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Efficient and modular synthesis of ibogaine and related alkaloids

Nature Chemistry volume 17, pages 412–420 (2025)Cite this article

Abstract

Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder. Here we report a gram-scale, seven-step synthesis of ibogaine from pyridine. Key features of this strategy enabled the synthesis of three additional iboga alkaloids, as well as an enantioselective total synthesis of (+)-ibogaine and the construction of four analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (−)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and is a potent modulator of the serotonin transporter. This work provides a platform for accessing iboga alkaloids and congeners for further biological study.

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Fig. 1: Synthetic strategies towards iboga alkaloids.
Fig. 2: Total synthesis of epiibogaine.
Fig. 3: Total synthesis of (±)-ibogaine and related compounds.
Fig. 4: Asymmetric synthesis of (+)-ibogaine, (−)-10-fluoroibogamine and (+)-10-fluoroibogamine.
Fig. 5: Biological effects of iboga alkaloids and related analogues.

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Data availability

All the data are available within the main text or Supplementary Information. Experimental and characterization data for all new compounds prepared during this study are provided in the Supplementary Information. Graphpad Prism files containing the data for the spinogenesis and SERT assays are available via Figshare at https://doi.org/10.6084/m9.figshare.24531316 (ref. 73).

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Acknowledgements

Sources for the left-hand panel of the graphical abstract (left to right): Büchi, 1966 (ref. 31; She, 2016 (ref. 33; Sinha, 2012 (ref. 32; the authors. We thank J. Cordova Guerrero for performing early pilot studies. This work was supported by funds from the National Institutes of Health (NIH; R01GM128997, R35GM148182 and R01DA056365 to D.E.O.), the National Science Foundation (XSEDE/ACCESS programme to D.J.T. for computational support) and a Camille Dreyfus Teacher-Scholar Award (D.E.O.). The Nikon high content analysis spinning disc confocal microscope used in this study was purchased using NIH Shared Instrumentation Grant 1S10OD019980-01A1. We thank the MCB Light Microscopy Imaging Facility, which is a University of California, Davis Campus Core Research Facility, for the use of this microscope. Funding for the NMR spectrometers was provided by the National Science Foundation (no. CHE-04-43516) and NIH (no. 08P0ES 05707C). Analysis for this project was performed in the University of California, Davis Campus Mass Spectrometry Facilities with instrument funding provided by the NIH (1S10OD025271-01A1). The natural ibogaine used in these studies was provided by the National Institute on Drug Abuse Drug Supply Program.

Author information

Authors and Affiliations

  1. Chemistry and Chemical Biology Graduate Program, University of California, Davis, Davis, CA, USA

    Rishab N. Iyer, David Favela, Andras Domokos, Guoliang Zhang, Andrian G. Basargin & Alexis R. Davis

  2. Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA

    Rishab N. Iyer, David Favela, Andras Domokos, Arabo A. Avanes, Samuel J. Carter, Andrian G. Basargin, Alexis R. Davis, Dean J. Tantillo & David E. Olson

  3. Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Program, University of California, Davis, Davis, CA, USA

    Arabo A. Avanes

  4. Department of Chemistry, University of California, Davis, Davis, CA, USA

    Samuel J. Carter, Dean J. Tantillo & David E. Olson

  5. Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA

    David E. Olson

  6. Center for Neuroscience, University of California, Davis, Davis, CA, USA

    David E. Olson

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  1. Rishab N. Iyer
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Contributions

R.N.I. completed the racemic total synthesis of ibogaine with assistance from D.F. and G.Z.; R.N.I. completed the asymmetric total synthesis of ibogaine. R.N.I. and D.F. optimized all reactions and synthesized the iboga alkaloids and analogues. R.N.I., D.F. and A.D. characterized all compounds. A.G.B. developed the liquid chromatography–mass spectrometry methods for chiral separation. A.D. conducted neuroplasticity assays with assistance from A.R.D.; A.A.A. and S.J.C. conducted SERT efflux and inhibition assays. D.J.T. performed energy calculations. The Supplementary Information was prepared by R.N.I. with assistance from D.F.; D.E.O. conceived the project, supervised the research and assisted with data analysis. D.E.O. wrote the manuscript with assistance from R.N.I. and input from all authors.

Corresponding author

Correspondence to David E. Olson.

