A second-generation total synthesis of (+)-phorboxazole A
Amos B Smith1, Thomas M Razler, Jeffrey P Ciavarri
1Department of Chemistry, The Penn Center for Molecular Discovery, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. smithab@sas.upenn.edu
The Journal of Organic Chemistry
|January 25, 2008
Summary
A new synthetic route for (+)-phorboxazole A was developed, enabling multigram production. This efficient method streamlines the creation of complex molecules for potential therapeutic applications.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Medicinal Chemistry
Background:
- Phorboxazole A is a complex marine natural product with potential biological activity.
- Previous syntheses of phorboxazole A were lengthy and low-yielding.
- A more efficient and scalable synthesis is needed for further study.
Purpose of the Study:
- To develop a highly convergent and efficient second-generation synthesis of (+)-phorboxazole A.
- To enable the production of multigram quantities of (+)-phorboxazole A.
- To establish a robust synthetic route for future medicinal chemistry efforts.
Main Methods:
- Improved Petasis-Ferrier union/rearrangement for tetrahydropyran assembly.
- Radical isomerization of Z-vinylsilanes for E/Z-vinyl bromide preparation.
- Convergent late-stage Stille union for macrocycle and side chain coupling.
Main Results:
- Successful synthesis of (+)-phorboxazole A with a 24-step longest linear sequence.
- Achieved an overall yield of 4.6%.
- Demonstrated scalability for multigram quantities of key intermediates.
Conclusions:
- A highly convergent and efficient second-generation synthesis of (+)-phorboxazole A has been established.
- The developed methodology allows for the scalable production of this complex natural product.
- This synthesis provides a foundation for further investigation into the biological properties and therapeutic potential of phorboxazole A.
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