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Cu-catalysed enantioselective radical heteroatomic S–O cross-coupling

Nature Chemistry volume 15, pages 395–404 (2023)Cite this article

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Abstract

The transition-metal-catalysed cross-coupling reaction has established itself as one of the most reliable and practical synthetic tools for the efficient construction of carbon–carbon/heteroatom (p-block elements other than carbon) bonds in both racemic and enantioselective manners. In contrast, development of the corresponding heteroatom–heteroatom cross-couplings has so far remained elusive, probably due to the under-investigated and often challenging heteroatom–heteroatom reductive elimination. Here we demonstrate the use of single-electron reductive elimination as a strategy for developing enantioselective S–O coupling under Cu catalysis, based on both experimental and theoretical results. The reaction manifests its synthetic potential by the ready preparation of challenging chiral alcohols featuring congested stereocentres, the expedient valorization of the biomass-derived feedstock glycerol, and the remarkable catalytic 4,6-desymmetrization of inositol. These results demonstrate the potential of enantioselective radical heteroatomic cross-coupling as a general chiral heteroatom–heteroatom formation strategy.

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Fig. 1: Challenges and development of transition-metal-catalysed enantioselective heteroatom–heteroatom cross-coupling.
Fig. 2: Substrate scope and synthetic applications.
Fig. 3: Desymmetrization of polyols from natural resources.
Fig. 4: Experimental mechanistic studies.
Fig. 5: Computational studies.

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Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2102449 (L*4), 2102446 (16), 2102451 (45), 2102448 (59), 2102450 (69) and 2102452 (72). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. de Meijere, A., Bräse, S. & Oestreich, M. (eds) Metal-Catalyzed Cross-Coupling Reactions and More (Wiley, 2014).

  2. 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  CAS  PubMed  PubMed Central  Google Scholar 

  3. Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhou, F., Liu, J. & Cai, Q. Transition metal catalyzed asymmetric aryl carbon-heteroatom bond coupling reactions. Synlett 27, 664–675 (2016).

    Article  CAS  Google Scholar 

  5. Chinn, A. J., Kim, B., Kwon, Y. & Miller, S. J. Enantioselective intermolecular C–O bond formation in the desymmetrization of diarylmethines employing a guanidinylated peptide-based catalyst. J. Am. Chem. Soc. 139, 18107–18114 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bartoszewicz, A., Matier, C. D. & Fu, G. C. Enantioconvergent alkylations of amines by alkyl electrophiles: copper-catalyzed nucleophilic substitutions of racemic α-halolactams by indoles. J. Am. Chem. Soc. 141, 14864–14869 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, C., Peters, J. C. & Fu, G. C. Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity. Nature 596, 250–256 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bai, J., Cui, X., Wang, H. & Wu, Y. Copper-catalyzed reductive coupling of aryl sulfonyl chlorides with H-phosphonates leading to S-aryl phosphorothioates. Chem. Commun. 50, 8860–8863 (2014).

    Article  CAS  Google Scholar 

  10. Mulina, O. M., Ilovaisky, A. I. & Terent’ev, A. O. Oxidative coupling with S–N bond formation. Eur. J. Org. Chem. 2018, 4648–4672 (2018).

    Article  CAS  Google Scholar 

  11. Mampuys, P., McElroy, C. R., Clark, J. H., Orru, R. V. A. & Maes, B. U. W. Thiosulfonates as emerging reactants: synthesis and applications. Adv. Synth. Catal. 362, 3–64 (2020).

    Article  CAS  Google Scholar 

  12. Peng, K. & Dong, Z.-B. Recent advances in sulfur-centered S–X (X = N, P, O) bond formation catalyzed by transition metals. Eur. J. Org. Chem. 2020, 5488–5495 (2020).

    Article  CAS  Google Scholar 

  13. Jang, H.-Y. Oxidative cross-coupling of thiols for S–X (X = S, N, O, P and C) bond formation: mechanistic aspects. Org. Biomol. Chem. 19, 8656–8686 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Korch, K. M. & Watson, D. A. Cross-coupling of heteroatomic electrophiles. Chem. Rev. 119, 8192–8228 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hartwig, J. F., Shaughnessy, K. H., Shekhar, S. & Green, R. A. in Organic Reactions (ed. Denmark, S. E.) 853–958 (Wiley, 2020).

