Synthesis of 6-isomer of 5,8-O-dimethyl ether of shikonin (13), a promising anticancer scaffold, always remains a huge challenge. Herein a key intermediate for 13, 2-(1-hydroxyl-4-methyl-3-pentenyl)-1,4,5,8-tetramethoxynaphthalene (10), was obtained on the large-scale synthesis | Regioselective semi-synthesis of 6-isomers of 5 8-O-dimethyl ether of shikonin derivatives via an intramolecular ring-closing ring-opening strategy as potent anticancer agents