Organic synthesis and methodology related to the Malaria drug artemisinin

Malaria is a global epidemic, resulting in the deaths of nearly one million people every year. Part 1 of this dissertation will focus on the history of Malaria and ways to combat this devastating disease. Artemisinin has emerged as the drug of choice for treatment of malaria due to its effectiveness against all strains of the malaria parasite. Access to artemisinin through isolation, bio-engineering, and chemical synthesis will be described. Our attempts to access the artemisinin family of anti-malarials through the total synthesis of dihydro-epi-deoxyarteannuin B and dihydroartemisinic acid will be discussed fully. Key features of the syntheses will include alkylation of menthone derivatives using Noyori's zincate enolate method and nucleophilic addition to a hindered ketone using either organocerium or acetylide nucleophiles. In addition, two alternative olefin metathesis approaches are described for the final cyclization.;Problems associated with the olefination of a key intermediate in our efforts toward dihydroartemisinic acid led us to develop a two-step olefination of ketones and aldehydes. Part II will discuss this olefination strategy which consists of acetylide addition to generate a propargyl alcohol followed by a Meyer-Schuster rearrangement to the corresponding alpha,beta-enone. A complete history of the Meyer-Schuster rearrangement will be presented, highlighting the short comings of the method prior to our work. A complete overview of our research pertaining to the Meyer-Schuster reaction will be given. Key topics will include development of a Au(III)-catalyzed rearrangement of propargyl ethynyl ethers into alpha,beta-unsaturated esters and its use in the olefination of hindered ketones, efforts to control the ( E/Z)-selectivity of the Meyer-Schuster rearrangement, and the search for more affordable catalysts.