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:

Tetrasubstituted allenes via the palladium-catalysed kinetic resolution of propargylic alcohols using a supporting ligand

Nature Catalysis volume 2, pages 997–1005 (2019)Cite this article

Subjects

Abstract

Efficient enantioselective construction of fully substituted allenes from simple starting materials is still a fundamental challenge due to the difficulty to discriminate between the four substituents at the 1- and 3-positions of the three-carbon axis of chirality. Here, we report a straightforward catalytic asymmetric synthesis of tetrasubstituted 2,3-allenoic acids from readily available racemic propargylic alcohols. Enabled by the co-catalysis of palladium and a Brønsted acid in the presence of a commercially available chiral ligand (DTBM-SEGphos) and an achiral monophosphine supporting ligand (PPh3), the kinetic resolution of propargylic alcohols proceeded efficiently in the presence of water and 1 atm CO, affording tetrasubstituted 2,3-allenoic acids in excellent enantioselectivity and atom economy with a good functional group compatibility. Performing a second kinetic resolution on the unreacted alcohol gave access to the other enantiomer of the product. These allenes are precursors to compounds with quaternary carbon centres and other chiral tetrasubstituted allene building blocks, which are of great interest.

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

Fig. 1: Approaches to tetrasubstituted allenes.
Fig. 2: Substrate scope study.
Fig. 3: Gram-scale reactions and synthetic applications.
Fig. 4: Kinetic studies and the reaction profile as monitored by 1H NMR and HPLC.
Fig. 5: Control experiments.
Fig. 6: SAESI-MS studies.
Fig. 7: Proposed mechanisms.

Similar content being viewed by others

Data availability

The X-ray crystallographic coordinates for the structures of (S)-2k, (S)-2v, (S)-2x and Pd((R)-DTBM-SEGphos)Cl2 C reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 1891253 ((S)-2k), 1855080 ((S)-2v), 1854910 ((S)-2x) and 1855156 (Pd((R)-DTBM-SEGphos)Cl2 C). These data can be obtained free of charge from http://www.ccdc.cam.ac.uk/data_request/cif. Experimental procedures and characterization of the new compounds are available in the Supplementary Information. All other data are available from the authors upon reasonable request.

References

  1. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zeng, X.-P., Cao, Z.-Y., Wang, Y.-H., Zhou, F. & Zhou, J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem. Rev. 116, 7330–7396 (2016).

    CAS  PubMed  Google Scholar 

  3. Hoffmann-Röder, A. & Krause, N. Synthesis and properties of allenic natural products and pharmaceuticals. Angew. Chem. Int. Ed. 43, 1196–1216 (2004).

    Google Scholar 

  4. Rivera-Fuentes, P. & Diederich, F. Allenes in molecular materials. Angew. Chem. Int. Ed. 51, 2818–2828 (2012).

    CAS  Google Scholar 

  5. Krause, N. & Hashimi, A. S. K. (eds) Modern Allene Chemistry (Wiley-VCH, 2004).

  6. Zimmer, R., Dinesh, C. U., Nandanan, E. & Khan, F. A. Palladium-catalyzed reactions of allenes. Chem. Rev. 100, 3067–3125 (2000).

    CAS  PubMed  Google Scholar 

  7. Ma, S. Transition metal-catalyzed/mediated reaction of allenes with a nucleophilic functionality connected to the α-carbon atom. Acc. Chem. Res. 36, 701–712 (2003).

    CAS  PubMed  Google Scholar 

  8. Ma, S. Some typical advances in the synthetic applications of allenes. Chem. Rev. 105, 2829–2871 (2005).

    PubMed  Google Scholar 

  9. Ma, S. Recent advances in the chemistry of allenes. Aldrichimica Acta 40, 91–102 (2007).

    CAS  Google Scholar 

  10. Ma, S. Electrophilic addition and cyclization reactions of allenes. Acc. Chem. Res. 42, 1679–1688 (2009).

    CAS  PubMed  Google Scholar 

  11. Aubert, C., Fensterbank, L., Garcia, P., Malacria, M. & Simonneau, A. Transition metal catalyzed cycloisomerizations of 1, n-allenynes and -allenenes. Chem. Rev. 111, 1954–1993 (2011).

    CAS  PubMed  Google Scholar 

  12. Yu, S. & Ma, S. Allenes in catalytic asymmetric synthesis and natural product syntheses. Angew. Chem. Int. Ed. 51, 3074–3112 (2012).

    CAS  Google Scholar 

  13. Ye, J. & Ma, S. Palladium-catalyzed cyclization reactions of allenes in the presence of unsaturated carbon–carbon bonds. Acc. Chem. Res. 47, 989–1000 (2014).

