Azetidine-derived bifunctional organocatalysts for Michael reactions

2-Cyano azetidines, easily accessible from β-amino alcohols, are precursors of stereodefined homochiral azetidinic or pyrrolidinic 1,2-diamines. A small library of these original diamines was screened as precatalysts for the enantioselective addition of 1,3-dicarbonyl compounds onto β-nitro styrenes. An azetidinic diamine derived from (−)-ephedrine and derivatized as a thiourea was found to catalyze the conjugate addition of acetylacetone with good levels of enantioselectivities (up to 84% ee). Interestingly, the absolute configuration of the Michael adduct depends on the nature of the 1,3 dicarbonyl nucleophile (diethyl malonate or acetylacetone), which is indicative of a different mechanism involved in the reaction of these two nucleophiles.

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1-((2R,3S,4S)-3-Phenyl-1,2,4-trimethylazetidinic)-3-(3,5-bis(trifluoromethyl)phenyl) thioureaC21H21F6N3S[α]D25=+12.7 (c 1.2, CH2Cl2)Source of chirality: (2R,3S,4S)-2-(1-amino-methyl)-1,4-dimethyl-3-phenyl-azetidineAbsolute configuration: (2R,3S,4S)

1-((2R,3S,4R,5R)-1,5-Dimethyl-2,4-diphenylpyrrolidinic)-3-(3,5-bis(trifluoromethyl)phenyl) thioureaC27H25F6N3S[α]D25=+68.5 (c 0.2, CH2Cl2)Source of chirality: (2R,3S,4R,5R)-3-amino-1,5-dimethyl-2,4-diphenyl-pyrrolidineAbsolute configuration: (2R,3S,4R,5R)

(R)-3-(1-(3-Nitrophenyl)-2-nitroethyl)pentane-2,4-dione (1g)C13H14N2O6Ee = 64%[α]D25=-21.7 (c 1.3, CH2Cl2)Source of chirality: organocatalysisAbsolute configuration: (R)

(R)-3-(1-(5-Bromothienyl)-2-nitroethyl)pentane-2,4-dioneC11H12BrNO4SEe = 74%[α]D25=-30.0 (c 0.2, CH2Cl2)Source of chirality: organocatalysisAbsolute configuration: (R)