Total Synthesis of (±)-Antroquinonol D

Abstract

Total synthesis of (±)-antroquinonol D, which is isolated from very expensive and rarely found Antrodia camphorata and which has potential anticancer properties, was achieved from 4-methoxyphenol. In addition, a Michael addition to dimethoxy cyclohexadienones was studied. The main step involved chelation and substrate-controlled diastereoselective reduction of cyclohexenone and lactonization. Lactone synthesis facilitated the diastereoselective reduction of ketone, which help control the desired stereochemistry at the crucial stereogenic center in the natural product. Other key reactions in the synthesis involved a Michael addition of dimethyl malonate on cyclohexadienone, dihydroxylation, and Wittig olefination. A sesquiterpene side chain was synthesized through coupling with geranyl phenyl sulfide and Bouveault-Blanc reduction.

Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target

“…Antroquinonol is currently in phase II trials (USA and Taiwan) for NSCLC and it was recently granted orphan drug status by the U S Food and Drug Administration for pancreatic cancer and acute myeloid leukemia [ 26 , 27 ]. The total synthesis of (+)-antroquinonol and (+)-antroquinonol D, two structurally unique quinonols with a sesquiterpene, has been reported [ 28 , 29 ].…”

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

“…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 , …”

“…[ α ] D 18 = +72.7 ( c = 0.28, CHCl 3 ); ref . [ α ] D 20 = +52.0 ( c = 0.364, MeOH); ref . [ α ] D 25 = +44.6 ( c = 1.2, CHCl 3 ).…”

Applications of Mitsunobu Reaction in total synthesis of natural products

“…The latter was underwent a‐phenylselenylation‐selenoxide elimination to give the antroquinonol‐type dimethylated cyclohexenoid core 161a . Alternatively, simple exposure of 160 to LHMDS led to methanol elimination and simultaneous PNB deprotection to give 161b , readily . Generally, with having of 161a and 161b , in hands the primary purpose of accessing the carbocyclic group as a core of antroquinonols has been accomplished.…”

“…[218] Alternatively, simple exposure of 160 to LHMDS led to methanol elimination and simultaneous PNB deprotection to give 161b, readily. [219] Generally, with having of 161a and 161b, in hands the primary purpose of accessing the carbocyclic group as a core of antroquinonols has been accomplished. They were subjected into Wittig olefination to give 162.…”