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Approaches to the Synthesis of Hydroperoxyeicosatetraenoic Acids (HPETES): 1. Directed Oxygenations, 2. Additions to Peroxycarbenium Ions

Jeffrey Allen Schultz, University of Nebraska - Lincoln

Abstract

Peroxide-containing natural products are a growing class of compounds with differing biological properties, encompassing a large variety of structural classes (terpenes, steroids, fatty acids and others). Hydroperoxyeicosatetraenoic acids (HPETES) are peroxide containing fatty acids that are metabolic products of the oxygenation of arachidonic acid (AA). The HPETES are formed by lipoxygenase enzymes, which insert the hydroperoxide group at differing positions of AA depending on the type of lipoxygenase. As part of a program targeting stereoselective synthesis of hydroperoxide containing natural products we became interested in highly functionalized peroxides as precursors to both HPETEs and alkoxy dioxins. A convenient approach to the desired synthons seemed to lie in the addition of singlet oxygen ( 1O2) to a 3-hydroxy-4Z-alkenoate, followed by hydroboration of the resulting alkene and elimination of the original hydroxyl directing group. The key step of this sequence, diastereoselective oxygenation of chiral 2-alkenols, has not been extensively studied other than for relatively simple models. In the course of doing preparative scale singlet oxygenations of electron deficient allylic alcohols we discovered several problems with Adam's reported experimental conditions. The problems included degradation of the photosensitizer during prolonged preparative scale reactions, removal of the degraded photosensitizer via flash chromatography, and the use of an expensive and environmentally unfriendly solvent, carbon tetrachloride. To circumvent these problems we explored the use of an electron deficient porphyrin, 5,10,15,20-tetrakis(heptafluoropropyl)porphyrin (TPFPP), as a photosensitizer of singlet oxygenations, and the use of a fluorous biphase as a reaction medium. Traditionally, the synthesis of peroxide natural products has been limited by the availability of methods for introducing the peroxide into a molecule and by the limited knowledge of the compatibility of peroxides with synthetic reagents. In the past decade, the Dussault group has (1) explored the compatibility of peroxides towards a variety of organic reactions; (2) pioneered the use of peroxycarbenium ions in which the peroxide group activates a neighboring center for carbon-carbon bond formation. The application of this new methodology towards the synthesis of HPETES will be discussed.

Subject Area

Organic chemistry

Recommended Citation

Schultz, Jeffrey Allen, "Approaches to the Synthesis of Hydroperoxyeicosatetraenoic Acids (HPETES): 1. Directed Oxygenations, 2. Additions to Peroxycarbenium Ions" (1999). ETD collection for University of Nebraska-Lincoln. AAI9946084.
https://digitalcommons.unl.edu/dissertations/AAI9946084

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