Article | Published:

Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst

Nature Chemistry volume 3, pages 473477 (2011) | Download Citation

Abstract

Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic asymmetric domino Michael–aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of compounds.

  • Compound C20H24N2O2

    (1R)-(6-Methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methanol

  • Compound C20H27N3O

    (1S)-((1S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine

  • Compound C25H26N2O2

    (1S)-(6-Phenoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methanol

  • Compound C26H26N2O3

    (1R)-(6-Hydroxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methyl benzoate

  • Compound C28H28F6N4S

    1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R)-((2R,4S,5R)-5-ethylquinuclidin-2-yl)(quinolin-4-yl)methyl)thiourea

  • Compound C29H30F6N4OS

    1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S)-((2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl)thiourea

  • Compound C29H41N5O

    (1S)-N-(Di(pyrrolidin-1-yl)methylene)-1-((1S,4S,5R)-5-ethylquinuclidin-2-yl)-1-(6-methoxyquinolin-4-yl)methanamine

  • Compound C41H41N5OS

    1-((S)-2'-Amino-[1,1'-binaphthalen]-2-yl)-3-((S)-((1S,2S,4S,5S)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl)thiourea

  • Compound C41H40N4O2S

    1-((S)-((1S,2S,4S,5S)-5-Ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl)-3-((S)-2'-hydroxy-[1,1'-binaphthalen]-2-yl)thiourea

  • Compound C41H41N5OS

    1-((R)-2'-Amino-[1,1'-binaphthalen]-2-yl)-3-((S)-((1S,2S,4S,5S)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl)thiourea

  • Compound C41H39N5OS

    1-((S)-2'-Amino-[1,1'-binaphthalen]-2-yl)-3-((R)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5S)-5-vinylquinuclidin-2-yl)methyl)thiourea

  • Compound C23H19NO2

    1-Benzyl-3-(2-oxo-2-phenylethyl)-oxindole

  • Compound C23H18FNO2

    1-Benzyl-3-(2-oxo-2-(4-fluoro-phenyl)ethyl)-oxindole

  • Compound C24H21NO3

    1-Benzyl-3-(2-oxo-2-(3-methoxy-phenyl)ethyl)-oxindole

  • Compound C21H17NO3

    1-Benzyl-3-(2-oxo-2-(2-furanyl)ethyl)-oxindole

  • Compound C21H17NO2S

    1-Benzyl-3-(2-oxo-2-(2-thiophenyl)ethyl)-oxindole

  • Compound C24H21NO3

    1-Benzyl-3-(2-oxo-2-phenylethyl)-5-methoxy-oxindole

  • Compound C18H17NO2

    1-Benzyl-3-(2-oxo-propyl)-oxindole

  • Compound C13H11NO4

    Methyl 2-(1-acetyl-2-oxoindolin-3-ylidene)acetate

  • Compound C18H13NO3

    1-Acetyl-3-(2-oxo-2-phenylethylidene)indolin-2-one

  • Compound C18H12ClNO3

    1-Acetyl-3-(2-(4-chlorophenyl)-2-oxoethylidene)indolin-2-one

  • Compound C18H12BrNO3

    1-Acetyl-5-bromo-3-(2-oxo-2-phenylethylidene)indolin-2-one

  • Compound C18H12FNO3

    1-Acetyl-5-fluoro-3-(2-oxo-2-phenylethylidene)indolin-2-one

  • Compound C13H10ClNO4

    Methyl 2-(1-acetyl-6-chloro-2-oxoindolin-3-ylidene)acetate

  • Compound C14H13NO4

    Ethyl 2-(1-acetyl-2-oxoindolin-3-ylidene)acetate

  • Compound C19H15NO3

    1-Acetyl-3-(2-oxo-2-(o-tolyl)ethylidene)indolin-2-one

  • Compound C36H30N2O6

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[5'-hydroxy-2'-methoxycarbonyl-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H32N2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H32N2O5

