This research will be supported by the Organic and Macromolecular Chemistry Program. The work will lead to the development of new routes to heterocyclic compounds containing three oxygen atoms. These are important constituent substructures in some important enviromental processes as well as having been discovered in a new antimalarial from mainland China, artemisin. This will establish methods for the preparation of novel functional ozonides (1,2,4-trioxolanes) and to develop new reactions of these species which can be applied to compounds of chemical significance. Although a great deal has been learned about the mechanism of alkene ozonolysis, very little is known of the chemistry of the product ozonides. Likewise, substituent effects on the oxonide ring have not been well-studied. The intramolecular carbonyloxide-ester cycloaddition will be further developed as a route to alkoxy oxonides, where the substituent exerts a strong electronic bias on the trioxolane system. Two approaches will be explored--first, ozonolysis of alkene esters where a rigid carbon framework holds the reactive groups in close proximity, and the ozonation of cyclic vinyl ethers, where the reactive groups are generated together. The alkoxy ozonides are selective oxygen transfer agents toward nucleophiles. This process will be studied both on mechanistic grounds, including labelling experiments to determine the regioselectivity of 0-transfer, and for synthetic utility--the oxidation of carbon nucleophiles is a problem of long standing. The ozonation of allylic halides will be investigated to elucidate the stereoelectronic effects for ozonide formation. The resulting beta-halo ozonides should be susceptible to ionization-ring expansion, thereby opening a new synthetic route to 5-alkoxy-1,2,4-trioxanes, the pharmacophore of the antimalarial artemisinin.
