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.