Regioselective route for arylnaphthalene lactones: Convenient synthesis of taiwanin C, justicidin E, and daurinol

Article abstract of DOI:10.1016/j.tetlet.2013.12.014

Arylnaphthalene lactones are natural products which can be isolated from a wide range of plants and have the significant biological activities including cytotoxicity, antimicrobial, diuretic, and ion channel blocking. The drawback of the previous intramolecular Diels-Alder 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 Diels-Alder reaction of an arylalkene-arylalkyne 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).

Full text of DOI:10.1016/j.tetlet.2013.12.014

Tetrahedron Letters 55 (2014) 818–820
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective route for arylnaphthalene lactones: convenient
synthesis of taiwanin C, justicidin E, and daurinol
a,
Ju-Eun Park a, Juyeun Lee b, Seung-Yong Seo a, , Dongyun Shin
⇑
⇑
a College of Pharmacy, Gachon University, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-799, Republic of Korea
b 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
a b s t r a c t
Article history:
Arylnaphthalene lactones are natural products which can be isolated from a wide range of plants and
have the significant biological activities including cytotoxicity, antimicrobial, diuretic, and ion channel
blocking. The drawback of the previous intramolecular Diels–Alder reaction of 3-arylprop-2-ynyl 3-aryl-
propiolates was to generate two regioisomers of arylnaphthalene lactone without selectivity. Herein, we
report a convenient and regioselective synthesis method in which the intramolecular Diels–Alder reac-
tion of an arylalkene–arylalkyne and subsequent DDQ oxidation was used for Type I and Type II arylnaph-
thalene 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).
Received 20 October 2013
Revised 1 December 2013
Accepted 5 December 2013
Available online 15 December 2013
Keywords:
Arylnaphthalene lactone
Intramolecular Diels–Alder
Regioselectivity
Lignan
Ó 2013 Elsevier Ltd. All rights reserved.
Daurinol
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 significant bio-
logical activities which include anti-cancer,1–3,8,9 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 arylprop-
anoid units in which aromatic rings are polyoxygenated (i.e.,
coniferyl alcohol).10 As the representative arylnaphthalene lac-
tones are shown in Figure 1, they are structurally classified as Type
I and Type II, and among them daurinol as a Type II arylnaphtha-
lene lactone is a potent anti-cancer agent isolated from Haplophyl-
lum 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-phenyldi-
hydronaphthofuran 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 OH’s in benzene ring,
Stevenson group utilized the intramolecular Diels–Alder 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-dichlorocyclo-
propyl)methanols.15 Recently, Au-catalyzed electrophilic addition
and benzannulation method for Type I was introduced by Balamur-
ugan group.16 While those previous methods for the constructions
of 1-phenylarylnaphthalene lactones are unique and efficient,
there are some limitations in terms of synthetic feasibility and reg-
ioselectivity 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
O
O
O
MeO
MeO
O
O
O
O
O
O
O
O
OMe
OMe
Retrochinensin
O
O
O
O
Type I
Retrojusticidin B
Justicidin E
MeO
HO
O
O
O
O
O
O
MeO
MeO
O
O
O
O
O
O
O
O
O
O
Type II
Justicidin B
Taiwanin C
Daurinol
⇑
Corresponding authors. Tel.: +82 32 899 6111; fax: +82 32 820 4829.
E-mail addresses: syseo@gachon.ac.kr (S.-Y. Seo), dyshin@gachon.ac.kr (D. Shin).
Figure 1. The representative Type I and Type II arylnaphthalene lactones.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.014

