Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites**

Abstract

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.

Emerging Conformational-Analysis Protocols from the RTCONF55-16K Reaction Thermochemistry Conformational Benchmark Set

“…One usual approach is to refine energies obtained from low-level MM/QM calculations on the lowest-energy conformer. , This can be improved by selecting a larger set of low-energy conformers to refine. Multilevel workflows have been developed for this purpose, leveraging a funnel-like strategy that utilizes a series of methods, each progressively more accurate to predict chemical properties such as p K a values. − One outstanding example of these approaches, the CRENSO protocol enables efficient, general metadynamics-based conformational sampling using CREST, , and further refinement of the ensemble starting from the semiempirical GFN2-xTB level to more accurate DFT functionals in CENSO. , This has proven to be a robust tool for the prediction of dynamic molecular properties in solution, such as NMR shift, , optical rotation, and conformational entropy , for large flexible molecules.…”

A Platform for the Synthesis of Corynantheine-Type Corynanthe Alkaloids

“…31,32 The first total synthesis of (−)-mitragynine pseudoindoxyl was recently reported (11 steps from (−)-carvone), and only 11-methoxy mitragynine pseudoindoxyl was synthesized in 2012. 33,34 Similarly, (−)-corynantheidine pseudoindoxyl (5) has eluded the synthetic community with only one semisynthesis. 30 The paucity of general routes toward preparing the corynantheine alkaloids coupled with their pharmacological potential inspired us to develop the new synthetic approach disclosed herein.…”

“…Indeed, even though spirooxindole and pseudoindoxyl corynantheine-type alkaloids are reported as far more potent at mice μ-opioid receptors than their parent indole alkaloids, , synthetic routes to these alkaloids have remained underdeveloped. To the best of our knowledge, only two total syntheses of racemic corynoxine ( 3 ) and corynoxine B ( 4 ) have been achieved to date. , The first total synthesis of (−)-mitragynine pseudoindoxyl was recently reported (11 steps from (−)-carvone), and only 11-methoxy mitragynine pseudoindoxyl was synthesized in 2012. , Similarly, (−)-corynantheidine pseudoindoxyl ( 5 ) has eluded the synthetic community with only one semisynthesis …”