Regiospecific synthesis of isopestacin, a naturally occurring isobenzofuranone antioxidant

Article abstract of DOI:10.1016/j.tetlet.2004.04.175

A DBU promoted aldol cyclocondensation of hydroxyisobenzofuranone 15 with cyclohexane-1,3-dione, followed by aromatization has resulted in the first short synthesis of isopestacin (1).

Full text of DOI:10.1016/j.tetlet.2004.04.175

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 5109–5112
Regiospecific synthesis of isopestacin, a naturally occurring
isobenzofuranone antioxidant
Pallab Pahari, Bidyut Senapati and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 29 January 2004; revised 22 April 2004; accepted 29 April 2004
Abstract—A DBU promoted aldol cyclocondensation of hydroxyisobenzofuranone 15 with cyclohexane-1,3-dione, followed by
aromatization has resulted in the first short synthesis of isopestacin (1).
Ó 2004 Elsevier Ltd. All rights reserved.
Isopestacin (1), an isobenzofuranone natural product
wasioslated in 2002 by Strobel and co-workersfrom
culture brothsof the endophytic fungus Pestalotiopsis
microspora.1 Itsstructure wasdetermined by analysisof
proton and carbon NMR data, and confirmed by X-ray
crystallography. It is the first member of the iso-
benzofuranone family of natural productsthat contains
a substituted benzene ring at C-3 of the benzofuranone
ring. Strikingly, the resorcinol moiety is attached to the
isobenzofuranone skeleton through its C-2 position.
Though the structure of isopestacin contains a chiral
center, the natural product isolated was composed of a
racemic mixture. This compound possesses antifungal
activity, and actsasan antioxidant toward both super-
oxide radicalsand hydroxy free radical,s the activity
being comparable to vitamin C.
The synthetic challenge posed by isopestacin along with
its structural resemblances to pestacin (2),2 recently
isolated from the same fungus as a potent antioxidant,
cryphonectric acid (3),3 and the aromatic subunit of the
PKC inhibitor balanol4 prompted usto initiate a ysn-
thetic program on isobenzofuranone natural products.
Herein, we report the first regiospecific synthesis of
isopestacin (1), and the methodology for the generation
of simple analogs thereof.
In principle, 3-aryl substituted isobenzofuranones can
be prepared either by acid catalyzed condensation5 of 3-
6
hydroxybenzofuranoneswith arenesor by addition
ortho-lithiated aromaticsto aromatic aldehyde.s How-
of
ever, the former approach isnot adaptable in the present
context due to regiochemical problems. For instance,
OH
O
OH
O
7
1
7a
1
O
HO
OH
6
O
OH
3
8
H3C
14
3a
3
5
HO
OH
9
10
4
OH
8
HO
O
HO
13
H3C
12
11
COOH
pestacin (2)
isopestacin (1)
cryphonectric acid (3)
Keywords: Isopestacin; Isobenzofuranone; Benzene-1,3-diol; Aromatization.
* Corresponding author. Tel.: +91-0322283318; fax: +91-0322282252; e-mail: dmal@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.175

