The polycyclic ether class of marine natural products presents formidable and challenging synthetic targets due to their structural complexity and exceptionally potent biological activities. Over the past decade, however, their extremely limited availability from natural sources has precluded detailed biological studies on polycyclic ethers. Therefore, the supply of useful quantities of these natural products by chemical total synthesis has been strongly demanded. We developed a highly convergent strategy for the rapid assembly of a huge polycyclic ether array, which features Suzuki-Miyaura cross-coupling reaction of alkylboranes, generated from exocyclic enol ethers, with cyclic ketene acetal triffates or phosphates combined with reductive ring-closure. The utility of this strategy was demonstrated by its application to the convergent total synthesis of the natural products gambierol and gymnocin-A. These practical synthetic routes allowed for the first time systematic studies of the structure-activity relationships of the polycyclic ether class of natural products.
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