Syntheses and structural plasticity of kratom pseudoindoxyl metabolites

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.