Abstract:
The semi-empirical PM3 method is used to investigate the synthesis of a prodrug of type I which can regenerate the short-lived anti-tumoral tetrazepinone. The reaction pathway examined involves four consecutive steps: the ring opening of benzo-tetrazepinone (1 → 2), the diazonium coupling (2 → 3), the double-proton transfer (4 → 6) and the dissociation (7 → 8). Geometry PM3 optimisation of all starting material, reaction intermediates and products lead to a qualitative study of this solvent-dependent synthesis. Energetics and substituent effects are analysed using a simple electron-withdrawing, electron-donating argument based on calculated Hammett constants. © 2001 Published by Elsevier Science B.V.