Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals

Abstract

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Reagent-controlled enantioselective radical C–C bond-forming cyclizations.
Figure 2: Origin of enantioselectivity in the cyclizations.

References

  1. 1

    Stockdale, T. P. & Williams, C. M. Pharmaceuticals that contain polycyclic hydrocarbon scaffolds. Chem. Soc. Rev. 44, 7737–7763 (2015).

    CAS  PubMed  Google Scholar 

  2. 2

    Dückert, H. et al. Natural product-inspired cascade synthesis yields modulators of centrosome integrity. Nat. Chem. Biol. 8, 179–184 (2012).

    Google Scholar 

  3. 3

    Oliver, D. W. & Malan, S. F. Medicinal chemistry of polycyclic cage compounds in drug discovery research. Med. Chem. Res. 17, 137–151 (2008).

    CAS  Google Scholar 

  4. 4

    Renaud, P. & Sibi, M. P. Radicals in Organic Synthesis (Wiley, 2001).

    Google Scholar 

  5. 5

    Curran, D. P., Porter, N. A. & Giese, B. Stereochemistry of Radical Reactions: Concepts, Guidelines, and Synthetic Applications (Wiley, 2008).

    Google Scholar 

  6. 6

    Chatgilialoglu, C. & Studer, A. Encyclopedia of Radicals in Chemistry, Biology and Materials (Wiley, 2012).

    Google Scholar 

  7. 7

    Bar, G. & Parsons, A. F. Stereoselective radical reactions. Chem. Soc. Rev. 32, 251–263 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Miyabe, H., Kawashima, A., Yoshioka, E. & Kohtani, S. Progress in enantioselective radical cyclizations. Chem. Eur. J. 23, 6225–6236 (2017).

    CAS  PubMed  Google Scholar 

  9. 9

    Sibi, M. P. & Porter, N. A. Enantioselective free radical reactions. Acc. Chem. Res. 32, 163–171 (1999).

    CAS  Google Scholar 

  10. 10

    Sibi, M. P., Manyem, S. & Zimmerman, J. Enantioselective radical processes. Chem. Rev. 103, 3263–3296 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Miyabe, H., Asada, R., Toyoda, A. & Takemoto, Y. Enantioselective cascade radical addition–cyclization–trapping reactions. Angew. Chem. Int. Ed. 45, 5863–5866 (2006).

    CAS  Google Scholar 

  12. 12

    Brimioulle, R. & Bach, T. Enantioselective Lewis acid catalysis of intramolecular enone [2+2] photocycloaddition reactions. Science 342, 840–843 (2013).

    CAS  Google Scholar 

  13. 13

    Sibi, M. P. & Hasegawa, M. Organocatalysis in radical chemistry. Enantioselective α-oxyamination of aldehydes. J. Am. Chem. Soc. 129, 4124–4125 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Arceo, E., Jurberg, I. D., Álvarez-Fernández, A. & Melchiorre, P. Photochemical activity of a key donor–acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes. Nat. Chem. 5, 750–756 (2013).

    CAS  Google Scholar 

  16. 16

    Hashimoto, T., Kawamata, Y. & Maruoka, K. An organic thiyl catalyst for enantioselective cyclization. Nat. Chem. 6, 702–705 (2014).

    CAS  Google Scholar 

  17. 17

    Brill, Z. G., Grover, H. K. & Maimone, T. J. Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade. Science 352, 1078–1082 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gansaüer, A., Lauterbach, T., Bluhm, H. & Noltemeyer, M. A catalytic enantioselective electron transfer reaction: titanocene-catalyzed enantioselective formation of radicals from meso-epoxides. Angew. Chem. Int. Ed. 38, 2909–2910 (1999).

    Google Scholar 

  19. 19

    Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay. Science 353, 1014–1018 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Zhu, R. & Buchwald, S. L. Enantioselective functionalization of radical intermediates in redox catalysis: copper-catalyzed asymmetric oxytrifluoromethylation of alkenes. Angew. Chem. Int. Ed. 52, 12655–12658 (2013).

    CAS  Google Scholar 

  21. 21

    Bovino, M. T. & Chemler, S. R. Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer. Angew. Chem. Int. Ed. 51, 3923–3927 (2012).

    CAS  Google Scholar 

  22. 22

    Amador, A. G., Sherbrook, E. M. & Yoon, T. P. Enantioselective photocatalytic [3+2] cycloadditions of aryl cyclopropyl ketones. J. Am. Chem. Soc. 138, 4722–4725 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Streuff, J., Feurer, M., Bichovski, P., Frey, G. & Gellrich, U. Enantioselective titanium(III)-catalyzed reductive cyclization of ketonitriles. Angew. Chem. Int. Ed. 51, 8661–8664 (2012).

    CAS  Google Scholar 

  24. 24

    Rono, L. J., Yayla, H. G., Wang, D. Y., Armstrong, M. F. & Knowles, R. R. Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization. J. Am. Chem. Soc. 135, 17735–17738 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Yang, D., Zheng, B.-F., Gao, Q., Gu, S. & Zhu, N.-Y. Enantioselective PhSe-group-transfer tandem radical cyclization reactions catalyzed by a chiral Lewis acid. Angew. Chem. Int. Ed. 45, 255–258 (2006).

    CAS  Google Scholar 

  26. 26

    McMurry, J. E. Carbonyl-coupling reactions using low-valent titanium. Chem. Rev. 89, 1513–1524 (1989).

    CAS  Google Scholar 

  27. 27

    Molander, G. A. Application of lanthanide reagents in organic synthesis. Chem. Rev. 92, 29–68 (1992).

