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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Total synthesis of diazonamide A
Robert R Knowles1, Joseph Carpenter, Simon B Blakey
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey, 08544, USA.
Chemical Science
|August 4, 2012
Summary
Researchers achieved the total synthesis of marine natural product diazonamide A. This involved creating a stereoselective quaternary center and furanoindoline core, alongside macrocycle formation strategies.
Area of Science:
- Organic Chemistry
- Natural Product Synthesis
- Medicinal Chemistry
Background:
- Marine natural products often possess unique chemical structures with significant biological activities.
- Diazoamide A is a complex marine natural product with a challenging molecular architecture.
- Efficient synthetic routes to complex natural products are crucial for further biological investigation and potential drug development.
Purpose of the Study:
- To achieve the first total synthesis of the marine natural product diazonamide A.
- To develop novel synthetic methodologies for constructing key structural motifs, including quaternary centers and macrocycles.
- To establish a scalable and stereoselective route to diazonamide A.
Main Methods:
- An iminium-catalyzed alkylation-cyclization cascade was employed for the stereoselective synthesis of the C(10) quaternary center and the furanoindoline core.
- A magnesium-mediated intramolecular macroaldolization was utilized for the formation of one of the 12-membered macrocycles.
- A palladium-catalyzed tandem borylation/annulation sequence was developed to construct the second 12-membered macrocycle.
Main Results:
- The total synthesis of diazonamide A was successfully accomplished.
- The synthetic route established a highly stereoselective construction of the C(10) quaternary center and the central furanoindoline core.
- The synthesis involved 20 steps in its longest linear sequence, achieving an overall yield of 1.8%.
Conclusions:
- The developed synthetic strategy provides a viable route to diazonamide A, demonstrating the power of modern synthetic organic chemistry.
- The novel methodologies employed in this synthesis can potentially be applied to the construction of other complex natural products.
- This work paves the way for further studies on the biological activity and potential therapeutic applications of diazonamide A.
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