J.-E. Park et al. / Tetrahedron Letters 55 (2014) 818–820
819
s-cis
analogs which exhibit potent anti-cancer activity, especially the
proliferative activity by inhibiting topoisomerase II and to be effi-
a
O
O
OH
ArA
ArB
D-A
D-A
A
A
O
A
cacious in animal xenograft model.17 To establish structure–activ-
ity 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 syn-
thesis method for both of Type I and II arylnaphthalene lactones. In
this Letter, we present efficient and scalable route for construction
of Type I and II arylnaphthalene lactones by intramolecular Diels–
Alder reaction in highly regioselective manners.
O
O
CO2H
B
B
Type I
O
s-cis
O
CO2H
OH
ArA
ArB
A
O
B
In our initial study following the previous reports by Stevenson
group in 1990,12 the intramolecular Diels–Alder (D–A) approach of
3-arylprop-2-ynyl 3-arylpropiolate was exploited under appropri-
ate conditions for the synthesis of arylnaphthalene lactones. How-
ever, 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 Diels–Alder reactions
of 3-arylprop-2-ynyl 3-arylpropiolates provided mixtures of
naphthalene lactones with similar isomeric ratios.
B
Type II
Scheme 2. Synthetic approaches to give the type I andtype II regioselectively.
CO2H
Br
O
O
O
O
a
O
b-c
O
O
Br
1
2
3
O
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 Diels–Alder reac-
tion, 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.
O
O
O
O
OEt
e
OH
d
4
5
O
O
O
O
O
O
O
O
f
g
3
+ 5
In this connection, the corresponding ester was prepared as the
intramolecular Diels–Alder precursors at first. 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, À78 °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 olefination of piperonal,
followed by reduction of the ester 4 with DIBAL-H afforded the de-
sired alcohol 5. In the reduction step, reaction temperature should
be keep to À78 °C, otherwise, a significant amount of fully satu-
rated 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 olefin saturation Scheme 3.
O
O
O
O
6
7
O
O
O
O
h
O
O
O
O
O
O
O
O
Taiwanin (8)
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, À78 °C, then ClCO2Me,
À78 °C to rt; (c) K2CO3, EtOH, rt; (d) Triethyl phosphonoacetate, NaH, THF, 0 °C; (e)
DIBAL-H, CH2Cl2, À78 °C; (f) DCC, DMAP, CH2Cl2, rt; (g) Ac2O, mw, 140 °C; (h) DDQ,
benzene, 80 °C.
With acid 3 and alcohol 5 in hands, coupling reaction was per-
formed using DCC and DMAP in CH2Cl2 to afford the ester 6, an
intramolecular Diels–Alder precursor. During this reaction, it was
observed that this coupling reaction is expectedly sensitive to
moisture. Cyclization was carried out under the thermal condition
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 Diels–Alder reaction instead of Ac2O,
however the reaction yield was lower than Ac2O or the reaction
does not work. After simple workup procedure the crude dihydro-
naphthalene 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 Diels–Alder reaction as might be expected.
O
O
A
O
O
B
Ac2O
A
140 °C
O
+
O
B
A
B
A
Type I
46
:
54
Type II
O
O
BnO
MeO
BnO
MeO
O
O
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
A
O
O
B
O
Ac2O
O
B
+
:
140 °C
A
B
above
a,b-unsaturated ester 4 was hydrolyzed to give the acid 9,
O
O
OBn
O
and the above gem-dibromoalkene 2 was converted under Corey-
Fuchs 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 Diels–Alder described above, 11 was cyclized
O
OMe
Type II
Type I
43
57
Scheme 1. Intramolecular Diels–Alder reaction of 3-arylprop-2-ynyl 3-
arylpropiolate.

820
J.-E. Park et al. / Tetrahedron Letters 55 (2014) 818–820
O
major drawback of intramolecular Diels–Alder reaction of 3-aryl-
O
O
O
a
prop-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
Diels–Alder 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 demon-
strated 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 arylnaph-
thalene lactones and their analogs to enhance their properties as
potential chemotherapeutic agents are ongoing.
OH
OH
4
2
O
O
O
9
c
O
O
O
b
O
O
11
10
O
O
O
O
O
O
O
d
e
O
O
O
O
12
Justicidin E (13)
Acknowledgments
Scheme 4. Synthesis of Justicidin
E
(13), a Type II arylnaphthalene lactone.
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 (NRF-
2012R1A1A1007057).
Reagents and conditions: (a) KOH, H2O/THF, rt; (b) n-BuLi, THF, À78 °C; then
(CH2O)n; (c) DCC, DMAP, CH2Cl2, rt; (d) Ac2O, mw, 140 °C; (e) DDQ, benzene, 80 °C.
BnO
MeO
O
BnO
a-c
d
OH
Supplementary data
isovanillin
O
MeO
14
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 files and InChiKeys of the most
important compounds described in this article.
O
15
O
BnO
MeO
HO
MeO
O
O
O
e
f-g
O
References and notes
O
O
16
17
O
O
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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
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another Type I arylnaphthalene lactone which was recently re-
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prepared from isovanillin through benzylation, Hornor–Emmons
olefination 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. Diels–Alder reaction
was carried out using the optimized condition to afford dihydro-
naphthalene 16. Subsequent aromatization by an oxidant and
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In summary, we established a convenient synthesis method for
Type I and Type II arylnaphthalene lactones, respectively. The