The iboga alkaloids

This academic chapter (2017) offers the latest insight into the iboga alkaloids and related compounds (e.g. 18-MC) in order to update knowledge on the most recent advancements in the field.

Abstract

“Iboga alkaloids are a particular class of indolomonoterpenes most often characterized by an isoquinuclidine nucleus. Their first occurrence was detected in the roots of Tabernanthe iboga, a sacred plant to the people of Gabon, which made it cult object. Ibogaine is the main representative of this class of alkaloids and its psychoactive properties are well documented. It has been proposed as a drug cessation treatment and has a wide range of activities in targeting opioids, cocaine, and alcohol. The purpose of this chapter is to provide a background on this molecule and related compounds and to update knowledge on the most recent advances made. Difficulties linked to the status of ibogaine as a drug in several countries have hampered its development, but 18-methoxycoronaridine is currently under evaluation for the same purposes and for the treatment of leishmaniasis. The chapter is divided into six parts: an introduction aiming at defining what is called an iboga alkaloid, and this is followed by current knowledge on their biosynthesis, which unfortunately remains a “black box” as far as the key construction step is concerned. Many of these alkaloids are still being discovered and the third and fourth parts of the chapter discuss the analytical tools in use for this purpose and give lists of new monomeric and dimeric alkaloids belonging to this class. When necessary, the structures are discussed especially with regard to absolute configuration determinations, which remain a point of weakness in their assignments. Part V gives an account of progress made in the synthesis, partial and total, which the authors believe is key to providing solid solutions to the industrial development of the most promising molecules. The last part of the chapter is devoted to the biological properties of iboga alkaloids, with particular emphasis on ibogaine and 18-methoxycoronaridine.”

Authors: Catherine Lavaud & Georges Massiot

Summary

1 Introduction

There are four levels of definition for the term “Iboga Alkaloids”, the most basic being the alkaloids isolated from a plant named “iboga”, the second being those psychoactive alkaloids from plants used in ceremonies and cults in Central Africa, and the third being the biogenetic alkaloids.

Iboga alkaloids are produced by a small number of plants of the family Apocynaceae, and two have emerged for the chemistry or biology they have inspired. Catharanthine (1) and ibogaine (2) are two of these alkaloids, and despite years of investigation, there is still fascinating chemistry being developed around this scaffold.

2 Biosynthesis

There is no recent publication on the biosynthesis of catharanthine and coronaridine, which are the two main iboga alkaloids. Preakuammicine is the well-accepted link in the sequence leading to the ibogans, while precondylocarpine is the precursor of the catharanthine series.

The biosynthesis of the iboga alkaloids is thought to proceed via a Diels-Alder-like reaction, and the question of its catalyst by means of an enzyme is of high relevance since examples of Diels-Alderases remain extremely rare.

There are a few known iboga alkaloids with the pseudo-aspidosperma or pseudo vinca arrangement, but no experimental work has been performed to explain their biosynthesis.

3 Structural Elucidation and Reactivity

The widespread availability of high-field NMR spectrometers and sophisticated pulse sequences allows chemists to determine the structure of moderate complexity molecules, such as the iboga alkaloids and even the “dimers”, leading to full unambiguous proton and carbon NMR assignments.

Chemical reactivity and partial and total synthesis were until recently integral parts of the structural elucidation process. However, with the advent of highly sensitive spectroscopic techniques, this approach is almost no longer utilized.

The iboga alkaloids undergo unusual oxidation reactions, which arise from the particular geometry of the isoquinuclidine ring system. These reactions went unnoticed for a long time, until the X-ray structure of oxindole 57 (ervaoffine A) was determined. The probability is high that derivatives with substitutions at C-3 originate from the intermediate carbinolamines. However, they do not lend themselves to reduction or Pictet-Spengler-like reactions and often show [M-2] fragments in mass spectrometers.

Classical oxidations occur at C-7 and C-2, yielding pseudo-indoxyl chromophores and intermediates to oxindole and N-acyl derivatives. These products are detected in natural products.

The N-oxides of catharanthine are easily prepared under acidic peroxide conditions, and this oxidation leads to the formation of anhydrovinblastine and the related antitumor alkaloids vinblastine, vincristine, vinorelbine, and vinflunine.

