Enantioselective Total Synthesis of Two Aromatized Halicyclamines

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Marine alkaloids like tetradehydrohalicyclamine B possess complex structures with potential biological activities.
• Previous synthetic efforts have not achieved asymmetric synthesis or controlled stereochemistry of these compounds.

Purpose of the Study:

• To disclose concise and divergent synthetic routes for (+)-tetradehydrohalicyclamine B and (-)-epi-tetradehydrohalicyclamine B.
• To establish the first reported asymmetric syntheses of these marine natural products.
• To enable controlled assembly of the challenging *trans* stereochemical relationship in the piperidine ring.

Main Methods:

• Utilized a 10-step synthetic sequence for each target molecule.
• Key transformations included enantioselective organocatalyzed Michael addition and macrocyclic aza-Wittig ligation.
• Employed reagent-controlled stereodivergent lactam reductions for core framework assembly.

Main Results:

• Successfully synthesized (+)-tetradehydrohalicyclamine B and (-)-epi-tetradehydrohalicyclamine B.
• Achieved the first asymmetric syntheses of these marine alkaloids.
• Established a method for controlled synthesis of the *trans* piperidine stereochemistry, previously unattainable.

Conclusions:

• The developed synthetic strategy is efficient and provides access to key marine alkaloids.
• This work overcomes previous limitations in synthesizing specific stereoisomers of tetradehydrohalicyclamine B.
• The use of highly oxidized starting materials streamlined the synthesis and avoided complex functional group manipulations.