A synthetic route to 1,3-dihydroisobenzofuran natural products: the synthesis of methyl ethers of pestacin

Article abstract of DOI:10.1016/j.tetlet.2009.04.079

A synthetic route to 1-(2,6-dihydroxyphenyl)phthalan natural products is described. It is typified by the synthesis of permethyl and monomethyl ethers (21 and 22) of pestacin (1), a 1,3-dihydroisobenzofuran natural product. The key step is hydrodeoxygenation of the corresponding isobenzofuranone 19 in 2 steps: reduction and intramolecular etherification. A route involving hydrodesulfurization of a thionophthalide to a phthalan (e.g., 8) is also reported.

Full text of DOI:10.1016/j.tetlet.2009.04.079

Tetrahedron Letters 50 (2009) 4042–4045
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A synthetic route to 1,3-dihydroisobenzofuran natural products:
the synthesis of methyl ethers of pestacin
*
Raju Karmakar, Pallab Pahari, Dipakranjan Mal
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route to 1-(2,6-dihydroxyphenyl)phthalan natural products is described. It is typified by the
synthesis of permethyl and monomethyl ethers (21 and 22) of pestacin (1), a 1,3-dihydroisobenzofuran
natural product. The key step is hydrodeoxygenation of the corresponding isobenzofuranone 19 in 2
steps: reduction and intramolecular etherification. A route involving hydrodesulfurization of a thionoph-
thalide to a phthalan (e.g., 8) is also reported.
Received 19 December 2008
Revised 15 April 2009
Accepted 21 April 2009
Available online 24 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pestacin
Phthalide
Hydrodeoxygenation
Phthalan
1. Introduction
ization of alkynes, and (vi) hydrogenation of benzoisofurans. None
of the approaches appeared to be well suited for the present target.
Phthalans (1,3-dihydroisobenzofurans) are a well-known class
of compounds. They exhibit fascinating pharmacological activities1
and chemistry.2 In 2003, pestacin (1),3 the first member of the
phthalan natural products4 was isolated as a racemic mixture from
the microorganism Pestalotiopsis microspora and assigned structure
1 on the basis of analysis of NMR and X-ray data (Fig. 1). It displays
potent antioxidant activity and moderate antifungal properties.
More recently, 7-bromo-1-(2,3-dibromo-4,5-dihydroxyphenyl)-
5,6-dihydroxy-1,3-dihydroisobenzofuran has been found applica-
ble for the treatment of malignant tumors.5 Thus, they represent
an important class of targets for chemical synthesis.
Consequently, we considered a cognate preparation of phthalide 4
and its conversion to 5, which on hydrodesulfurization was ex-
pected to furnish the target, that is, 1 (Scheme 1).
2. Results and discussion
The study for the hydrodesulfurization is depicted in Scheme 2.
Phthalide 6,6 obtained in 2 steps from the commercially available
starting materials, was converted to thionolactone 7 in 72% yield
by interaction with Lawesson reagent.8 The structure of phthalide
7 was unequivocally established by analysis of spectroscopic data.
When it was subjected to treatment with Raney nickel, the desired
phthalan 8 was obtained. But the yield was far from satisfactory
(<5%). Attempted reduction of 7 with tributyltin hydride also re-
sulted in an intractable mixture of products.
Our recent studies on the total synthesis6 of isopestacin (2) and
cryphonectric acid (3) have shown that the regioselective synthesis
of 3-(2,6-dihydroxyaryl)phthalides can be achieved by the combi-
nation of two key reactions: (i) condensation of phthalaldehydic
acids with appropriate cyclohexane-1,3-diones and (ii) aromatiza-
tion of the resulting cyclohexenylphthalide moieties. An obvious
extension of the strategy is the synthesis of structurally analogous
pestacin (1) in a similar manner from the respective phthalide 4.
However, we were concerned about the formation of the phthalan
motif, since there is a lack of methods for hydrodeoxygenation of
readily accessible phthalides. The existing routes7 to 3-arylphtha-
lans encompass (i) cycloetherification of the ortho substituted aro-
matics, (ii) deoxygenation of lactols, (iii) oxa-Pictet-Spengler
reaction, (iv) intramolecular Diels–Alder reaction, (v) cyclotrimer-
Alternatively, formyl hydroxy ester 9a and formyl hydroxy acid
10a were planned to be utilized. However, their condensation with
cyclohexane-1,3-dione (11) could not be effected by the use of
DBU or p-TSA,6 probably due to the presence of free phenolic OH
groups. When the benzyl-protected acid 10b, prepared from 9b,
was reacted with 1,3-dione 11 in the presence of DBU, 3-cyclo-
hexenylphthalide 12 was obtained in good yield.9 To our surprise,
the desired aromatization of 12 did not take place with either
10
11
Hg(OAc)2 or CuCl2 to give 13, prohibiting further progress on
the synthesis of phthalan 14 (Scheme 3).
In a revised plan (Scheme 4), permethylated phthalide 15 was
targeted, hoping that its demethylation, followed by reduction
and cyclization would permit the synthesis of pestacin (1). The
* Corresponding author.
E-mail address: dmal@chem.iitkgp.ernet.in (D. Mal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.079

