Natural cyclic ethers isolated from marine plants, such as algae and dinoflagellates, have recently attracted much attention to their notable bioactivities and complicated structures. Prelaureatin 1 has been isolated from red alga Laurencia nipponica as an 8-membered cyclic ether which belongs to a laurenan family of C15-acetogenins involving laureatin 3, isolaureatin 4, and laurallene 5. These laurenan compounds show interesting bioactivities, represented by potent insecticidal activity of 3 and 4. Our previous chemoenzymatic studies using bromoperoxidase from Laurencia nipponica or lactoperoxidase have demonstrated that 1 is a key precursor in the biosynthetic route to 3, 4, and 5. These results have also shown a possibility of the chemical syntheses of all these laurenan compounds from 1. On the other hand, ciguatoxin (CTX) 2 has been isolated as a causative toxin of ciguatera seafood poisoning from moray eel Gymnothorax javanicus firstly by Scheuer. Later, Yasumoto et al. have clarified that the structure of 2 is characterized by 13-fused cyclic ethers including 7-, 8-, and 9-membered rings and that the original source of 2 is the dinoflagellate Gambierdiscus toxicus. Strong activation of voltage-sensitive sodium ion channel has been reported as a remarkable bioactivity of 2. As a part of our studies toward total syntheses of 1 and 2, new synthetic routes starting from sugar derivatives for the construction of medium-sized cyclic ether parts included in 1 and 2 have been developed. In order to construct a medium-sized cyclic ether structure by a ring-closing olefin metathesis (RCM) reaction, the stereoselective synthesis of a chiral di-sec-alkyl ether as a precursor for the RCM reaction must be considered. In fact, an asymmetric synthesis of the chiral di-sec-alkyl ether has been difficult and an important challenge in organic chemistry. In this context, we developed a synthetic method for the chiral di-sec-alkyl ether structure adopting the cleavage reaction of a hexose ring in a chiral C-glycoside prepared from a natural monosaccharide. Here, we disclose the detail of the method and the application to the total synthesis of 1 as well as syntheses of the D-, E-, F-, and I-ring parts of 2.
