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New methodology for the synthesis of unsaturated hydroperoxides. Total synthesis of chondrillin and enantio-plakorin
Abstract
The formation of organic peroxides is important to several normal biological processes, such as, fatty acid metabolism, prostaglandin synthesis and steroid synthesis. Lipid peroxidation has also been linked with detrimental biological processes and conditions, such as, aging, disease, and cancer. At present, a great deal of the biological consequences of lipid peroxidation remain unknown because of the inability to isolate or prepare suitable quantities of the desired peroxides. In addition, to lipid peroxidation several peroxide and hydroperoxide containing compounds have shown therapeutic potential, as antimalarial, antifungal, or anticancer agents. The large number of biologically active peroxide containing compounds has brought growing awareness of the need for improved tools for peroxide synthesis. As part of a research program targeting the stereoselective synthesis of peroxides, we investigated the reaction of allylstannanes and allylsilanes with singlet oxygen. Our investigations on several substrate systems have shown that allylstannanes undergo regioselective dioxygenation to produce hydroperoxy alkenylstannanes as the major product. Our results indicate that allylsilanes are inferior to allylstannanes as directing groups, and a reversal of abstraction regioselectivity is observed for Z-allylsilanes. We also explored the synthetic utility of vinylstannane hydroperoxides derived through the singlet oxygenation of allylstannanes. We were able to efficiently transform peroxy alkenylstannanes into peroxy vinyl iodides, which compelled us into investigating palladium-catalyzed cross-coupling reactions, as a new unprecedented modular approach to peroxide synthesis. We demonstrate that functionalized peroxides successfully participate in a wide variety of palladium-catalyzed carbon-carbon bond forming reactions, allowing an efficient synthesis of peroxyenones, peroxydienes, peroxyenoates, and peroxyenals. An alternative strategy was undertaken for the first enantioselective synthesis of chondrillin. Chondrillin, a biologically active peroxide containing compound, was the first of a family of alkoxydioxin natural products to be isolated. The synthesis of chondrillin utilized hydroxyl directed singlet oxygenation, followed by peroxyl radical rearrangement to generate the key 1,4-dioxygen relationship. As a result of our work on alkoxydioxin natural products, we have shown that the literature assignments for chondrillin to be incorrect.
Subject Area
Organic chemistry|Pharmaceuticals
Recommended Citation
Eary, Charles Todd, "New methodology for the synthesis of unsaturated hydroperoxides. Total synthesis of chondrillin and enantio-plakorin" (1998). ETD collection for University of Nebraska-Lincoln. AAI9908469.
https://digitalcommons.unl.edu/dissertations/AAI9908469