Asymmetric syntheses of piperidino-benzodiazepines through ‘cation-pool’ host/guest supramolecular approach and their DNA-binding studies

The asymmetric synthetic approach to piperidino-benzodiazepine 4a (a homolog of DC-81) has been developed. The absolute stereochemistry of 4 and 5 has been assigned to be (S) at C-12a position. This procedure features the use of a ‘cation-pool’ strategy and also a host/guest supramolecular co-catalysis approach. In this study, the chloroformate of 8-phenylmenthyl has been employed as a chiral auxiliary and includes one-pot conditions for anodic oxidation, which are followed by nucleophilic addition to an N-acyliminium ion. In addition, intramolecular azido reductive-cyclization and nitro reductive dithioacetal deprotective tandem-cyclization approaches have also been utilized for the syntheses of these compounds 4a,b and 5a,b. Some of the representative compounds exhibited an enhanced DNA-binding ability in comparison to the natural product DC-81.

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(S)-2-Methyl 1-((1R,2S,5R)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl) piperidine-1,2-dicarboxylateC24H35NO4[α]D31=-49.9 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)-1-(1R,2S,5R)

(S)-((1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl) 2-(bis(ethylthio)methyl)piperidine-1-carboxylateC27H43NO2S2[α]D31=-85.7 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)-1-(1R,2S,5R)

(S)-3-Hydroxy-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-oneC14H16N2O3[α]D31=+256 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (12aS)

(S)-3-(Benzyloxy)-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-oneC21H22N2O3[α]D31=+295 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (12aS)

(S)-3-Hydroxy-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepine-6,12(5H,6aH)-dioneC14H16N2O4[α]D31=+172 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (12aS)

(S)-3-(Benzyloxy)-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepine-6,12(5H,6aH)-dioneC21H22N2O4[α]D31=+248 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (12aS)