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Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres

Abstract

The asymmetric construction of all-carbon quaternary centres within acyclic settings represents a long-standing challenge for synthetic chemists. Alongside polar and radical methods, rearrangement reactions represent an attractive platform, but still broadly applicable methods are in high demand. Here we report an asymmetric, radical sulfinyl-Smiles rearrangement to access acyclic amides that bear an α-all-carbon quaternary centre. Our strategy uses enantioenriched N-arylsulfinyl acrylamides as acceptors for a variety of radicals produced in situ under mild photoredox conditions. The sulfinamido group not only directs the 1,4-migration of the aryl moiety onto the α-carbon of the amide, which thus governs its absolute configuration, but also functions as a traceless chiral auxiliary. The amides obtained in this multicomponent process are prevalent in pharmaceuticals, agrochemicals and bioactive natural products, and can be transformed into valuable chiral α,α-disubstituted acids, oxindoles as well as into β,β-disubstituted amines, highlighting the synthetic potential of this transformation.

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Fig. 1: Strategies towards the enantioselective synthesis of all-carbon quaternary centres in acyclic systems.
Fig. 2: Synthetic utility of α-all-carbon substituted amides.
Fig. 3: Mechanistic studies.

Data availability

Crystallographic data for structure 2.9 reported in this article has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 1854836 (Supplementary Fig. 7). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All the other data that support the findings of this study are available within the article and its Supplementary Information.

References

  1. 1.

    Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    CAS  Google Scholar 

  2. 2.

    Lovering, F. Escape from flatland 2: complexity and promiscuity. Med. Chem. Commun. 4, 515–519 (2013).

    CAS  Google Scholar 

  3. 3.

    Ling, T. & Rivas, F. All-carbon quaternary centers in natural products and medicinal chemistry: recent advances. Tetrahedron 43, 6729–6777 (2016).

    Google Scholar 

  4. 4.

    Carreira, E. M. & Kvaerno, L. Classics in Stereoselective Synthesis (Wiley-VCH, 2009).

    Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Liu, Y., Han, S. J., Liu, W. B. & Stoltz, B. M. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc. Chem. Res. 48, 740–751 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Marek, I. et al. All-carbon quaternary stereogenic centers in acyclic systems through the creation of several C–C bonds per chemical step. J. Am. Chem. Soc. 136, 2682–2694 (2014).

    CAS  Google Scholar 

  8. 8.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kummer, D. A., Chain, W. J., Morales, M. R., Quiroga, O. & Myer, A. G. Stereocontrolled alkylative construction of quaternary carbon centers. J. Am. Chem. Soc. 130, 13231–13233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Minko, Y., Pasco, M., Lercher, L., Botoshansky, M. & Marek, I. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–carbon bond activation. Nature 505, 199–203 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Alam, R., Vollgraff, T., Eriksson, L. & Szabó, K. J. Synthesis of adjacent quaternary stereocenters by catalytic asymmetric allylboration. J. Am. Chem. Soc. 137, 11262–11265 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Mo, X. & Hall, D. G. Dual catalysis using boronic acid and chiral amine: acyclic quaternary carbons via enantioselective alkylation of branched aldehydes with allylic alcohols. J. Am. Chem. Soc. 138, 10762–10765 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Holmes, M., Nguyen, K. D., Schwartz, L. A., Luong, T. & Krische, M. J. Enantioselective formation of CF3-bearing all-carbon quaternary stereocenters via C–H functionalization of methanol: iridium catalyzed allene hydrohydroxymethylation. J. Am. Chem. Soc. 139, 8114–8117 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Starkov, P., Moore, J. T., Duquette, D. C., Stoltz, B. M. & Marek, I. Enantioselective construction of acyclic quaternary carbon stereocenters: palladium-catalyzed decarboxylative allylic alkylation of fully substituted amide enolates. J. Am. Chem. Soc. 139, 9615–9620 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Alexy, E. J., Zhang, H. & Stoltz, B. M. Catalytic enantioselective synthesis of acyclic quaternary centers: palladium-catalyzed decarboxylative allylic alkylation of fully substituted acyclic enol carbonates. J. Am. Chem. Soc. 140, 10109–10112 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Zhu, Y., Zhang, L. & Luo, S. Asymmetric α-photoalkylation of β-ketocarbonyls by primary amine catalysis: facile access to acyclic all-carbon quaternary stereocenters. J. Am. Chem. Soc. 136, 14642–14645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Murphy, J. J., Bastida, D., Paria, S., Fagnoni, M. & Melchiorre, P. Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals. Nature 532, 218–222 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lenhart, D., Bauer, A., Pöthig, A. & Bach, T. Enantioselective visible-light-induced radical-addition reactions to 3-alkylidene indolin-2-ones. Chem. Eur. J. 22, 6519–6523 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wu, L., Wang, F., Chen, P. & Liu, G. Enantioselective construction of quaternary all-carbon centers via copper-catalyzed arylation of tertiary carbon-centered radicals. J. Am. Chem. Soc. 141, 1887–1892 (2019).

