Tetrahedron Letters
A short and efficient asymmetric synthesis of komaroviquinone
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Yutaka Suto , Kento Kaneko, Noriyuki Yamagiwa, Genji Iwasaki
Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Naka-Orui, Takasaki, Gunma 370-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric total synthesis of komaroviquinone (1), which is a natural product isolated from Draco-
cephalum komarovi and shows novel potent trypanocidal activity, was achieved in five steps from the
known starting materials. The synthetic route is shorter and more efficient than the reported methods
and also useful for the scale-up synthesis.
Received 28 July 2010
Revised 21 September 2010
Accepted 24 September 2010
Ó 2010 Published by Elsevier Ltd.
Trypanosoma cruzi (T. cruizi) is a parasitic protozoan transmitted
by bloodsucking triatomine insects and the infection by T. cruizi is
known as Chagas’ disease, which is a main health problem in ende-
mic countries across Central and South America.1 The disease is
potentially life-threatening and acute and/or chronic one is associ-
ated with severe complications. However, there are no efficacious
vaccines, and anti-chagastic drugs in use such as nifurtimox and
benznidazole have undesirable side effects.2 In addition, the emer-
gence of parasitic drug resistance is also problematic. Thus, the
development of new anti-chagastic agents is an urgent require-
ment and of particular interest.
Recently, novel chemotherapeutic targets for Chagas’ disease
have been identified with reports that both synthetic compounds3
and natural products4 showed attractive trypanocidal activity. Var-
ious natural products such as flavonoids and terpenoids have been
identified as trypanocidal agents. Among them, komaroviquinone
(1),5 isolated from Dracocephalum komarovi, exhibited a remark-
ably high trypanocidal activity specifically against trypomastigotes
of T. cruzi, known as an infective form in mammalian host. The IC50
value in vitro of komaroviquinone (1) was reported to be 9 nM
against trypomastigotes of T. cruzi.6 The mechanistic study on try-
panocidal activity of komaroviquinone (1) has been carried out,
and its activity is experimentally estimated to be due to reactive
oxygen species generated by the reduction of drugs.6 The key en-
zyme involved in the generation of reactive oxygen species is
known as T. cruzi old yellow enzyme (TcOYE),7 which is expressed
in all stages of the parasite life cycle. The old yellow enzymes have
been identified in yeasts, plants, and bacteria but not in animals.
These results clearly indicate that komaroviquinone (1) is a good
candidate to develop new anti-chagastic drugs. To date, two groups
have reported the total synthesis of komaroviquinone (1),8 how-
ever, one8a of them is not feasible for the asymmetric synthesis,
and the other8c is relatively lengthy and not suitable for further
investigations. Therefore, to develop new anti-chagastic agents, it
is required to establish a well-designed and efficient asymmetric
synthetic route to komaroviquinone (1), which is amenable to ana-
logs and comprehensive SAR studies. Herein, we report the short
and efficient asymmetric synthesis of komaroviquinone (1) from
the easily accessible starting materials.
The preliminary retro-synthetic analysis is shown in Scheme 1.
Based on the retro-synthetic analysis, the construction of the
key intermediate
2
having trans 10-hydroxy-1,1-dim-
ethyloctahydrodibenzo [a,d] cycloheptene-7-one core structure is
crucial. Komaroviquinone (1) was synthesized from the intermedi-
ate 2 by reported procedure.8a Under the oxidative conditions of
the aromatic part of the intermediate 2, the seven membered hem-
iketal was simultaneously formed. The intermediate 2 should be
obtained via intra-molecular nucleophilic addition to the lactone
moiety of 3. Lactone 3 would be synthesized from 4 through hydro-
lysis and cyclization under acidic conditions. Negishi coupling
reaction between vinyl iodide 5 and benzyl bromide 6 would afford
the ester 4. Both vinyl iodide 510 and benzyl bromide 68b,9 are
known compounds and can be synthesized in three and six steps
from commercially available compound, respectively.
Negishi coupling reaction11 of benzyl bromide 6 with vinyl iodide
5, which was prepared in 98% ee from 4,4-dimethyl-2-cyclohexen-
1-one, was initially carried out, and the reaction smoothly pro-
ceeded at room temperature in the presence of 2.5 mol % of
Pd(PPh3)2Cl2 to give 4 in 82% yield (Scheme 2). Hydrolysis of the es-
ter moiety of 4, and the following cyclization reaction afforded lac-
tone 3 in 93% yield in a highly diastereoselective manner. The
relative configuration of 3 was confirmed by NOESY. Iodination of
3 was carried out using NIS in the presence of catalytic amount of
acid. After treatment of 7 with isopropylmagnesium chloride at
À40 °C, the subsequent intra-molecular nucleophilic cyclization
proceeded smoothly at the same temperature to afford compound
2 in 96% yield.12 Compound 2 exists in equilibrium with hemiketal
8 in solution8a as revealed by the 1H and 13C NMR spectra (see Sup-
plementary data and Ref. 8a). The direct oxidation of this mixture of
2 and 8 with Ag(II)O in diluted HNO3 gave komaroviquinone (1) as
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Corresponding author. Tel.: +81 27 352 1180; fax: +81 27 352 1118.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
Suto, Yutaka
