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 ($\mathit{-}$)-phaeocaulisin A was achieved by Procter and coworkers in 2022. Two years later, we reported a total synthesis of ($\mathit{\pm }$)-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 ($\mathit{\pm }$)-phaeocaulisin A, which also led to the discovery of an analogue with potent anticancer activity against triple negative or HER2+ breast cancer.

Keywords

Sesquiterpene - Phaeocaulisin A - Total synthesis - Aldol cyclization - Cyclopropanol - Palladium catalysis - Carbonylation - γ-Ketoester

Publication History

Received: 06 July 2025

Accepted after revision: 28 August 2025

Accepted Manuscript online:
19 September 2025

Article published online:
24 October 2025

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