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Scalable Synthesis of (-)-Thapsigargin.
Hang Chu1, Joel M Smith1, Jakob Felding2
1Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
ACS Central Science
|February 3, 2017
Summary
Total synthesis of complex natural products thapsigargin and nortrilobolide was achieved. This concise route offers scalable access to analogues of these bioactive compounds.
Area of Science:
- Organic Chemistry
- Natural Product Synthesis
- Medicinal Chemistry
Background:
- Thapsigargin and nortrilobolide are complex, highly oxygenated sesquiterpenes with significant biological activity.
- Previous access to analogues was limited by challenging isolation and lengthy semisynthetic approaches.
- Prior total syntheses were lengthy, involving 36-42 steps.
Purpose of the Study:
- To develop a more concise and scalable total synthesis of thapsigargin and nortrilobolide.
- To enable access to analogues of these bioactive natural products.
- To explore novel synthetic strategies for complex oxygenated sesquiterpenes.
Main Methods:
- Utilized two-phase terpene synthesis logic for a streamlined approach.
- Applied the classic photosantonin rearrangement.
- Employed precisely choreographed installation of multiple oxygenations on the guaianolide skeleton.
Main Results:
- Achieved total syntheses of thapsigargin and nortrilobolide.
- Developed a scalable and more concise synthetic route compared to previous methods.
- Demonstrated the utility of the employed synthetic strategies for complex natural product synthesis.
Conclusions:
- The reported synthetic route provides efficient and scalable access to thapsigargin, nortrilobolide, and their analogues.
- This work advances the synthesis of complex, highly oxygenated sesquiterpenes.
- The developed methodology can facilitate further biological evaluation and drug discovery efforts.