic substitutions with readily accessible aryl- or hetero-aryllithium reagents and aluminum chlorides. Angew. Chem. Int. Ed. 122, 8548–8552 (2010).

    Article  Google Scholar 

  16. Feringa, B. L., Badorrey, R., Peña, D., Harutyunyan, S. R. & Minnaard, A. J. Copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic enones Proc. Natl Acad. Sci. USA 101, 5834–5838 (2004).

    Article  CAS  Google Scholar 

  17. Harutyunyan, S. R., den Hartog, T., Geurts, K., Minnaard, A. J. & Feringa, B. L. Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents. Chem. Rev. 108, 2824–2852 (2008).

    Article  CAS  Google Scholar 

  18. Thaler, T. & Knochel, P. Copper-catalyzed asymmetric Michael addition of magnesium, zinc, and aluminum organometallic reagents: efficient synthesis of chiral molecules. Angew. Chem. Int. Ed. 48, 645–648 (2009).

    Article  CAS  Google Scholar 

  19. Corey, E. J., Naef, R. & Hannon, F. J. Enantioselective conjugate addition of rationally designed chiral cuprate reagents to 2-cycloalkenones J. Am. Chem. Soc. 108, 7114–7116. (1986).

    Article  CAS  Google Scholar 

  20. Denmark, S. E. & Stiff, C. M. Effect of ligand structure in the bisoxazoline mediated asymmetric addition of methyllithium to imines. J. Org. Chem. 65, 5875–5878 (2000).

    Article  CAS  Google Scholar 

  21. Tanaka, K., Matsui, J. & Suzuki, H. Chiral amplification and the catalytic process in the enantioselective conjugate addition of chiral alkoxydimethylcuprate to (E)-cyclopentadec-2-en-1-one. J. Chem. Soc. Perkin Trans. 1, 153–157 (1993).

    Article  Google Scholar 

  22. Beng, T. K. & Gawley, R. E. Highly enantioselective catalytic dynamic resolution of N-Boc-2-lithiopiperidine: synthesis of (R)-(+)-N-Boc-pipecolic acid, (S)-(–)-coniine, (S)-(+)-pelletierine, (+)-conhydrine, and (S)-(–)-ropivacaine and formal synthesis of (–)-lasubine II and (+)-cermizine C. J. Am. Chem. Soc. 132, 12216–12217 (2010).

    Article  CAS  Google Scholar 

  23. Bilke, J. L., Moore, S. P., O'Brien, P. & Gilday, J. Catalytic asymmetric synthesis of piperidines from pyrrolidine: concise synthesis of L-733,060. Org. Lett. 11, 1935–1938 (2009).

    Article  CAS  Google Scholar 

  24. Tomioka, K., Inoue, I., Mitsuru, I., Kenji, S. & Koga, K. Catalytic asymmetric addition of organolithiums to aldimines. Tetrahedron Lett. 24, 3095–3098 (1991).

    Article  Google Scholar 

  25. Inoue, I., Mitsuru, I., Kenji, S., Koga, K. & Tomioka, K. Asymmetric 1,2-addition of organolithiums to aldimines catalyzed by chiral ligand. Tetrahedron 50, 4429–4438 (1994).

    Article  Google Scholar 

  26. Alexakis, A. & Amiot, F. Enantioselective addition of organolithium reagents on isoquinoline. Tetrahedron: Asymmetry 13, 2117–2122 (2002).

    Article  CAS  Google Scholar 

  27. Denmark, S. E., Nakajima, N. & Nicaise, O. J.-C. Asymmetric addition of organolithium reagents to imines. J. Am. Chem. Soc. 116, 8797–8798 (1994).

    Article  CAS  Google Scholar 

  28. Denmark, S. E. & Nicaise, O. J.-C. Ligand-mediated addition of organometallic reagents to azomethine functions. Chem. Commun. 999–1004 (1996).

  29. Luderer, M. R. et al. Asymmetric addition of achiral organomagnesium reagents or organolithiums to achiral aldehydes or ketones: a review. Tetrahedron: Asymmetry 20, 981–998 (2009).

    Article  CAS  Google Scholar 

  30. Gessner, V. H., Däschlein, C. & Strohmann, C. Structure formation principles and reactivity of organolithium compounds. Chem. Eur. J. 15, 3320–3334 (2009).

    Article  CAS  Google Scholar 

  31. Paquin, J.-F. & Lautens, M. Allylic substitution reactions, in Comprehensive Asymmetric Catalysis: Suppl. 2 (eds, Jacobsen, E. N., Pfaltz, A. & Yamamoto, H.) 73–95 (Springer-Verlag, 2004).

    Google Scholar 

  32. Dai, L.-X. & Hou, X.-L. (eds) Chiral Ferrocene Ligands in Asymmetric Catalysis (Wiley-VCH, 2010).

    Google Scholar 

  33. van Zijl, A. W., Arnold, L. A., Minnaard, A. J. & Feringa, B. L. Highly enantioselective copper-catalyzed allylic alkylation with phosphoramidite ligands. Adv. Synth. Catal. 346, 413–420 (2004).

    Article  CAS  Google Scholar 

  34. Alexakis, A. & Croset, K. Tandem copper-catalyzed enantioselective allylation-metathesis Org. Lett. 4, 4147–4149 (2002).

    Article  CAS  Google Scholar 

  35. Van Veldhuizen, J. J., Campbell, J. E., Giudici, R. E. & Hoveyda, A. H. A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reactions. J. Am. Chem. Soc. 127, 6877–6882 (2005).

    Article  CAS  Google Scholar 

  36. Geurts, K., Fletcher, S. P. & Feringa, B. L. Copper catalyzed asymmetric synthesis of chiral allylic esters J. Am. Chem. Soc. 128, 15572–15573 (2006).

    Article  CAS  Google Scholar 

  37. Harutyunyan, S. R. et al. On the mechanism of the copper-catalyzed enantioselective 1,4-addition of Grignard reagents to α,β-unsaturated carbonyl compounds. J. Am. Chem. Soc. 128, 9103–9118 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge the Netherlands Organization for Scientific Research (NWO-CW) and the National Research School Catalysis (NRSC-C) for financial support. M.P. thanks the Xunta de Galicia for an Angeles Alvariño contract and Fondo Social Europeo. M.F.-M. thanks the Spanish Ministry of Science and Innovation (MICINN) for a postdoctoral fellowship.

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Authors and Affiliations

  1. Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands

    Manuel Pérez, Martín Fañanás-Mastral, Pieter H. Bos, Alena Rudolph, Syuzanna R. Harutyunyan & Ben L. Feringa

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  1. Manuel Pérez
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Contributions

M.P. and M.F.-M. studied solvent effects and optimized the reaction conditions. P.H.B. performed ligand screening. A.R. performed copper salt screening. S.R.H. carried out NMR studies. M.P., M.F.-M, P.H.B. and A.R. evaluated the scope of the organolithium addition reaction. All authors contributed to designing the experiments, analysing the data and editing the manuscript. S.R.H. and B.L.F. guided the research and wrote the manuscript.

Corresponding authors

Correspondence to Syuzanna R. Harutyunyan or Ben L. Feringa.

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The authors declare no competing financial interests.

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Pérez, M., Fañanás-Mastral, M., Bos, P. et al. Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds. Nature Chem 3, 377–381 (2011). https://doi.org/10.1038/nchem.1009

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