Affiliation:
1. Institute of Organic Chemistry Research Centre for Natural Sciences Magyar tudósok körútja 2 1117 Budapest Hungary
2. Hevesy György PhD School of Chemistry Eötvös Loránd University Pázmány Péter sétány 1/A 1117 Budapest Hungary
3. Department of Chemistry Eötvös Loránd University Pázmány Péter sétány 1/A 1117 Budapest Hungary
4. Department of Pharmacology and Pharmacotherapy Semmelweis University Nagyvárad tér 4 1089 Budapest Hungary
Abstract
AbstractMitragynine 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.