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Total synthesis of (+)-brefeldin A
1State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China. yikangwu@mail.sioc.ac.cn
Organic Letters
|March 15, 2008
Summary
(+)-Brefeldin A, a potent bioactive natural product, was efficiently synthesized using a novel route. Key steps include chiral auxiliary removal, side chain addition, stereoselective ketone reduction, and Shiina lactonization for constructing this complex molecule.
Area of Science:
- Organic Chemistry
- Natural Product Synthesis
- Medicinal Chemistry
Background:
- (+)-Brefeldin A is a macrocyclic lactone natural product with significant biological activities, including potent inhibition of protein transport.
- The complex structure of (+)-Brefeldin A presents a considerable challenge for total synthesis.
- Efficient and stereocontrolled synthetic routes are crucial for accessing Brefeldin A and its analogs for further biological evaluation.
Purpose of the Study:
- To develop an efficient and stereoselective total synthesis of (+)-Brefeldin A.
- To establish a robust synthetic strategy amenable to analog preparation.
- To showcase the utility of key synthetic transformations in complex molecule construction.
Main Methods:
- Construction of the core five-membered ring via tandem lithium-iodine exchange and carbanion-mediated cyclization.
- Introduction of the C10-C16 side chain using a rhodium-catalyzed Michael addition of vinyl boronic acid.
- Stereoselective reduction of the C7 ketone utilizing samarium(II) iodide (SmI2).
- Final macrocyclization through 2-methyl-6-nitrobenzoic anhydride-mediated (Shiina) lactonization.
Main Results:
- Successful synthesis of (+)-Brefeldin A in an efficient manner.
- High stereoselectivity achieved in the ketone reduction step.
- Demonstration of a convergent and reliable synthetic route.
- The developed methodology provides access to the natural product and potential analogs.
Conclusions:
- The presented synthetic route offers an efficient and viable method for accessing (+)-Brefeldin A.
- The key steps employed are highly effective for constructing the complex architecture of the natural product.
- This synthesis provides a foundation for exploring structure-activity relationships of Brefeldin A analogs.
