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Enantioconvergent and regioselective reductive coupling of propargylic esters with chlorogermanes by nickel catalysis

Nature Catalysis volume 7, pages 12–20 (2024)Cite this article

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Abstract

Enantioconvergent cross-electrophile coupling has emerged as a potent technique in the creation of chiral molecules. However, existing research has primarily focused on transformations involving radical precursors such as alkyl halides. Here we innovate by harnessing Ni−C homolysis to achieve enantioconvergent reactions using non-radical precursors. Specifically we explore the reductive germylation of non-redox-active alcohol derivatives, renowned for their stereospecific reactivity. This approach enables the stereoconvergent coupling of propargylic esters (for example, OBoc, OAc and OPiv) with electrophiles, demonstrating exceptional propargylic selectivity. Furthermore, this work unveils the potential for development of a catalytic method to produce enantioenriched organogermanes, a largely unexplored research area. We illustrate the broad applicability of propargylic esters as substrates, investigate the effects of chlorogermanes and highlight the potential for further product derivatization.

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Fig. 1: Exploring the stereoconvergent reaction of non-redox-active substrate.
Fig. 2: Impact of propargylic leaving groups.
Fig. 3: Reaction scope of propargylic esters and chlorogermanes.
Fig. 4: Synthetic applications.
Fig. 5: Mechanistic investigations and proposed mechanism.
Fig. 6: The impact of Cl–GeR3.
Fig. 7: Hammett plot for enantiomeric ratio.

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Data availability

All data supporting the findings of this work are available within the article and its Supplementary Information files, or from the corresponding author upon request. Crystallographic data for the structures reported in this article have been deposited at Cambridge Crystallographic Data Centre under deposition no. CCDC 2205556 (5). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/.

References

  1. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Lucas, E. L. & Jarvo, E. R. Stereospecific and stereoconvergent cross-couplings between alkyl electrophiles. Nat. Rev. Chem. 1, 0065 (2017).

    Article  Google Scholar 

  4. Poremba, K. E., Dibrell, S. E. & Reisman, S. E. Nickel-catalyzed enantioselective reductive cross-coupling reactions. ACS Catal. 10, 8237–8246 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Goldfogel, M. J., Huang, L. & Weix, D. J. in Nickel Catalysis in Synthesis: Methods and Reactions (ed. Ogoshi, S.) 183–222 (Wiley-VCH, 2020).

  6. Yin, H. & Fu, G. C. Mechanistic investigation of enantioconvergent kumada reactions of racemic α-bromoketones catalyzed by a nickel/bis(oxazoline) complex. J. Am. Chem. Soc. 141, 15433–15440 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Cherney, A. H. & Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles. J. Am. Chem. Soc. 136, 14365–14368 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zhao, Y. & Weix, D. J. Enantioselective cross-coupling of meso-epoxides with aryl halides. J. Am. Chem. Soc. 137, 3237–3240 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Xu, J., Bercher, O. P., Talley, M. R. & Watson, M. P. Nickel-catalyzed, stereospecific C−C and C−B cross-couplings via C−N and C−O bond activation. ACS Catal. 11, 1604–1612 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ye, J. & Ma, S. Conquering three-carbon axial chirality of allenes. Org. Chem. Front. 1, 1210–1224 (2014).

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Nishibayashi, Y., Wakiji, I. & Hidai, M. Novel propargylic substitution reactions catalyzed by thiolate-bridged diruthenium complexes via allenylidene intermediates. J. Am. Chem. Soc. 122, 11019–11020 (2000).

    Article  CAS  Google Scholar 

  15. Nakajima, K., Shibata, M. & Nishibayashi, Y. Copper-catalyzed enantioselective propargylic etherification of propargylic esters with alcohols. J. Am. Chem. Soc. 137, 2472–2475 (2015).

    Article  PubMed  CAS  Google Scholar 

  16. Watanabe, K. et al. Nickel-catalyzed asymmetric propargylic amination of propargylic carbonates bearing an internal alkyne group. Org. Lett. 20, 5448–5451 (2018).

    Article  PubMed  CAS  Google Scholar 

  17. Liu, S., Tanabe, Y., Kuriyama, S., Sakata, K. & Nishibayashi, Y. Ruthenium-catalyzed enantioselective propargylic phosphinylation of propargylic alcohols with phosphine oxides. Angew. Chem. Int. Ed. Engl. 60, 11231–11236 (2021).

    Article  PubMed  CAS  Google Scholar 

  18. Xu, X., Peng, L., Chang, X. & Guo, C. Ni/Chiral sodium carboxylate dual catalyzed asymmetric O‑propargylation. J. Am. Chem. Soc. 143, 21048–21055 (2021).

    Article  PubMed  CAS  Google Scholar 

  19. Ardolino, M. J. & Morken, J. P. Construction of 1,5-enynes by stereospecific Pd-catalyzed allyl−propargyl cross-couplings. J. Am. Chem. Soc. 134, 8770–8773 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Elsevier, C. J., Kleijn, H., Boersma, J. & Vermeer, P. Synthesis, structure, and reactivity of some (σ-allenyl)- and (σ-prop-2-ynyl)palladium(II) complexes. Organometallics 5, 716–720 (1986).

