Part I. Synthesis of novel antimalarial, antiproliferative and anticancer artemisinin-based triozane dimers. Part II. Silicon-mediated ring expansion of n-sized conjugated cycloalkenones into homoallylic n+3 lactones: Total synthesis of Phoracatholide I a

Artemisinin is a sesquiterpene endoperoxide used to treat malaria. Dimeric structures of artemisinin have been shown to exhibit antiproliferative and antitumor properties. Early artemisinin-based dimers were plagued by inherent instability in the linkers. A new series of C-10 carba dimers was prepared to overcome the instability problem. The new dimers exhibit high antimalarial, antiproliferative and anticancer activity. They are also thermally and hydrolytically stable. Of particular interest is a series of amino-containing dimers. One of the dimers, an aniline-containing derivative, exhibits high in vivo antimalarial activity as well as strongly inhibiting the growth of several cancer cell lines.; A new methodology was developed in which n-sized conjugated cycloalkenones undergo silicon-mediated ring expansion into homoallylic n+3 lactones. Nucleophilic addition of silicon to various 2-cycloalkenones results in the formation of beta-silyl enol ethers. Cleavage of the enol ether releases the enolate, which in the presence of BF3·OEt 2 opens diverse epoxides to undergo alpha-alkylation producing gamma-lactols and gamma-hydroxyketones. Hypervalent iodine promoted oxidative fragmentation then yields unsaturated 3-atom ring expanded 8 to 10 membered homoallylic lactones with good control of alkene geometry. The methodology was used to synthesize the natural products Phoracantholide I and Cephalosporolide D.