Beatty and Stephenson bridged the gap between catharanthine and pseudo-tabersonine and -vincadifformine alkaloids by using visible light irradiation of catharanthine and a polyfluorinated catalyst. The reaction product was a 2:1 mixture of enantiomers, and the final product was obtained through oxidative photoirradiation of 22.

4 New Molecules

The list of compounds biogenetically linked to the iboga unit continues to be fed by new alkaloids, but the isoplumeran and isoeburnan variants remain scarce. The isolation of alkaloids of the iboga class is limited to only a few species in the genera Ervatamia, Tabernaemontana, Voacanga, and Catharanthus.

4.1.1 Ibogamine and Coronaridine Derivatives

Many of the newly isolated structures are simple derivatives of ibogamine or coronaridine, with a limited range of oxidations.

Four new 19-hydroxy derivatives have been reported: (19S )-hydroxyibogamine (25) , 19-epi-isovoacristine (26) , and ervatamines A (28) and H (27) . The relative configuration of C-19 was determined by comparison of the 13C NMR chemical shifts of C-15 and C-21, as proposed by Wenkert in 1976 .

Five new alkaloids were found to contain an additional degree of oxidation and a ketone at C-19: isovoacryptine (29)[32], conodusines A-C (30 – 32)[36], and ()-ervatamine I (33)[16]. The structure of ervatamine I was determined by X-ray analysis and chemical correlation with heyneanine. The absolute configuration of ervatamine I was determined by the optical rotation, but the possibility of conodusine B being an artefact was discussed but could not be established definitively.

A Japanese group isolated a new bioactive alkaloid, voacangalactone (16), from Voacanga africana, which has a double bond between C-19 and C-20 or C-15 and C-20.

Ibogaine, found in Tabernaemontana corymbosa from Malaysia, can be nucleophilically attacked on C-11 to give a group of iboga alkaloids diversely substituted at C-11, including pairs of diastereomers that were not separated even though the authors discussed the relative configurations of the new chiral centers.

4.1.2 3-Alkyl- or 3-Oxo-ibogamine/-coronaridine Derivatives

The three hydroxy indolenines (41-43), which share the same origin as 39, were observed to undergo further oxidation at C-3. The origin of the acetone fragment is more dubious, but could come from the solvent used for chromatography.

There are many monomeric iboga alkaloids with miscellaneous alkyl or alkoxy substituents on C-3, including (3R/S)-ethoxyheyneanine (44) and (3R/S)-ethoxy-19-epi-heyneanine (45). These alkaloids exhibited similar NOE effects as coronaridine (3S*) and were X-ray structure determined.

4.1.3 5- and/or 6-Oxo-ibogamine/-coronaridine Derivatives

The iboga alkaloids have carbonyl groups at positions prone to oxidation. The carbonyl groups in 19-epi-5-Oxovoacristine (50), 5,6-diones of ibogamine and ibogaine (51) and (52) were determined by 13CNMR chemical shifts and NOE correlations, and the absolute configuration was established by ECD. The simplest compound 55 (6-oxo-ibogaine) is unique and unexpected, and it has been detected as a natural product for the first time.

4.1.4 Rearranged Ibogamine/Coronaridine Alkaloids

Ervaoffine D (56) is the only described iboga alkaloid with the 2,7-bond cleaved into a ketone and an amide. Its structure was proved unequivocally by X-ray crystallography inclusive of the absolute configuration, and its ECD spectra were compared with those of ervaoffine A (57) and ervatamine F (12). The third alkaloid, 59, was isolated by two different groups in 2014 and 2015, and was given different trivial names. Its absolute configuration was established from the similarity of Cotton effects with those obtained by calculated ECD for both enantiomers.

Tabertinggine and voatinggine are two exceptionally rearranged iboga alkaloids, for which their skeletons remain unique. A common biogenetic pathway was proposed for both compounds.

4.1.5 Catharanthine and Pseudoeburnamonine Derivatives

All the monomers described in this Section are assumed to belong to the ibogaine/coronaridine series, except for alioline (63) which has a C9 unit added. The origin of the C9 fragment is unclear.

