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Total synthesis of (±)-bisabosqual A
Christopher W am Ende1, Zhou Zhou, Kathlyn A Parker
1Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, USA.
Journal of the American Chemical Society
|December 28, 2012
Summary
Researchers synthesized bisabosqual A, a novel squalene synthase inhibitor, using a 14-step route. The key tandem radical cyclization efficiently built the complex tetracyclic core with high stereocontrol.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Synthetic Chemistry
Background:
- Squalene synthase is a key enzyme in cholesterol biosynthesis.
- Inhibitors of squalene synthase are potential therapeutic agents for hypercholesterolemia.
- Bisabosqual A is a novel inhibitor with a complex tetracyclic structure.
Purpose of the Study:
- To develop a synthetic route for the novel squalene synthase inhibitor, bisabosqual A.
- To establish an efficient and stereoselective synthesis of the tetracyclic core structure.
Main Methods:
- A 14-step synthesis from commercially available starting materials.
- A doubly convergent synthetic strategy.
- A key tandem 5-exo, 6-exo radical cyclization to construct the tetracyclic core.
- Regioselective deoxygenation and stereoselective organometallic addition reactions.
Main Results:
- Successful synthesis of bisabosqual A.
- Efficient assembly of the fully functionalized tetracyclic core.
- Introduction of three stereogenic centers with high control.
- Demonstration of regioselective and stereoselective transformations.
Conclusions:
- A viable synthetic route to bisabosqual A has been established.
- The key radical cyclization is an effective method for constructing complex polycyclic systems.
- The synthesis highlights efficient methods for functional group manipulation and stereocenter introduction.
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