Total Synthesis of (-)-Enigmazole A by the Macrocyclization/Transannular Pyran Cyclization Strategy

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• (-)-Enigmazole A is a complex marine natural product with potential biological activity.
• Efficient and stereoselective synthesis of complex molecules is crucial for further biological evaluation and development.

Purpose of the Study:

• To disclose a novel and efficient 18-step synthetic route to (-)-enigmazole A.
• To establish a modular strategy for assembling the complex macrocyclic structure.

Main Methods:

• Modular assembly of three key building blocks.
• Macrocyclic ring-closing metathesis to form the 18-membered ring.
• Desilylative transannular oxa-Michael addition for stereoselective tetrahydropyran ring construction.

Main Results:

• A total of 18 steps were required for the synthesis of (-)-enigmazole A.
• The synthesis successfully employed a macrocyclic ring-closing metathesis strategy.
• Stereoselective construction of the 2,6-cis-substituted tetrahydropyran ring was achieved via oxa-Michael addition.

Conclusions:

• The developed 18-step synthesis provides an efficient route to (-)-enigmazole A.
• The modular approach and key reactions demonstrate a viable strategy for constructing complex macrocycles.
• This synthesis paves the way for further studies on the biological properties of (-)-enigmazole A.