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

Abstract

(+)‐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.

Current Advances on the Structure, Bioactivity, Synthesis, and Metabolic Regulation of Novel Ubiquinone Derivatives in the Edible and Medicinal Mushroom Antrodia cinnamomea

“…60 Total synthesis of antroquinonol and antroquinonol D was accomplished using enantioselective Michael reactions, which require short linear synthetic sequences (only six steps). 61 As shown in Figure 2, antroquinonol and antroquinonol D could be synthesized from benzoquinone monoketals by enantioselective Michael reaction as the strategic step. It is worth noting that, upon treatment with K 2 CO 3 in MeOH in the sixth step, the chlorine atom was replaced by the methoxy group and the inversion of configuration occurred in C-6 to form antroquinonol.…”

“…Finally, the yields of antroquinonol and antroquinonol D were 10.4 and 15.2%, respectively. 61 Villaume et al used a conjugate addition to a substituted quinone through a similar six-step reaction to synthesize antroquinonol. 43 The synthesis commences with the formation of quinone monoketal from commercial benzaldehyde, resulting in enantioenriched antroquinonol in an overall yield of 13% with 96% enantiomeric excess (ee).…”

“…In 2015, a short synthesis of antroquinonol was proposed to originate from 2,3,4-trimethoxyphenol and undergo a seven-step synthesis . Total synthesis of antroquinonol and antroquinonol D was accomplished using enantioselective Michael reactions, which require short linear synthetic sequences (only six steps) . As shown in Figure , antroquinonol and antroquinonol D could be synthesized from benzoquinone monoketals by enantioselective Michael reaction as the strategic step.…”

“…Otherwise, antroquinonol D was obtained when the substituent changes from a chlorine atom to a hydrogen atom and without the methoxy substituent at the C-3 position. Finally, the yields of antroquinonol and antroquinonol D were 10.4 and 15.2%, respectively . Villaume et al used a conjugate addition to a substituted quinone through a similar six-step reaction to synthesize antroquinonol .…”

“…Chemical total synthesis route for antroquinonol and antroquinonol D. , OTf, trifluormethanesulfonate; LHMDS, lithium hexamethyldisilazide; THF, tetrahydrofuran; DMF, N , N -dimethylformamide; and LS-Selectride, lithium trisiamylborohydride.…”