Syntheses and structural plasticity of kratom pseudoindoxyl metabolites

02 February 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


Pain management is one of the oldest challenges for medicine. Although opioids have been used in the treatment of moderate-to-severe acute and chronic pain for centuries, they cause various adverse effects and addiction. The intertwined societal, economic and public health issues of pain management and the risks of opioid abuse continue to receive attention and drive the development of safer analgesics. Recently, a kratom metabolite, mitragynine pseudoindoxyl has attracted increasing attention as a promising analgesic alternative for pain management with considerably fewer side effects. Here, we describe the first enantioselective and scalable total synthesis of this natural product in addition to its C-20 epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6 tricyclic system of these alkaloids is formed via a protecting group-free cascade relay process in which oxidized tryptamine and secologanin analogs are used. Furthermore, we uncovered that mitragynine pseudoindoxyl exists and acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments, thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogs, which can guide the development of next-generation analgesics.


total synthesis
mitragynine pseudoindoxyl
natural product

Supplementary materials

SUPPORTING INFORMATION Syntheses and structural plasticity of kratom pseudoindoxyl metabolites
Experimental details, including procedures, photographs of experimental setup, characterization data, NMR spectra, biological and computational studies.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.