Tacamonidine (11), a new molecule with the isoeburnan skeleton, was isolated by NMR spectroscopy and differs from tacamonine (10) by an OH group.

4.1.6 Miscellaneous Representatives and Another Enigma

Four new alkaloids were isolated from Tabernaemontana corymbosa and named tabercarpamines G – J. Their structures were established by NMR spectroscopy without any attempt at the determination of their absolute configurations.

The tabercarpamines are not exceptional in structure, but their mere existence is puzzling. A biosynthesis scheme has been conceived, but the aldehyde has never been identified.

4.2 Dimers

The count of new dimeric alkaloids containing an iboga moiety amounts to 49, and all but one contain the vobasinyl residue always substituted at position C-30 (vobasine numbering). The vobasinyl cation is an especially long-lived species lending itself to slow kinetics reactions. Most newly isolated bisindoles are derived from five vobasan-type monomers: vobasinol, dregamine, vincadiffine, pagicerine, and difforlemenine. The iboga moiety is more diverse, but it is possible that chemical modifications occur after coupling.

Two alkaloids stand alone in the gallery of the iboga bisindoles: biscarpamontine A (75) and vobatensine E (76), which are the result of a unique coupling between the iboga and aspidosperma units. The structures of 75 and 76 were established by NMR spectroscopy and only relative configurations are given.

Generally, the structural elucidation strategy used for bisindoles has been similar. High-resolution mass spectra, carbon NMR spectra, COSY, HSQC, and HMBC NMR experiments are used to determine the structures of two moieties.

4.2.1 Bisindoles with an Ibogamine Moiety

There are four bisindoles that lack an alkoxy substituent on the aromatic ring of ibogamine: (19R)- and (19S )-hydroxytabernamine, and tabernamidines A and B. The structure of vobatensine A was proven definitively by a partial synthesis from vobasinol and 19-epi-iboxygaine.

4.2.3 Bisindoles with an Isovoacangine (11-Methoxy-coronaridine) Moiety

There are many alkaloids of this type, with vincadiffine (72) and derivatives in the iboga category, and vobasinol (70) and derivatives in a non-iboga group.

Cononitarine B and ervachinine C are bisindoles composed of a coronaridine moiety linked to a vincadiffine unit, and 17-acetyl-tabernaecorymbosine A is a 19-oxo derivative of ervachinine C. Conodiparine C and D differ in the location of attachment on the aromatic ring.

Four alkaloids, conodirinines A and B, tabernaricatines C and D, have an extra tetrahydro-1,3-oxazine ring bridging C-16 and N-4. The methylene bridge may be the result of a formaldehyde condensation or oxidation of the N-methyl into an iminium.

Tabernaricatines A and B (106, 107) and tabercorine C (108) possess a tetrahydro-1,3-oxazine ring and were proposed based on NMR data and NOE correlations with conodiparine B (100). The structures of 106 and 107 were considered as flat and the biosynthesis of 108 was proposed.

Muntafara sessifolia yielded 30 -oxo-tabernaelegantines, which were determined by NMR spectroscopy. They are believed to be the oxidation products of the well-known tabernaelegantines, although this has not been proven.

Four 3-hydroxy-tabernaelegantines were characterized, with three of these having a C-12 – C-30 bridge and one having a C-10 – C-30 bridge. The configuration of C-3 was deduced from its 13C NMR chemical shift value.

The iboga alkaloids C-3 can capture nucleophiles, and the (R)-configuration of C-3 was determined by the observation of a strong NOE interaction between the aldehyde proton and H-5b. The absolute configuration of C-3 was established by the CD exciton chirality method.

4.2.4 Bisindoles with an Iboga-Indolenine or Rearranged Moiety

There are only two 7-hydroxy-indolenines in the iboga series, tabercorine B (122) and vobatensine D (123), and they have the (7R)-configuration, which was deduced by comparison of the NMR data with those of the hydroxyindolenine of voacangine.

4.2.5 Bisindoles with a Chippiine Moiety

Tabercarpamines A and B were found to have vobasinol and chippiine moieties, and their absolute configurations were determined by NMR spectroscopy and mass spectrometry.

