Letter
Total Synthesis of (+)-Antroquinonol and (+)-Antroquinonol D
Rohidas S. Sulake and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan
S
* Supporting Information
ABSTRACT: The first total synthesis of (+)-antroquinonol
and (+)-antroquinonol D, two structurally unique quinonols
with a sesquiterpene side chain, is described. The route
features an iridium-catalyzed olefin isomerization−Claisen
rearrangement reaction (ICR), lactonization, and Grubbs
olefin metathesis. The requisite α,β-unsaturation was achieved
via the selenylation/oxidation protocol and elimination of β-methoxy group to provide two natural products from a common
intermediate.
Antrodia camphorata has a long history as a medicinal fungus. A.
camphorata is widely used in traditional folk medicines for
alcohol detoxification, treatment of cancer, hypertension,
fatigue, viral infection, and liver diseases.1 Important bioactive
compounds isolated from A. camphorata include polysacchar-
ides, maleic/succinic acid derivatives, benzenoids, and
benzoquinone derivatives.2 Antroquinonol and antroquinonols
B−D (Figure 1) are isolated from very expensive and rarely
none followed by a diastereoselective reduction of cyclo-
hexenone and the synthesis of the sesquiterpene side chain.5
Herein, we report the first total synthesis of (+)-antroquinonol
and (+)-antroquinonol D which features a Claisen rearrange-
ment and ring-closing metathesis followed by a lactonization
for the development of three stereogenic centers.
Quinonol compounds under several conditions readily
aromatize through enolization followed by dehydration to
generate a more stable aromatic ring,5,6 which makes the
synthesis of this type of compound more challenging. In order
to rule out the potential labile nature of β-methoxy group of
enone and the possibility of aromatization we focused on the
installment of α,β-unsaturated ketone at the final stages.
Retrosynthetically, (+)-antroquinonol (1) and antroquinonol
D (4) could be synthesized from cyclohexanone 5 through α,β-
unsaturation and elimination of β-methoxy group, respectively.
The sesquiterpene side chain could be accessed by olefination
of the lactol derived from lactone 6. The syn configuration
between C4−OH and sesquiterpene side chain could be
generated through lactonization of the corresponding acid
available from cyclohexene 7. Claisen rearrangement of bis-allyl
ether 8 followed by allylation and ring-closing metathesis could
provide cyclohexene 7. Finally a key starting material bis-allyl
ether 8 could arise from catalytic asymmetric diethylzinc
addition followed by allylation of known (E)-5-(4-
methoxybenzyloxy)pent-2-enal (Figure 2).7
Synthesis of optically pure bis-allyl ether 8 was considered as
the most crucial step in the synthesis, as the Claisen
rearrangement reactions are highly stereospecific and enantio-
merically enriched starting materials provide products of high
optical purity. The enantioselective addition of diethylzinc to
the known aldehyde 9 with catalytic (+)-MIB (morpholino
isoborneol) in pentane and toluene as solvent followed by
allylation with NaH in THF provided the requisite bis-allyl
ether 8 with a 93% ee (Scheme 1).8 Claisen rearrangement of
allyl vinyl ether offered direct access to the aldehyde.9 A survey
Figure 1. Quinolic derivatives isolated from A. camphorata.
found mycelia and fruiting bodies of A. camphorata.3 These
compounds are characterized by a unique, unstable quinonol
framework with a sesquiterpene side chain.
The use of antroquinonol for the treatment of multiple forms
of cancer has been tested in vivo. The compound has shown
promising inhibition of cell growth for at least three kinds of
cancer cell lines (NSCLC, liver, and breast cancer).4a
Antroquinonol (Hocena) capsule was recognized as break-
through anticancer drug and received the approval from US
FDA for clinical trial phase II study. Antroquinonol D is also a
potent anticancer agent and was identified as a new DNMT1
inhibitor, which induced DNA demethylation, and reversed the
silencing of multiple tumor suppressor genes, induced cancer
cell death, and inhibited cell migration.3c Despite owning
impressive therapeutic profiles,4 detailed biological studies of
these compounds are hampered due to the rare availability and
high cost of natural sources. Its low natural abundance makes
total synthesis of (+)-antroquinonol particularly important for
the preparation of sufficient quantities for further biological
evaluation and to determine the absolute configuration. In the
course of these efforts, total synthesis of ( )-antroquinonol D
was achieved through the Michael addition on cyclohexadie-
Received: January 6, 2015
© XXXX American Chemical Society
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Org. Lett. XXXX, XXX, XXX−XXX