3-Heteroalkyloxindole : an interesting precursor for the synthesis of polycondensed heterocyclic systems with potential biological activity

Considering the general interest on the indole nucleus as well as of its derivatives such as indolin-2-one, which is inserted in a large number of alkaloids and in some pharmacological active compounds, the researches were focused on the synthesis of different classes of indole compounds of potential biological interest. First, a very efficient protocol for the preparation of ethyl 4,2'-dioxaspiro[cyclohexane-1,3'-indoline] nucleus 23 was planned, which is a very versatile synthon. Starting from 23, the spiro[perhydroazepine-5,3'-indoline] nucleus 24 functionalized in both positions 2 of the azepine and 2' of the indoline ring with an oxo group was obtained. Azepino-indole system is present in several alkaloids, such as Gelsominum, in particular gelsemoxomine, as well as in more simple compounds characterized by insecticide activity such as spiro[perhydro-azepine-4,3'-indoline] functionalized at nitrogen atoms with proper substituents. Starting from the key intermediate 24, several synthetic targets were achieved such as: i) the regioselective reductions of its carbonyl functions aiming to obtain the 2'-oxospiro[perhydro-azepine-4,3'-indoline] 26, the 4-oxospiro[perhydro-azepine-4,3'-indoline] derivative 27 and the complete reduced spiro[perhydro-azepine-4,3'-indoline] nucleus 28. ii) the preparation of alkaloids containing tetrahydropyrroleindole nucleus 29 functionalized with a chain in position 3a, which, as I reported above, is the biological scaffold present into alkaloids of the Calabar bean and of the genus Pseudophryne and Flustramine. iii) the preparation of the hexahydropyraneindole nucleus 30, functionalized with a chain in position 4a of the ring. Studies on the preparation of the above compounds in enantiopure form were also performed. The best result was found performing an asymmetric synthesis of azepinoindole nucleus 24 by the way of an asymmetric Schmidt reaction. In the retrosynthetic scheme it is shown the preparation of the enantiopure compounds 24' starting from 23 via azepine compound 31. Finally, starting from 4,2'-dioxaspiro[cyclohexane-1,3'-indoline] 23, the lactone 32 was synthetized. Compound 32 is the key intermediate for the preparation of tetrahydrofuraneindole 33, another important nucleus present in the Physovenine, one of the alkaloids of the Calabar bean.