5110
P.Pahari et al./ Tetrahedron Letters 45 (2004) 5109–5112
the reaction of resorcinol with 3-hydroxybenzofuranone
in the presence of an acid catalyst is reported to give the
product in which the resorcinol moiety is substituted at
C-4 whereas the synthesis of isopestacin (1) requires
substitution at C-2. The possibility of using the ortho-
lithiation methodology wasavoided in view of the
requirement for a protection–deprotection protocol.
Alternatively, we conceived the aldol reaction of
phthalaldehydic acidswith cyclohexane-1,3-dione asa
key-step to permit regiospecificity in the synthesis.
fully characterized astheir acetatesor enol ethers, that is
5b, 6c, 9b.8 When applied to cyclohexane-1,3-dione,
isobenzofuranone 4 gave the adduct 9a in 70% yield.
Thiswasalos prepared by reacting 3-bromophthalide
with cyclohexane-1,3-dione in the presence of 1 equiv of
DBU in acetonitrile.
The next most important task was to aromatize the
adduct 9a. Of the many possibilities, we chose to
investigate the action of I2/CH3OH9 on 9a. The reaction
provided the desired dimethoxy aromatic product 11
(Scheme 1). Asanticipated, attempted demethylation of
11 to the corresponding phenol 12 by AlCl3 or BBr3
proved to be difficult. For direct conversion of 9a to
phenol 12, we turned our attention to the use of CuCl2/
LiCl,10 a system that has been occasionally reported for
oxidative aromatization of cyclohexenones. Treatment
of 9a with CuCl2/LiCl afforded 12 in 45% yield, along
with an unidentified product asa minor component. A
remarkable improvement in the yield of the oxidative
aromatization wasnoted with Hg(OAc) 2/NaOAc11 as
Phthalaldehydic acid is known to exist in the iso-
benzofuranone form 4, and reactswith dimedone in
refluxing ethanol containing piperidine to yield 3-(5,5-
dimethylcyclohexane-1,3-dion-2-yl)benzofuranone.7 We
observed that the same reaction could be effected more
efficiently in the presence of DBU at room temperature.
Accordingly, the reaction wasgeneralized for a few
simple b-keto carbonyl compounds. The results are
summarized in Table 1. The products 5a,7a 6a,b,7b and
7,7c which existed in both keto and enol forms, were
Table 1. Reaction of phthalaldehydic acidswith 1,3-dicarbonyl compounds
Starting )materialsProduct (s
% Yield
Derivative
O
O
O
O
O
O
O
95
O
+
O
OH
OEt
O
OH
4
5a
5b
O
O
O
O
O
O
+
81
55
86
+
4
O
O
O
6c
OEt
O
O
O
O
H
O
6a
6b
O
O
O
O
O
O
O
+
4
+
OEt
OEt
OEt
O
O
O
O
O
7c
H
7a
7b
O
O
O
O
O
4
+
O
8

P.Pahari et al./ Tetrahedron Letters 45 (2004) 5109–5112
5111
Table 1 (continued)
Starting )materialsProduct (s
% Yield
Derivative
O
O
O
O
O
O
O
70
O
O
OH
OAc
4
+
9b
9a
OH
O
O
OH
O
O
O
74
+
O
OH
OH
10
O
O
O
O
O
I2, MeOH
O
Hg(OAc)2, NaOAc
AcOH, reflux
HO
OH
O
OH
MeO
OMe
9a
12 (95%)
11 (77%)
Scheme 1.
oxidizing agent and the desired product 12 wasobtained
in an excellent 95% yield.
furanone 1512 in four steps via directed ortho-lithiation
of the N,N-diethylamide of acid 14, which, in turn, was
prepared in two steps from anisole 13. Condensation of
15 with cyclohexane-1,3-dione in refluxing ethanol
containing 1.5 equiv of DBU furnished 16 in 60% yield.
Oxidative aromatization of 16 with Hg(OAc)2/NaOAc
yielded 17 (93%). Room temperature demethylation of
Having standardized the model study, we proceeded to
perform the synthesis of isopestacin (1) starting from
commercially available 2,5-dimethylanisole (13)
(Scheme 2). Thiswasconverted to the hydroxybenzo-
OMe
OMe
O
OMe
Me
COOH
a, b
60% (overall)
c, d
O
Me
30% (overall)
14
Me
Me
15
13
OH
e
OR
O
OMe
O
O
f
O
Me
HO
Me
OH
O
OH
16
R = Me
17
g
1 R = H
Scheme 2. Reagentsand condition:s (a) K 2S2O8, CuSO4Æ5H2O, CH3CN/H2O; (b) NH2SO3H, NaClO2, THF/H2O; (c) SOCl2, reflux; Et2NH,
CH2Cl2; (d) sec-BuLi, TMEDA, DMF; HCl, AcOH; (e) 1,3-cyclohexanedione, DBU, CH3CN, reflux, 60%; (f) Hg(OAc)2, NaOAc, AcOH, reflux,
93%; (g) AlCl3, CH2Cl2, 65%.