  16. Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525–3550 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Elrod, L. T., Boxwala, H., Haq, H., Zhao, A. W. & Waterman, R. As–As bond formation via reductive elimination from a zirconocene bis(dimesitylarsenide) compound. Organometallics 31, 5204–5207 (2012).

    Article  CAS  Google Scholar 

  18. Neumann, J. J., Suri, M. & Glorius, F. Efficient synthesis of pyrazoles: oxidative C–C/N–N bond-formation cascade. Angew. Chem. Int. Ed. 49, 7790–7794 (2010).

    Article  CAS  Google Scholar 

  19. Kohl, S. W. et al. Consecutive thermal H2 and light-induced O2 evolution from water promoted by a metal complex. Science 324, 74–77 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Hartwig, J. F. Carbon–heteroatom bond formation catalysed by organometallic complexes. Nature 455, 314–322 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Torres, G. M., Liu, Y. & Arndtsen, B. A. A dual light-driven palladium catalyst: breaking the barriers in carbonylation reactions. Science 368, 318–323 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Cook, T. R., Surendranath, Y. & Nocera, D. G. Chlorine photoelimination from a diplatinum core: circumventing the back reaction. J. Am. Chem. Soc. 131, 28–29 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. van Leest, N. P. et al. in Advances in Organometallic Chemistry (eds Pérez, P. J. et al.) 71–180 (Academic Press, 2018).

  24. Fang, C. et al. Mechanistically guided predictive models for ligand and initiator effects in copper-catalyzed atom transfer radical polymerization (Cu-ATRP). J. Am. Chem. Soc. 141, 7486–7497 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang, F.-L. et al. Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp3)–C(sp) cross-coupling of tertiary electrophiles with alkynes. Nat. Chem. 14, 949–957 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Proctor, R. S. J., Colgan, A. C. & Phipps, R. J. Exploiting attractive non-covalent interactions for the enantioselective catalysis of reactions involving radical intermediates. Nat. Chem. 12, 990–1004 (2020).

    Article  PubMed  Google Scholar 

  27. Zhang, C., Li, Z.-L., Gu, Q.-S. & Liu, X.-Y. Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates. Nat. Commun. 12, 475 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Beletskaya, I. & Moberg, C. Element-element additions to unsaturated carbon-carbon bonds catalyzed by transition metal complexes. Chem. Rev. 106, 2320–2354 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Waldman, A. J., Ng, T. L., Wang, P. & Balskus, E. P. Heteroatom-heteroatom bond formation in natural product biosynthesis. Chem. Rev. 117, 5784–5863 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ertl, P., Altmann, E. & McKenna, J. M. The most common functional groups in bioactive molecules and how their popularity has evolved over time. J. Med. Chem. 63, 8408–8418 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Leitao, E. M., Jurca, T. & Manners, I. Catalysis in service of main group chemistry offers a versatile approach to p-block molecules and materials. Nat. Chem. 5, 817–829 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Melen, R. L. Frontiers in molecular p-block chemistry: from structure to reactivity. Science 363, 479–484 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Gu, Q.-S., Li, Z.-L. & Liu, X.-Y. Copper(I)-catalyzed asymmetric reactions involving radicals. Acc. Chem. Res. 53, 170–181 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Dong, X.-Y. et al. A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Glass, R. S. Sulfur radicals and their application. Top. Curr. Chem. 376, 22 (2018).

    Article  Google Scholar 

  36. Patai, S. & Rappoport, Z. (eds) The Chemistry of Sulphonic Acids, Esters and Their Derivatives (Wiley, 1991).

  37. Nájera, C., Foubelo, F., Sansano, J. M. & Yus, M. Enantioselective desymmetrization reactions in asymmetric catalysis. Tetrahedron 106–107, 132629 (2022).

