Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and diastereoselectivities. The products were converted to chiral γ-lactams conveniently without a loss in the enantioselectivity.

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(R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-phenylacetateC21H18N2O487% Ee[α]D20=-28.6 (c 0.21, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-1-(4-methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-phenylacetateC22H20N2O584% Ee[α]D20=-29.1 (c 0.20, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-phenylacetateC22H20N2O489% Ee[α]D20=-31.0 (c 0.20, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-((S)-1-(4-chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-cyano-2-phenylacetateC21H17ClN2O491% Ee[α]D20=-38.0 (c 0.25, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-((S)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-cyano-2-phenylacetateC21H17BrN2O494% Ee[α]D20=-36.1 (c 0.38, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-1-(4-fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-phenylacetateC21H17FN2O484% Ee[α]D20=-27.9 (c 0.28, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)-2-phenylacetateC21H17N3O681% Ee[α]D20=-33.5 (c 0.20, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-(m-tolyl)pyrrolidin-3-yl)-2-phenylacetateC22H20N2O487% Ee[α]D20=-30.5 (c 0.21, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-((S)-1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-cyano-2-phenylacetateC21H17ClN2O491% Ee[α]D20=-38.9 (c 0.19, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-((S)-1-(3-bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-cyano-2-phenylacetateC21H17BrN2O490% Ee[α]D20=-34.4 (c 0.25, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-((S)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-cyano-2-phenylacetateC22H20N2O463% Ee[α]D20=-0.5 (c 0.21, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(p-tolyl)acetateC22H20N2O491% Ee[α]D20=-36.0 (c 0.25, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(4-methoxyphenyl) acetateC22H20N2O588% Ee[α]D20=-34.2 (c 0.26, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(R)-Ethyl 2-(4-bromophenyl)-2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)acetateC21H17BrN2O485% Ee[α]D20=-22.7 (c 0.63, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(S)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)butanoateC17H18N2O471% Ee[α]D20=-3.3 (c 0.21, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)

(3R,4S)-Ethyl 5-oxo-4-(2-oxo-2-(phenylamino)ethyl)-3-phenylpyrrolidine-3-carboxylateC21H22N2O484% Ee[α]D20=-42.3 (c 0.30, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)