Ten-Step\nTotal Synthesis of (±)-Phaeocaulisin\nA Enabled by Cyclopropanol Ring-Opening Carbonylation

We report an efficient\ntotal synthesis of (±)-phaeocaulisin\nA, a guaianolide sesquiterpene natural product possessing a complex\ntetracyclic skeleton embedded with an oxaspirolactone and a fused\nbicyclic lactone, four oxygen-containing stereocenters, and an 8-oxabicyclo[3.2.1]octane\ncore. Our synthesis features a novel palladium-catalyzed cyclopropanol\nring-opening carbonylation to access a key γ-ketoester, a chemo-\nand stereoselective aldol cyclization to form the seven-membered carbocycle,\nand a cascade ketalization–lactonization to construct the desired\ntetracyclic skeleton. With these strategically important C–C\nand C–O bond formation transformations, a 10-step total synthesis\nof (±)-phaeocaulisin A was achieved. We further developed the\ncyclopropanol ring-opening carbonylation chemistry to provide an alternative\napproach to prepare γ-ketoesters. Biologically, the penultimate\nintermediate with an α-methylene γ-butyrolactone moiety\nwas identified as a promising lead compound with anticancer proliferation\nactivity against a panel of triple-negative or HER2+ breast cancer\ncell lines.