    (3R,3''R,2'S,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H31FN2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[5-fluoro-oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H31BrN2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[5-bromo-oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H31ClN2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-(4-chloro-benzoyl)-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C41H31FN2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-(4-fluoro-phenyl)-5'-hydroxy]-cyclopentane-3',3''-oxindole]

  • Compound C42H34N2O6

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-(3-methoxy-phenyl)]-cyclopentane-3',3''-oxindole]

  • Compound C39H30N2O6

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-(2-furanyl)-5'-hydroxy]-cyclopentane-3',3''-oxindole]

  • Compound C39H30N2O5S

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-(2-thiophenyl)]-cyclopentane-3',3''-oxindole]

  • Compound C39H29ClN2O5S

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-(4-chloro-benzoyl)-5'-hydroxy-5'-(2-thiophenyl)]-cyclopentane-3',3''-oxindole]

  • Compound C39H29FN2O5S

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[5-fluoro-oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-(2-thiophenyl)]-cyclopentane-3',3''-oxindole]

  • Compound C42H34N2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-(2-methyl-benzoyl)-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C36H30N2O5

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-methyl]-cyclopentane-3',3''-oxindole]

  • Compound C37H32N2O7

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[5'-hydroxy-2'-methoxycarbonyl-5'-(3-methoxyphenyl)]-cyclopentane-3',3''-oxindole]

  • Compound C34H28N2O7

    (3S,3''S,2'R,5'R)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[5'-(2-furanyl)-5'-hydroxy-2'-methoxycarbonyl]-cyclopentane-3',3''-oxindole]

  • Compound C36H29ClN2O6

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[6-chloro-oxindole-3,1'-[5'-hydroxy-2'-methoxycarbonyl-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C37H32N2O7

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[5'-hydroxy-2'-methoxycarbonyl-5'-phenyl]-cyclopentane-3',3''-(5-chloro-oxindole)]

  • Compound C37H32N2O6

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-benzyl-dispiro[oxindole-3,1'-[2'-ethoxycarbonyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C23H18BrNO2

    1-(4-Bromo-benzyl)-3-(2-oxo-2-phenylethyl)-oxindole

  • Compound C41H31BrN2O5

    (3S,3''S,2'R,5'S)-1-Acetyl-1''-(4-bromo-benzyl)-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

  • Compound C39H30N2O4

    (3S,3''S,2'R,5'S)-1''-Benzyl-dispiro[oxindole-3,1'-[2'-benzoyl-5'-hydroxy-5'-phenyl]-cyclopentane-3',3''-oxindole]

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.

    , , & The art and science of total synthesis at the dawn of the twenty-first century. Angew. Chem. Int. Ed. 39, 44–122 (2000).

  2. 2.

    & The essence of total synthesis. Proc. Natl Acad. Sci. USA 101, 11929–11936 (2004).

  3. 3.

    , & Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 45, 7134–7186 (2006).

  4. 4.

    & Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

  5. 5.

    & Aiming for the ideal synthesis, J. Org. Chem. 75, 4657–4673 (2010).

  6. 6.

    et al. Absolute stereochemistry of citrinadins A and B from marine-derived fungus. J. Org. Chem. 70, 9430–9435 (2005).

  7. 7.

    , , & Cyclopiamines A and B, novel oxindole metabolites of penicillium cyclopium westling. J. Chem. Soc. Perkin Trans. 1 1751–1761 (1979).

  8. 8.

    & Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem. Int. Ed. 46, 8748–8758 (2007).

  9. 9.

    et al. Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175–1180 (2010).

  10. 10.

    , , , & A library of spirooxindoles based on a stereoselective three-component coupling reaction. J. Am. Chem. Soc. 126, 16077–16086 (2004).

  11. 11.

    et al. Structure-based design of potent non-peptide MDM2 inhibitors. J. Am. Chem. Soc. 127, 10130–10131 (2005).

  12. 12.

    Asymmetric creation of quaternary carbon centers. Chem. Rev. 93, 2037–2066 (1993).