    CAS  Google Scholar 

  22. 22.

    Lin, J. S. et al. Cu/chiral phosphoric acid-catalyzed asymmetric three-component radical-initiated 1,2-dicarbofunctionalization of alkenes. J. Am. Chem. Soc. 141, 1074–1083 (2019).

    CAS  Google Scholar 

  23. 23.

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

    Google Scholar 

  24. 24.

    Gu, Z., Herrmann, A. T., Stivala, C. E. & Zakarian, A. Stereoselective construction of adjacent quaternary chiral centers by the Ireland–Claisen rearrangement: stereoselection with esters of cyclic alcohols. Synlett. 2010, 1717–1722 (2010).

    Google Scholar 

  25. 25.

    Ma, D., Miao, C.-B. & Sun, J. Catalytic enantioselective House–Meinwald rearrangement: efficient construction of all-carbon quaternary stereocenters. J. Am. Chem. Soc. 141, 13783–13787 (2019).

    CAS  Google Scholar 

  26. 26.

    Holden, C. M. & Greaney, M. F. Modern aspects of the Smiles rearrangement. Chem. Eur. J. 23, 8992–9008 (2017).

    CAS  Google Scholar 

  27. 27.

    Snape, T. J. A truce on the Smiles rearrangement: revisiting an old reaction—the Truce–Smiles rearrangement. Chem. Soc. Rev. 37, 2452–2458 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Clayden, J., Dufour, J., Grainger, D. M. & Helliwell, M. Substituted diarylmethylamines by stereospecific intramolecular electrophilic arylation of lithiated ureas. J. Am. Chem. Soc. 129, 7488–7489 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tetlow, D. J. et al. Sequential double α-arylation of N-allylureas by asymmetric deprotonation and N→C aryl migration. Org. Lett. 12, 5442–5445 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tait, M. et al. Amines bearing tertiary substituents by tandem enantioselective carbolithiation–rearrangement of vinylureas. Org. Lett. 15, 34–37 (2013).

    CAS  Google Scholar 

  31. 31.

    Maury, J., Zawodny, W. & Clayden, J. Stereospecific intramolecular arylation of 2- and 3-pyridyl substituted alkylamines via configurationally stable α-pyridyl organolithiums. Org. Lett. 19, 472–475 (2017).

    CAS  Google Scholar 

  32. 32.

    Zawodny, W. et al. Chemoenzymatic synthesis of substituted azepanes by sequential biocatalytic reduction and organolithium-mediated rearrangement. J. Am. Chem. Soc. 140, 17872–17877 (2018).

    CAS  Google Scholar 

  33. 33.

    Loven, R. & Speckamp, W. N. Heterocyclic steroids XXVII. A novel 1,4 arylradical rearrangement. Tetrahedron Lett. 16, 1567–1570 (1972).

    Google Scholar 

  34. 34.

    Motherwell, W. B. & Pennell, A. M. K. A novel route to biaryls via intramolecular free radical ipso substitution reactions. J. Chem. Soc. Chem. Commun. 1991, 877–879 (1991).

    Google Scholar 

  35. 35.

    Allart-Simon, I., Gérard, S. & Sapi, J. Radical Smiles rearrangement: an update. Molecules 21, 878–889 (2016).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Henderson, A. R. P., Kosowan, J. R. & Wood, T. E. The Truce–Smiles rearrangement and related reactions: a review. Can. J. Chem. 95, 483–504 (2017).

    CAS  Google Scholar 

  37. 37.

    Kong, W. et al. Stereoselective synthesis of highly functionalized indanes and dibenzocycloheptadienes through complex radical cascade reactions. Angew. Chem. Int. Ed. 54, 2487–2491 (2015).

    CAS  Google Scholar 

  38. 38.

    Whalley, D. M., Duong, H. A. & Greaney, M. F. Alkene carboarylation through catalyst-free, visible-light-mediated Smiles rearrangement. Chem. Eur. J. 25, 1927–1930 (2019).

    CAS  Google Scholar 

  39. 39.

    Monos, T. M., McAtee, R. C. & Stephenson, C. R. J. Arylsulfonylacetamides as bifunctional reagents for alkene aminoarylation. Science 361, 1369–1373 (2018).

    CAS  Google Scholar 

  40. 40.

    Rabet, P. T. G., Boyd, S. & Greaney, M. F. Metal-free intermolecular aminoarylation of alkynes. Angew. Chem. Int. Ed. 56, 4183–4186 (2017).

    CAS  Google Scholar 

  41. 41.

