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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with computational analysis Qualitative Peer reviewed |
|---|---|
| Interventions | peroxo compounds and iodine |
| Topics | Ibogaine |
| Keywords | Drug development Drug discovery Medicinal chemistry Pharmaceutical research Drug candidates Neuropsychiatric drugs Chemical oxidation Oxidative stability Chemical reactivity Redox chemistry Oxidation reactions Molecular structure Chemical structure Structure-activity relationship Stereochemistry Molecular geometry Natural products chemistry Natural compounds Phytochemistry Bioactive molecules Alkaloids |
| Citations | 7 |
| Key findings | The C16-carboxymethyl ester in voacangine stabilizes the molecule toward oxidation compared to ibogaine, yet enhances reactivity at the isoquinuclidinic nitrogen, and the absolute stereochemistry at C7 in voacangine's 7-hydroxyindolenine is S, not R. |
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.