BASE-CATALYZED C-2 EXCHANGE AND EPIMERIZATION OF COCAINE ANALOGS - METHYL 3-BETA-SUBSTITUTED 8-METHYL-8-AZABICYCLO[3.2.1]OCTANE-2-CARBOXYLATES

The kinetic and thermodynamic parameters associated with epimeric 2-carbomethoxy-3-beta-substituted tropanes have been investigated by means of base-catalyzed deuterium incorporation, epimerization, and by molecular modeling. The equilibration results, as well as the molecular mechanics calculations, showed the 2-alpha-epimers to be more stable than the 2-beta-epimers. However, it was found that the energies of the transitions states for deprotonation at C-2 from the beta-face were higher than those for deprotonation from the alpha-face. These results are contrary to what would have been predicted based on the assumption that the more exothermic reaction pathway would involve a more stabilized transition state.