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Synthesis of peroxide containing natural products: Development and application of ozonolysis methodologies
Abstract
Over the past two decades the number of known natural products containing peroxide linkages has increased dramatically. Many of these compounds exhibit a high degree of bioactivity across a wide spectrum of maladies, including cancer, malaria, and fungal infections. Unfortunately, the natural availability of most of these compounds is insufficient for therapeutic purposes. The rarity of methods for installing the peroxide moiety has limited the total synthesis of these molecules to a relatively small number of examples. Cyclic peroxides in particular have received a great deal of synthetic attention recently. The active components of Yinghaosu, an herbal remedy for malaria, have been isolated and synthesized, albeit in low yield. A new and efficient route to the bicyclic core of Yinghaosu has been developed. The peroxide is installed via the selective ozonolysis of carvone in the presence of protic solvents. In situ intra-molecular cyclization of the resultant peroxyketal leads to direct formation of the bicyclic core of Yinghaosu in one step. Elaboration of the core into the natural product via peroxycarbenium ion chemistry was unsuccessful. During the course of our studies on the synthesis of Yinghaosu analogues, we discovered an unexplored and potentially useful method for ozonolysis of alkenes. The oxidation of alkenes using ozone, followed by a reductive workup is a well known and frequently used method for conversion of alkenes to ketones. In the absence of a reductive workup the ozonolysis of alkenes in the presence of nucleophilic solvents, such as methanol, leads to the formation of isolable peroxyacetals. However, application of this reaction to the synthesis of peroxyacetals is often limited by solvent nucleophilicity. Addition of Lewis acids to ozonolysis reactions was studied in an effort to modify the reactivity of the intermediate carbonyl oxide with respect to nucleophiles. The use of non-nucleophilic alkoxy Lewis acids during the ozonolysis of alkenes leads to the formation of products normally associated with nucleophilic attack of the alcohols on the intermediate carbonyl oxide. This new reaction allows the synthesis of normally hard to obtain peroxyacetals in high yield. Furthermore, it offers the potential to deliver nucleophiles in a stereocontrolled environment, creating a new method for the formation of asymmetric hydroperoxy acetals. In an effort to prove the viability of an asymmetric ozonolysis we designed and attempted the synthesis of another class of peroxide containing natural products, the peroxy plakoric acids. The key structural feature for this class of biologically active peroxides is the presence of a chiral perketal. The key step for the synthesis of these compounds would be the selective ozonolysis of an alkene in the presence of both an unsaturated ester and terminal alkyne, using an appropriate nucleophile to create the desired perketal. The racemic synthesis was attempted, and ultimately led us to a better understanding of the subtleties of electronic effects involved with the selective ozonolysis of substituted alkenes.
Subject Area
Organic chemistry
Recommended Citation
Raible, Joseph M, "Synthesis of peroxide containing natural products: Development and application of ozonolysis methodologies" (2004). ETD collection for University of Nebraska-Lincoln. AAI3131557.
https://digitalcommons.unl.edu/dissertations/AAI3131557