Total Synthesis of Pallamolides A−E

• Published in: Angewandte Chemie International Edition 2024-05, Vol.63 (20), p.e202319127-n/a
• Main Authors: Zhang, Yu, Chen, Lijun, Jia, Yanxing
• Format: Article
• Language: English
• Subjects: Asymmetric synthesis; Diterpenoids; Ketones; Natural products; Reductive cyclization; Sequential Michael addition; Stereoselectivity; Synthesis; Total synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202319127

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. 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.