  13. 13.

    & The catalytic enantioselective construction of molecules with quaternary carbon stereocenters. Angew. Chem. Int. Ed. 37, 388–401 (1998).

  14. 14.

    Catalytic enantioselective Diels–Alder reactions: methods, mechanistic fundamentals, pathways, and applications. Angew. Chem. Int. Ed. 41, 1650–1667 (2002).

  15. 15.

    , , , & Organocatalytic synthesis of spiro [pyrrolidin-3,3′-oxindoles] with high enantiopurity and structural diversity. J. Am. Chem. Soc. 131, 13819–13825 (2009).

  16. 16.

    et al. Targeting structural and stereochemical complexity by organocascade catalysis: construction of spirocyclic oxindoles having multiple stereocenters Angew. Chem. Int. Ed. 48, 7200–7203 (2009).

  17. 17.

    , & Enantioselective construction of spirocyclic oxindolic cyclopentanes by palladium-catalyzed trimethylenemethane-[3+2]-cycloaddition. J. Am. Chem. Soc. 129, 12396–12397 (2007).

  18. 18.

    et al. Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nature Chem. 2, 735–740 (2010).

  19. 19.

    & The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 103, 2945–2963 (2003).

  20. 20.

    & Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

  21. 21.

    . Organocatalysis lost: modern chemistry, ancient chemistry, and an unseen biosynthetic apparatus. Angew. Chem. Int. Ed. 47, 42–47 (2008).

  22. 22.

    The advent and development of organocatalysis. Nature 455, 304–308 (2008).

  23. 23.

    , , & Asymmetric aminocatalysis—gold rush in organic chemistry. Angew. Chem. Int. Ed. 47, 6138–6171 (2008).

  24. 24.

    , & . Organocatalytic asymmetric domino Knoevenagel/Diels–Alder reactions: a bioorganic approach to the diastereospecific and enantioselective construction of highly substituted spiro[5,5]undecane-1,5,9-triones. Angew. Chem. Int. Ed. 42, 4233–4237 (2003).

  25. 25.

    , , & Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861–863 (2006).

  26. 26.

    , & Asymmetric organocatalytic domino reactions. Angew. Chem. Int. Ed. 46, 1570–1581 (2007).

  27. 27.

    , & A general approach to high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans via cascade Barbas–Michael and acetalization reactions. Org. Biomol. Chem. 9, 2715–2721 (2011).

  28. 28.

    , & Organocatalytic cascade reactions as a new tool in total synthesis. Nature Chem. 2, 167–178 (2010).

  29. 29.

    et al. Asymmetric organic catalysis with modified cinchona alkaloids. Acc. Chem. Res. 37, 621–631 (2004).

  30. 30.

    , , & Highly enantioselective conjugate addition of malonate and β-ketoester to nitroalkenes: asymmetric C–C bond formation with new bifunctional organic catalysts based on cinchona alkaloids. J. Am. Chem. Soc. 126, 9906–9907 (2004).

  31. 31.

    , & Enantioselective organocatalytic Michael addition of malonate esters to nitro olefins using bifunctional cinchonine derivatives. Chem. Commun. 4481–4483 (2005).

  32. 32.

    , , & Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional cinchona organocatalysts. Org. Lett. 7, 1967–1970 (2005).

  33. 33.

    & Urea- and thiourea-substituted cinchona alkaloid derivatives as highly efficient bifunctional organocatalysts for the asymmetric addition of malonate to nitroalkenes: inversion of configuration at C9 dramatically improves catalyst performance. Angew. Chem. Int. Ed. 44, 6367–6370 (2005).

  34. 34.

    et al. Enantioselective Diels–Alder reaction of simple α,β-unsaturated ketones with a cinchona alkaloid catalyst. J. Am. Chem. Soc. 130, 2422–2423 (2008).

  35. 35.

    , , & Organocatalytic asymmetric tandem Michael–Henry reactions: a highly stereoselective synthesis of multifunctionalized cyclohexanes with two quaternary stereocenters. Org. Lett. 10, 2437–2440 (2008).

