Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites

Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro‐5‐5‐6‐tricyclic system of these alkaloids was formed through a protecting‐group‐free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl 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 analogues, which can guide the development of next‐generation analgesics. Although opioids have been used in the treatment of pain for centuries, they cause various adverse effects and addiction. Recently, kratom alkaloids emerged as promising analgesic alternatives for pain management with considerably fewer side effects. The first scalable total synthesis of mitragynine pseudoindoxyl, the most potent atypical opioid kratom metabolite, is now reported, as well as the discovery of its structural plasticity.