R. Karmakar et al. / Tetrahedron Letters 50 (2009) 4042–4045
4043
OH
OH
HO
O
O
1
1
1
H3C
O
3
O
3
O
3
OH
H3C
HO
OH
OH
OH
HO
HO
COOH
pestacin (1)
cryphonectric acid (3)
isopestacin (2)
Figure 1. Structure of pestacin and allied natural products.
O
O
S
H3C
H3C
H3C
O
O
OH
OH
OH
OH
HO
OH
HO
OH
HO
4
5
1
Scheme 1. Hydrodesulfurization route to pestacin (1).
O
S
Lawesson reagent,
toluene, reflux
O
O
O
Ra-Ni, THF
OMe
OMe
OMe
< 5%
72%
MeO
MeO
MeO
6
8
7
Scheme 2. Model study on hydrodesulfurization of 7.
HO
OR
LiOH, THF-H2O (5:1)
rt
cyclohexane-1,3-dione (11),
DBU, CHCl3, rt, 12h
OBn
OR
O
CHO
CO2Me
CHO
O
50%
55%
CO2H
O
12
10a R = H
10b R= Bn
9a R = H
Hg(OAc)2, NaOAc,
9b R = Bn
AcOH, reflux
x
HO
HO
OBn
OBn
OH
O
OH
O
O
13
14
Scheme 3. Approach to O-benzyl ether of pestacin (14).
starting unsymmetrically substituted hydroxybenzoic acid 16a
was prepared from acetone and diethyl oxalate by the reported
3-step procedure12 and derivatized to 16b by the reaction with
crucial condensation of 18 with cyclohexane-1,3-dione (11) was
performed to yield 3-cyclohexenylphthalide 19 in excellent yield
under the previously established conditions involving DBU. Treat-
ment of 19 with iodine and methanol16 at reflux afforded trim-
ethoxyarylphthalide 15 in moderate yield. It was then expectedly
reduced with LiAlH4 to diol 20 in almost quantitative yield. The ini-
tial attempts to effect the ring closure of 20 to 21 with TsCl or
MeI–K2CO3 in acetone.13 It was then formylated with Cl2CHOMe–
14a
TiCl4
to furnish a 1:1 mixture of formyl esters14b from which
the desired one 17 was isolated. The formyl ester 17 was hydro-
lyzed by LiOH15 to give phthalaldehydic acid 18 in 90% yield. The

4044
R. Karmakar et al. / Tetrahedron Letters 50 (2009) 4042–4045
OMe
OR
CO2Et
CO2Et
LiOH, THF-
H2O (5:1), 2h
Cl2CHOMe, TiCl4, CH2Cl2
CHO
3 steps
90%
1h, 50%
O
CO2Me
CO2R
17
16a R = H
MeI, K2CO3, acetone
reflux, 97%
16b R = Me
MeO
HO
OMe
OMe
OMe
cyclohexane-1,3-dione (11)
DBU, CHCl3, rt, 12h
,
O
OMe
CHO
I2, MeOH, reflux, 1h
O
O
50%
95%
CO2H
O
O
18
19
15
MeO
OMe
MeO
OMe
trifluoroethanol,
TsOH, rt, 1 min
o
OMe
OMe
LiAlH4,THF, 0 C
OH
OH
O
99%
98%
21
20
Scheme 4. Synthesis of permethylated pestacin (21).
17
MsCl–NEt3 produced permethylated pestacin 21 in low yields.
However, Kirmse and Kund system: trifluoroethanol–tosic acid18
proved to be the best, giving 21 in 98% yield. To our dismay, the de-
sired demethylation of 21 to the target 1 remained to be the daunt-
ing task. Several reagents, known for demethylation of methyl aryl
ethers, were examined. They were BBr3ÁSMe2–1,2-dichloroeth-
tion to phthalide 19 furnishing resorcinolylphthalide 23 in 91%
yield. Exposure of 23 to LAH in THF gave deoxygenated alcohol
24 along with the diol 25 as a minor product. Optimization of
the same reaction with respect to time served to give phthalan
22 directly. The intermediate diol 25 was not isolated. The at-
tempts to demethylate compound 22 by various methods were
unsuccessful.
In summary, the first synthetic route to 1-(2,6-dihydroxy-
phenyl)phthalan natural products is illustrated by the synthesis
of permethyl ether 21 and monomethyl ether 22 of pestacin (1).
The synthesis has been achieved via (i) cyclocondensation of cyclo-
hexane–1,3-dione (11) with a phthalaldehydic acid and (ii) forma-
tion of the phthalan moiety by reduction of a phthalide followed by
ane19
,
BBr3, HBr–AcOH, LiI–collidine,20 EtSH–NaH, Et2N
(CH2)2SHÁHCl–t-BuONa,21 iodocyclohexane–DMF,22 and AlCl3.
None were found to be suitable for the purpose, probably due to
the sensitivity of the furan ring to acids.23
In order to define the problem of demethylation of 21, we
decided to prepare monomethyl ether of pestacin, that is, 22
(Scheme 5). Application of mercuric acetate promoted aromatiza-
HO
HO
OMe
OMe
Hg(OAc)2, NaOAc,
AcOH, reflux
HO
LiAlH4, THF,
0 oC, 20 min
O
OMe
OH
OH
O
50%
O
91%
O
O
O
19
22
23
LiAlH4,THF, 0 oC,
2 - 4h
HO
OMe
HO
OMe
OH
OH
+
OH
OH
(80%)
OH
(10%)
25
24
Scheme 5. Synthesis of monomethyl ether of pestacin (22).

R. Karmakar et al. / Tetrahedron Letters 50 (2009) 4042–4045
4045
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Acknowledgments
This work was supported by the Council of Scientific and Indus-
trial Research (CSIR) and the Department of Science and Technol-
ogy (DST), New Delhi. R.K. is grateful to CSIR, New Delhi, for
research fellowship. The NMR facility was supported by the FIST
program of the DST.
Supplementary data
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