Article | Published:

Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals

Nature Chemistry volume 9, pages 11981204 (2017) | Download Citation

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.

  • Compound

    methyl 2-acetyl-2-(but-3-en-1-yl)hex-5-enoate

  • Compound

    methyl (1S,2R,3S)-1-(but-3-en-1-yl)-2-hydroxy-2,3-dimethylcyclopentane-1-carboxylate

  • Compound

    methyl (1S,2R,3S)-1-((E)-hex-3-en-1-yl)-2-hydroxy-2-methyl-3-propylcyclopentane-1-carboxylate

  • Compound

    methyl (1S,2R,3S)-1-((Z)-hex-3-en-1-yl)-2-hydroxy-2-methyl-3-propylcyclopentane-1-carboxylate

  • Compound

    methyl (1S,2R,3R)-2-hydroxy-3-isopropyl-2-methyl-1-(4-methylpent-3-en-1-yl)cyclopentane-1-carboxylate

  • Compound

    methyl (1S,2R,3R)-2-hydroxy-2-methyl-1-(penta-3,4-dien-1-yl)-3-vinylcyclopentane-1-carboxylate

  • Compound

    methyl (1S,2R,3R)-1-((E)-5-acetoxypent-3-en-1-yl)-2-hydroxy-2-methyl-3-vinylcyclopentane-1-carboxylate

  • Compound

    methyl (1R,2R)-1-(buta-2,3-dien-1-yl)-2-hydroxy-2-methyl-3-methylenecyclopentane-1-carboxylate

  • Compound

    isopropyl (1S,2R,3S)-1-(but-3-en-1-yl)-2-hydroxy-2,3-dimethylcyclopentane-1-carboxylate

  • Compound

    (1S,2R,3S)-1-(but-3-en-1-yl)-2-hydroxy-N,N,2,3-tetramethylcyclopentane-1-carboxamide

  • Compound

    methyl (1S,5S,8R)-8-hydroxy-8-methylbicyclo[3.2.1]octane-1-carboxylate

  • Compound

    methyl (1S,3aR,5S,6aR)-1-(but-3-en-1-yl)-6a-hydroxy-5-methyloctahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,5S,6aR)-1-(but-3-en-1-yl)-6a-hydroxy-5-isopropyloctahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,5S,6aR)-1-(but-3-en-1-yl)-6a-hydroxy-5-(3-phenylpropyl)octahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,4S,5R,6aR)-4-ethyl-1-((E)-hex-3-en-1-yl)-6a-hydroxy-5-methyloctahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,6aR)-1-(but-3-en-1-yl)-6a-hydroxy-5,5-dimethyloctahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,5S,6aR)-1-(but-3-en-1-yl)-6a-hydroxy-5-vinyloctahydropentalene-1-carboxylate

  • Compound

    methyl (1S,3aR,4R,5S,6aR)-6a-hydroxy-5-methylhexahydro-1,4-ethanopentalene-1(2H)-carboxylate

  • Compound

    methyl (1S,3aR,4R,5R,6aR)-6a-hydroxy-5-isopropylhexahydro-1,4-ethanopentalene-1(2H)-carboxylate

  • Compound

    methyl (1S,3aR,4R,5S,6aR)-6a-hydroxy-5-(3-phenylpropyl)hexahydro-1,4-ethanopentalene-1(2H)-carboxylate

  • Compound

    (1R,2R)-1,2-diphenylethane-1,2-diol

  • Compound

    (1R,1'R)-2,2'-(1,2-phenylenebis(oxy))bis(1-phenylethan-1-ol)

  • Compound

    (1R,1'R)-2,2'-((1,2-phenylenebis(methylene))bis(oxy))bis(1-phenylethan-1-ol)

  • Compound

    ((2S,2'S)-ethane-1,2-diylbis(pyrrolidine-1,2-diyl))bis(diphenylmethanol)

  • Compound

    (1R,1'R)-2,2'-(ethane-1,2-diylbis(benzylazanediyl))bis(1-phenylethan-1-ol)

  • Compound

    (1R,1'R)-2,2'-(benzylazanediyl)bis(1-phenylethan-1-ol)

  • Compound

    (R)-N-benzyl-2-methoxy-N-((R)-2-methoxy-2-phenylethyl)-2-phenylethan-1-amine

  • Compound

    (1R,1'R)-2,2'-(neopentylazanediyl)bis(1-phenylethan-1-ol)

  • Compound

    (1R,1'R)-2,2'-(benzylazanediyl)bis(1-(naphthalen-1-yl)ethan-1-ol)

  • Compound

    (1R,1'R)-2,2'-(benzylazanediyl)bis(1-(3,5-dimethylphenyl)ethan-1-ol)

  • Compound

    ((1R,5S,8R)-8-hydroxy-8-methylbicyclo[3.2.1]octan-1-yl)methyl 4-bromobenzoate

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Pharmaceuticals that contain polycyclic hydrocarbon scaffolds. Chem. Soc. Rev. 44, 7737–7763 (2015).

