This research is directed toward gaining an improved understanding of the chemical events underlying the biological activity of antimalarial peroxides such as artemisinin, and to developing access to simple electron- rich, cyclic peroxides as analogs which may have improved pharmacological properties. A route to amino ozonides (1,2,4-trioxolanes), based upon intramolecular amide oxide - carbonyl cyclization, will be developed. Access to amide oxides, a new type of 1,3-dipole, will be obtained by ozonolysis of enamines, taking advantage of recently elucidated substituent effects on the regioselectivity of alkene ozonolysis. The electron-donation from N to the ozonide will be modified through use of a series of N-substituents, and will provide a set of ozonides with fine-tuning of the electron-rich peroxide. Access to these compounds will permit a detailed study of their oxygen transfer chemistry, and will allow comparison with parallel studies of artemisinin and its derivatives. Kinetic investigation of the reaction of artemisinin to various oxygen acceptors will lead to characterization of the oxygen transfer chemistry which is central to the biomedical mode of action of this antimalarial, and similar measurements on the amino ozonides will help to establish the electronic requirements to aid in the design of these electron-rich ozonides as potential drugs. A novel route for access to the 1,2,4-trioxane ring system of artemisinin by ring expansion of ozonides has been developed. Extension of this method to cyclohexene-derived ozonides will lead to B-C ring analogs of artemisinin, and ultimately will be used for the tactical total synthesis of artemisinin itself.
