Synthesis of (+)-Antroquinonol and Analogues by Using Enantioselective Michael Reactions of Benzoquinone Monoketals

(+)-Antroquinonol is an anticancer agent that was first isolated from the rare mushroom Antrodia cinnamomea, which is indigenous to Taiwan. In this study, (+)-antroquinonol is synthesized from benzoquinone monoketals by using an enantioselective Michael reaction as the strategic step followed by an alkylation, reduction, hydrolysis of a ketal, and inversion of configuration sequence of reactions. Because the enantioselective Michael reaction to the electron-rich 2,3,4,4-tetramethoxycyclohexa-2,5-dien-1-one was problematic, the reaction was facilitated by introducing an electron-withdrawing chloro group to replace the methoxy substituent at the C-2 position. Upon treatment with K2CO3 in MeOH in the final step, the chloro substituent was then replaced by the methoxy group concurrently with the inversion of configuration at C-6 to afford (+)-antroquinonol in a one-pot operation. This modular type of synthetic method can also be applied to efficient total syntheses of other antroquinonol analogues that contain the 4-hydroxycyclohex-2-enone core by starting from their corresponding benzoquinone monoketals.