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

Abstract

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. A ring-closing/ring-opening strategy was applied to avoid the undesired reactivity posed by the side chain and racemization of the chiral centre. Incorporation of bulky substituent 4-((tertbutoxycarbonyl)amino)phenyl to hydroxyl group in the side chain redistributed electron density of naphthalene core (10), overwhelmingly favoring the generation of 13 when oxidized by cerium(IV) ammonium nitrate followed by hydrolysis. As a result, three 6-isomers (14a-14c) with very potent antitumor activity were easily synthesized. This study opened an novel avenue to selectively prepare 6-isomers of 5,8-dimethoxy1-1,4-naphthaquinones, bearing the synthetically challenging side chain such as 2-hydroxyl-5-methylpentenyl group.