Syntheses of some tri- and tetracyclic heterocycles containing an indole moiety

This thesis deals with the development of new synthetic methods leading to fused tri- and tetracyclic heterocycles, many of which have interesting biological activity such as antiviral and DNA intercalating properties.

The reactions between isatins and 2-aminobenzylamine in acetic acid can give, depending on the conditions, either complex spirooxindoles or indolo[3,2-c]quinolin-6-ones. Proposed mechanisms are presented (involving a simpler form of spirooxindoles). These spirooxindoles can easily be obtained from isatins and 2-aminobenzylamine in methanol (Paper I).

The previously unknown, but incorrectly claimed, linear isomer of indolo[3,2-c]quinolin-6one, i.e. indolo[2,3-b]quinolin-11-one, has been prepared for the first time by thermal (260 degrees C) cyclization of methyl 2 -phenylamino-indole-3 -carboxylate, which was in turn prepared in two steps from methyl indole-3 -carboxylate. The benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b]indol-11-one could be prepared similarly (Papers I and II).

Suitable 2-chloro-3-formylindoles have been used for the preparation of the alkaloids neocryptolepine, thienodolin and derivatives thereof (Papers III and IV).

Finally, synthetic work towards potential metabolites of the lead compound B-220 is presented. We have described a method for reduction of the biologically interesting indolo[2,3b)quinoxalines with zinc, which are subsequently trapped with an appropriate anhydride to provide the corresponding mono or diacylated 5,1 1-dihydroindolo[2,3b]quinoxalines in good yields (paper V). Synthesis of hydroxy derivatives of B-220 can be effected from the appropriate methoxyisatins. Futher derivatives like the vinyl-, Nmethylaminoethyl- and Noxido derivatives of B-220 have also been synthesised.

List of scientific papers

I. Bergman J, Engqvist R, Stalhandske C, Wallberg H (2003). Studies of the reactions between indole-2,3-diones (isatins) and 2-aminobenzylamine. Tetrahedron. 59: 1033-48.

II. Engqvist R, Bergman J (2004). Synthesis of benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b]indol-11-one. Tetrahedron. 59: 9649-53.

III. Engqvist R, Bergman (2003). An improved synthesis of neocryptolepine. Oppi Briefs 36(4): 386-90. [Submitted]

IV. Engqvist R, Javaid A, Bergman J (2004). Synthesis of thienodolin. Eur J Org Chem. 2589-2592.

V. Engqvist R, Stensland B, Bergman J (2004). Reduction of indolo[2,3-b]quinoxalines. [Manuscript]