    Article  CAS  Google Scholar 

  21. Yoshida, M., Okada, T. & Shishido, K. Enantiospecific synthesis of 1,3-disubstituted allenes by palladium-catalyzed coupling of propargylic compounds with arylboronic acids. Tetrahedron 63, 6996–7002 (2007).

    Article  CAS  Google Scholar 

  22. Ito, H., Sasaki, Y. & Sawamura, M. Copper(I)-catalyzed substitution of propargylic carbonates with diboron: selective synthesis of multisubstituted allenylboronates. J. Am. Chem. Soc. 130, 15774–15775 (2008).

    Article  PubMed  CAS  Google Scholar 

  23. Hazra, C. K. & Oestreich, M. Copper(I)-catalyzed regio- and chemoselective single and double addition of nucleophilic silicon to propargylic chlorides and phosphates. Org. Lett. 14, 4010–4013 (2012).

    Article  PubMed  CAS  Google Scholar 

  24. Ruchti, J. & Carreira, E. M. Rh-catalyzed stereospecific synthesis of allenes from propargylic benzoates and arylboronic acids. Org. Lett. 18, 2174–2176 (2016).

    Article  PubMed  CAS  Google Scholar 

  25. Guo, K., Zeng, Q., Villar-Yanez, A., Bo, C. & Kleij, A. W. Ni-catalyzed decarboxylative silylation of alkynyl carbonates: access to chiral allenes via enantiospecific conversions. Org. Lett. 24, 637–641 (2022).

    Article  PubMed  CAS  Google Scholar 

  26. Wang, H. et al. Pd-Catalyzed enantioselective syntheses of trisubstituted allenes via coupling of propargylic benzoates with organoboronic acids. J. Am. Chem. Soc. 142, 9763–9771 (2020).

    Article  PubMed  CAS  Google Scholar 

  27. Oelke, A. J., Sun, J.-W. & Fu, G. C. Nickel-catalyzed enantioselective cross-couplings of racemic secondary electrophiles that bear an oxygen leaving group. J. Am. Chem. Soc. 134, 2966–2969 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lu, F.-D. et al. Asymmetric propargylic radical cyanation enabled by dual organophotoredox and copper catalysis. J. Am. Chem. Soc. 141, 6167–6172 (2019).

    Article  PubMed  CAS  Google Scholar 

  29. Smith, S. W. & Fu, G. C. Nickel-catalyzed asymmetric cross-couplings of racemic propargylic halides with arylzinc reagents. J. Am. Chem. Soc. 130, 12645–12647 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Schley, N. D. & Fu, G. C. Nickel-catalyzed negishi arylations of propargylic bromides: a mechanistic investigation. J. Am. Chem. Soc. 136, 16588–16593 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Huo, H., Gorsline, B. J. & Fu, G. C. Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles. Science 367, 559–564 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Jin, Y., Wen, H., Yang, F., Ding, D. & Wang, C. Synthesis of multisubstituted allenes via nickel-catalyzed cross-electrophile coupling. ACS Catal. 11, 13355–13362 (2021).

    Article  CAS  Google Scholar 

  33. Calcaterra, A. & D’Acquarica, I. The market of chiral drugs: chiral switches versus de novo enantiomerically pure compounds. J. Pharm. Biomed. Anal. 147, 323–340 (2018).

    Article  PubMed  CAS  Google Scholar 

  34. Ramesh, R. & Reddy, D. S. Quest for novel chemical entities through incorporation of silicon in drug scaffolds. J. Med. Chem. 61, 3779–3798 (2018).

    Article  PubMed  CAS  Google Scholar 

  35. Menchikov, L. G. & Ignatenko, M. A. Biological activity of organogermanium compounds (a review). Pharm. Chem. J. 46, 635–638 (2013).

    Article  CAS  Google Scholar 

  36. Xi, Y. et al. Application of trimethylgermanyl-substituted bisphosphine ligands with enhanced dispersion interactions to copper-catalyzed hydroboration of disubstituted alkenes. J. Am. Chem. Soc. 142, 18213–18222 (2020).

    Article  PubMed  CAS  Google Scholar 

  37. Fricke, C. & Schoenebeck, F. Organogermanes as orthogonal coupling partners in synthesis and catalysis. Acc. Chem. Res. 53, 2715–2725 (2020).

    Article  PubMed  CAS  Google Scholar 

  38. Mao, W. & Oestreich, M. Enantioselective synthesis of α-chiral propargylic silanes by copper-catalyzed 1,4-selective addition of silicon nucleophiles to enyne-type α,β,γ,δ-unsaturated acceptors. Org. Lett. 22, 8096–8100 (2020).

    Article  PubMed  CAS  Google Scholar 

  39. Yang, L.-L., Ouyang, J., Zou, H.-N., Zhu, S.-F. & Zhou, Q.-L. Enantioselective insertion of alkynyl carbenes into Si–H bonds: an efficient access to chiral propargylsilanes and allenylsilanes. J. Am. Chem. Soc. 143, 6401–6406 (2021).

