RESUMEN
RTCONF55-16K is a new, reactive conformational data set based on cost-efficient methods to assess different conformational analysis protocols. Our reference calculations underpinned the accuracy of the CENSO (Grimme et al. J. Phys. Chem. A, 2021, 125, 4039) procedure and resulted in alternative recipes with different cost-accuracy compromises. Our general-purpose and economical protocols (CENSO-light and zero, respectively) were found to be 10-30 times faster than the original algorithm, adding only 0.4-0.7 kcal/mol absolute error to the relative free energy estimates.
RESUMEN
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.