Abstract
Ladder-shaped polyether marine toxins produced by marine dinoflagellates are known to have diverse biological activities, such as neurotoxicity, cytotoxicity, and antifungal activity. The distinguishing structures of trans-fused cyclic ethers of sizes ranging from five- to nine-membered rings have attracted the attention of a number of synthetic chemists. However, the stepwise synthesis of more than ten rings is practically impossible due to the large number of transformations required. It is therefore important to develop an efficient method for the construction of large toxins. We herein report a new convergent strategy for the synthesis of this class of molecules. Our synthetic strategy is based on the alkylation of an oxiranyl anion generated from epoxy sulfone I with triflate II followed by 6-endo cyclization of III. The six-membered ketone IV could serve as a precursor of the seven-membered ring VI by a ring expansion reaction. After a reductive etherification reaction of ketones IV and VI, a second six-membered ether ring would be generated. Through the use of this strategy, two new six-six-membered and six-seven-membered ring systems V and VII were constructed. Application of our convergent approach was demonstrated by the synthesis of pentacyclic polyethers 21 and 23 starting from the monocyclic triflate 16 and the bicyclic epoxysulfone 17. The polyether 23 corresponds to the framework of the FGHIJ ring system of gymnocin-A. The present method features a flexible approach toward polycyclic arrays consisting of six- and seven-membered ether rings starting from the same starting materials.
