Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites.

Péter Angyal, Kristóf Hegedüs, Bence Balázs Mészáros, János Daru, Ádám Dudás, Anna Rita Galambos, Nariman Essmat, Mahmoud Al-Khrasani, Szilárd Varga, Tibor Soós

Angewandte Chemie (International ed. in English) 2023 Aug 28

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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. © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Citation

Péter Angyal, Kristóf Hegedüs, Bence Balázs Mészáros, János Daru, Ádám Dudás, Anna Rita Galambos, Nariman Essmat, Mahmoud Al-Khrasani, Szilárd Varga, Tibor Soós. Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites. Angewandte Chemie (International ed. in English). 2023 Aug 28;62(35):e202303700