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

Nature Chemistry 3, 473–477 (2011) | Download Citation

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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]

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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

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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.

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    Crystallographic data for compound 3e

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    Crystallographic data for compound 3p

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

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