Biosynthesis of an Anti-Addiction Agent from the Iboga Plant

(−)-Ibogaine and (−)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (−)-voacangine, and de-esterified voacangine, which is converted to (−)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (−)-ibogaine and (−)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels–Alder reactions.

T reatment of opiate addiction remains challenging, with over 45,000 people in the United States dying in 2017 and a 500% increase in yearly opioid overdose deaths since the year 2000. 1 (−)-Ibogaine (1) ( Figure 1A), a plant-derived iboga-type alkaloid, has anti-addictive properties that were discovered by Howard Lotsof in 1962 when he noticed that ingesting this compound mitigated heroin cravings and acute opiate withdrawal symptomatology. 2,3 Although the toxicity of (−)-ibogaine (1) has slowed its formal approval for addiction treatment in many countries, increased knowledge of its mode of action, side-effects, and the discovery of (−)-ibogaine (1) analogs clearly indicates its potential as an anti-addictive agent. 2−4 The plant that synthesizes (−)-ibogaine (1), Tabernanthe iboga (Iboga), is difficult to cultivate, prompting interest in developing biocatalytic methods for (−)-ibogaine (1) production.

Journal of the American Chemical Society
Communication TiDPAS2 or precondylocarpine acetate (7) with TiDPAS1/ TiDPAS2, excess NADPH, and the second CS homologue from T. iboga led to the formation of the reduced iboga alkaloid coronaridine (2) (Figure 1E), as evidenced by mass fragmentation and comparison to an authentic standard ( Figure 1F, Figures S9−13). Although several side products were also observed in this in vitro enzymatic reaction ( Figure  1F), coronaridine (2) was the major product. This T. iboga CS homologue was thus named TiCorS (coronaridine synthase, 71.9% sequence identity to CrCS). To assign the stereochemistry of coronaridine (2), the enzymatic product was isolated and subjected to CD analysis, which upon comparison to previous literature reports as well as authentic standards of (−)-coronaridine (2) (isolated from Tabernaemontana divaricata) 6 and (+)-coronaridine (5) (obtained from total synthesis) 11 ( Figure 1G) indicated that the enzymatic product is (−)-coronaridine (2). Therefore, the biosynthetic pathways for both (+) and (−)-iboga alkaloid scaffolds have now been elucidated.

Journal of the American Chemical Society
Communication on the indole of (−)-voacangine (3) is required for spontaneous decarboxylation ( Figure S20).
(−)-Ibogaine (1) has a storied history dating back hundreds of years to the Congo Basin and the Bwiti religion, though it was the serendipitous discovery of the anti-addictive properties of (−)-ibogaine (1) that captured the attention of modern medicine. Here we report the biosynthesis of (−)-voacangine (3) and an esterase that may improve semisynthesis of (−)-ibogaine (1). In addition to its extraordinary bioactivity, (−)-ibogaine (1) provides an opportunity to compare the formal Diels−Alder enzymatic synthesis of (−) and (+)-iboga enantiomers. The discovery and initial investigation of TiCorS suggest a possible mechanism for this cyclization and a basis for future enzyme engineering for this emerging class of cyclases. There are approximately 100 iboga alkaloids identified in nature, 10 both of + and − optical series, and discovery of this pathway now provides full access to both medicinally important scaffolds, 17 in addition to providing the first biocatalytic method for production of the anti-addictive alkaloid (−)-ibogaine (1).

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10