The principal investigator notes that this proposal describes the application of peroxycarbenium ions to the asymmetric synthesis of three classes of peroxide-containing natural products: hydroperoxyeicosatetraenoic acids (HPETEs), alkoxydioxines, and 1,2-dioxane propionates. He reports that produced in man through dioxygenation of arachidonic acid, HPETES are involved in many aspects of inflammation and that the alkoxydioxines and dioxane propionates are cyclic peroxides which have been found to exhibit activity against fungal, bacterial, and cancer cell lines. He also indicates that no asymmetric synthesis exists for any of the molecules described in this proposal; approaches to these and related natural products have been hampered by the nonselectivity of existing methods for peroxide synthesis. It is noted that peroxycarbenium ions, a new class of reactive intermediates generated via Lewis acid-mediated activation of monoperoxyacetals, undergo addition of electron-rich alkenes to introduce new carbon-carbon bonds while simultaneously establishing peroxide-bearing stereocenters. The proposed studies are to target the asymmetric synthesis of new peroxide-bearing centers through addition of chiral nucleophiles to prochiral peroxycarbenium ions. It is indicated that the proposed syntheses of 8-, 9-, 11-, and 12-HPETE, as well as the proposed route to the alkoxydioxines, are based upon the asymmetric synthesis of 3-peroxyalkanoates through reaction between prochiral silyl peroxycarbenium ions and silyl ketene acetals derived from a chiral acetate. It is noted that the silyl peroxycarbenium ions will arise through ionization of a silylated hydroperoxyacetal, itself available through singlet oxygenation of a dienol ether and that the proposed route to the dioxane propionates is to be based upon the corresponding reaction between silyl peroxycarbenium ions and silyl ketene acetals derived from a chiral propionate.