    CAS  Google Scholar 

  28. 28

    Szostak, M., Fazakerley, N. J., Parmar, D. & Procter, D. J. Cross-coupling reactions using samarium(II) iodide. Chem. Rev. 114, 5959–6039 (2014).

    CAS  PubMed  Google Scholar 

  29. 29

    Girard, P., Namy, J. L. & Kagan, H. B. Divalent lanthanide derivatives in organic synthesis. 1. Mild preparation of samarium iodide and ytterbium iodide and their use as reducing or coupling agents. J. Am. Chem. Soc. 102, 2693–2698 (1980).

    CAS  Google Scholar 

  30. 30

    Nicolaou, K. C., Ellery, S. P. & Chen, J. S. Samarium diiodide mediated reactions in total synthesis. Angew. Chem. Int. Ed. 48, 7140–7165 (2009).

    CAS  Google Scholar 

  31. 31

    Edmonds, D. J., Johnston, D. & Procter, D. J. Samarium(II)-iodide-mediated cyclizations in natural product synthesis. Chem. Rev. 104, 3371–3404 (2004).

    CAS  PubMed  Google Scholar 

  32. 32

    Procter, D. J., Flowers, R. A. II & Skrydstrup, T. Organic Synthesis using Samarium Diiodide (RSC Publishing, 2009).

  33. 33

    Mikami, K. & Yamaoka, M. Chiral ligand control in enantioselective reduction of ketones by SmI2 for ketyl radical addition to olefins. Tetrahedron Lett. 39, 4501–4504 (1998).

    CAS  Google Scholar 

  34. 34

    Kikukawa, T., Hanamoto, T. & Inanaga, J. Diastereo- and enantioselective hydrodimerization of β-monosubstituted acrylic acid amides induced by chiral samarium(II) complexes. Tetrahedron Lett. 40, 7497–7500 (1999).

    CAS  Google Scholar 

  35. 35

    Riber, D., Hazell, R. & Skrydstrup, T. Studies on the SmI2-promoted pinacol-type cyclization: synthesis of the hexahydroazepine ring of balanol. J. Org. Chem. 65, 5382–5390 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Molander, G. A . & Kenny, C. Intramolecular reductive coupling reactions promoted by samarium diiodide. J. Am. Chem. Soc. 111, 8236–8246 (1989).

    CAS  Google Scholar 

  37. 37

    Sadasivam, D. V., Sudhadevi Antharjanam, P. K., Prasad, E. & Flowers, R. A. II Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig ketyl–olefin coupling: the role of HMPA in post-electron transfer steps. J. Am. Chem. Soc. 130, 7228–7229 (2008).

    CAS  PubMed  Google Scholar 

  38. 38

    Teprovich, J. A. Jr, Balili, M. N., Pintauer, T. & Flowers, R. A. II . Mechanistic studies of proton-donor coordination to samarium diiodide. Angew. Chem. Int. Ed. 46, 8160–8163 (2007).

    CAS  Google Scholar 

  39. 39

    Nakamura, Y. et al. Enantioselective protonation of samarium enolates derived from α-heterosubstituted ketones and lactone by SmI2-mediated reduction. Tetrahedron 55, 4595–4620 (1999).

    CAS  Google Scholar 

  40. 40

    Evans, D. A., Nelson, S. G., Gagné, M. R. & Muci, A. R. A chiral samarium-based catalyst for the asymmetric Meerwein–Ponndorf–Verley reduction. J. Am. Chem. Soc. 115, 9800–9801 (1993).

    CAS  Google Scholar 

  41. 41

    Yacovan, A. & Hoz, S. Reactions of SmI2 with olefins: mechanism and complexation effect on chemoselectivity. J. Am. Chem. Soc. 118, 261–262 (1996).

    CAS  Google Scholar 

  42. 42

    Prasad, E. & Flowers, R. A. II . Mechanistic impact of water addition to SmI2: consequences in the ground and transition state. J. Am. Chem. Soc. 127, 18093–18099 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Chopade, P. R., Prasad, E. & Flowers, R. A. II . The role of proton donors in SmI2-mediated ketone reduction: new mechanistic insights. J. Am. Chem. Soc. 126, 44–45 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Hutton, T. K., Muir, K. W. & Procter, D. J. Switching between novel samarium(II)-mediated cyclizations by a simple change in alcohol cosolvent. Org. Lett. 5, 4811–4814 (2003).

    CAS  PubMed  Google Scholar 

  45. 45

    Justicia, J., Jiménez, T., Morcillo, S. P., Cuerva, J. M. & Oltra, J. E. Mixed disproportionation versus radical trapping in titanocene(III)-promoted epoxide openings. Tetrahedron 65, 10837–10841 (2009).

    CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by The Leverhulme Trust (Postdoctoral Fellowship to N.K.; RPG-2012-761) and the EPSRC (DTA Studentship to M.P.) (Established Career Fellowship to D.J.P.; EP/M005062/1).

Author information

Affiliations

Authors

Contributions

N.K. and D.J.P. conceived the study and co-wrote the manuscript. N.K. designed and performed experiments and M.P.P. performed experiments. J.J.W.M. performed the computational study.

Corresponding author

Correspondence to David J. Procter.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 17318 kb)

Supplementary information

Crystallographic data for compound 2a (CIF 2576 kb)

Supplementary information

Crystallographic data for compound 4 (CIF 551 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kern, N., Plesniak, M., McDouall, J. et al. Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals. Nature Chem 9, 1198–1204 (2017). https://doi.org/10.1038/nchem.2841

Download citation

Further reading