5112
P.Pahari et al./ Tetrahedron Letters 45 (2004) 5109–5112
Table 2. Comparison of the NMR data of synthetic isopestacin with those of the natural product
Position
1
3
3a
4
5
6
7
7a
8
9, 13
10
11
12
14
1H data of the
natural product
1H data of the
synthetic product
13C data of the
natural product
13C data of the
synthetic product
6.92
6.52
6.64
6.29 (d)
6.96 (t)
6.27 (d)
2.3
J ¼ 8:2 Hz J ¼ 8:2 Hz J ¼ 8:2 Hz
6.29 (d) 6.98 (t) 6.29 (d)
6.93
6.53
6.66
2.32
22.14
22.01
J ¼ 8:1 Hz J ¼ 8:1 Hz J ¼ 8:1 Hz
173.84 77.24 154.87 114.54 149.00 116.53 157.33 111.71 110.32 158.95 107.96
173.70 77.05 154.79 114.38 148.87 116.37 157.19 111.55 110.10 158.82 107.76
131.53
131.41
107.96
107.76
13
178 with anhydrousAlCl
in dichloromethane pro-
6. (a) Danieul, M.-P.; Laursen, B.; Hazell, R.; Skrydstrup, T.
J.Org.Chem. 2000, 65, 6052–6060; (b) Snieckus, V. Chem.
Rev. 1990, 90, 879–933; (c) Owton, W. M. J.Chem.Soc,.
Perkin Trans.1 1994, 2131–2135; (d) Owton, W. M.;
Brunavs, M.; Dobson, D. R.; Steggles, D. J. J.Chem.Soc.,
Perkin Trans.1 1995, 931–934; (e) Falk, H.; Schoppel, G.
Monatsch.Chem. 1991, 122, 739–744; (f) Iwao, M.;
3
vided isopestacin (1) (mp: 269–270 °C; lit.1 mp: 218–
220 °C) in 65% yield. The spectroscopic data (Table 2) of
the synthetic material were in complete agreement with
those1 of the natural product. Additionally, the TLC
behavior of the synthetic compound matched that of an
authentic sample of the natural product.
Kuraishi, T. Bull.Chem.Soc.Jpn.
4060.
1987, 60, 4051–
In conclusion, the first synthesis of isopestacin (1) has
been completed in a regiospecific manner starting from
2,5-dimethylanisole (13). The methodology developed,
that iscyclocondensation of phthalaldehydic acidswith
cyclic 1,3-dionesfollowed by oxidative aromatization
should provide an access to a wide variety of isopestacin
analogs. The feasibility of introducing asymmetric
induction in the cyclocondensation step by the use of
enantiomerically pure amine bases is being explored.
7. (a) Nagarajan, K.; Shenoy, S. J. Indian J.Chem. 1992,
31B, 73–87; (b) Lee, D. Y.; Cho, C. S.; Jiang, L. H.; Wu,
X.; Shim, D. C.; Oh, D. H. Synth.Commun. 1997, 27,
3449–3455; (c) Donati, C.; Prager, R. H.; Weber, B. Aust.
J.Chem. 1989, 42, 787–795.
8. The new compounds gave satisfactory elemental analysis,
EIMS and NMR data. Selected spectral data: compound
8: Mp 215 °C; mmax (KBr, cmꢀ1) 1750; 1H NMR (d6-
DMSO + CDCl3, 200 MHz): d 8.05–7.77 (m, 4H), 7.72 (t,
2H, J ¼ 7:30), 7.59 (t, 1H, J ¼ 7:30), 7.49 (d, 1H,
J ¼ 7:40), 6.18 (d, 1H, J ¼ 2:3), 3.67 (d, 1H, J ¼ 2:3).
13C NMR (d6-DMSO, 125 MHz): d 197.98, 196.55, 170.28,
148.79, 143.01, 142.62, 137.42, 135.39, 131.46,
130.40, 126.10, 125.81, 124.04, 123.83, 123.68, 78.36,
