Synthesis of quinazolinone-based aziridine diols as chiral ligands: dual stereoselectivity in the asymmetric ethylation of aryl aldehydes

A new class of quinazoline-based enantiomerically pure aziridine diols 4a–d were prepared from the aziridination of mesityl oxide 3 with in situ generated 3-acetoxyaminoquinazolinone (S)-2b followed by NaBH4 reduction. Aziridine diols 4a–d were purified by means of column chromatography on silica gel and their stereochemistries were assigned by X-ray crystallography and NMR analysis. These aziridine diols 4 were evaluated as chiral ligands in the asymmetric addition of diethylzinc to aryl aldehydes, and ligand (S,R,R)-4a yielded (R)-1-phenylpropanol derivatives with up to 92% ee, while the diastereomer (S,S,R)-4c gave the opposite enantiomers (S)-1-phenylpropanol derivatives with up to 86% ee. The results demonstrate that switching the configuration of the aziridine alcohol moiety in ligand gives a remarkable reversal of enantioselectivity in the asymmetric addition of diethylzinc to aryl aldehydes.

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3-[(3R)-3-Acetyl-2,2-dimethylaziridin-1-yl]-2-[(1S)-1-hydroxyethyl]quinazolin-4(3H)-oneC16H19N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (R,S)[α]D20 = −16 (c 1, DCM)

3-[(3S)-3-Acetyl-2,2-dimethylaziridin-1-yl]-2-[(1S)-1-hydroxyethyl]quinazolin-4(3H)-oneC16H19N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,S)[α]D20 = +73 (c 1, DCM)

2-[(1S)-1-Hydroxyethyl]-3-{(3R)-3-[(1R)-1-hydroxyethyl]-2,2-dimethylaziridin-1-yl}quinazolin-4(3H)-oneC16H21N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,R,R)[α]D20 = −103 (c 1, DCM)

2-[(1S)-1-Hydroxyethyl]-3-{(3R)-3-[(1S)-1-hydroxyethyl]-2,2-dimethylaziridin-1-yl}quinazolin-4(3H)-oneC16H21N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,R,S)[α]D20 = −192 (c 1, DCM)

2-[(1S)-1-Hydroxyethyl]-3-{(3S)-3-[(1R)-1-hydroxyethyl]-2,2-dimethylaziridin-1-yl}quinazolin-4(3H)-oneC16H21N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,S,R)[α]D20 = +240 (c 1, DCM)

2-[(1S)-1-Hydroxyethyl]-3-{(3S)-3-[(1S)-1-hydroxyethyl]-2,2-dimethylaziridin-1-yl}quinazolin-4(3H)-oneC16H21N3O3Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,S,S)[α]D20 = +126 (c 1, DCM)

(1S)-1-{3-[(3R)-3-Acetyl-2,2-dimethylaziridin-1-yl]-4-oxo-3,4-dihydroquinazolin-2-yl}ethyl 4-nitrobenzoateC23H22N4O6Ee: 99%Source of chirality: (S)-Lactic acidAbsolute configuration: (S,R)[α]D20 = +220 (c 1, DCM)