| A simple, enviornmentally-friendly, silicon-mediated two-step procedure was investigated whereby simple, n-sized cycloalkenones react with monosubstituted epoxides and oxetanes to produce, after oxidative fragmentation, Z-homoallylic medium sized lactones. Many lactone examples were prepared by varying the functionality in the sidechain component of the epoxide. In addition, further ring enlargement has been achieved into ring-expanded lactones and lactams by one additional synthetic step involving either silyl-deprotection and translactonization or Staudinger reduction and lactamization. When the cycloalkenone component of the reaction is replaced with cyclopentanone, a similar methodology was developed, which lead to the formation of regiospecifically, monosubstituted delta-lactams via a four-step ring-enlargement/ring-contraction procedure. This new methodology was highlighted by the total synthesis of natural (-)-halosaline and its isomer (-)-epihalosaline.;A number of analogs were also prepared to add synthetic value to a pre-existing series of antimalarial, artemisinin-based dimer compounds. Through this research, the identification of a highly active series, the phosphothioates, was made via in vivo murine testing, which prolonged mouse survival up to 30 days: the aceptable standard for a malaria-cure. In an effort to produce a more hydrolytically-stable version of the currently available artemisinin-based chemotherapeutics, a highly electron-withdrawing flourine atom was placed on the alpha-position of artemisinin. A series of analogs were prepared, demonstrating increased stability to acid-catalyzised hydrolysis, however no new antimalarial compound was identified after in vivo murine testing. |
