Total Synthesis of (+)-Shearilicine

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Indole diterpenoids are a class of natural products with complex structures and diverse biological activities.
• Shearilicine is a specific indole diterpenoid whose total synthesis has not been previously reported.
• Accessing highly oxidized indole diterpenoids presents significant synthetic challenges.

Purpose of the Study:

• To report the first total synthesis of the natural product shearilicine.
• To develop a generalizable synthetic route applicable to highly oxidized indole diterpenoids.
• To explore efficient strategies for constructing the core carbazole substructure.

Main Methods:

• An 11-step synthetic sequence was designed and executed.
• A native chiral auxiliary strategy was employed for enantiospecific synthesis.
• An intramolecular Heck cyclization was utilized for carbazole ring formation.

Main Results:

• The total synthesis of shearilicine was successfully completed.
• A generalizable precursor for highly oxidized indole diterpenoids was established.
• Computational studies elucidated noncovalent interactions facilitating the key Heck cyclization step.

Conclusions:

• The developed synthetic route provides efficient access to shearilicine and related indole diterpenoids.
• The use of a chiral auxiliary ensures enantiospecificity in the synthesis.
• The intramolecular Heck cyclization is a key transformation, optimized through computational insights.