A combined approach toward syntheses of epoxyguaiane sesquiterpenes is presented. By use of a fungus sesquiterpene cyclase, guaian-6,10(14)-diene was produced through metabolic engineering of the isoprenoid pathway in E. coli. (-)-Englerin A, (-)-oxyphyllol, (+)-orientatol E, and (+)-orientalol F have been synthesized in two to six steps. This strategy provided rapid access to the epoxyguaiane core structure and would facilitate syntheses of (-)-englerin A and its analogues for evaluation of their therapeutic potentials in drug discovery.