Tetrahedron Letters 55 (2014) 818820

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Regioselective route for arylnaphthalene lactones: convenient

synthesis of taiwanin C, justicidin E, and daurinol
Ju-Eun Park a, Juyeun Lee b, Seung-Yong Seo a,, Dongyun Shin a,
a
b

College of Pharmacy, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-799, Republic of Korea
College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Geonggo-do 426-791, Republic of Korea

a r t i c l e

i n f o

Article history:
Received 20 October 2013
Revised 1 December 2013
Accepted 5 December 2013
Available online 15 December 2013
Keywords:
Arylnaphthalene lactone
Intramolecular DielsAlder
Regioselectivity
Lignan
Daurinol

a b s t r a c t
Arylnaphthalene lactones are natural products which can be isolated from a wide range of plants and
have the signicant biological activities including cytotoxicity, antimicrobial, diuretic, and ion channel
blocking. The drawback of the previous intramolecular DielsAlder reaction of 3-arylprop-2-ynyl 3-arylpropiolates was to generate two regioisomers of arylnaphthalene lactone without selectivity. Herein, we
report a convenient and regioselective synthesis method in which the intramolecular DielsAlder reaction of an arylalkenearylalkyne and subsequent DDQ oxidation was used for Type I and Type II arylnaphthalene lactones, respectively. We demonstrated the synthesis of three lignans, taiwanin C (Type I),
justicidin E (Type II), and daurinol (Type I and anti-cancer activity).
2013 Elsevier Ltd. All rights reserved.

Naturally occurring arylnaphthalene lactones are subclass of

lignans and isolated from many dietary or medicinal plants. They
are gradually attracting much attention due to their signicant biological activities which include anti-cancer,13,8,9 antimicrobial,
antiviral,4 antiplatelet,5,6 and ion channel blocking.7 According to
the reported biosynthetic pathways of arylnaphthalene lactone
lignans, they are assembled by some enzymes from two arylpropanoid units in which aromatic rings are polyoxygenated (i.e.,
coniferyl alcohol).10 As the representative arylnaphthalene lactones are shown in Figure 1, they are structurally classied as Type
I and Type II, and among them daurinol as a Type II arylnaphthalene lactone is a potent anti-cancer agent isolated from Haplophyllum dauricum, which has been traditionally used for treatment of
cancer in Mongolia, Russia, and China.
So far, several elegant approaches for the synthetic route of
arylnaphthalene lactones were reported. In earliest studies,
1-phenylnaphthalene anhydride obtained by dimerization of
phenylpropionic acid was reduced under Zn/AcOH or 1-phenyldihydronaphthofuran was converted by using Jones reagent into
the both types of lactones. For the synthesis of the arylnaphthalene
lactone bearing aryl ethers and/or phenolic OHs in benzene ring,
Stevenson group utilized the intramolecular DielsAlder reaction
of 3-arylprop-2-yn-1-yl 3-arylpropiolate or 3-arylprop-2-en-1-yl
3-arylpropiolate.11,12 Mori group13 and Anastas group14 reported

Pd- and Ag-catalyzed [2+2+2] cocyclization for the synthesis of

arylnaphthalene lactone, respectively, and Tanabe group reported
the regiocontrolled benzannulation of diaryl(gem-dichlorocyclopropyl)methanols.15 Recently, Au-catalyzed electrophilic addition
and benzannulation method for Type I was introduced by Balamurugan group.16 While those previous methods for the constructions
of 1-phenylarylnaphthalene lactones are unique and efcient,
there are some limitations in terms of synthetic feasibility and regioselectivity for Type I and Type II. The lack of mild, reliable, and
scalable methods for the arylnaphthalene lactones came to our
attention during recent efforts to prepare arylnaphthalene lactone
O

E-mail addresses: syseo@gachon.ac.kr (S.-Y. Seo), dyshin@gachon.ac.kr (D. Shin).

0040-4039/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.014

O
O

MeO

Retrojusticidin B

OMe

Justicidin E

Retrochinensin
HO

O
MeO

Type II

OMe

O
O

MeO

O
O
O

O
Justicidin B

O
O

O
O
Type I

O
O

Corresponding authors. Tel.: +82 32 899 6111; fax: +82 32 820 4829.

O
MeO

O
MeO
O

O
O
Taiwanin C

O
O
Daurinol

Figure 1. The representative Type I and Type II arylnaphthalene lactones.

