Rapid access to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether by a CuBr2-mediated multi-step reaction: Concise total syntheses of hericenone J and 5′-deoxohericenone C (hericene A)

Article abstract of DOI:10.1016/j.tet.2011.09.104

A practical route to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether, a versatile intermediate in the synthesis of hericenones and related bioactive polyphenols, was developed. The synthesis features a combination of tandem Michael addition-Claisen condensation and CuBr₂-mediated multi-step reactions. With this product in hand, total syntheses of hericenone J and 5′-deoxohericenone C (hericene A) were achieved.

Full text of DOI:10.1016/j.tet.2011.09.104

Tetrahedron 67 (2011) 9087e9092
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rapid access to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether by
a CuBr2-mediated multi-step reaction: concise total syntheses of hericenone
J and 50-deoxohericenone C (hericene A)
,
b
a
a
a
b
Shoji Kobayashi a , Ami Ando , Hiroyuki Kuroda , Shota Ejima , Araki Masuyama , Ilhyong Ryu
*
a Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan
b Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical route to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether, a versatile intermediate in the
synthesis of hericenones and related bioactive polyphenols, was developed. The synthesis features
a combination of tandem Michael addition-Claisen condensation and CuBr2-mediated multi-step re-
actions. With this product in hand, total syntheses of hericenone J and 50-deoxohericenone C (hericene A)
were achieved.
Received 7 September 2011
Received in revised form 20 September 2011
Accepted 21 September 2011
Available online 28 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hericenone
Hericene
Multi-step reaction
Copper(II) bromide (CuBr2)
Stille coupling
1. Introduction
biological features, including stimulation of nerve growth factor
(NGF) synthesis,2c suppression of endoplasmic reticulum (ER)
Development of efficient one-pot reactions with multi-
functionalization remains a great challenge in organic synthesis.1
In pharmaceutical and agrochemical synthesis, for example, sim-
ple, reliable, and cost-effective methods are highly desirable for the
preparation of building blocks. For instance, 6-bromo-5,7-
dihydroxyphthalide 5-methyl ether (1a) and its 4-methyl de-
rivatives 1b are potential precursors of bioactive polyphenols such
as hericenones,2 hericerin,3 hericenes,4 and mycophenolic acid5
(Fig. 1). These molecules incorporate as a key feature a highly
functionalized, penta- or hexasubstituted aromatic ring, which
necessitates rigorous regiocontrol in their synthesis. Previous
methods to obtain 1b or mycophenolic acid include functionaliza-
tion of resorcinols,6 aromatization of 1,3-dioxocyclohexanes,7 tan-
dem Michael addition-Dieckmann cyclizations,8 DielseAlder
reactions with appropriate dienes,9 or aromatic annulation.10 In
contrast, 1a, which is a key component of the hericenone skeleton,
has yet to be synthesized, and only one total synthesis of her-
icenone A has been reported.2b Other members of the hericenone
family have not been synthesized in spite of their attractive
stress-dependent cell death2e and inhibition of collagen-induced
platelet aggregation.2f Herein, we wish to report a concise, four-
step synthesis of 1a from commercial reagents featuring a CuBr2-
mediated multi-step reaction, which culminated in the first total
synthesis of hericenone J and hericene A (50-deoxohericenone C).
* Corresponding author. Tel./fax: þ81 6 6954 4081; e-mail address: koba@
chem.oit.ac.jp (S. Kobayashi).
Fig. 1. Structures of bioactive polyphenols and their synthetic intermediates.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.104