    Article  Google Scholar 

  38. Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, J. Y., You, Y. S. & Kang, S. H. Asymmetric synthesis of all-carbon quaternary stereocenters via desymmetrization of 2,2-disubstituted 1,3-propanediols. J. Am. Chem. Soc. 133, 1772–1774 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Tsuda, Y., Kuriyama, M. & Onomura, O. Synthesis of optically active oxazoline derivatives via catalytic asymmetric desymmetrization of 1,3-diols. Chem. Eur. J. 18, 2481–2483 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Yamamoto, K., Tsuda, Y., Kuriyama, M., Demizu, Y. & Onomura, O. Copper-catalyzed enantioselective synthesis of oxazolines from aminotriols via asymmetric desymmetrization. Chem. Asian J. 15, 840–844 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Hong, M. S., Kim, T. W., Jung, B. & Kang, S. H. Enantioselective formation of tert-alkylamines by desymmetrization of 2-substituted serinols. Chem. Eur. J. 14, 3290–3296 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. You, Y. S., Kim, T. W. & Kang, S. H. Asymmetric formation of tert-alkylamines from serinols by a dual function catalyst. Chem. Commun. 49, 9669–9671 (2013).

    Article  CAS  Google Scholar 

  44. Jung, B., Hong, M. S. & Kang, S. H. Enantioselective synthesis of tertiary alcohols by the desymmetrizing benzoylation of 2-substituted glycerols. Angew. Chem. Int. Ed. 46, 2616–2618 (2007).

    Article  CAS  Google Scholar 

  45. Jung, B. & Kang, S. H. Chiral imine copper chloride-catalyzed enantioselective desymmetrization of 2-substituted 1,2,3-propanetriols. Proc. Natl Acad. Sci. USA 104, 1471–1475 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. You, Z., Hoveyda, A. H. & Snapper, M. L. Catalytic enantioselective silylation of acyclic and cyclic triols: application to total syntheses of cleroindicins D, F and C. Angew. Chem. Int. Ed. 48, 547–550 (2009).

    Article  CAS  Google Scholar 

  47. Manville, N., Alite, H., Haeffner, F., Hoveyda, A. H. & Snapper, M. L. Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. Nat. Chem. 5, 768–774 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yasohara, Y., Miyamoto, K., Kizaki, N., Hasegawa, J. & Ohashi, T. A practical chemoenzymatic synthesis of a key intermediate of antifungal agents. Tetrahedron Lett. 42, 3331–3333 (2001).

    Article  CAS  Google Scholar 

  49. Mota, C. J. A., Pinto, B. P. & de Lima, A. L. Glycerol: A Versatile Renewable Feedstock for the Chemical Industry (Springer, 2017).

  50. Giustra, Z. X. & Tan, K. L. The efficient desymmetrization of glycerol using scaffolding catalysis. Chem. Commun. 49, 4370–4372 (2013).

    Article  CAS  Google Scholar 

  51. Thomas, M. P., Mills, S. J. & Potter, B. V. L. The ‘other’ inositols and their phosphates: synthesis, biology and medicine (with recent advances in myo-inositol chemistry). Angew. Chem. Int. Ed. 55, 1614–1650 (2016).

    Article  CAS  Google Scholar 

  52. Metrano, A. J. & Miller, S. J. Peptide-based catalysts reach the outer sphere through remote desymmetrization and atroposelectivity. Acc. Chem. Res. 52, 199–215 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Fiori, K. W., Puchlopek, A. L. A. & Miller, S. J. Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst. Nat. Chem. 1, 630–634 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jordan, P. A., Kayser-Bricker, K. J. & Miller, S. J. Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: enantioselective synthesis of d-myo-inositol-6-phosphate. Proc. Natl Acad. Sci. USA 107, 20620–20624 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Russell, G. A., Tashtoush, H. & Ngoviwatchai, P. Alkylation of β-substituted styrenes by a free radical addition-elimination sequence. J. Am. Chem. Soc. 106, 4622–4623 (1984).

    Article  CAS  Google Scholar 

  56. Truce, W. E. & Heuring, D. L. Preparation and photodecomposition of α-toluenesulfonyl iodide. J. Org. Chem. 39, 245–246 (1974).

    Article  Google Scholar 

  57. King, J. F., Lam, J. Y. L. & Skonieczny, S. Mechanisms of hydrolysis and related nucleophilic displacement reactions of alkanesulfonyl chlorides: pH dependence and the mechanism of hydration of sulfenes. J. Am. Chem. Soc. 114, 1743–1749 (1992).

    Article  CAS  Google Scholar 

  58. Demizu, Y., Matsumoto, K., Onomura, O. & Matsumura, Y. Copper complex catalyzed asymmetric monosulfonylation of meso-vic-diols. Tetrahedron Lett. 48, 7605–7609 (2007).

