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.