Cu-catalyzed enantioselective allylic alkylation with organolithium reagents

Abstract

This protocol describes a method for the catalytic enantioselective synthesis of tertiary and quaternary carbon stereogenic centers, which are widely present in pharmaceutical and natural products. The method is based on the direct reaction between organolithium compounds, which are cheap, readily available and broadly used in chemical synthesis, and allylic electrophiles, using chiral copper catalysts. The methodology involves the asymmetric allylic alkylation (AAA) of allyl bromides, chlorides and ethers with organolithium compounds using catalyst systems based on Cu–Taniaphos and Cu–phosphoramidites. The protocol contains a complete description of the reaction setup, a method based on 1H-NMR, gas chromatography–mass spectrometry (GC—MS) and chiral HPLC for assaying the regioselectivity and enantioselectivity of the product, and isolation, purification and characterization procedures. Six Cu-catalyzed AAA reactions between different organolithium reagents and allylic systems are detailed in the text as representative examples of these procedures. These reactions proceed within 1–10 h, depending on the nature of the allylic substrate (bromide, chloride, or ether and disubstituted or trisubstituted) or the chiral ligand used (Taniaphos or phosphoramidite). However, the entire protocol, including workup and purification, generally requires an additional 4–7 h to complete.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pd- and Cu-catalyzed AAA methodologies.
Figure 2: Cu-catalyzed AAA using organolithium compounds; preferred chiral ligands for different combinations of allylic substrates and organolithium reagents.
Figure 3: Examples of Cu-catalyzed AAA reactions.
Figure 4: Examples of Cu-catalyzed AAA reactions.
Figure 5
Figure 6: Taking a solution of allyl halide with a syringe to transfer to the reaction vessel.
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11: HPLC traces of phenacyl ester of (S)-Arundic acid 4.

References

  1. 1

    Modern Organocopper Chemistry (eds. Krause, N., Karlström, A.S.E. & Bäckvall, J.E.) 259–288 (Wiley-VCH, 2004).

  2. 2

    Yorimitsu, H. & Oshima, K. Recent progress in asymmetric allylic substitutions catalyzed by chiral copper complexes. Angew. Chem. Int. Ed. 44, 4435–4439 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Geurts, K., Fletcher, S.P., van Zijl, A.W., Minnaard, A.J. & Feringa, B.L. Copper catalyzed asymmetric allylic substitution reactions with organozinc and Grignard reagents. Pure Appl. Chem. 80, 1025–1037 (2008).

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    Falciola, C.A. & Alexakis, A. Copper catalyzed asymmetric allylic alkylation. Eur. J. Org. Chem. 22, 3765–3780 (2008).

    Article  Google Scholar 

  7. 7

    Langlois, J.B. & Alexakis, A. Copper-catalyzed enantioselective allylic substitution. Top. Organomet. Chem. 38, 235–268 (2012).

    Article  Google Scholar 

  8. 8

    Baslé, O., Denicourt-Nowicki, A., Crévisy C. & Mauduit, M. Copper-Catalyzed Asymmetric Synthesis (eds. Alexakis, A., Krause, N. & Woodward, S.) Chapter 4 (Wiley-VCH, 2014).

  9. 9

    Hornillos, V., Gualtierotti, J.-B. & Feringa, B.L. Asymmetric allylic substitutions using organometallic reagents. Top. Organomet. Chem. 58, 1–39 (2016).

    CAS  Article  Google Scholar 

  10. 10

    Trost, B.M. & Crawey, M.L. Asymmetric transition-metal-catalyzed allylic alkylations: applications in total synthesis. Chem. Rev. 103, 2921–2944 (2008).

    Article  Google Scholar 

  11. 11

    Trost, B.M. Asymmetric allylic alkylation, an enabling methodology. Chem. Rev. 69, 5813–5837 (2004).

    CAS  Google Scholar 

  12. 12

    Lu, Z. & Ma, S.M. Metal-catalyzed enantioselective allylation in asymmetric synthesis. Angew. Chem. Int. Ed. 47, 258–297 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Pérez, M. et al. Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds. Nat. Chem. 3, 377–381 (2011).

    Article  Google Scholar 

  14. 14

    Fañanás-Mastral, M. et al. Enantioselective synthesis of tertiary and quaternary stereogenic centers: copper/phosphoramidite-catalyzed allylic alkylation with organolithium reagents. Angew. Chem. Int. Ed. 51, 1922–1925 (2012).

    Article  Google Scholar 

  15. 15

    Guduguntla, S., Fañanás-Mastral, M. & Feringa, B.L. Synthesis of optically Active β- or γ-alkyl-substituted alcohols through copper-catalyzed asymmetric allylic alkylation with organolithium reagents. J. Org. Chem. 78, 8274–8280 (2013).

    CAS  Article  Google Scholar 

  16. 16

    Fañanás-Mastral, M., Vitale, R., Pérez, M. & Feringa, B.L. Enantioselective synthesis of all-carbon quaternary stereogenic centers via copper-catalyzed asymmetric allylic alkylation of (Z)-allyl bromides with organolithium reagents. Chem. Eur. J. 21, 4209–4212 (2015).

    Article  Google Scholar 

  17. 17

    Pérez, M. et al. Asymmetric allylic alkylation of acyclic allylic ethers with organolithium reagents. Chem. Eur. J. 18, 11880–11883 (2012).

    Article  Google Scholar 

  18. 18

    Bos, P.H. et al. Copper-catalyzed asymmetric ring opening of oxabicyclic alkenes with organolithium reagents. Chem. Commun. 48, 1748–1750 (2012).

