Asymmetric synthesis of chiral β-hydroxy-α-amino acid derivatives by organocatalytic aldol reactions of isocyanoesters with β,γ-unsaturated α-ketoesters

The first organocatalytic asymmetric aldol reaction of isocyanoesters with various β,γ-unsaturated α-ketoesters has been described. Using cinchona alkaloid-derived bifunctional thiourea as the catalyst, chiral β-hydroxy-α-amino acid derivatives can be obtained in excellent yields and enantioselectivities (up to 95% yield and 92% ee) after acidic hydrolysis. This protocol provides a straightforward method to access multiple substituted β-hydroxy-α-amino acid derivatives with high enantiomeric purity.

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1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-cyclohexylthioureaC33H40N4OS[α]D20=+88.5 (c 0.72, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-phenylthioureaC33H34N4OS[α]D20=+73.5 (c 0.52, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-Benzyl-3-(4-((S)-benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)thioureaC34H36N4OS[α]D20=-87.2 (c 0.56, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-phenethylthioureaC35H38N4OS[α]D20=+86.7 (c 0.54, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-((S)-1-phenylethyl)thioureaC35H38N4OS[α]D20=+160.1 (c 0.32, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,3S,4S,5R), (S)

1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-(2-phenylpropan-2-yl)thioureaC36H40N4OS[α]D20=+94.4 (c 0.41, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-Benzhydryl-3-(4-((S)-benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)thioureaC40H40N4OS[α]D20=+85.8 (c 0.72, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-(4-((S)-Benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-(2,2-diphenylethyl)thioureaC41H42N4OS[α]D20=+68.0 (c 0.92, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)

1-Benzyl-3-(4-((S)-benzyloxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)sulfamideC33H36N4O3S[α]D20=+39.2 (c 0.96, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R), (S)