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Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes

Abstract

The asymmetric one-step net addition of unactivated propargylic C–H bonds to aldehydes leads to an atom-economic construction of versatile chiral homopropargylic alcohols, but has not yet been realized. Here we show its implementation in an intramolecular manner under mild reaction conditions. This chemistry—via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand—achieves asymmetric catalytic deprotonation of propargylic C–H (pKa > 30) by a tertiary amine group (pKa ≈ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pKa ≈ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The cyclopentane/cyclohexane-fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans-selectivities with or without a preexisting substrate chiral centre. Density functional theory studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm additional metal–ligand cooperation.

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Fig. 1: Asymmetric propargylation of aldehydes.
Fig. 2: Oak Ridge thermal ellipsoid plots of crystal structures.
Fig. 3: DFT-calculated energetics of the reaction of 3a in DCE.
Fig. 4: Further transformations of the products.

Data availability

Experimental procedures, characterization of compounds and DFT calculations are available in the Supplementary Information. The X-ray diffraction data for 11, 6p and (S)-L3AuCl are deposited to the Cambridge Crystallographic Data Centre (CCDC) with the reference numbers 1988012, 1988013 and 1988482, respectively. All data are available from the authors on reasonable request.

References

  1. 1.

    Ding, C.-H. & Hou, X.-L. Catalytic asymmetric propargylation. Chem. Rev. 111, 1914–1937 (2011).

    CAS  Article  Google Scholar 

  2. 2.

    Yang, X., Kalita, S. J., Maheshuni, S. & Huang, Y.-Y. Recent advances on transition-metal-catalyzed asymmetric tandem reactions with organoboron reagents. Coord. Chem. Rev. 392, 35–48 (2019).

    CAS  Article  Google Scholar 

  3. 3.

    Alvarez, L. X., Christ, M. L. & Sorokin, A. B. Selective oxidation of alkenes and alkynes catalyzed by copper complexes. Appl. Catal. A 325, 303–308 (2007).

    CAS  Article  Google Scholar 

  4. 4.

    Cheng, D. & Bao, W. Propargylation of 1,3-dicarbonyl compounds with 1,3-diarylpropynes via oxidative cross-coupling between sp3 C–H and sp3 C–H. J. Org. Chem. 73, 6881–6883 (2008).

    CAS  Article  Google Scholar 

  5. 5.

    Grigg, R. D., Rigoli, J. W., Pearce, S. D. & Schomaker, J. M. Synthesis of propargylic and allenic carbamates via the C–H amination of alkynes. Org. Lett. 14, 280–283 (2012).

    CAS  Article  Google Scholar 

  6. 6.

    Wang, T., Zhou, W., Yin, H., Ma, J.-A. & Jiao, N. Iron-facilitated oxidative dehydrogenative C–O bond formation by propargylic C–H functionalization. Angew. Chem. Int. Ed. 51, 10823–10826 (2012).

    CAS  Article  Google Scholar 

  7. 7.

    Lu, H., Li, C., Jiang, H., Lizardi, C. L. & Zhang, X. P. Chemoselective amination of propargylic C(sp3)–H bonds by cobalt(ii)-based metalloradical catalysis. Angew. Chem. Int. Ed. 53, 7028–7032 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Fernández-Salas, J. A., Eberhart, A. J. & Procter, D. J. Metal-free CH–CH-type cross-coupling of arenes and alkynes directed by a multifunctional sulfoxide group. J. Am. Chem. Soc. 138, 790–793 (2016).

    Article  Google Scholar 

  9. 9.

    Hu, G., Xu, J. & Li, P. Sulfur mediated propargylic C–H alkylation of alkynes. Org. Chem. Front. 5, 2167–2170 (2018).

    CAS  Article  Google Scholar 

  10. 10.

    Ju, M. et al. Silver-catalyzed enantioselective propargylic C–H bond amination through rational ligand design. J. Am. Chem. Soc. 142, 12930–12936 (2020).

    CAS  Article  Google Scholar 

  11. 11.

    Wang, Y., Zhu, J., Durham, A. C., Lindberg, H. & Wang, Y.-M. α-C–H Functionalization of π-bonds using iron complexes: catalytic hydroxyalkylation of alkynes and alkenes. J. Am. Chem. Soc. 141, 19594–19599 (2019).

    CAS  Article  Google Scholar 

  12. 12.

    Li, T. & Zhang, L. Bifunctional biphenyl-2-ylphosphine ligand enables tandem gold-catalyzed propargylation of aldehyde and unexpected cycloisomerization. J. Am. Chem. Soc. 140, 17439–17443 (2018).

    CAS  Article  Google Scholar 

  13. 13.

    Wang, Z., Wang, Y. & Zhang, L. Soft propargylic deprotonation: designed ligand enables Au-catalyzed isomerization of alkynes to 1,3-dienes. J. Am. Chem. Soc. 136, 8887–8890 (2014).

    CAS  Article  Google Scholar 

  14. 14.

    Wang, Z., Ying, A., Fan, Z., Hervieu, C. & Zhang, L. Tertiary amino group in cationic gold catalyst: tethered frustrated lewis pairs that enable ligand-controlled regiodivergent and stereoselective isomerizations of propargylic esters. ACS Catal. 7, 3676–3680 (2017).

    Article  Google Scholar 

  15. 15.

