Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga africana Root Bark

Abstract

Iboga alkaloids are a group of monoterpenoid indole alkaloids with promising and intriguing biological activities. Ibogaine is the representative member of the series and has become widely known as a potent atypical psychedelic with promising effects to treat substance use disorder. Nowadays, an efficient and scalable enantioselective total synthesis of ibogaine and related iboga alkaloids is still lacking, so direct extraction from natural sources or semi-synthetic schemes are the methods of choice to obtain them in a preparative scale. In particular, ibogaine can be obtained either by a low yielding direct isolation from Tabernanthe iboga or using a semi-synthetic procedure from voacangine, an iboga alkaloid occurring in a higher yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine from V. africana root bark as a precursor of the iboga scaffold. Using a direct acetone-based extraction procedure (0.5 kg of root bark), voacangine was isolated in ∼0.8% of root bark dried weight, while the major alkaloids isolated from the bark were identified as iboga-vobasinyl dimers (∼3.7%) such as voacamine and voacamidine. Since these alkaloids contain the voacangine moiety in their structure, the cleavage of the dimers was further optimized, affording an extra amount of voacangine in ∼50% isolated molar yield. In this manner, the total amount of voacangine obtained by application of the whole procedure to the plant material (extraction and dimer cleavage) could almost duplicate the content originally found in the root bark.

Validated Quantitative 1H NMR Method for Simultaneous Quantification of Indole Alkaloids in Uncaria rhynchophylla

“…Moreover, this is a great advantage when it is difficult to obtain pure standard compounds. The proposed methodology has the potential as a fast and reliable method for the quality control of TCMs and may be extended to other herbal medicines, especially alkaloid-containing medicines. , …”

“…The proposed methodology has the potential as a fast and reliable method for the quality control of TCMs and may be extended to other herbal medicines, especially alkaloid-containing medicines. 32,33 Active hydrogen protons are commonly the most important and frequently encountered functionalities in natural products, for example, OH groups in phenolics and NH groups in alkaloids. In 1 H NMR spectra, active hydrogen protons usually appear as broad signals, and their linewidth is inversely proportional to the intermolecular proton exchange rate, which depends mainly on the concentration of the solute molecule and of the residual H 2 O.…”

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

“…Flash column chromatography was performed using silica gel (Kieselgel 60, EM reagent, 230–400 mesh). Voacangine, 2 , was isolated and purified from V. africana rootbark, and ibogaine, 1 , was prepared through decarboxylation of voacangine according to our previously published protocol . Complete NMR spectra of the natural products are shown in Section 2 of the Supporting Information.…”

“…In order to access safer compounds as potential drugs for SUDs, different medicinal chemistry approaches have been employed to explore the iboga chemical space, including the preparation of structurally related analogs − and structure simplification studies. − Our group is working on a program aimed at mapping the structure–activity relationship of iboga-inspired analogs using ibogaine ( 1 ), voacangine ( 2 ), and other iboga alkaloids as parent compounds . Voacangine ( 2 ) is obtained in good yield by our recently published protocol from the root bark of Voacanga africana , while ibogaine is produced by a well-established methodology through decarboxylation of voacangine (direct isolation form T. iboga is avoided because of low purification yields and limited availability of the shrub) (see Figure ). Toward this aim, insights into the reactivity of the iboga skeleton are needed, especially regarding its stability under oxidative conditions and the positions of the skeleton that are able to be functionalized.…”

¿Es posible desarrollar investigaciones clínicas utilizando sustancias psicodélicas en Uruguay? Pasado y presente de las investigaciones sobre el potencial medicinal de los psicodélicos

“…En lo que respecta a ibogaína, hemos desarrollado para su preparación métodos de semisíntesis en pureza adecuada para ensayos biológicos. 69 También hemos contribuido a explicar sus interesantes propiedades antiadictivas al descubrir que esta induce procesos de plasticidad a nivel del tejido nervioso, 70 y posee un interesante efecto del tipo antidepresivo en modelos animales. 71 A su vez, hemos descrito por primera vez que el estado de vigilia que produce en roedores tiene características electroencefalográficas compartidas con el sueño REM, lo que puede explicar los reportes subjetivos como «generador de sueños».…”