819

J.-E. Park et al. / Tetrahedron Letters 55 (2014) 818820

analogs which exhibit potent anti-cancer activity, especially the

proliferative activity by inhibiting topoisomerase IIa and to be efcacious in animal xenograft model.17 To establish structureactivity relationship of arylnaphthalene lactones and eventually to
produce more potent anti-cancer agent, it was urgently necessary
to develop more versatile, practical, and highly regioselective synthesis method for both of Type I and II arylnaphthalene lactones. In
this Letter, we present efcient and scalable route for construction
of Type I and II arylnaphthalene lactones by intramolecular Diels
Alder reaction in highly regioselective manners.
In our initial study following the previous reports by Stevenson
group in 1990,12 the intramolecular DielsAlder (DA) approach of
3-arylprop-2-ynyl 3-arylpropiolate was exploited under appropriate conditions for the synthesis of arylnaphthalene lactones. However, one major drawback of the process is still to produce
mixtures of Type I and Type II products, which implies that two
arylalkyne moieties might have similar HOMO/LUMO energy, so
both can function as either diene or dienophile. As shown in
Scheme 1, it was observed that both of the DielsAlder reactions
of 3-arylprop-2-ynyl 3-arylpropiolates provided mixtures of
naphthalene lactones with similar isomeric ratios.
To solve this problem, we envisioned that the structural change
from one of arylalkynes to arylalkene, which could possess more
diene-like conformation (s-cis conformation) for DielsAlder reaction, could give the desired regioselectivity. Moreover, successful
application of this protocol could provide a convenient synthetic
route toward both the Type I and Type II arylnaphthalene lactones
via aryldihydronaphthalenes as shown in Scheme 2.
In this connection, the corresponding ester was prepared as the
intramolecular DielsAlder precursors at rst. Piperonal 1 was
converted to gem-dibromoalkene 2, which was subjected to the
Corey-Fuchs alkyne synthesis condition (2.5 equiv of n-BuLi in
THF, 78 C) to generate alkyne anion, followed by addition of
methyl chloroformate to give the desired propiolic ester. Acid
intermediate 3 was obtained by hydroylsis with K2CO3 in ethanol
in high yield. 3-Arylallyl alcohol 5 was prepared through two steps
from piperonal 1. Hornor-Emmons olenation of piperonal,
followed by reduction of the ester 4 with DIBAL-H afforded the desired alcohol 5. In the reduction step, reaction temperature should
be keep to 78 C, otherwise, a signicant amount of fully saturated 3-arylpropanol inseparable by column chromatography was
generated along with the product 5. In case of LAH in THF, the yield
is also low owing to olen saturation Scheme 3.
With acid 3 and alcohol 5 in hands, coupling reaction was performed using DCC and DMAP in CH2Cl2 to afford the ester 6, an
intramolecular DielsAlder precursor. During this reaction, it was
observed that this coupling reaction is expectedly sensitive to
moisture. Cyclization was carried out under the thermal condition

O
O
A

Ac2O
O

140 C

B
+

O
B

Type I

BnO

B
O

O
A

MeO

Type II
O

BnO

46 : 54

Ac2O
140 C

O
O

OBn

O
O
Type I

Scheme 1. Intramolecular
arylpropiolate.

MeO

DielsAlder

reaction

OMe
43 : 57

of

Type II

3-arylprop-2-ynyl

3-

s-cis
OH

ArA

D-A

O
ArB

CO2 H

B
Type I
O

s-cis
CO 2H

Ar A

O
O

D-A

OH
ArB

B
Type II

Scheme 2. Synthetic approaches to give the type I andtype II regioselectively.

CO2 H

Br

b-c

Br

O
1

O
O

OEt

OH

O
4

3 + 5

O
O

O
6

O
O
h

O
O

O
O

O
O
Taiwanin (8)

O
O
not isolated

Scheme 3. Synthesis of taiwanin C (8), a type I arylnaphthalene lactone. Reagents

and conditions: (a) PPh3, CBr4, CH2Cl2, rt; (b) n-BuLi, THF, 78 C, then ClCO2Me,
78 C to rt; (c) K2CO3, EtOH, rt; (d) Triethyl phosphonoacetate, NaH, THF, 0 C; (e)
DIBAL-H, CH2Cl2, 78 C; (f) DCC, DMAP, CH2Cl2, rt; (g) Ac2O, mw, 140 C; (h) DDQ,
benzene, 80 C.

