Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine.

The iboga alkaloids, such as ibogaine and voacangine, are promising scaffolds for developing drugs to treat neuropsychiatric disorders. This work examines how these molecules react under oxidation with dioxygen, peroxo compounds, and iodine. The C16-carboxymethyl ester group in voacangine makes the molecule more stable toward oxidation than ibogaine, particularly in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines form. However, the ester increases reactivity at the isoquinuclidinic nitrogen, leading to C3-oxidized products via regioselective iminium formation. Density functional theory calculations explain this differential reactivity. Additionally, NMR experiments and theoretical calculations revise the absolute stereochemistry at C7 in voacangine's 7-hydroxyindolenine to S, correcting earlier reports of R configuration.

Study at a glance

Abstract

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C16-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C3-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C7 in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.