Total Synthesis of (+)-Discorhabdin V

Area of Science:

• Natural Product Synthesis
• Organic Chemistry
• Medicinal Chemistry

Background:

• Discorhabdins are pyrroloiminoquinone alkaloids with diverse biological activities.
• Many discorhabdins feature a challenging carbon-nitrogen bridge.
• Previous synthetic efforts have yielded few discorhabdin natural products, especially nitrogen-bridged variants.

Purpose of the Study:

• To achieve the first total synthesis of (+)-discorhabdin V.
• To fully assign the stereochemistry of (+)-discorhabdin V.
• To develop a scalable synthetic strategy for nitrogen-bridged discorhabdins.

Main Methods:

• Convergent synthesis involving N-alkylation, oxidative aminocyclization, and bromination cascade.
• Intramolecular Heck reaction to construct the quaternary carbon center and carbon-nitrogen bridge.
• Reductive N,O-acetal cyclization for piperidine ring formation.
• Stereochemical assignment using NOESY, DP4 NMR calculations, and circular dichroism.

Main Results:

• Successful total synthesis of (+)-discorhabdin V.
• Established relative and absolute stereochemistry through comprehensive spectroscopic analysis.
• Developed a multigram-scale synthesis of key intermediates.
• This work represents one of only two total syntheses of nitrogen-bridged discorhabdins.

Conclusions:

• The first total synthesis and stereochemical assignment of (+)-discorhabdin V have been accomplished.
• The developed synthetic strategy is efficient and scalable.
• This synthesis provides access to nitrogen-bridged discorhabdins for future biological evaluation.