The asymmetric organocatalytic 1,3-dipolar cycloaddition of alkyl pyruvate-derived nitrones and α,β-unsaturated aldehydes

The catalytic asymmetric 1,3-dipolar cycloaddition of pyruvate-derived nitrones to α,β-unsaturated aldehydes was investigated in the presence of various chiral amines. Highly functionalized isoxazolidines containing a quaternary stereocenter were obtained in moderate yields with up to 92% ee. To the best of our knowledge, this is the first example of an enantioselective 1,3-dipolar cycloaddition of ketonitrones. The model product was subsequently transformed into a 2-pyrrolidinone derivative in two steps.

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(3R,4S,5R)-2-Benzyl-4-formyl-3-methoxycarbonyl-3,5-dimethylisoxazolidineC15H19NO4Ee = 47%[α]D = −42.1 (c 1, CH2Cl2) 47% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4S,5R)

(3R,4S,5R)-2-Benzyl-3-ethoxycarbonyl-4-formyl-3,5-dimethylisoxazolidineC16H21NO4Ee = 53%[α]D = −48.9 (c 1, CH2Cl2) 53% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4S,5R)

(3R,4S,5R)-2-Benzyl-3-benzyloxycarbonyl-4-formyl-3,5-dimethylisoxazolidineC21H23NO4Ee = 35%[α]D = −33.4 (c 1, CH2Cl2) 35% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4S,5R)

(3R,4S,5R)-4-formyl-3-methoxycarbonyl-2,3,5-trimethylisoxazolidineC9H15NO4Ee = 41%[α]D = −36.0 (c 1.5, CH2Cl2) 41% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4S,5R)

(3R,4S,5R)-2-Benzyl-3-ethoxycarbonyl-5-ethyl-4-formyl-3-methylisoxazolidineC18H28N2O4SEe = 17%[α]D = +7.9 (c 1.1, CH2Cl2) 17% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4S,5R)

(3R,4R,5R)-2-Benzyl-4-hydroxymethyl-3-methoxycarbonyl-3,5-dimethylisoxazolidineC15H21NO4Ee = 47%[α]D = −42.6 (c 1, CH2Cl2) 47% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4R,5R)

(3R,4R,5R)-2-Benzyl-3-ethoxycarbonyl-4-hydroxymethyl-3,5-dimethylisoxazolidineC16H23NO4Ee = 88%[α]D = −59.1 (c 0.85, CHCl3) 88% ee from HPLCSource of chirality: (5S)-2,2,3-trimethyl-5-phenylmethyl-4-imidazolidinone monohydrochlorideAbsolute configuration: (3R,4R,5R)

(3R,4R,5R)-2-Benzyl-3-benzyloxycarbonyl-4-hydroxymethyl-3,5-dimethylisoxazolidineC21H25NO4Ee = 35%[α]D = −30.7 (c 1.35, CH2Cl2) 35% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4R,5R)

(3R,4R,5R)-2-Benzyl-3-methoxycarbonyl-3,5-dimethyl-4-tosyloxymethylisoxazolidineC16H23NO6SEe = 41%[α]D = −27.0 (c 0.3, CH2Cl2) 41% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4R,5R)

(3R,4R,5R)-2-Benzyl-3-ethoxycarbonyl-5-ethyl-4-hydroxymethyl-3-methylisoxazolidineC17H25NO4Ee = 17%[α]D = +4.5 (c 2.15, CH2Cl2) 17% ee from HPLCSource of chirality: (2S,2′S)-N,N′-((S)-1,1′-binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)Absolute configuration: (3R,4R,5R)

(2S,2′S)-N,N′-((S)-1,1′-Binaphthyl-2,2′-diyl)bis(2-amino-3-phenylpropanamide)C38H34N4O2[α]D = −129.0 (c 0.7, CH2Cl2)Source of chirality: (S)-1,1′-binaphthyl-2,2′-diamineAbsolute configuration: (Sa,2S,2′S)

(2S,2′S)-N,N′-((S)-1,1′-Binaphthyl-2,2′-diyl)bis(2-aminopropanamide)C26H26N4O2[α]D = −39.0 (c 0.7, CH2Cl2)Source of chirality: (S)-1,1′-binaphthyl-2,2′-diamineAbsolute configuration: (Sa,2S,2′S)

(2S,2′S)-N,N′-((S)-1,1′-Binaphthyl-2,2′-diyl)bis(2-amino-4-methyl-pentanamide)C32H38N4O2[α]D = −23.0 (c 0.7, CH2Cl2)Source of chirality: (S)-1,1′-binaphthyl-2,2′-diamineAbsolute configuration: (Sa,2S,2′S)