    Article  CAS  Google Scholar 

  59. Xu, J. et al. Remote C−H activation of quinolines through copper-catalyzed radical cross-coupling. Chem. Asian J. 11, 882–892 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the help of W. Jiang and his colleagues from SUSTech for enantiopurity characterization, and the assistance of SUSTech Core Research Facilities. Financial support from the National Key R&D Program of China (nos. 2021YFF0701604 and 2021YFF0701704, X.-Y.L.), the National Natural Science Foundation of China (nos. 22025103, 92256301, and 21831002, X.-Y.L.; 22001111, Y.-F.C.; 22001109 and 22271133, Q.-S.G.; 21873081 and 22122109, X.H.), the Guangdong Innovative Program (no. 2019BT02Y335, X.-Y.L.), Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002, X.-Y.L.), Shenzhen Science and Technology Program (nos. KQTD20210811090112004, X.-Y.L. and Q.-S.G.; JCYJ20200109141001789, X.-Y.L.), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (no. SN-ZJU-SIAS-006, X.H.), Beijing National Laboratory for Molecular Sciences (no. BNLMS202102, X.H.), CAS Youth Interdisciplinary Team (no. JCTD-2021-11, X.H.), Fundamental Research Funds for the Central Universities (nos. 226-2022-00140 and 226-2022-00224, X.H.), the Center of Chemistry for Frontier Technologies and Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province (no. PSFM2021-01, X.H.) and the State Key Laboratory of Clean Energy Utilization (no. ZJUCEU2020007, X.H.) is gratefully acknowledged.

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Author notes

  1. These authors contributed equally: Yong-Feng Cheng, Zhang-Long Yu, Yu Tian, Ji-Ren Liu.

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Yong-Feng Cheng, Zhang-Long Yu, Yu Tian, Han-Tao Wen, Na-Chuan Jiang, Jun-Qian Bian, Dan-Tong Xu & Xin-Yuan Liu

  2. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China

    Ji-Ren Liu, Guo-Xiong Xu & Xin Hong

  3. Beijing National Laboratory for Molecular Sciences, Beijing, China

    Ji-Ren Liu, Guo-Xiong Xu & Xin Hong

  4. Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, Hangzhou, China

    Ji-Ren Liu, Guo-Xiong Xu & Xin Hong

  5. Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Zhong-Liang Li & Qiang-Shuai Gu

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Contributions

Y.-F.C., Z.-L.Y. and Y.T. designed the experiments and analysed the data. Y.-F.C., Z.-L.Y., Y.T., H.-T.W., N.-C.J., J.-Q.B., D.-T.X. and Z.-L.L. performed the experiments. X.H. designed the DFT calculations. J.-R.L. and G.-X.X. performed the DFT calculations. All authors participated in writing the manuscript. Q.-S.G. and X.-Y.L. conceived of and supervised the project.

Corresponding authors

Correspondence to Qiang-Shuai Gu, Xin Hong or Xin-Yuan Liu.

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The authors declare no competing interests.

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Peer review information

Nature Chemistry thanks Hye-Young Jang, Allan Watson and Yanying Zhao for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Information

Supplementary Figs. 1–46, Tables 1–20, experimental procedures, synthetic procedures, characterization data, density functional theory (DFT) calculations and mechanistic discussion.

Supplementary Data 1

Crystallographic data for compound 16; CCDC reference 2102446.

Supplementary Data 2

Crystallographic data for compound 45; CCDC reference 2102451.

Supplementary Data 3

Crystallographic data for compound 59; CCDC reference 2102448.

Supplementary Data 4

Crystallographic data for compound 69; CCDC reference 2102450.

Supplementary Data 5

Crystallographic data for compound 72; CCDC reference 2102452.

Supplementary Data 6

Crystallographic data for compound L*4; CCDC reference 2102449.

Supplementary Data 7

Tables of energies and coordinates in XYZ format.

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Cheng, YF., Yu, ZL., Tian, Y. et al. Cu-catalysed enantioselective radical heteroatomic S–O cross-coupling. Nat. Chem. 15, 395–404 (2023). https://doi.org/10.1038/s41557-022-01102-z

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