  2. 2.

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

  3. 3.

    & Medicinal chemistry of polycyclic cage compounds in drug discovery research. Med. Chem. Res. 17, 137–151 (2008).

  4. 4.

    & Radicals in Organic Synthesis (Wiley, 2001).

  5. 5.

    , & Stereochemistry of Radical Reactions: Concepts, Guidelines, and Synthetic Applications (Wiley, 2008).

  6. 6.

    & Encyclopedia of Radicals in Chemistry, Biology and Materials (Wiley, 2012).

  7. 7.

    & Stereoselective radical reactions. Chem. Soc. Rev. 32, 251–263 (2003).

  8. 8.

    , , & Progress in enantioselective radical cyclizations. Chem. Eur. J. 23, 6225–6236 (2017).

  9. 9.

    & Enantioselective free radical reactions. Acc. Chem. Res. 32, 163–171 (1999).

  10. 10.

    , & Enantioselective radical processes. Chem. Rev. 103, 3263–3296 (2003).

  11. 11.

    , , & Enantioselective cascade radical addition–cyclization–trapping reactions. Angew. Chem. Int. Ed. 45, 5863–5866 (2006).

  12. 12.

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

  13. 13.

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

  14. 14.

    & Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008).

  15. 15.

    , , & Photochemical activity of a key donor–acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes. Nat. Chem. 5, 750–756 (2013).

  16. 16.

    , & An organic thiyl catalyst for enantioselective cyclization. Nat. Chem. 6, 702–705 (2014).

  17. 17.

    , & Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade. Science 352, 1078–1082 (2016).

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    & Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer. Angew. Chem. Int. Ed. 51, 3923–3927 (2012).

  22. 22.

    , & Enantioselective photocatalytic [3+2] cycloadditions of aryl cyclopropyl ketones. J. Am. Chem. Soc. 138, 4722–4725 (2016).

  23. 23.

    , , , & Enantioselective titanium(III)-catalyzed reductive cyclization of ketonitriles. Angew. Chem. Int. Ed. 51, 8661–8664 (2012).

  24. 24.

    , , , & Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization. J. Am. Chem. Soc. 135, 17735–17738 (2013).

  25. 25.

    , , , & Enantioselective PhSe-group-transfer tandem radical cyclization reactions catalyzed by a chiral Lewis acid. Angew. Chem. Int. Ed. 45, 255–258 (2006).

  26. 26.

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

  27. 27.

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

  28. 28.

    , , & Cross-coupling reactions using samarium(II) iodide. Chem. Rev. 114, 5959–6039 (2014).

  29. 29.

    , & 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).

  30. 30.

    , & Samarium diiodide mediated reactions in total synthesis. Angew. Chem. Int. Ed. 48, 7140–7165 (2009).

  31. 31.

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

  32. 32.

    , & Organic Synthesis using Samarium Diiodide (RSC Publishing, 2009).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

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

  37. 37.

    , , & 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).

  38. 38.

    , , & . Mechanistic studies of proton-donor coordination to samarium diiodide. Angew. Chem. Int. Ed. 46, 8160–8163 (2007).

  39. 39.

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

  40. 40.

    , , & A chiral samarium-based catalyst for the asymmetric Meerwein–Ponndorf–Verley reduction. J. Am. Chem. Soc. 115, 9800–9801 (1993).

  41. 41.

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

  42. 42.

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

  43. 43.

    , & . The role of proton donors in SmI2-mediated ketone reduction: new mechanistic insights. J. Am. Chem. Soc. 126, 44–45 (2004).

  44. 44.

    , & Switching between novel samarium(II)-mediated cyclizations by a simple change in alcohol cosolvent. Org. Lett. 5, 4811–4814 (2003).

  45. 45.

    , , , & Mixed disproportionation versus radical trapping in titanocene(III)-promoted epoxide openings. Tetrahedron 65, 10837–10841 (2009).

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

  1. The School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK

    • Nicolas Kern
    • , Mateusz P. Plesniak
    • , Joseph J. W. McDouall
    •  & David J. Procter

Authors

  1. Search for Nicolas Kern in:

  2. Search for Mateusz P. Plesniak in:

  3. Search for Joseph J. W. McDouall in:

  4. Search for David J. Procter in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David J. Procter.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound 2a

  2. 2.

    Supplementary information

    Crystallographic data for compound 4

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.2841