Enantioselective Michael addition of cyclic ketones to nitroolefins catalyzed by a novel fluorine-insertion organocatalyst

A novel fluorine-insertion organocatalyst, which was designed based on the fluorine–ammonium ion gauche effect, was synthesized and used successfully to catalyze the asymmetric Michael addition of cyclic ketones to nitroolefins. High yields and excellent diastereo- and enantioselectivities were achieved under mild conditions. A possible stereochemical model is also proposed.

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N-Boc-trans-4-hydroxy-l-proline methyl esterC11H19NO5[α]D20=-65.8 (c 0.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (2S,4R)

N-Boc-cis-4-fluoro-l-proline methyl esterC11H18FNO4[α]D20=-59.6 (c 0.7, CHCl3)Source of chirality: the precursor and fluorination of hydroxyAbsolute configuration: (2S,4S)

N-Boc-cis-4-Fluoro-l-prolinalC10H16FNO3[α]D20=-80.7 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2S,4S)

(S,S)-2-((Pyrrolidin-1-yl)methyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl esterC14H25FN2O2[α]D20=-50.1 (c 1.1, CHCl3)Source of chirality: the precursorAbsolute configuration: (2S,4S)

(S,S)-2-((Pyrrolidin-1-yl)methyl)-4-fluoro-pyrrolidineC19H17FN2[α]D20=13.5 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (2S,4S)

(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanoneC14H17NO396% ee[α]D20=-29.6 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-p-methoxyphenylethyl]cyclohexanoneC15H19NO493% ee[α]D20=-23.5 (c 1.1, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-p-tert-butylphenylethyl]cyclohexanoneC18H25NO388% ee[α]D20=-15.6 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-p-chlorophenylethyl]cyclohexanoneC14H16CINO391% ee[α]D20=-27.0 (c 1.5, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-p-bromophenylethyl]cyclohexanoneC14H16BrNO398% ee[α]D20=-25.7 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-ortho-bromophenylethyl]cyclohexanoneC14H16BrNO396% ee[α]D20=-54.0 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-(2,4-dichlorophenyl)-ethyl]cyclohexanoneC14H15Cl2NO399% ee[α]D20=-59.6 (c 0.9, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-1-(Naphthalene-1-yl)-2-nitroethyl]cyclohexanoneC18H19NO398% ee[α]D20=-84.5 (c 0.5, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(S)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanoneC12H15NO498% ee[α]D20=-13.2 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,S)

(S)-2-[(S)-2-Nitro-1-cyclohexylethyl]cyclohexanoneC14H23NO384% ee[α]D20=-25.0 (c 0.3, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,S)

(R)-Tetrahydro-3-[(R)-2-nitro-1-phenylethyl]pyran-4-oneC13H15NO495% ee[α]D20=-36.2 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (R,R)

2-Nitro-1-phenylethyl cyclopentanone (syn and anti)C13H15NO32:1 dr (syn/anti), 88% ee (syn), 86% ee (anti)[α]D20=-44.2 (c 1.0, CHCl3).Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-2-Nitro-1-phenylethyl]cycloheptanoneC15H19NO380% ee[α]D20=-14.6 (c 1.0, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(S)-2-[(R)-1-(2,3-Dimethoxyphenyl)-2-nitroethyl]cyclohexanoneC11H13NO349% ee[α]D20=-1.5 (c 0.6, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,R)

(E)-(S)-2-((S)-1-Nitro-4-phenylbut-3-en-2-yl)cyclohexanoneC16H19NO399% ee[α]D20=-60.1 (c 1.1, CHCl3)Source of chirality: enantioselective Michael additionAbsolute configuration: (S,S)