Synthesis of Xanthorrhizol and Cyclization of Its Intermediate

Abstract

The phenolic sesquiterpene xanthorrhizol, 5-(1, 5-dimethyl-4-hexenyl)-2-methylphenol[1a] was synthesized through a new synthetic route, and the cyclization of its intermadiate was investigated. Starting from 4-(p-toluoyl)butyric acid [7], 2-methyl-6-(3-hydroxy-4-methylphenyl)-2-heptanol [4a] and its methyl ether [4b] were synthesized via 5-(3-methoxy-4-methylphenyl)hexanoic acid [12b]. [1a] and its methyl ether [1b] were obtained by dehydrating [4a] and [4b] with SOCl₂ or POCl₃, respectively. The dehydration of [4] with formic acid yielded [1] along with 8-hydroxy-ar-himachalene [14a] or its methyl ether [14b]. By heating with p-toluenesulfonic acid [4b] afforded a mixture of dihydroxanthorrhizol methyl ether [15b], 5-methoxycalamenene [16b] and 7-methoxycalamenene [17b]. The cyclization of [4b] with HBr gave a mixture of the phenolic compounds [15a], [16a] and [17a]. These results indicate that [14] was isomerized to [16] and [17] with an acid catalyst such as p-toluenesulfonic acid or HBr. Each of hydroxy- and methoxycalamenene [16] and [17] was a diastereomer mixture consisting of about cis-isomer 20% and transisomer 80%. Dehydrogenation of [17a] and [17b] gave 7-hydroxycadalene [18a] and its methyl ether [18b], respectively.