Synthesis of (±)-Setigerumine I: Biosynthetic Origins of the Elusive Racemic Papaveraceae Isoxazolidine Alkaloids**
Ana V. Serna
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
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Prof. Dr. László Kürti
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
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Dr. Juha H. Siitonen
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
Search for more papers by this authorAna V. Serna
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
Search for more papers by this authorCorresponding Author
Prof. Dr. László Kürti
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
Search for more papers by this authorCorresponding Author
Dr. Juha H. Siitonen
Department of Chemistry, Rice University, 6500 Main Street, Houston, TX, 77030 USA
Search for more papers by this authorA previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.33774/chemrxiv-2021-m9ltg).
Graphical Abstract
The first synthesis of (±)-Setigerumine I, an isoxazolidine Papaveraceae alkaloid, is realized through a biomimetic strategy. The synthesis sheds light to the possible biosynthetic origins of these elusive natural product family members.
Abstract
The biosynthetic origins of the structurally related racemic isoxazolidine Papaveraceae alkaloids Setigerumine I, Dactylicapnosinine and Dactylicapnosine have remained elusive since their original isolation over two decades ago. Herein we report the first biosynthetic hypothesis for their formation and, inspired by it, the first synthesis of (±)-Setigerumine I with accompanying computational rationale. Based on the results, these isoxazolidine alkaloids arise from racemizing oxidative rearrangements of prominent isoquinoline alkaloids Noscapine and Hydrastine. The key steps featured in this synthesis are a room temperature Cope elimination and a domino oxidation/inverse-electron demand 1,3-dipolar cycloaddition of an axially chiral, yet configurationally unstable, intermediate. The work opens this previously inaccessible family of natural products for biological studies.
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