Total Synthesis of Pallamolides A−E

Abstract We have achieved the first total synthesis of pallamolides A−E. Of these compounds, pallamolides B−E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one‐pot SmI 2 ‐mediated intramolecular ketyl–enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid‐mediated deprotection/oxa‐Michael addition/β‐hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey–Bakshi–Shibata reduction enabled the asymmetric synthesis of pallamolides A−E.