    Abrams, R. & Clayden, J. Photocatalytic difunctionalization of vinyl ureas by radical addition polar Truce–Smiles rearrangement cascades. Angew. Chem. Int. Ed. 59, 11600–11606 (2020).

    CAS  Google Scholar 

  42. 42.

    Kong, W., Casimiro, M., Merino, E. & Nevado, C. Copper-catalyzed one-pot trifluoromethylation/aryl migration/desulfonylation and C(sp2)–N bond formation of conjugated osyl amides. J. Am. Chem. Soc. 135, 14480–14483 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kong, W., Casimiro, Fuentes, N., Merino, E. & Nevado, C. Metal-free aryltrifluoromethylation of activated alkenes. Angew. Chem. Int. Ed. 52, 13086–13090 (2013).

    CAS  Google Scholar 

  44. 44.

    Kong, W., Merino, E. & Nevado, C. Arylphosphonylation and arylazidation of activated alkenes. Angew. Chem. Int. Ed. 53, 5078–5082 (2014).

    CAS  Google Scholar 

  45. 45.

    Kagan, H. B. in Organosulfur Chemistry in Asymmetric Synthesis (eds Toru, T. & Bolm, C) 1–29 (Wiley-VCH, 2008).

  46. 46.

    Fischer, H. & Radom, L. Factors controlling the addition of carbon‐centered radicals to alkenes—an experimental and theoretical perspective. Angew. Chem. Int. Ed. 40, 1340–1371 (2001).

    CAS  Google Scholar 

  47. 47.

    Macmillan, D. W. C., Stephenson, C. R. J. & Yoon, T. P. Visible Light Photocatalysis in Organic Chemistry (Wiley-VCH, 2018).

  48. 48.

    Kaldre, D., Klose, I. & Maulide, N. Stereodivergent synthesis of 1,4-dicarbonyls by traceless charge–accelerated sulfonium rearrangement. Science 361, 664–667 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated electrochemical potentials of common organic molecules for applications to single-electron redox chemistry. Synlett 27, 714–723 (2016).

    CAS  Google Scholar 

  50. 50.

    Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Tang, S. et al. Visible-light-induced perfluoroalkylation/arylmigration/desulfonylation cascades of conjugated tosyl amides. Tetrahedron Lett. 58, 329–332 (2017).

    CAS  Google Scholar 

  53. 53.

    Sheng, R.-L., Okada, K. & Sekiguchi, S. Aromatic nucleophilic substitution. 9. Kinetics of the formation and decomposition of anionic σ complexes in the Smiles rearrangements of N-acetyl-β-aminoethyl 2-X-4-nitro-1-phenyl or N-acetyl-β-aminoethyl 5-nitro-2-pyridyl ethers in aqueous dimethyl sulfoxide. J. Org. Chem. 43, 441–447 (1978).

    Google Scholar 

  54. 54.

    Knipe, A. C. & Sridhar, N. Role of intramolecular catalysis in the kinetics of Smiles rearrangement of N-[2-(p-nitrophenoxy)ethylene]diamine. J. Chem. Soc. Chem. Commun. 1979, 791–792 (1979).

    Google Scholar 

  55. 55.

    Lennox, A. J. J. Meisenheimer complexes in SNAr reactions: intermediates or transition states? Angew. Chem. Int. Ed. 57, 14686–14688 (2018).

    CAS  Google Scholar 

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Acknowledgements

We thank P. Fiechter for the synthesis of the racemic substrate 2.32 and A. Linden for the X-ray diffraction analysis of 2.9. This work was supported by the European Research Council (ERC starting grant agreement no. 307948), the Swiss National Science Foundation (SNF 200020_146853) and the Comunidad de Madrid Research Talent Attraction Program (2018-T1/IND-10054 to E.M.).

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C.H., M.S.K., T.S. and M.M. performed the experiments. E.M. performed DFT calculations. E.M. and C.N. conceptualized the project, supervised, analysed the data and co-wrote the manuscript.

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Correspondence to Estíbaliz Merino or Cristina Nevado.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Yannick Landais and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

General information, reaction optimization data, experimental procedures, additional experiments, compound characterization data including spectroscopic and analytical data for all new compounds, X-ray crystallographic data, NMR and HPLC spectral data, computational details containing the Cartesian coordinates of computational structures, Supplementary Figs. 1–10, Tables 1–5 and references.

Supplementary Data

Crystallographic data for compound 2.9. CCDC 1854836.

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Hervieu, C., Kirillova, M.S., Suárez, T. et al. Asymmetric, visible light-mediated radical sulfinyl-Smiles rearrangement to access all-carbon quaternary stereocentres. Nat. Chem. 13, 327–334 (2021). https://doi.org/10.1038/s41557-021-00668-4

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