Stereoselective in-vitro aromatic-ring oxygenations of chiral 1,4-benzodiazepin-2-ones

Biological N(1)-demethylation and C(3)-hydroxylation of two enantiomeric 1,4-benzodiazepin-2-ones 1 and 2 (cf. scheme 2) were found to be nonstereoselective. Aromatic-ring hydroxylation, however, took place in the (S)-series only, leading to 3′- and 4′-hydroxylated, N(1)-demethylated, metabolites ( 54 and 56 , cf. scheme 5: these structures were unambiguously confirmed by comparing their UV., CD., and mass spectra with those of authentic specimens). Several compounds, theoretically conceivable as products of hydroxylation in the aromatic A-ring of 1 and 2 by mechanisms including the NIH-shift (cf. scheme 3), were synthesized but none of these compounds was yet isolated from in vitro incubation mixtures.