    Article  PubMed  CAS  Google Scholar 

  40. Pang, X., Su, P.-F. & Shu, X.-Z. Reductive cross-coupling of unreactive electrophiles. Acc. Chem. Res. 55, 2491–2509 (2022).

    Article  PubMed  CAS  Google Scholar 

  41. Guo, P. et al. Dynamic kinetic cross-electrophile arylation of benzyl alcohols by nickel catalysis. J. Am. Chem. Soc. 143, 513–523 (2021).

    Article  PubMed  CAS  Google Scholar 

  42. Ma, W.-Y. et al. Cobalt-catalyzed enantiospecific dynamic kinetic cross-electrophile vinylation of allylic alcohols with vinyl triflates. J. Am. Chem. Soc. 143, 15930–15935 (2021).

    Article  PubMed  CAS  Google Scholar 

  43. Su, P.-F. et al. Nickel-catalyzed reductive C−Ge coupling of Aryl/Alkenyl electrophiles with chlorogermanes. Angew. Chem. Int. Ed. Engl. 60, 26571–26576 (2021).

    Article  PubMed  CAS  Google Scholar 

  44. You, M.-X., Su, P.-F., She, Z.-H. & Shu, X.-Z. Nickel-catalyzed cross-electrophile C−Ge coupling of benzyl pivalates and chlorogermanes. Sci. China Chem. https://doi.org/10.1007/s11426-023-1768-3 (2023).

  45. Tian, Z.-X. et al. Highly enantioselective cross-electrophile aryl-alkenylation of unactivated alkenes. J. Am. Chem. Soc. 141, 7637–7643 (2019).

    Article  PubMed  CAS  Google Scholar 

  46. Race, N. J., Faulkner, A., Shaw, M. H. & Bower, J. F. Dichotomous mechanistic behavior in Narasaka–Heck cyclizations: electron rich pd-catalysts generate iminyl radicals. Chem. Sci. 7, 1508–1513 (2016).

    Article  PubMed  CAS  Google Scholar 

  47. Newcomb, M. & Chestney, D. L. A hypersensitive mechanistic probe for distinguishing between radical and carbocation intermediates. J. Am. Chem. Soc. 116, 9753–9754 (1994).

    Article  CAS  Google Scholar 

  48. Lin, X. et al. Visible light-promoted radical cyclization of silicon-tethered alkyl iodide and phenyl alkyne. An efficient approach to synthesize benzosilolines. ChemComm 52, 6189–6192 (2016).

    CAS  Google Scholar 

  49. Diccianni, J., Lin, Q. & Diao, T. Mechanisms of nickel-catalyzed coupling reactions and applications in alkene functionalization. Acc. Chem. Res. 53, 906–919 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zhao, Z.-Z., Pang, X., Wei, X.-X., Liu, X.-Y. & Shu, X.-Z. Nickel-catalyzed reductive C(sp2)−Si coupling of chlorohydrosilanes via Si−Cl cleavage. Angew. Chem. Int. Ed. Engl. 61, e202200215 (2022).

    Article  PubMed  CAS  Google Scholar 

  51. Lipp, A., Badir, S. O. & Molander, G. A. Stereoinduction in metallaphotoredox catalysis. Angew. Chem. Int. Ed. Engl. 60, 1714–1726 (2021).

    Article  PubMed  CAS  Google Scholar 

  52. Wang, F. et al. Divergent synthesis of CF3-substituted allenyl nitriles by ligand-controlled radical 1,2- and 1,4-addition to 1,3-enynes. Angew. Chem. Int. Ed. Engl. 57, 7140–7145 (2018).

    Article  PubMed  CAS  Google Scholar 

  53. Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to dramatically improved reaction conditions for the Cu-catalyzed asymmetric hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the National Natural Science Foundation of China (grant nos. 22271127 and 22071084 to X.-Z.S.) and the Fundamental Research Funds for the Central Universities (grant no. lzujbky-2022-ey01 to X.-Z.S.) for their financial support. We thank the NMR facility at SKLAOC and F. Qi for their expert assistance. We thank W. Yu at Lanzhou University for helpful discussions.

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Authors and Affiliations

  1. State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China

    Guan-Yu Han, Pei-Feng Su, Qiu-Quan Pan, Xue-Yuan Liu & Xing-Zhong Shu

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Contributions

X.-Z.S. conceived and supervised the project. X.-Z.S. and G.-Y.H. designed the experiments. G.-Y.H., P.-F.S. and Q.-Q.P. performed the experiments and analysed the data. X.-Y.L. provided valuable suggestions.

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Correspondence to Xing-Zhong Shu.

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Nature Catalysis thanks Srikrishna Bera, An-Xin Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Tables 1–5, Figs. 1–3, methods and references.

Supplementary Data 1

Crystallographic data for compound 5.

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Han, GY., Su, PF., Pan, QQ. et al. Enantioconvergent and regioselective reductive coupling of propargylic esters with chlorogermanes by nickel catalysis. Nat Catal 7, 12–20 (2024). https://doi.org/10.1038/s41929-023-01052-w

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