A one-step synthesis of enantiopure 2-substituted 4,5-dihydro-1,4-benzodiazepine-3-ones via intramolecular azide cycloaddition

Starting from the appropriate azides bearing the (S)-1-phenylethylamine and the l-alanine benzylester as chiral pendants, a facile and effective synthetic route to the title compounds in their enantiopure form was developed with excellent product yields obtained. Basic hydrolysis of the ester group of title compounds 3a–c gave the corresponding, readily functionalisable carboxylic acids. Catalytic reduction of 2-benzyl derivatives 3c and 3f gave 4-functionalised 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones in enantiopure forms.

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2-{N-[1-(S)-(1-Benzyloxycarbonyl)ethyl]-N-(1-oxo-2-(E)-butenyl)}methylamino phenylazideC21H22N4O3[α]D25=-15.2 (c 0.21, CHCl3)Source of chirality: the corresponding aminoderivativeAbsolute configuration: (S)

2-[N-(1-(S)-Phenylethyl)-N-(1-oxo-2-(E)-butenyl)]methylamino phenylazideC19H20N4O[α]D25=-66.0 (c 0.24, CHCl3)Source of chirality: the corresponding aminoderivativeAbsolute configuration: (S)

2-Ethyl-4-[1-(S)-(1-benzyloxycarbonyl)ethyl]-4,5-dihydro-1,4-benzodiazepin-3-oneC21H22N2O3[α]D25=+241.0 (c 0.22, CHCl3)Source of chirality: the corresponding azidoderivativeAbsolute configuration: (S)

2-Benzyl-4-[1-(S)-(1-benzyloxycarbonyl)ethyl]-4,5-dihydro-1,4-benzodiazepin-3-oneC26H24N2O3[α]D25=+135.1 (c 0.20, CHCl3)Source of chirality: the corresponding azidoderivativeAbsolute configuration: (S)

2-Ethyl-4-(1-(S)-phenylethyl)-4,5-dihydro-1,4-benzodiazepin-3-oneC19H20N2O[α]D25=+54.6 (c 0.24, CH2Cl2)Source of chirality: the corresponding azidoderivativeAbsolute configuration: (S)

2-Benzyl-4-(1-(S)-phenylethyl)-4,5-dihydro-1,4-benzodiazepin-3-oneC24H22N2O[α]D25=+107.1 (c 0.14, CHCl3)Source of chirality: the corresponding azidoderivativeAbsolute configuration: (S)

2-Methyl-4-[1-(S)-(1-hydroxycarbonyl)ethyl]-4,5-dihydro-1,4-benzodiazepin-3-oneC13H14N2O3[α]D25=+76.0 (c 0.17, CHCl3)Source of chirality: the corresponding benzylesterAbsolute configuration: (S)

2-Ethyl-4-[1-(S)-(1-hydroxycarbonyl)ethyl]-4,5-dihydro-1,4-benzodiazepin-3-oneC14H16N2O3[α]D25=+129.6 (c 0.23, CHCl3)Source of chirality: the corresponding benzylesterAbsolute configuration: (S)

2-Benzyl-4-[1-(S)-(1-hydroxycarbonyl)ethyl]-4,5-dihydro-1,4-benzodiazepin-3-oneC12H14N2O3[α]D25=+289.6 (c 0.38, CHCl3)Source of chirality: the corresponding benzylesterAbsolute configuration: (S)

4-[1-(S)-(1-Hydroxycarbonyl)ethyl]-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-oneC17H18N2O3[α]D25=-35.1 (c 0.77, CHCl3)Source of chirality: the corresponding 2-benzyl-4,5-dihydro-1,4-benzodiazepin-3-oneAbsolute configuration: (S)

4-(1-(S)-Phenylethyl)-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-oneC19H18N2O3[α]D25=-107.1 (c 0.14, CHCl3)Source of chirality: the corresponding 2-benzyl-4,5-dihydro-1,4-benzodiazepin-3-oneAbsolute configuration: (S)