  36. 36.

    , , , & Facile domino access to chiral bicyclo[3.2.1]octanes and discovery of a new catalytic activation mode. Org. Lett. 12, 2682–2685 (2010).

  37. 37.

    , & Asymmetric vinylogous aldol reaction of silyloxy furans with a chiral organic salt. J. Am. Chem. Soc. 132, 9558–9560 (2010).

  38. 38.

    , , & Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride. Nature Chem. 2, 380–384 (2010).

  39. 39.

    & Phosphonium salts as chiral phase-transfer catalysts: asymmetric Michael and Mannich reactions of 3-aryloxindoles. Angew. Chem. Int. Ed. 47, 4559–4561 (2009).

  40. 40.

    , & . Thiourea-catalyzed highly enantio- and diastereoselective additions of oxindoles to nitroolefins: application to the formal synthesis of (+)-physostigmine. J. Am. Chem. Soc. 131, 8758–8759 (2009).

  41. 41.

    , & Enantioselective base-free phase-transfer reaction in water-rich solvent. J. Am. Chem. Soc. 131, 16620–16621(2009).

  42. 42.

    , & . Dimeric quinidine-catalyzed enantioselective aminooxygenation of oxindoles: an organocatalytic approach to 3-hydroxyoxindole derivatives. J. Am. Chem. Soc. 132, 5574–5575 (2010).

  43. 43.

    , , , & Asymmetric quadruple aminocatalytic domino reactions to fused carbocycles incorporating a spirooxindole motif. Org. Lett. 12, 2766–2769 (2010).

  44. 44.

    & Stereocontrolled creation of all-carbon quaternary stereocenters by organocatalytic conjugate addition of oxindoles to vinyl sulfone. Angew. Chem. Int. Ed. 49, 7753–7756 (2010).

  45. 45.

    et al. Highly organocatalytic asymmetric Michael–ketonealdol–dehydration domino reaction: straightforward approach to construct six-membered spirocyclicoxindoles. Chem. Commun. 46, 8064–8066 (2010).

  46. 46.

    , & Catalytic asymmetric synthesis of oxindoles bearing a tetrasubstituted stereocenter at the C-3 position. Adv. Synth. Catal. 352, 1381–1407 (2010).

  47. 47.

    et al. Asymmetric iminium ion catalysis with a novel bifunctional primary amine thiourea: controlling adjacent quaternary and tertiary stereocenters. Chem. Eur. J. 15, 7846–7849 (2009).

  48. 48.

    , , , & Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 127, 119–125 (2005).

  49. 49.

    et al. Stereocontrolled creation of adjacent quaternary and tertiary stereocenters by a catalytic conjugate addition. Angew. Chem. Int. Ed. 44, 105–108 (2005).

  50. 50.

    , , & Theoretical studies on the bifunctionality of chiral thiourea-based organocatalysts: competing routes to C–C bond formation. J. Am. Chem. Soc. 128, 13151–13160 (2006).

Download references

Acknowledgements

The authors acknowledge the Skaggs Institute for Chemical Biology for funding. N.R.C. thanks Fundação para a Ciência e Tecnologia (SFRH/BPD/46589/2008) for financial support. The authors also thank A.L. Rheingold for X-ray crystallographic analysis.

Author information

Affiliations

  1. The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Bin Tan
    • , Nuno R. Candeias
    •  & Carlos F. Barbas III
  2. Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa

    • Nuno R. Candeias

Authors

  1. Search for Bin Tan in:

  2. Search for Nuno R. Candeias in:

  3. Search for Carlos F. Barbas in:

Contributions

B.T. and N.C. designed and carried out the chemical experiments. C.B. designed the experiments and supervised the project. All authors discussed the results, contributed to writing the manuscript, and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Carlos F. Barbas III.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound 3e

  2. 2.

    Supplementary information

    Crystallographic data for compound 3p

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.1039

Further reading