Asymmetric Synthesis of Potential Biologically \ud active 1,4-Benzoxazepine, 4,1-Benzoxazepine and their Derivatives

The benzoxazepine belongs to a group of heterocyclic compounds, which have acquired \ud tremendous importance in medicinal chemistry and pharmaceutical industry. The 1,4-/ 4,1\ud benzoxazepines are renowned for their mild tranquilizing effect along with their remarkable \ud prospective towards a variety of biological activities e.g; anti-cancer, anti-HIV, analgesics, \ud anti-hypertensive etc. The enantiomeric purity is highly desirable in the pharmaceutical \ud industry since our biological system have chiral environment. Both enantiomers of racemic \ud drugs have different interaction; as usually only one isomer of a drug is biologically active, \ud while its other isomers/ antipode may display lethal, toxic or undesired side-effects. \ud Owing to their tremendous biological activities and medicinal applications of 1,4/ \ud 4,1-benzoxazepines, the work presented here is concerned with asymmetric synthesis. \ud Different approaches towards the synthesis of chiral 1,4-/ 4,1-benzoxazepine-2,5-diones \ud were adopted involving coupling of various derivatives of 2-hydroxybenzamides and 2\ud aminobenzoic acids with methyl (S)-2-tosyllactate, (S)-?-chloroesters and (S)-2\ud chlorocarboxylic acid chlorides. \ud R2\ud Cl\ud O\ud Cl\ud X\ud N H\ud O\ud Z\ud OH\ud N\ud O\ud O\ud X\ud Z O\ud R2\ud N\ud O\ud O\ud Cl\ud R2\ud Z\ud XCOOH\ud N\ud X\ud Z\ud O\ud R2\ud Cl\ud X H H H H H Cl Cl H H Cl Br Z H H H Me Me Me Me H Me Me Br R1 H H H H H H H Ph H H H R2 iPr Bn iBu iPr iBu iPr iBu iBu Me Me Me %Yield 70 50 71 62 86 65 62 80 78 66 50 ee (%) 68 - 53 - 70 65 81 - - - \ud R1\ud +\ud R1 R1 YY Y Y + Et3N DMF X = H, Me Y = H, Cl Z = H, Cl, NO2 R1 = Me, H, Ph R2 = Me, Bn, iPr, iBu K2CO3 DMF \ud The synthesized compounds were characterized by FTIR, UV/Vis, NMR (both 1H and 13C \ud NMR), MS (HR ESI MS, LR EIMS) and XRD. The ee of 4,1-benzoxazepines were \ud determined by adding chiral shift agent europium[III] tris[3-(heptafluoropropyl hydroxymethylene)-(?)-camphorate] in the NMR tube before running the 1H NMR \ud spectrum. The NMR not only helped in structure elucidation and stereoselectivity but also \ud helped in determining the configuration of dominating enantiomer. The synthesized \ud compounds were screened against different bacterial strains and some compounds were \ud found to exhibit good anti-bacterial activities. A few chiral 4,1-benzoxazepines showed \ud good anti-inflammatory activity in initial trials