Synthesis of a prodrug: a semi-empirical PM3 study

The semi-empirical PM3 method is used to investigate the synthesis of a pro drug of type I which can regenerate the short-lived anti-tumoral tetrazepin one. The reaction pathway examined involves four consecutive steps: the rin g opening of benzo-tetrazepinone (1 --> 2), the diazonium coupling (2 --> 3 ), the double-proton transfer (4 --> 6) and the dissociation (7 --> 8). Geo metry 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-wit hdrawing, electron-donating argument based on calculated Hammett constants. (C) 2001 Published by Elsevier Science B.V.