Total Synthesis of Chartelline C

Area of Science:

• Organic Chemistry
• Marine Natural Products
• Total Synthesis

Background:

• Chartellines are cytotoxic marine alkaloids with complex, highly oxidized structures.
• Their unique chemical architecture, including a spirocyclic β-lactam and halogenated moieties, presents significant synthetic challenges.
• Despite their isolation in the 1980s, only one synthesis of any chartelline has been reported, highlighting the difficulty of their preparation.

Purpose of the Study:

• To develop a new and efficient synthetic route to chartelline C.
• To overcome the key challenges in synthesizing chartellines, including stereocontrolled enamide formation, alkene isomerization, spirocyclic β-lactam construction, and late-stage chlorination.
• To explore the reactivity of chartelline C with nucleophiles, suggesting potential avenues for biological activity studies.

Main Methods:

• A multi-step synthesis starting from macrolactam 21, an intermediate used in securine and securamine alkaloid synthesis.
• Stereoselective acid-catalyzed elimination for *cis*-enamide formation, involving in situ ketone masking.
• Photolytic isomerization of a *trans*-alkene, potentially via energy transfer.
• Solid-state reaction on activated alumina for constructing the strained spirocyclic β-lactam.
• Photoredox-mediated halogenation for late-stage enamide chlorination.

Main Results:

• Successful synthesis of chartelline C (3) from macrolactam 21.
• Development of unconventional methods to address stereochemical and structural challenges.
• Demonstration of photoredox-mediated halogenation for efficient enamide chlorination.
• Identification of *N*-haloanomeric amides and *N*-haloguanidines as potential halogen atom transfer agents.
• Observation that chartelline C reacts with sulfur nucleophiles.

Conclusions:

• The developed synthetic route provides a viable pathway to chartelline C, overcoming significant synthetic hurdles.
• The study introduces novel methodologies for constructing complex alkaloids, including solid-state reactions and photoredox catalysis.
• The reactivity studies suggest potential for chartelline C in further biological investigations.