    CAS  PubMed  Google Scholar 

  14. Alcaide, B., Almendros, P. & Aragoncillo, C. Cyclization reactions of bis(allenes) for the synthesis of polycarbo(hetero)cycles. Chem. Soc. Rev. 43, 3106–3135 (2014).

    CAS  PubMed  Google Scholar 

  15. Muñoz, M. P. Silver and platinum-catalysed addition of O–H and N–H bonds to allenes. Chem. Soc. Rev. 43, 3164–3183 (2014).

    PubMed  Google Scholar 

  16. Yu, S. & Ma, S. How easy are the syntheses of allenes? Chem. Commun. 47, 5384–5418 (2011).

    CAS  Google Scholar 

  17. Chu, W.-D., Zhang, Y. & Wang, J. Recent advances in catalytic asymmetric synthesis of allenes. Catal. Sci. Technol. 7, 4570–4579 (2017).

    CAS  Google Scholar 

  18. Wang, Y., Zhang, W. & Ma, S. A room-temperature catalytic asymmetric synthesis of allenes with ECNU-Phos. J. Am. Chem. Soc. 135, 11517–11520 (2013).

    CAS  PubMed  Google Scholar 

  19. Poh, J.-S. et al. Rapid asymmetric synthesis of disubstituted allenes by coupling of flow-generated diazo compounds and propargylated amines. Angew. Chem. Int. Ed. 56, 1864–1868 (2017).

    CAS  Google Scholar 

  20. Jiang, Y., Diagne, A. B., Thomson, R. J. & Schaus, S. E. Enantioselective synthesis of allenes by catalytic traceless petasis reactions. J. Am. Chem. Soc. 139, 1998–2005 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, W. & Ma, S. Palladium-catalyzed enantioselective alkoxycarbonylation of propargylic carbonates with (R)-or (S)-3,4,5-(MeO)3-MeOBIPHEP. Chem. Eur. J. 23, 8590–8595 (2017).

    CAS  PubMed  Google Scholar 

  22. Dai, J., Duan, X., Zhou, J., Fu, C. & Ma, S. Catalytic enantioselective simultaneous control of axial chirality and central chirality in allenes. Chin. J. Chem. 36, 387–391 (2018).

    CAS  Google Scholar 

  23. Xu, X. et al. Nickel(ii)-catalyzed asymmetric propargyl [2, 3] wittig rearrangement of oxindole derivatives: a chiral amplification effect. Angew. Chem. Int. Ed. 57, 8734–8738 (2018).

    CAS  Google Scholar 

  24. Poulsen, P. H. et al. Organocatalytic formation of chiral trisubstituted allenes and chiral furan derivatives. Angew. Chem. Int. Ed. 57, 10661–10665 (2018).

    CAS  Google Scholar 

  25. Trost, B. M., Zell, D., Hohn, C., Mata, G. & Maruniak, A. Enantio- and diastereoselective synthesis of chiral allenes by palladium-catalyzed asymmetric [3+2] cycloaddition reactions. Angew. Chem. Int. Ed. 57, 12916–12920 (2018).

    CAS  Google Scholar 

  26. Wu, S. et al. A C–H bond activation-based catalytic approach to tetrasubstituted chiral allenes. Nat. Commun. 6, 7946–7954 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Wu, S., Huang, X., Fu, C. & Ma, S. Asymmetric SN2′-type C–H functionalization of arenes with propargylic alcohols. Org. Chem. Front. 4, 2002–2007 (2017).

    CAS  Google Scholar 

  28. Armstrong, R. J. et al. Enantiodivergent synthesis of allenes by point-to-axial chirality transfer. Angew. Chem. Int. Ed. 57, 8203–8208 (2018).

    CAS  Google Scholar 

  29. Zhang, W. & Ma, S. Palladium/H+-cocatalyzed kinetic resolution of tertiary propargylic alcohols. Chem. Commun. 54, 6064–6067 (2018).

    CAS  Google Scholar 

  30. Hammel, M. & Deska, J. Enantioselective synthesis of axially chiral tetrasubstituted allenes via lipase-catalyzed desymmetrization. Synthesis 44, 3789–3796 (2012).

    CAS  Google Scholar 

  31. Hayashi, T., Tokunaga, N. & Inoue, K. Rhodium-catalyzed asymmetric 1,6-addition of aryltitanates to enynones giving axially chiral allenes. Org. Lett. 6, 305–307 (2004).

    CAS  PubMed  Google Scholar 

  32. Qian, D., Wu, L., Lin, Z. & Sun, J. Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols. Nat. Commun. 8, 567–575 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Hashimoto, T., Sakata, K., Tamakuni, F., Dutton, M. J. & Maruoka, K. Phase-transfer-catalysed asymmetric synthesis of tetrasubstituted allenes. Nat. Chem. 5, 240–244 (2013).

