Total Synthesis of (±)-Corymine

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Indole alkaloids represent a significant class of natural products with diverse biological activities.
• The hexacyclic indole alkaloid (±)-corymine presents a challenging synthetic target due to its complex polycyclic structure.

Purpose of the Study:

• To report the first total synthesis of the hexacyclic indole alkaloid (±)-corymine.
• To develop and demonstrate novel synthetic strategies applicable to complex indole alkaloid frameworks.

Main Methods:

• The synthesis commenced with readily available N-protected tryptamine.
• Key transformations included malonate addition to 3-bromooxindole, intramolecular O-propargylation forming a 12-membered cyclic enol ether, stereospecific propargyl Claisen rearrangement, dimethyldioxirane (DMDO) oxidation, and samarium(II) iodide (SmI2)-mediated reductive cleavage.

Main Results:

• The total synthesis of (±)-corymine was accomplished in 21 steps.
• An overall yield of 3.4% was achieved for the synthetic route.
• Stereospecific formation of the α-allenyl ketone and highly stereoselective installation of a hydroxyl group were achieved.

Conclusions:

• The described synthetic route provides a viable pathway to (±)-corymine.
• The employed methodologies offer valuable tools for the synthesis of other complex indole alkaloids.
• This synthesis advances the field of natural product total synthesis and medicinal chemistry.