I. Total synthesis of peroxyacarnoic acids and peroxyplakoric acids. II. New synthetic methodology for organic peroxides and application of peroxides as enzyme inhibitors

Over the past several decades a number of peroxide containing natural products have been isolated. Marine organisms, especially the marine sponge of the genus Plakortis are rich sources of cyclic peroxides and peroxyketals. Many of these compounds exhibit antifungal, antitumor, antimalarial, and cytotoxic activities. As part of our interest in peroxide-containing natural products, we became interested in the peroxyacarnoic acids and peroxyplakoric acids, synthetically challenging alkoxydioxanes possessing interesting biological activity. The synthetic challenge for Peroxyacarnoic acids and Peroxyplakoric acids is the need to introduce both an oxidation-sensitive polyunsaturated side chain and a reduction-sensitive 1,2-dioxane in the same molecule. The key steps in the synthesis of the peroxyacarnoates include regioselective ozonolysis, conjugate addition of a 6-hydroperoxy-2,3-enoate, and the use of an alkynyl-substituted 1,2-dioxane as a substrate for Sonogashira coupling reactions. The asymmetric approach to the peroxyplakoric acids also relies upon Pd-mediated coupling reaction for installation of the polyunsaturated side chain but employs a stereospecific intramolecular nucleophilic substitution for installation of the 1,2-dioxane core, with the stereochemistry of the precursor determined by an asymmetric aldol reaction. The use of the Curtius rearrangement and the Wolff homologation for synthesis of functionalized peroxides was explored. The Curtius rearrangement was demonstrated to be successful for the preparation of 2-, 3-, and 4-peroxy amines, the synthesis of which had not been explored much in the past. The Wolff rearrangement was proven to be efficient in the elongation of peroxide functionalized carboxylic acids and may find application in the synthesis of marine peroxide natural products. Finally, investigation of peroxides as cysteine protease inhibitors using papain as model enzyme and synthesis of monothioesters of tricarballylic acid were also discussed in this dissertation