    CAS  Article  Google Scholar 

  19. 19

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

  20. 20

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

    Article  Google Scholar 

  21. 21

    Lithium Compounds in Organic Synthesis. (eds. Luisi, R. & Capriati, V.) (Wiley-VCH, 2014).

  22. 22

    Anctil, E.J. & Snieckus, V. Metal Catalyzed Cross-Coupling Reactions. Vol. 1; (eds. de Meijere A. & Diederich, F.) (Weinheim, Germany, 2004; pp 761–813 ).

  23. 23

    Ireland, T., Grossheimann, G., Wieser-Jeunesse, C. & Knochel, P. Ferrocenyl ligands with two phosphanyl substituents in the α,ɛ positions for the transition metal catalyzed asymmetric hydrogenation of functionalized double bonds. Angew. Chem. Int. Ed. 38, 3212–3215 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Ireland, T., Tappe, K., Grossheimann, G. & Knochel, P. Synthesis of a new class of chiral 1,5-diphosphanylferrocene ligands and their use in enantioselective hydrogenation. Chem. Eur. J. 8, 843–852 (2002).

    CAS  Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Prakash, J. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).

    Article  Google Scholar 

  27. 27

    Myers, E.D., Butts, C.P. & Aggarwal, V.K. BF3·OEt2 and TMSOTf: a synergistic combination of Lewis acids. Chem. Commun. 4434–4436 (2006).

  28. 28

    Gualandi, A., Emer, E., Guiteras-Capdevila, M. & Cozzi, P.G. Highly enantioselective αalkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate: a formal organocatalytic αalkylation of aldehydes by the carbenium ion. Angew. Chem. Int. Ed. 50, 7842–7846 (2011).

    CAS  Article  Google Scholar 

  29. 29

    Lombardi, M., Morganti, S. & Trombini, C.J. 3-Bromopropenyl esters in organic synthesis: indium- and zinc-mediated entries to alk-1-ene-3,4-diols. J. Org. Chem. 68, 997–1006 (2003).

    Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    Tissot-Croset, K., Polet, D., Gille, S., Hawner, C. & Alexakis, A. Synthesis and use of a phosphoramidite ligand for the copper-catalyzed enantioselective allylic substitution. Tandem allylic substitution-ring closing metathesis. Synthesis, 2586–2590 (2004).

  32. 32

    Feringa, B.L., Pineschi, M., Arnold, L.A., Imbos, R. & De Vries, A.H.M. Highly enantioselective catalytic conjugate addition and tandem conjugate addition–aldol reactions of organozinc reagents. Angew. Chem., Int. Ed. 36, 2620–2623 (1997).

    CAS  Article  Google Scholar 

  33. 33

    Choi, Y.H., Choi, J.Y., Yang, H.Y. & Kim, Y.H. Copper-catalyzed conjugate addition on macrocyclic, cyclic, and acyclic enones with a chiral phosphoramidite ligand having a C2-symmetric amine moiety. Tetrahedron: Asymmetry 13, 801–804 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Teichert, J.F. & Feringa, B.L. Catalytic asymmetric synthesis of 2,5-naphthylpyrrolidine. Synthesis 7, 1200–1204 (2010).

    Google Scholar 

  35. 35

    Kofron, W.G. & Baclawski, L.M. A convenient method for estimation of alkyllithium concentrations. J. Org. Chem. 41, 1879–1880 (1976).

    CAS  Article  Google Scholar 

  36. 36

    Love, B.E. & Jones, E.G. The use of salicylaldehyde phenylhydrazone as an indicator for the titration of organometallic reagents. J. Org. Chem. 64, 3755–3756 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Sigma-Aldrich. Determination of water content in dichloromethane, methylene chloride using Karl Fischer titration. http://www.sigmaaldrich.com/technical-documents/articles/analytical-applications/karl-fischer/water-determination-in-dichloromethane-methylene-chloride.html.

  38. 38

    Closs, G.L. Carbenes from alkyl halides and organolithium compounds. IV. Formation of alkylcarbenes from methylene chloride and alkyllithium compounds. J. Am. Chem. Soc. 84, 809–813 (1962).

    CAS  Article  Google Scholar 

  39. 39

    Still, W.C., Kahn, M. & Mitra, A. Rapid chromatographic technique for preparative separations with moderate resolution. J. Org. Chem. 43, 2923–2925 (1978).

    CAS  Article  Google Scholar 

  40. 40

    López, F., van Zijl, A.W., Minnaard, A.J. & Feringa, B.L. Highly enantioselective cu-catalysed allylic substitutions with Grignard reagents. Chem. Commun. 409–411 (2006).

  41. 41

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

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported financially by the European Research Council (Advanced Investigator Grant no. 227897 to B.L.F.). The Netherlands Organization for Scientific Research (NWO-CW); funding from the Ministry of Education, Culture and Science (Gravitation program 024.001.035); The Royal Netherlands Academy of Arts and Sciences (KNAW); and NRSC-Catalysis are gratefully acknowledged.

Author information

Affiliations

Authors

Contributions

V.H. and B.L.F. wrote the manuscript. All authors contributed to designing the experiments, analyzing the data and editing the manuscript. B.L.F. guided the research.

Corresponding author

Correspondence to Ben L Feringa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hornillos, V., Guduguntla, S., Fañanás-Mastral, M. et al. Cu-catalyzed enantioselective allylic alkylation with organolithium reagents. Nat Protoc 12, 493–505 (2017). https://doi.org/10.1038/nprot.2016.179

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

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