It is the aim of this proposal to introduce a methodology for the synthesis of a variety of polycyclic ether systems. The key step in this methodology is the formation of a epoxy cyclic ether by a selective intramolecular cyclization of one of two equilibrating alpha,beta-epoxy alcohols. This is accomplished by an SN2 displacement of an alkyl halide or mesylate by the alkoxide of the alpha,beta-epoxy alcohol. The second ether ring is then formed by a standard acid catalyzed epoxy alcohol cyclization. This methodology will allow the synthesis of any number of bicyclic ether ring systems. These include fused, spiro, bis-cyclic ether carbinols, or 1,2- cyclic ethers of various ring sizes. Further variations to the general reaction may be accomplished by using other electrifies instead of simple leaving groups. For example, using an ester or a nitrile functionality would result in a bicyclic ether-lactone; using an alpha,beta-unsaturated carbonyl group or an allylic leaving group would give a higher order bicyclic ether as the product. This methodology will be applied to the synthesis of the polycyclic ether cores of a class of compounds known as ionophore antibiotics. These compounds have been shown to have a variety of biological activities, and have been the intense focus of a number of syntheses.
