Polyunsaturated fatty acid hydroperoxides such as hydroperoxyeicosatetraenoic acids (HPETEs) are involved in a variety of physiological processes, including anaphalaxis, atherosclerosis, inflammation, and tumor promotion. Despite the importance of HPETE's and related hydroperoxides, there are no general methods for the synthesis of isomerically pure unsaturated hydroperoxides. This proposal details an unprecedented yet versatile strategy for hydroperoxide synthesis based upon the execution of synthetic transformations in the presence of reversibly masked hydroperoxides. Preliminary results support the feasibility of synthetic transformations in the presence of ketalized hydroperoxides. Wittig or Horner-Emmons olefination of peroxyaldehydes furnishes new unsaturated hydroperoxides resulting from addition to the carbonyl without scission or elimination of the adjacent peroxide; addition of carbanion or hydride nucleophiles proceeds with similar chemoselectivity. The use of enzymatically derived peroxyaldehydes is shown to allow the synthesis of optically active unsaturated hydroperoxides. The first portion of the proposed research details the application of existing synthetic methods to provide a general route to unsaturated hydroperoxides, including HPETE's. Improved olefination methods are proposed to circumvent limitations observed in preliminary investigations. Chemoselective reduction of peroxydienes, supported by preliminary data, is proposed as an alternative method for the synthesis of optically active allyl hydroperoxides. Organometallic couplings in the presence of a masked peroxide are proposed as a versatile method for introduction of unsaturated hydroperoxide fragments. The present lack of suitable peroxide-containing synthons represents a troublesome limitation on our proposed strategy and the second portion of this proposal discusses several methods for the synthesis of functionalized hydroperoxide fragments. Optically active propargyl peroxides are proposed as versatile precursors for the stereospecific synthesis of a wide variety of unsaturated hydroperoxides. The nucleophilic opening of optically active epoxy alcohols with monoprotected hydrogen peroxide is proposed as a route to optically active peroxyaldehyde starting materials, while nucleophilic opening of optically active vinyl epoxides offers an efficient route to allyl, dienyl, or bisallyl peroxides.