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Competing interests

D.E.O. is a co-founder of Delix Therapeutics, Inc.; serves as the Chief Innovation Officer and Head of the Scientific Advisory Board; and has sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed technology from the University of California, Davis related to analogues of iboga alkaloids. D.E.O., R.N.I. and A.D. have submitted a patent application related to the work described here. The sponsors of this research were not involved in the conceptualization, design, decision to publish or preparation of the manuscript. The remaining authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Regioselective reduction of 3-ethylpyridine.

Product distribution determined by integration of LC-MS spectra obtained using positive ionization mode. All reactions were run at 0.1 M. While compound 11 was isolable, compound 10 could never be isolated and was assigned based on its mass and the fact that mixtures of 10 and 11 would convert to 11 over time. aBoth methanol and ethanol were tested.

Extended Data Fig. 2 Optimization of 7-membered ring closure.

Isolated yields are shown. All reactions were conducted on a 1 mmol scale at a concentration of 0.1 M using a 1:1 mixture of S1 and S2 and purified via silica gel chromatography (gradient elution, 20:1 → 10:1 DCM/MeOH). Product S4 was isolated as a mixture of endo and exo epimers.

Extended Data Fig. 3 Optimization of MHAT coupling.

Isolated yields are shown. All reactions were conducted on a 1 mmol scale and purified via silica gel chromatography (gradient elution, 10:1 → 7:3 hexanes/EtOAc). Products S5 and S6 were isolated as a mixture of C16 endo and exo epimers.

Extended Data Fig. 4 Alternative hydroethylation strategy.

Isolated yields are shown. All reactions were conducted on a 1 mmol scale and purified via silica gel chromatography (gradient elution, 10:1 → 7:3 hexanes/EtOAc). Products S6, S7, and S8 were tentatively assigned based on LC-MS analysis and isolated as a mixture of endo and exo epimers. PC = propylene carbonate.

Extended Data Fig. 5 Optimization of a photoredox-catalysed decarboxylation.

Isolated yields are shown. All reactions were conducted on a 0.64 mmol scale and purified via silica gel chromatography (gradient elution, 10:1 → 7:3 hexanes/EtOAc). DIPEA – N,N-diisopropylethylamine, TRIP thiol = 2,4,6-Triisopropylbenzenethiol.

Extended Data Fig. 6 Comparison of 1H NMR data obtained from natural and synthetic ibogaine.

(a) 1H NMR data demonstrates that synthetic and natural ibogaine are indistinguishable. (b) a 1:1 molar ratio of natural ibogaine and CH2Br2 was treated with 1 equiv. of synthetic ibogaine. Spiking increased the ibogaine signal integration without impacting that of CH2Br2. Natural ibogaine was obtained from the National Institute on Drug Abuse (NIDA) as the hydrochloride salt. Natural Ibogaine • HCl was basified using 1 M NaOH and DCM as the extraction solvent.

Extended Data Fig. 7 Comparison of infrared spectroscopy data obtained from natural and synthetic ibogaine.

Infrared spectroscopy data demonstrate that synthetic and natural ibogaine are indistinguishable. Natural ibogaine was obtained from the National Institute on Drug Abuse (NIDA) as the hydrochloride salt. Natural Ibogaine • HCl was basified using 1 M NaOH and DCM as the extraction solvent.

Extended Data Fig. 8 Total synthesis of iboga alkaloids.

The overall yields and step counts for the total syntheses of various iboga alkaloids from commercially available starting materials are shown. Principal investigators are indicated by colour.

Extended Data Fig. 9 Efforts towards an enantioselective synthesis of iboga alkaloids.

(a) Attempts to achieve an enantioselective Diels-Alder reaction using chiral acid catalysts were unsuccessful. (b) Attempts to achieve an enantioselective Diels-Alder reaction using chiral organocatalysts were unsuccessful. (c) Placing a chiral menthol-derived auxiliary on the diene did not lead to any diastereoselectivity in the Diels-Alder reaction. Lack of diastereoselectivity was confirmed by converting S13 to desethylibogaine and then performing chiral HPLC analysis. (d) Placing a chiral auxiliary on the dienophile resulted in a range of diastereoselectivities depending on the reaction conditions. (e) Chiral HPLC analysis revealed that enantiopure S19 could be obtained following a diastereoselective Diels-Alder reaction of S15 and subsequent functional group interconversions.

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Detailed synthetic procedures and experimental data for all compounds, 1H and 13C NMR spectra and details on computations.

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Iyer, R.N., Favela, D., Domokos, A. et al. Efficient and modular synthesis of ibogaine and related alkaloids. Nat. Chem. 17, 412–420 (2025). https://doi.org/10.1038/s41557-024-01714-7

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