to give dihydronaphthalene 7 along with a small amount of the

aromatized product 8. After screening several reaction conditions,
microwave-assisted thermal reaction (Ac2O, mw, 140 C, 30 min)
followed by in situ oxidation was found to be optimal in terms of
reaction time and chemical yield. Xylene and toluene were also
used as the solvent for the DielsAlder reaction instead of Ac2O,
however the reaction yield was lower than Ac2O or the reaction
does not work. After simple workup procedure the crude dihydronaphthalene 7 was readily converted to fully aromatized taiwanin
C, a Type I arylnaphthalene lactone 8 by DDQ in benzene in 85%
yield for two steps.18 There were very few regioisomers generated
by DielsAlder reaction as might be expected.
Similarly, to carry out the regioselective synthesis of Type II
arylnaphthalene lactone, we turned to the synthesis of justicidin
E, of which carbonyl position is different from taiwanin C. The
above a,b-unsaturated ester 4 was hydrolyzed to give the acid 9,
and the above gem-dibromoalkene 2 was converted under CoreyFuchs condition into the corresponding arylpropargyl alcohol 10.
The resulting acid 9 and alcohol 10 were coupled using DCC and
DMAP to afford the precursor ester 11. Under the same condition
of intramolecular DielsAlder described above, 11 was cyclized

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J.-E. Park et al. / Tetrahedron Letters 55 (2014) 818820

major drawback of intramolecular DielsAlder reaction of 3-arylprop-2-ynyl 3-arylpropiolates as developed before was to generate
two regioisomers of arylnaphthalene lactone without selectivity.
Whereas in this study using arylalkene-arylalkyne, intramolecular
DielsAlder reaction in which arylalkyne moiety functions as only
dienophile afforded Type I and Type II dihydroarylnaphthalene
lactones regioselectively, followed by DDQ oxidation to afford the
corresponding arylnaphthalene lactones. Especially, we demonstrated with the synthesis of the representative arylnaphthalene
lactones taiwanin C (Type I), justidicin E (Type II), and daurinol
(Type I and anti-cancer agent). Further investigations of arylnaphthalene lactones and their analogs to enhance their properties as
potential chemotherapeutic agents are ongoing.

O
O

OH
O

OH
O

O
O

O
O

11

10

O
e

O
O
Justicidin E (13)

O
12

Acknowledgments

Scheme 4. Synthesis of Justicidin E (13), a Type II arylnaphthalene lactone.

Reagents and conditions: (a) KOH, H2O/THF, rt; (b) n-BuLi, THF, 78 C; then
(CH2O)n; (c) DCC, DMAP, CH2Cl2, rt; (d) Ac2O, mw, 140 C; (e) DDQ, benzene, 80 C.

BnO
isovanillin

a-c

BnO

OH

This work was supported by Basic Science Research Program

through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (NRF2012R1A1A1007057).

MeO

Supplementary data

MeO
14

15

O
BnO
e

HO
O

MeO

f-g

O
MeO

Supplementary data associated with this article can be found,

in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.014. These data include MOL les and InChiKeys of the most
important compounds described in this article.

References and notes

O
16

O
17

Scheme 5. Synthesis of daurinol (17), a Type I arylnaphthalene lactone. Reagents

and conditions: (a) BnBr, K2CO3, EtOH, 50 C; (b) triethyl phosphonoacetate, NaH,
THF, 0 C; (c) n-BuLi, THF, 78 C, then (CH2O)n, 78 C to rt; (d) acid 3, DCC, DMAP,
THF, rt; (e) Ac2O, 140 C; (f) DDQ, benzene, 80 C; (g) H2, Pd/C, MeOH, rt.

into dihydronaphthalene 12 in good yield and the reaction was

completed within 2 h. 12 was subsequently aromatized to the
desired justicidin E, a Type II arylnaphthalene lactone 13 by DDQ
in benzene Scheme 4.
As a convenient and practical method for the regioselective
synthesis of Type I and Type II arylnaphthalene lactones was established, we applied this method for the synthesis of daurinol,
another Type I arylnaphthalene lactone which was recently reported to have potent anti-cancer activity. Allylic alcohol 14 was
prepared from isovanillin through benzylation, HornorEmmons
olenation and subsequent DIBAL reduction. Immediately, the
above 3-arylpropiolic acid 3 was coupled with the alcohol 14 using
DCC and DMAP in CH2Cl2 to afford ester 15. DielsAlder reaction
was carried out using the optimized condition to afford dihydronaphthalene 16. Subsequent aromatization by an oxidant and
hydrogenolysis of benzyl ether afforded the desired daurinol, Type
I arylnaphthaleme lactone 17. Overall yield from the ester 15 to
naphthalene lactone was ca. 70% scheme 5.
In summary, we established a convenient synthesis method for
Type I and Type II arylnaphthalene lactones, respectively. The

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