Development of the Highly Efficient Methodology for the Construction of Medium-sized Cyclic Ethers and its Application to Polycyclic Ether Compounds.

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1. Development of a catalytic and a recycle system of the medium-sized cyclic ethers constructionWe disclosed cyclization of hydroxy epoxides by use Eu(fod)_3 for the construction of medium-sized cyclic ethers. In order to develop into the efficient methodology from the point of view of an atomic economy, a catalytic and a recycle system of the methodology were examined. For these purposes, ionic liquid/organic solvent and fluorous solvent/organic solvent system were used. A catalytic amount of Lewis acid was expected to be concentrated under the conditions and accelerate the reaction. However, these attempts proved fruitless. Surveying of Lewis acid for the reaction revealed Y(hfa)_3 is an efficient Lewis acid, although it was not applicable to a catalytic use.2. Development of the methodology for the highly efficient and stereoselective construction of the polycyclic ether skeletonStereoselective construction of polycyclic ether skeleton was examined using the above mentioned methodo … More logy.1) Extension of the 7-membered cyclic ether : The phosphonate including an epoxy moiety was set as a chiral synthon. A sequence of Horner-Emmons type reaction using the reagent, anti-selective reduction of the carbonyl group induced by stereochemistry of the neighboring epoxy group provided a precursor with required stereochemistry of hydroxy and epoxy groups. Successive cyclization by use of Eu(fod)_3 gave the 7-membered cyclic ether-extended product.2) Extension of the 8- and 9-membered cyclic ethers : The chiral diepoxide derived from (+)-mannitol was set as a chiral synthon for these purposes. Addition of alkynic anion to the diepoxide applying the Yamaguchi's protocol afforded a precursor with required stereochemistry of hydroxy and epoxy groups. Successive cyclization by use of Y(hfa)_3 gave the 8- and 9-membered cyclic ether-extended product. As described above, extension of 7-, 8-, and 9-memberd cyclic ether systems for the synthesis of polycyclic ethers was established.3. Synthetic study of polycyclic ether compoundsThe above methodology was applied to synthesis of polycyclic ether compounds. The BCD-ring, the 6,6,7-fused ring system, of hemibrevetoxin B and the DE-ring, the 7,8-ring system, of ciguatoxin 3C were successfully synthesized. Less