5 Synthesis

The total synthesis of most industrially important alkaloids is almost no longer in use in the structural elucidation domain. The exception is the 18-OMe derivative of coronaridine (127) which is in the pre-development phase.

The historical route developed by Trost involves a bond being formed between C-2 of indole and the isoquinuclidine bearing a suitably placed double bond. Attempts to make this reaction catalytic have been made, but so far the genuine nucleus of iboga has not surrendered.

The synthesis of (19R)-ibogaminol (138)byH€ock and Borschberg uses a single acid treatment to close the seven-membered ring, but the key step is the diastereo- and enantio-selective synthesis of the isoquinuclidine 139.

Yang and Carter constructed the isoquinuclidine system using organocatalysis based on the proline derivative 140. The enantioselectivities obtained are excellent, but several steps are required before reaching the natural products.

The synthesis of voacangalactone (16) by Harada et al. qualifies as a high-yielding multiple-step total synthesis, since every single step is high yielding. This synthesis uses a Friedel-Crafts reaction followed by a diborane reduction to close the seven-membered ring of an azepino-indole.

The synthesis of 18-OMe-coronaridine (127) is state of the art: short, convergent, enantioselective, and high yielding. It starts with an azepino-indole, 145, and is followed by a Diels-Alder type cyclization to give the title compound in overall good yield and less than ten steps.

6.1.1 Elements of Context

Ibogaine (2) is certainly included in any top list of alkaloids for its mystique and aura, but it has been the object of a fierce battle between its pros and cons when used as a drug abuse treatment.

Ibogaine (2) was once available on the market as an antifatigue and stimulant agent. It was withdrawn from the market in 1970 but reappeared in 1985 when Howard Lotsof was granted a patent for “a rapid method for interrupting the narcotic addiction syndrome”.

6.1.2 Security Problems and Fatalities

Security of use is a major concern for health authorities, and several patients have passed away after ingesting ibogaine. However, there does not appear to be a general pattern linking such deaths to the intake of ibogaine.

6.1.3 Analytics

During forensic investigations, the levels of ibogaine (2) and related products in body fluids were determined. Liquid chromatography-MS with electrospray ionization was used to rapidly discriminate between ibogaine (2) and noribogaine (12-hydroxy-ibogamine, 149) produced by demethylation of 2 with cytochrome CYP2D6.

6.1.4 Mechanism of Action

Paskulin et al. raised the question of the duration of the effects of 2, which is much longer than its pharmacokinetic parameters would allow. Two proteomic studies were performed on whole rat brain and on yeast subjected or not to 2.

Ibogaine has a complex pharmacological profile and its rapid transformation into 149 is probably the second major reason why it is difficult to bring one of these molecules to the market.

6.2 18-Methoxy-coronaridine (18-MC)

A search for an alternative molecule to ibogaine was undertaken, and 18-OMe-coronaridine (127) was found to have promising properties against Leishmania amazonensis. It is fully synthetic and therefore patentable, and has its own particular mechanism of action.

A small pharmaceutical company named Savant HWP is conducting preclinical testing on 18-MC to gain approval as a drug cessation treatment.

6.3.1 Cytotoxicity and Antiproliferative Activity

Many laboratories use in-house available assays to investigate the biological properties of new natural products, but it may not always be possible to perform studies using experimental tumor-bearing mouse models.

In a screening procedure for inhibitors of the Wnt pathway, T divaricata gave a positive response, which led to the isolation of four bioactive iboga alkaloids. The best compound was 3, which was shown to down-regulate mRNA and therefore decrease the -catenin protein level and inhibit the Wnt signaling pathway, which controls, among other factors, cell proliferation.

6.3.2 Central Nervous System Effects

Ibogaine (2) has very potent effects on the central nervous system, and several new compounds have been synthesized. These compounds may be used in the treatment of Parkinson’s disease, obesity, metabolic syndrome, and related disorders.

6.3.3 Miscellaneous Biological Activities

Ervatamines A-I, including iboga alkaloids, coronaridine, heyneanine, their 20 -oxo derivatives and pandine, showed anti-inflammatory activity in vitro and moderate to good antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum.

7 Conclusion and Perspectives

Iboga-type alkaloids are set apart owing to their unique biological properties, and could be used for drug cessation treatment.