New methodology for synthesis of hydroperoxides and peroxides. I. Application to the total syntheses of 5(S)-HPETE and 15(S)-HPETE. II. Peroxycarbenium-mediated synthesis of peroxides from perketals

Hydroperoxyeiscosatetraenoic acids (HPETEs) are biologically important polyunsaturated hydroperoxides produced upon enzyme-catalyzed dioxygenation of arachidonic acid. These unstable natural products are the precursors of prostaglandins, leukotrienes and lipoxins, substances known to be mediators of asthma, inflammation and anaphalyxis. Despite the importance of HPETEs and related unsaturated hydroperoxides, remarkably few methods have been developed for their synthesis and all existing methods produce the molecules in racemic form. Previous attempts to synthesize unsaturated hydroperoxides were frustrated by their instability. We have developed an efficient synthetic methodology for producing optically active diene hydroperoxides from enzymatic oxygenation of natural or unnatural fats and construction of carbon-carbon bonds in the presence of protected hydroperoxides. This methodology has been applied to the syntheses of 5-HPETE and 15-HPETE in enantiomerically pure form. We also developed a new method for peroxide synthesis from a perketal based upon peroxycarbenium-mediated C-C bond formation