NEW SYNTHETIC APPROACHES TO UNSATURATED HYDROPEROXIDES

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.