ABBREVIATED IBOGAINE CONGENERS - SYNTHESIS AND REACTIONS OF TROPAN-3-YL-2 AND 3-INDOLES - INVESTIGATION OF AN UNUSUAL ISOMERIZATION OF 2-SUBSTITUTED INDOLES USING COMPUTATIONAL AND SPECTROSCOPIC TECHNIQUES

The syntheses of several N-methyltropan-3-ylindoles, designed as conge ners of ibogaine, are described. The synthetic approach to N-methyltro pan-3-yl-2-indole revealed that the tropanyl 3'-center was quite sensi tive to acid-catalyzed epimerization. The carbocyclic analog, N-methyl -2-[bicyclo[3.2.1]-oct-3-anyl] indole, also underwent this rearrangeme nt. However, N-methyltropan-3-yl-3-indole was insensitive to acid or b ase, even under more vigorous conditions. This simple isomerization is quite rare for 2-substituted indoles, especially for cases where the center of reaction is not additionally activated, and normally only ta kes place under extreme reaction conditions. The mechanism of this rea ction was investigated using ab initio molecular orbital calculations, NMR spectroscopy and deuterium labeling studies. These results indica te that, in contrast to those previously obtained for more reactive 2- substituted indoles, the reaction can best be explained using a simple exchange mechanism involving the exocyclic enamine tautomer of the in dole ring as an intermediate. The difference in reactivity is suggeste d to arise from a decrease in the relative energy of the exocyclic ena mine tautomer due to the presence of increased strain in the endo bicy clic 2-substituent. The title compounds displayed modest pharmacologic al activity in a variety of biological assays.