A simple and direct strategy for the stereocontrolled total synthesis of several proven or potential cytotoxic guaianolides is proposed. The synthetic studies are based on a novel acid catalyzed cyclization which efficiently generates a cis-fused hydroazulene intermediate appropriately functionalized for conversion into the guaianolide family of sesquiterpene lactones. The synthesis exploits the unique reactivity of tropone, a highly functionalized seven membered ring system as the key precursor to the bicyclo [5.3.0] decane species. The principal target molecule zaluzanin C, has demonstrated antileukemic activity and the other target species have structural features such as the Alpha-methylene-Gamma-lactone group, which suggest potential anticancer activity as well. To date, very few guaianolide syntheses have been reported and in view of the large number of these natural products with anticancer potential, further effort must be directed toward developing efficient syntheses of these compounds.