Total Synthesis of Pallamolides A−E

Sequential Michael addition reactions formed the bicyclo[2.2.2]octane core of pallamolides A−E in the first total synthesis of these densely functionalized natural products. The approach also featured a SmI₂-mediated intramolecular ketyl–enoate cyclization to generate the oxabicyclo[3.3.1]nonane moiety and an acid-mediated deprotection/oxa-Michael addition/β-hydroxy elimination cascade to assemble the tetracyclic skeleton of the pallamolides.

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 SmI₂-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.

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