Abstract
(−)-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.
Highlights
We show that (−)-ibogaine (1) biosynthesis uses the same starting substrate as observed in (+)-iboga biosynthesis, but the key formal Diels−Alder cyclization step proceeds via a distinct mechanism to generate the reduced iboga alkaloid (−)-coronaridine (2) (Figure 1A)
Upon discovery of the pathway for the structurally related, antipodal iboga alkaloid (+)-catharanthine (4) from the plant Catharanthus roseus (Figure 1A),[5] we hypothesized that T. iboga homologues of these C. roseus enzymes were responsible for biosynthesis of the (−)-iboga scaffold. (+)-Catharanthine (4) is synthesized by oxidation of stemmadenine acetate (6) by precondylocarpine acetate synthase (PAS) to yield precondylocarpine acetate (7), which is reduced by dihydroprecondylocarpine acetate synthase (DPAS) to give dihydroprecondylocarpine acetate (8)
T. iboga dihydroprecondylocarpine acetate synthase 1 (TiDPAS1) (76.3% sequence identity to CrDPAS involved in catharanthine biosynthesis) and T. iboga dihydroprecondylocarpine acetate synthase 2 (TiDPAS2) (86.3% sequence identity to CrDPAS) were tested with CrPAS and stemmadenine acetate (6)
Summary
Figure 1. (+) and (−)-Iboga alkaloids. (A) Anti-addiction agents (−)-ibogaine (1) and (−)-voacangine (3) are antipodal to (+)-catharanthine (4), a precursor to the anticancer drug vincristine. (B) Biosynthesis of (+)-catharanthine (4). (−)-catharanthine (4) is not observed as an intermediate in these enzymatic assays nor has (−)-catharanthine (4) been identified from natural sources While it is obvious how vincadifformine (11) can be formed directly from secodine (10) (Figure 1C), there is no logical mechanism by which any secodine (10) isomer can be cyclized to form (−)-coronaridine (2). To gather evidence for an alternative mechanism, we isolated the dehydrosecodine-like product of precondylocarpine acetate (7) and TiDPAS1/2 that is formed under limiting NADPH conditions (9, m/z 337), which was observed with DPAS from C. roseus.[5] This compound 9 can be incubated with TiTabS to generate tabersonine (12), confirming it to be the dehydrosecodine substrate for the cyclases (Figure S14).
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