Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine.
Bruno González, Nicolás Veiga, Gonzalo Hernández, Gustavo Seoane, Ignacio Carrera
Journal of natural products June 23, 2023 DOI: 10.1021/acs.jnatprod.3c00189
Summary
Subtle structural differences in natural compounds can drastically alter their behavior. Research explored how ibogaine and voacangine, promising for neuropsychiatric disorders, react to oxidation. Using various oxidizing agents and advanced computational and NMR techniques, it was found that a small ester group in voacangine significantly stabilizes it against oxidation, particularly in one part of the molecule. Intriguingly, this same group also enhances reactivity elsewhere, leading to specific oxidized forms. This work successfully revised a previously reported molecular shape, confirming a crucial structural detail. These insights are vital for developing improved drug candidates.
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.