Catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides: diastereo- and enantioselective synthesis of imidazolidines

The first catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides have been established via SPINOL-derived chiral phosphoric acid-catalyzed pseudo four-component reactions of aldehydes and 2-aminomalonates, resulting in the stereoselective construction of chiral imidazolidine scaffolds with two stereogenic centers in generally high yields and with good stereoselectivities (up to 81% yield, all >20:1 dr, up to 93% ee). This protocol provides easy access to synthetically and pharmaceutically important chiral imidazolidines via the formation of one ring system, two stereogenic centers, and four new bonds in a single step.

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(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl-2,5-bis(4-nitrophenyl)imidazolidine-4,4-dicarboxylateC28H32N4O12[α]D20 = –7 (c 0.33, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Dimethyl-1-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-2,5-bis(4-nitrophenyl)imidazolidine-4,4-dicarboxylateC24H24N4O12[α]D20 = −34 (c 0.43, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(3-nitrophenyl)imidazolidine-4,4-dicarboxylateC28H32N4O12[α]D20 = +27 (c 0.36, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Dimethyl-1-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-2,5-bis(3-nitrophenyl)imidazolidine-4,4-dicarboxylateC24H24N4O12[α]D20 = −63 (c 0.42, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(2-nitrophenyl)imidazolidine-4,4-dicarboxylateC28H32N4O12[α]D20 = −109 (c 0.24, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Dimethyl-1-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-2,5-bis(2-nitrophenyl)imidazolidine-4,4-dicarboxylateC24H24N4O12[α]D20 = −48 (c 0.19, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-2,5-bis(4-cyanophenyl)-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)imidazolidine-4,4-dicarboxylateC30H32N4O8[α]D20 = −29 (c 0.24, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Dimethyl-2,5-bis(4-cyanophenyl)-1-(1,3-dimethoxy-1,3-dioxopropan-2-yl)imidazolidine-4,4-dicarboxylateC26H24N4O8[α]D20 = +17 (c 0.39, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-2,5-bis(3-cyanophenyl)-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)imidazolidine-4,4-dicarboxylateC30H32N4O8[α]D20 = +36 (c 0.39, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(4-(methoxycarbonyl)phenyl)imidazolidine-4,4-dicarboxylateC32H38N2O12[α]D20 = −15 (c 0.27, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(4-(trifluoromethyl)phenyl)imidazolidine-4,4-dicarboxylateC30H32F6N2O8[α]D20 = −13 (c 0.21, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2R,5S)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(4-fluorophenyl)imidazolidine-4,4-dicarboxylateC28H32F2N2O8[α]D20 = −49 (c 0.12, CHCl3)Source of chirality: the catalystAbsolute configuration: (2R,5S)

(2S,5R)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(2-fluorophenyl)imidazolidine-4,4-dicarboxylateC28H32F2N2O8[α]D20 = −20 (c 0.21, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl-2,5-bis(3-cyano-4-fluorophenyl)-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)imidazolidine-4,4-dicarboxylateC30H30F2N4O8[α]D20 = +21 (c 0.11, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2S,5R)-Diethyl 1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-diphenylimidazolidine-4,4-dicarboxylateC28H34N2O8[α]D20 = +108 (c 0.08, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5R)

(2R,5S)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-bis(4-methoxyphenyl)imidazolidine-4,4-dicarboxylateC30H38N2O10[α]D20 = +5 (c 0.21, CHCl3)Source of chirality: the catalystAbsolute configuration: (2R,5S)

(2S,5S)-Diethyl-1-(1,3-diethoxy-1,3-dioxopropan-2-yl)-2,5-di(thiophen-2-yl)imidazolidine-4,4-dicarboxylateC24H30N2O8S2[α]D20 = −39 (c 0.20, CHCl3)Source of chirality: the catalystAbsolute configuration: (2S,5S)