Combined organo- and gold-catalyzed enantioselective synthesis of bicyclic enones

By combining organocatalysis with gold catalysis highly enantioenriched bicyclic enones are available via an operationally simple one-pot procedure. Iminium-ion activation by cinchona alkaloid-derived primary amine catalysts induces the Michael addition of propargylated malononitriles and cyanoacetates to α,β-unsaturated ketones. The resulting intermediates undergo an exo-dig cyclization, forming a new C–C bond followed by double-bond isomerization to give highly functionalized bicyclic enones in good yields and high enantioselectivities.

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(S)-2-(3-Oxocyclohexyl)-2-(prop-2-ynyl)malononitrileC12H12N2O[α]D25=-17.1 (c 1, CH2Cl2), 92% eeSource of chirality: asymmetric synthesisAbsolute configuration (S)

(R)-3-Methyl-4-oxo-5,6,7,7a-tetrahydro-1H-indene-1,1(2H,4H)-dicarbonitrileC12H12N2O[α]D25=-7.6 (c 0.44, CH2Cl2), 90% eeSource of chirality: asymmetric synthesisAbsolute configuration (R)

(S)-Methyl-1-cyano-3-methyl-4-oxo-2,4,5,6,7,7a-hexa-hydro-1H-indene-1-carboxylateC13H15NO3[α]D25=+7.7 (c 0.5, CH2Cl2), 96% ee major diastereoisomer, 97% ee minor diastereoisomer, dr 2:1Source of chirality: asymmetric synthesisAbsolute configuration (S)

(S)-Isopropyl 1-cyano-3-methyl-4-oxo-2,4,5,6,7,7a-hexahydro-1H-indene-1-carboxylateC15H19NO3[α]D25=+14.0 (c 0.5, CH2Cl2), 95% ee major diastereoisomer, 97% ee minor diastereoisomer, dr 2:1Source of chirality: asymmetric synthesisAbsolute configuration (S)

(R)-4-Methyl-5-oxo-2,3,6,7,8,8a-hexahydronaphthalene-1,1(5H)-dicarbonitrileC13H14N2O[α]D25=-29.0 (c 0.5, CH2Cl2), 91% eeSource of chirality: asymmetric synthesisAbsolute configuration (R)

(R)-3,6,6-Trimethyl-4-oxo-5,6,7,7a-tetrahydro-1H-indene-1,1(2H,4H)-dicarbonitrileC14H16N2O[α]D25=-11.0 (c 0.5, CH2Cl2), 89% eeSource of chirality: asymmetric synthesisAbsolute configuration (R)

(6R,7aR)-6-Ethyl-3-methyl-4-oxo-2,4,5,6,7,7a-hexahydro-1H-indene-1,1-dicarbonitrileC14H16N2O[α]D25=+5.1 (c 0.55, CH2Cl2), 94% ee major diastereoisomer, 76% ee minor diastereoisomer, dr 5:1Source of chirality: asymmetric synthesisAbsolute configuration (6R,7aR)

(R)-3-Methyl-4-oxo-4,5,6,6a-tetrahydropentalene-1,1(2H)-dicarbonitrileC11H10N2O[α]D25=-11.3 (c 0.5, CH2Cl2), 23% eeSource of chirality: asymmetric synthesisAbsolute configuration (R)

(4R,7aR)-4-Hydroxy-3-methyl-5,6,7,7a-tetrahydro-1H-indene-1,1(2H,4H)-dicarbonitrileC12H14N2O[α]D25=+9.1 (c 2.0, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration (4R,7aR); dr >99:1