55.92.
Acknowledgements
Compound 9b: Mp 125 °C; mmax (KBr, cmꢀ1) 1752; 1H
NMR (CDCl3, 200 MHz): d 7.90 (d, 1H, J ¼ 7:3), 7.63 (dt,
1H, J ¼ 7:3, 1.0), 7.51 (t, 1H, J ¼ 7:3), 7.28 (dd, 1H,
J ¼ 7:3, 1.0), 6.60 (s, 1H), 2.70–2.50 (m, 4H), 2.15–1.95
(m, 2H), 1.83 (s, 3H).
We are grateful to the CSIR, New Delhi for financial
support of this work. P.P. and B.S. gratefully
acknowledge receipt of Junior Research Fellowships
from the CSIR, New Delhi. We are thankful to Dr.
Samik Nanda of TexasA&M for providing uswith a
few relevant articles. We are also thankful to Professor
G. Strobel for supplying us with an authentic sample of
the natural product.
1
Compound 10: Mp 250 °C; IR mmax (KBr, cmꢀ1) 1732; H
NMR (d6-DMSO + CDCl3, 200 MHz): d 7.41 (s, 1H), 7.06
(t, 1H, J ¼ 7:8), 6.59 (d, 1H, J ¼ 7:8), 6.42 (d, 1H,
J ¼ 7:8), 5.08 (s, 1H), 2.63–2.40 (m, 2H), 2.30–2.15 (m,
2H), 2.0–1.75 (m, 2H). 13C NMR (d6-DMSO, 50 MHz): d
196.50, 169.12, 169.02, 164.79, 156.18, 154.79, 153.11,
141.56, 135.37, 128.81, 122.79, 122.26, 114.79, 114.43,
113.57, 112.45, 111.47, 109.74, 72.99, 36.49, 32.93, 31.38,
26.58, 20.20, 19.56 (mixture of keto and enol forms).
References and notes
1
1. (a) Ford, E.; Strobel, G.; Harper, J. K. PCT Int.Appl.
2003, 59; (b) Strobel, G.; Ford, E.; Worapong, J.; Harper,
J. K.; Arif, A. M.; Grant, D. M.; Fung, P. C. W.; Chau, R.
M. W. Phytochemistry 2002, 60, 179–183.
2. Harper, J. K.; Arif, A. M.; Ford, E.; Strobel, G.; Porco, J.
A., Jr.; Tomer, D. P.; Oneill, K. L.; Heider, E. M.; Grant,
D. M. Tetrahedron 2003, 59, 2471–2476.
Compound 17: Mp 304 °C; IR mmax (KBr, cmꢀ1) 1723; H
NMR (d6-DMSO + CDCl3, 200 MHz): d 8.9 (br s, 1H),
6.82 (t, 1H, J ¼ 8:0), 6.77 (s, 1H), 6.61 (s, 1H), 6.55 (s,
1H), 6.21 (d, 2H, J ¼ 8:0), 3.87 (s, 3H), 2.28 (s, 3H). 13C
NMR (d6-DMSO, 50 MHz): d 168.94, 156.98, 153.80,
146.34, 129.56, 113.75, 111.70, 110.44, 108.47, 106.44,
73.70, 55.20, 21.72.
3. Arnone, A.; Assante, G.; Nasini, G.; Strada, S.; Vercesi,
A. J.Nat.Prod. 2002, 65, 48–50.
4. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S.
F.; Janzen, W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J.
B. J.Am.Chem.Soc. 1993, 115, 6452–6453.
9. Kotnis, A. S. Tetrahedron Lett. 1990, 31, 481–484.
10. Kosower, E. M.; Wu, G. S. J.Org.Chem. 1963, 28, 633–
638.
11. Oliver, J. E.; Wilzer, K. R.; Waters, R. M. Synthesis 1990,
1117–1119.
5. (a) Singh, E.; Gupta, P. C. J.Indian Chem.Soc. 1973, 50,
676–679; (b) Paradkar, M. V.; Ranade, A. A.; Kulkarni,
M. S.; Godbole, H. M.; Joseph, A. R. J.Chem.Res.(S)
1998, 332–333.
12. Khanapure, S. P.; Reddy, R. T.; Biehl, E. R. J.Org.Chem.
1987, 52, 5685–5690.
13. Mal, D.; Roy, H. N. J.Chem.Soc,. Perkin Trans.1
3167–3171.
1999,