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Comprehensive Summary We report an efficient and convergent strategy for the total synthesis of UCS1025A and its diastereomer tetra‐epi‐UCS1025A. UCS1025A is a representative member of the naturally occurring pyrrolizidinone polyketides, from which members with potent antibacterial, antifungal, and anticancer activities have been identified. Our approach features a tandem carbonylative Stille cross coupling and Diels‐Alder reaction to forge a key C—C bond and build thetrans‐decalin system. This tandem process utilizes carbon monoxide as a one‐carbon linchpin to stitch a vinyl triflate and a vinylstannane together and form the desired enone moiety for the subsequent intramolecular Diels‐Alder cyclization. Our synthesis also provides a versatile approach for the synthesis of other related pyrrolizidinone‐containing polyketides.
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This content will become publicly available on January 1, 2027
Total Synthesis of (±)-Phaeocaulisin A Enabled Chemistry Innovation and Biological Discovery
Abstract Guaianolide sesquiterpene natural products are of great biological and synthetic importance. Among them, phaeocaulisin A with a unique tetracyclic skeleton was isolated in 2013 and found to exhibit anticancer cell proliferation activity and anti-inflammatory activity. The first total synthesis of ( − )-phaeocaulisin A was achieved by Procter and coworkers in 2022. Two years later, we reported a total synthesis of ( ± )-phaeocaulisin A. The key steps of our total synthesis include a novel palladium-catalyzed cyclopropanol ring-opening carbonylative esterification to access a key γ-ketoester, a regio- and stereo-selective aldol cyclization to build the 7-membered carbocycle, and a cascade ketalization/lactonization to construct the tetracyclic skeleton. This Synpact article reflects our journey toward ( ± )-phaeocaulisin A, which also led to the discovery of an analogue with potent anticancer activity against triple negative or HER2+ breast cancer.
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- Award ID(s):
- 2349014
- PAR ID:
- 10680318
- Publisher / Repository:
- Thieme
- Date Published:
- Journal Name:
- Synlett
- Volume:
- 37
- Issue:
- 02
- ISSN:
- 0936-5214
- Page Range / eLocation ID:
- 141 to 144
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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