    Li, X., Ma, X., Wang, Z., Liu, P.-N. & Zhang, L. Bifunctional phosphine ligand enabled gold-catalyzed alkynamide cycloisomerization: access to electron-rich 2-aminofurans and their Diels–Alder adducts. Angew. Chem. Int. Ed. 58, 17180–17184 (2019).

    CAS  Article  Google Scholar 

  16. 16.

    Li, X., Wang, Z., Ma, X., Liu, P.-N. & Zhang, L. Designed bifunctional phosphine ligand-enabled gold-catalyzed isomerizations of ynamides and allenamides: stereoselective and regioselective formation of 1-amido-1,3-dienes. Org. Lett. 19, 5744–5747 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Wang, H., Li, T., Zheng, Z. & Zhang, L. Efficient synthesis of α-allylbutenolides from allyl ynoates via tandem ligand-enabled Au(i) catalysis and the Claisen rearrangement. ACS Catal. 9, 10339–10342 (2019).

    CAS  Article  Google Scholar 

  18. 18.

    Li, T., Yang, Y., Li, B., Bao, X. & Zhang, L. Gold-catalyzed silyl-migrative cyclization of homopropargylic alcohols enabled by bifunctional biphenyl-2-ylphosphine and DFT studies. Org. Lett. 21, 7791–7794 (2019).

    CAS  Article  Google Scholar 

  19. 19.

    Cheng, X., Wang, Z., Quintanilla, C. D. & Zhang, L. Chiral bifunctional phosphine ligand enabling gold-catalyzed asymmetric isomerization of alkyne to allene and asymmetric synthesis of 2,5-dihydrofuran. J. Am. Chem. Soc. 141, 3787–3791 (2019).

    CAS  Article  Google Scholar 

  20. 20.

    Schnabel, C. et al. Total synthesis of natural and non-natural Δ5,6Δ12,13-jatrophane diterpenes and their evaluation as MDR modulators. J. Org. Chem. 76, 512–522 (2011).

    CAS  Article  Google Scholar 

  21. 21.

    Dahlmann, H. A., McKinney, A. J., Santos, M. P. & Davis, L. O. Organocatalyzed intramolecular carbonyl–ene reactions. Molecules 21, 713 (2016).

    Article  Google Scholar 

  22. 22.

    Amarasinghe, K. K. D. & Montgomery, J. Enantioselective total synthesis of (+)-testudinariol a using a new nickel-catalyzed allenyl aldehyde cyclization. J. Am. Chem. Soc. 124, 9366–9367 (2002).

    CAS  Article  Google Scholar 

  23. 23.

    Zhou, J., Yang, M., Akdag, A. & Schneller, S. W. C-4′ Truncated carbocyclic formycin derivatives. Tetrahedron 62, 7009–7013 (2006).

    CAS  Article  Google Scholar 

  24. 24.

    Basak, A., Chakrabarty, K., Ghosh, A. & Das, G. K. Theoretical study on the isomerization of propargyl derivative to conjugated diene under Au(i)-catalyzed reaction: a DFT study. Comput. Theor. Chem. 1083, 38–45 (2016).

    CAS  Article  Google Scholar 

  25. 25.

    Fu, J. et al. Gold-catalyzed rearrangement of allylic oxonium ylides: efficient synthesis of highly functionalized dihydrofuran-3-ones. Angew. Chem. Int. Ed. 52, 4198–4202 (2013).

    CAS  Article  Google Scholar 

  26. 26.

    Xiao, Y.-C. & Moberg, C. Silaborative carbocyclizations of 1,7-enynes. Diastereoselective preparation of chromane derivatives. Org. Lett. 18, 308–311 (2016).

    CAS  Article  Google Scholar 

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Acknowledgements

L.Z. thanks NIH (grant no. R01GM123342) and NSF CHE (grant no. 1800525) for financial support, and NSF (grant no. MRI-1920299) for the acquisition of Bruker 500 MHz and 400 MHz NMR instruments. The DFT studies were performed using the computational facilities purchased with funds from the National Science Foundation (grant no. CNS-1725797) and administered by the Center for Scientific Computing (CSC). The CSC is supported by the California NanoSystems Institute and the Materials Research Science and Engineering Center (MRSEC; NSF grant no. DMR 1720256) at UC Santa Barbara.

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Contributions

T.L. conducted the experiments and prepared a draft of the manuscript. X.C. synthesized the ligands and their gold catalysts and helped with the manuscript. P.Q. secured a postdoctoral fellowship from Wenzhou University for T.L. and participated in the chemistry design. L.Z. designed the chemistry and supervised its implementation and finalized the manuscript.

Corresponding authors

Correspondence to Pengcheng Qian or Liming Zhang.

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The authors declare no competing interests.

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Peer review information Nature Catalysis thanks Ryan Vander Linden and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Experimental procedures, DFT-optimized structure coordinates, X-ray diffraction data, chiral HPLC chromatographs and NMR spectra.

Supplementary Data 1

X-ray crystal data of compound 11.

Supplementary Data 2

X-ray crystal data of compound 6p.

Supplementary Data 3

X-ray crystal data of compound (S)-L3AuCl.

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Li, T., Cheng, X., Qian, P. et al. Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes. Nat Catal 4, 164–171 (2021). https://doi.org/10.1038/s41929-020-00569-8

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