The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs

Abstract

Covering: 2000 up to 2020 Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. This review will cover recent advances in both the biosynthesis and chemical synthesis of iboga alkaloids as well as their use as next-generation neurotherapeutics. Whenever appropriate, we provide historical context for the discoveries of the past decade and indicate areas that have yet to be resolved. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, it is clear that the iboga alkaloids will continue to stoke scientific innovation for years to come.

Figure 1.

Structures of iboga alkaloids and related compounds

Figure 2.

Newly isolated iboga alkaloid during the period 2010–2020

Figure 3.

Racemic angryline gives rise to three chiral natural products through the intermediacy of achiral dehydrosecodine. Isolable compounds are highlighted in blue.

Figure 4.

Cycloaddition approaches to the isoquinuclidine of iboga alkaloids

Figure 5.

Transannular cyclization approaches to the isoquinuclidine of iboga alkaloids

Figure 6.

Hodgson’s radical rearrangement approach to the isoquinuclidine cyclization approaches to the isoquinuclidine of iboga alkaloids

Figure 7.

Construction of the tetrahydroazepine through C2–C16 bond formation. Though Trost and co-workers did not report the number of equivalents of Pd that were used to effect cyclization, subsequent work by Sames and co-workers suggests that > 1 equivalent of Pd was likely necessary.

Figure 8.

Construction of the tetrahydroazepine through C7–amine linkage

Figure 9.

Construction of the 7-membered ring through ring expansion

Figure 10.

Construction of the indole

Figure 11.

Coldham’s alkylation/cycloaddition strategy to iboga alkaloids

Figure 12.

Nemoto’s asymmetric synthesis of 144. PG = protecting group.

Figure 13.

Oguri’s intermediate 185 enables access to multiple families of alkaloids

Figure 14.

Structures of several iboga analogs. Blue headings indicate analogs that have been tested in biological assays. Red headings indicate analogs that have not yet been tested in biological assays. Select IC₅₀ values are indicated (μM). For complete biological testing details, see Table S2.

Scheme 1.

Proposed mechanism for the oxidative rearrangement of ibogaine to form ervaoffine A and C

Scheme 2.

Proposed mechanism for the formation of tabertinggine and voatinggine

Scheme 3.

Biosynthesis of strictosidine

Scheme 4.

Biosynthesis of stemmadenine. Compounds that have been isolated are highlighted in blue.

Scheme 5.

Biosynthesis of iboga and aspidosperma alkaloids. Compounds that have been isolated are highlighted in blue. *Compound 1 can be produced from 3 following slow, spontaneous decarboxylation. This reaction can be accelerated with heat. No spontaneous decarboxylation of 4 was observed even after heating.

Scheme 6.

Luo’s 2016 asymmetric synthesis of (+)-ibogamine

Scheme 7.

Takayama’s 2012 asymmetric synthesis of (–)-voacangalactone

Scheme 8.

She’s 2016 racemic syntheses of (±)-1, (±)-37, (±)-49, (±)-51, and (±)-177

Scheme 9.

Oguri’s 2014 biomimetic synthesis of (–)-catharanthine