    CAS  PubMed  Google Scholar 

  34. Mbofana, C. T. & Miller, S. J. Diastereo- and enantioselective addition of anilide-functionalized allenoates to N-acylimines catalyzed by a pyridylalanine-based peptide. J. Am. Chem. Soc. 136, 3285–3292 (2014).

    CAS  PubMed  Google Scholar 

  35. Wang, G. et al. Diastereoselective and enantioselective alleno-aldol reaction of allenoates with isatins to synthesis of carbinol allenoates catalyzed by gold. ACS Catal. 6, 2482–2486 (2016).

    CAS  Google Scholar 

  36. Tang, Y. et al. Asymmetric three-component reaction for the synthesis of tetrasubstituted allenoates via allenoate-copper intermediates. Chem 4, 1658–1672 (2018).

    CAS  Google Scholar 

  37. Tap, A., Blond, A., Wakchaure, V. N. & List, B. Chiral allenes via alkynylogous mukaiyama aldol reaction. Angew. Chem. Int. Ed. 55, 8962–8965 (2016).

    CAS  Google Scholar 

  38. Ma, S., Yu, Z. & Wu, S. CuCl-catalyzed cycloisomerization reaction of 1,2-allenyl carboxylic acids. A cost-effective synthesis of β-unsubstituted butenolides. Tetrahedron 57, 1585–1588 (2001).

    CAS  Google Scholar 

  39. Ma, S. & Yu, Z. Pd(ii)-catalyzed coupling cyclization of 2,3-allenoic acids with allylic halides. An efficient methodology for the synthesis of β-allylic butenolides. J. Org. Chem. 68, 6149–6152 (2003).

    CAS  PubMed  Google Scholar 

  40. Ma, S. & Gu, Z. PdCl2-catalyzed two-component cross-coupling cyclization of 2,3-allenoic acids with 2,3-allenols. An efficient synthesis of 4-(1′,3′-dien-2′-yl)-2(5H)-furanone derivatives. J. Am. Chem. Soc. 127, 6182–6183 (2005).

    CAS  PubMed  Google Scholar 

  41. Song, S., Zhou, J., Fu, C. & Ma, S. Catalytic enantioselective construction of axial chirality in 1,3-disubstituted allenes. Nat. Commun. 10, 507–515 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. Zhang, J.-T., Wang, H.-Y., Zhu, W., Cai, T.-T. & Guo, Y.-L. Solvent-assisted electrospray ionization for direct analysis of various compounds (complex) from low/nonpolar solvents and eluents. Anal. Chem. 86, 8937–8942 (2014).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support from the National Natural Science Foundation of China (grant no. 21690063 to S.M., grant no. 21801041 to H.Q. and 21532005 to Y.G.), the National Basic Research Program (2015CB856600 to S.M.) and Shanghai Sailing Program (18YF1402000 to H.Q.) is acknowledged. We thank H. Fang at Fudan University for help with the X-ray analysis and J. Xiao in this group for reproducing the results of (S)-2q and (S)-2aa and the gram-scale synthesis of (S)-2k and (R)-2k, presented in Fig. 2 and Fig. 3a.

Author information

Authors and Affiliations

  1. Research Centre for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, Shanghai, China

    Wei-Feng Zheng, Wanli Zhang, Chaofan Huang, Penglin Wu, Hui Qian & Shengming Ma

  2. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Lei Wang, Yin-Long Guo & Shengming Ma

Authors
  1. Wei-Feng Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wanli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chaofan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Penglin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yin-Long Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shengming Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.M. and H.Q. directed the research and developed the concept of the reaction with W.-F.Z., who also performed the experiments and prepared the Supplementary Information. W.Z., C.H. and P.W. were involved in the synthesis of substrates. Y.-L.G. directed the SAESI-MS reaction with L.W., who also collected and analysed the SAESI-MS spectra data. W.-F.Z., H.Q. and S.M. checked the experimental data. W.-F.Z., H.Q. and S.M. wrote the manuscript, with contributions from the other authors.

Corresponding authors

Correspondence to Hui Qian, Yin-Long Guo or Shengming Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Tables 1–14, Supplementary Figs. 1–24 and Supplementary References

Compound (S)-2k

Crystal data for compound (S)-k

Compound (S)-2v

Crystal data for compound (S)-2v

Compound (S)-2x

Crystal data for compound (S)-2x

Compound C

Crystal data for compound C

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, WF., Zhang, W., Huang, C. et al. Tetrasubstituted allenes via the palladium-catalysed kinetic resolution of propargylic alcohols using a supporting ligand. Nat Catal 2, 997–1005 (2019). https://doi.org/10.1038/s41929-019-0346-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-019-0346-z

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