CEPHALOTAXINE ANALOGS - STEREOSPECIFIC SYNTHESIS OF SPIRO-FUSED 3-BENZAZEPINE AND 1,3-BENZODIAZEPINE DERIVATIVES

The previously reported spirolactam 3 was converted into aldehyde derivative 17 (55% yield) via alkylation of 3 with bromo-tert-butyl acetate followed by transesterification to methyl ester 16 and reduction of 16 with diisobutylaluminum hydride. Treatment of aldehyde 17 with hydrochloric acid afforded benzazepinol 21 (90%), which was readily dehydrated using boron trifluoride-etherate to yield derivative 22 (90%). An alternative approach to the fused benzazepine system 33 started from 3,4-dimethoxyphenylacetic acid (23), which was converted into nitrostyrene derivative 26. Cycloaddition of butadiene (derived from butadiene sulphone) to 26 yielded 27 (70—75%), which underwent stereospecific reaction with methyl acrylate to yield nitro diester 28 (87%). Reduction of 28 with zinc-HCl gave lactam-ester 29 (90%), which cyclized in a stereospecific reaction with diisobutyl aluminum hydride to furnish benzazepinol 33 (91%), the structure of which was confirmed by single-crystal X-ray analysis. Analogous reactions starting from nitropiperonal afforded dinitro ester 37 (62% yield for three steps), which was reduced by zinc-HCl to yield amine-lactam 38 (55%), which, in turn, was cyclized with formaldehyde to give benzodiazepine derivative 40 (71%). © 1990, American Chemical Society. All rights reserved.