A short synthesis of (±)-antroquinonol in an unusual scaffold of 4-hydroxy-2-cyclohexenone

Abstract

Antroquinonol, which was first isolated from a mushroom, Antrodia cinnamomea, found in Taiwan, is an anticancer compound with a unique core structure of 4-hydroxy-2,3-dimethoxycyclohex-2-enone carrying methyl, farnesyl and hydroxyl substituents in the 4,5-cis-5,6-trans configuration. A short synthesis of (±)-antroquinonol is accomplished in seven steps from 2,3,4-trimethoxyphenol, which is oxidized in methanol to a highly electron-rich substrate of 2,3,4,4-tetramethoxycyclohexadienone and then a Michael reaction with dimethylcuprate is performed as the key step, followed by alkylation, reduction and epimerization to incorporate the required substituents at three contiguous stereocenters.

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

“…However, this relatively active reagent could not be applied to the enantioselective Michael addition of 2a , even in the presence of the chiral ligand, under the optimized conditions because of competition from a 1,2‐addition reaction and facile aromatization to give 2,3,4‐trimethoxy‐5‐methylphenol. Although we were able to repeat the previously reported Michael reaction of 4,4‐dimethoxycyclohexa‐2,5‐dien‐1‐one by using Me 2 Zn, Cu(OTf) 2 , and chiral ligand ( S , R , R )‐ B to obtain the desired conjugate addition product ( R )‐3‐methyl‐4,4‐dimethoxycyclohex‐2‐en‐1‐one in 72 % yield with 99 % ee , the enantioselective Michael reaction of 2a was problematic, because the four electron‐donating methoxy substituents make 2a a poor Michael acceptor toward a nucleophilic reagent . The similar problem of reluctant Michael reactions of highly electron‐rich system has also been encountered by the Baran and Chen groups , …”

“…Thus, the ( R )‐binaphthol‐derived phosphoramidite chiral ligand ( R , S , S )‐ A , based on Feringa's protocol, was chosen for the enantioselective Michael reaction. In our previous study, MeMgBr–CuCl was determined as the best nucleophilic reagent for the conjugate addition to benzoquinone monoketal 2a in tetrahydrofuran (THF). However, this relatively active reagent could not be applied to the enantioselective Michael addition of 2a , even in the presence of the chiral ligand, under the optimized conditions because of competition from a 1,2‐addition reaction and facile aromatization to give 2,3,4‐trimethoxy‐5‐methylphenol.…”

“…With the optically active 3b and 3d in hand, the subsequent alkylation and reduction reactions were smoothly carried out by using our previous experimental protocols that suggest the appropriate reducing agent and reaction conditions to attain the desired stereochemical outcome. For the synthesis of (+)‐antroquinonol, the conjugate addition product ( S )‐ 3b was treated with lithium hexamethyldisilazide and farnesyl bromide to give the alkylation product, which was then subjected to a base‐catalyzed isomerization to afford 4b predominating in the cis configuration.…”

“…In contrast, our first‐generation synthesis of (±)‐antroquinonol and (±)‐antroquinonol D only requires six steps and uses Michael reactions of the appropriate benzoquinone monoketals with a dimethylcuprate reagent as the strategic key step . In our preliminary study, we indicated that the asymmetric Michael addition of 3,4,4‐trimethoxycyclohexadienone with a methylmetal reagent could be carried out and that the 1,4‐adduct could be elaborated through a similar procedure to give optically active antroquinonol D. Recently, Dhar, Baran, and co‐workers examined many routes to synthesize (+)‐antroquinonol but found the asymmetric Michael reaction of the appropriate benzoquinone monoketal as the only viable method . Their report has prompted us to disclose our independent research on the enantioselective Michael reactions of benzoquinone monoketals 2a – 2j (Tables and ), which is a continuation of our previous studies and can be applied to the syntheses of (+)‐antroquinonol and (+)‐antroquinonol D (Scheme ).…”

“…In our preliminary study, we indicated that the asymmetric Michael addition of 3,4,4‐trimethoxycyclohexadienone with a methylmetal reagent could be carried out and that the 1,4‐adduct could be elaborated through a similar procedure to give optically active antroquinonol D. Recently, Dhar, Baran, and co‐workers examined many routes to synthesize (+)‐antroquinonol but found the asymmetric Michael reaction of the appropriate benzoquinone monoketal as the only viable method . Their report has prompted us to disclose our independent research on the enantioselective Michael reactions of benzoquinone monoketals 2a – 2j (Tables and ), which is a continuation of our previous studies and can be applied to the syntheses of (+)‐antroquinonol and (+)‐antroquinonol D (Scheme ). Benzoquinone monoketals 2a – 2j were readily prepared from the corresponding phenols by oxidation with [bis(trifluoroacetoxy)iodo]benzene (PIFA) in anhydrous methanol …”