This proposal describes a general asymmetric synthetic route to guaianolide sesquiterpenes and the sesquiterpene dimer arteminolide. Guaianolide sesquiterpenes have a wide array of biological activity, yet very few syntheses have been described. The construction the guaianolide skeleton relies on a stereoselective tandem conjugate addition-enolate trapping strategy to build a highly functionalized cyclopentanone. The synthesis features a ring-closing olefin metathesis reaction,, involving a silyl enol ether and a terminal alkene, to form the seven-membered ring. Development of Diels-Alder cycloaddition methods are described for the reaction of silyloxycyclopentadienes with alpha-methylene lactones. These results will produce a convergent strategy for the formation of sesquiterpene dimers such as arteminolide, a novel farnesyl: protein transferase (FPTase) inhibitor. As FPTase inhibitors are believed to help potential as therapeutic agents for the treatment of some kinds of cancer, compounds such as arteminolide are valuable lead compounds. These methods will allow for the total synthesis of either enantiomer.