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S. Kobayashi et al. / Tetrahedron 67 (2011) 9087e9092
Table 1
2. Results and discussion
CuBr2-mediated multi-step reaction of 6
2.1. Practical synthesis of 6-bromo-5,7-dihydroxyphthalide
5-methyl ether
The synthesis commenced with borane reduction of monoethyl
fumarate (2) (Scheme 1).11 The resultant alcohol was protected as
its MOM ether to afford the Michael accepter 3. A subsequent
tandem Michael addition-Claisen condensation reaction was re-
alized by mixing 3 (1 equiv), 4 (1.5 equiv), and NaOEt (1þ0.2 equiv)
in the appropriate order with careful control of temperature and
concentrations.12 Although the isolated yield of 6 was modest, its
ready accessibility in gram quantities compelled us to investigate
further transformations.
Entry
Reagenta (equiv)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
CuBr2 (6)
CuBr2 (6)
CuBr2 (4.2)
CuBr2 (4.3)
CuBr2 (4.3)
NBS (2)
MeOH
MeOH
MeOH
CHCl3/MeOH (2:1)
CHCl3/MeOH (2:1)
CCl4 then HCl/MeOH
1
3
24
20
37
31
25c
Trace
48
5
70
6d
52e
a
The number in parentheses refers to equivalents of the reagent.
Isolated yield.
4,6-Dibromo-5,7-dihydroxyphthalide 5-methyl ether was obtained in 28% yield
b
c
along with 25% of 1a.
d
Ketone 6 was treated with NBS in CCl4 for 1 h. After concentration, the residue
was dissolved in HCl/MeOH and refluxed for 21 h.
e
Combined yield of 2:1 regioisomeric mixture of 1a and its 7-methoxy isomer.
Fig. 3. NOE and HMBC correlations for 1a.
Scheme 1. Synthesis of cyclic 1,3-diketone 6.
accordingly, undertook a solvent screening. Remarkably, a hetero-
geneous system14 consisting of 4.3 equiv of CuBr2 in CHCl3/MeOH
(2:1) with an extended time reproducibly afforded the phthalide 1a
in good yield (entries 4 and 5). This result was superior to the
NBSeHCl/MeOH system, where a 2:1 regioisomeric mixture of 1a
and its 7-methoxy isomer was produced (entry 6).
The next task was regioselective installation of the bromine and
methoxy groups with concomitant aromatization. If the conven-
tional method involving halogenated aromatization is conducted,
more than three steps would be required to reach the target mol-
ecule. Indeed, treatment of 6 with Br2/AcOH afforded highly crys-
talline 4,6-dibromo-5,7-dihydroxyphthalide (7) as the major
product in 45% yield (Fig. 2), which would necessitate laborious
regioselective methylation and debromination to access the
phthalide 1a. Therefore, we searched for more efficient conditions.
Scheme
2 shows one possible mechanism for the un-
precedented CuBr2-mediated one-pot multi-step reaction. In prin-
ciple, 2 mol of CuBr2 are necessary for one bromination of 1 mol of
ketone,13 and three possible bromination sites exist at C4, C6, and
C7a. Among them, the most acidic C6-H and C7a-H hydrogens were
replaced by bromine to give A, which is in equilibrium with its enol
form B. Additioneelimination sequence of MeOH/H2O then took
place at the least hindered C5-position and produced the
methoxylated enone C, which underwent elimination of HBr to give
D. This was followed by aromatization and acid-catalyzed lactoni-
zation to afford 1a. Although we were unsuccessful in isolating any
of the reaction intermediates, this mechanism is most likely to
explain the observed regiochemical outcome.
Fig. 2. Structure of 7.
Inspired by previous work on the bromination of cyclic 1,3-
diketones by CuBr2,13 we attempted the bromination of 6. In-
terestingly, treatment of 6 with 6 equiv of CuBr2 in MeOH succes-
sively induced multi-step reactions involving regioselective
bromination, regioselective methoxylation, aromatization and lac-
tonization, giving rise to the desired product 1a in 31% yield (Table 1,
entry 1). The structure of 1a was unambiguously confirmed by NOE
and HMBC experiments (Fig. 3). A byproduct, 4,6-dibromo-5,7-
dihydroxyphthalide 5-methyl ether, was obtained in 28% yield in
the 3 h reaction (entry 2). To avoid byproduct formation, the amount
of CuBr2 was reduced to 4.2 equiv, however the yield of 1a decreased
considerably and many byproducts appeared (entry 3). We sus-
pected that this poor reproducibility arose from the higher solubility
of CuBr2 in MeOH, which induced non-selective overreactions, and
Scheme 2. Plausible reaction course leading to 1a.

S. Kobayashi et al. / Tetrahedron 67 (2011) 9087e9092
9089
2.2. Total syntheses of hericenone J and hericene A
3. Conclusion
After establishing a practical route to 1a, we turned our atten-
tion to the natural product synthesis with 1a. Due to the synthetic
and biological interest, hericene A4 (50-deoxohericenone C), the
leading polyphenol of this family, was selected as the initial syn-
thetic target. After protection of the phenolic hydroxy group as its
MOM ether, aryl bromide 8 was treated with geranyl bromide via
an arylcopper reagent15 (Scheme 3, conditions A). However, the
desired product 9 was obtained in only 15% yield, which was not
improved by altering bases (t-BuLi, n-BuLi, and i-PrMgCl$LiCl16),
copper reagents (CuCN$2LiCl and CuBr$Me2S), additives (HMPA
and DMPU), or temperature. Isolation of considerable amounts of
byproducts lacking a MOM group indicated that the lactone car-
bonyl and two MOM oxygens contributed to chelation with metal
cations, which hampered the desired halogen-metal exchange re-
action. After many attempts, we found that coupling was successful
under modified Stille conditions17,18 in the presence of geranyl
tributyltin19 (2 equiv), (Ph3P)2PdCl2 (10 mol %), and CsF (2 equiv) in
87% yield (Scheme 3, conditions B). Addition of CsF was crucial to
obtain the product reproducibly.20 This is a remarkable example of
a successful Stille reaction of the electron-rich, bisortho-substituted
aromatic bromide.21 Acid-catalyzed removal of the MOM group in 9
furnished hericenone J (10), the spectra of which were identical to
those of the natural product.2e
In summary, we have achieved a concise synthesis of 6-bromo-
5,7-dihydroxyphthalide 5-methyl ether (1a), a key synthetic in-
termediate of hericenones and related bioactive polyphenols, by
a combination of tandem Michael addition-Claisen condensation
and CuBr2-mediated multi-step reactions. The current synthesis is
straightforward, regioselective, and practical, and therefore, pro-
vides a new entry into the integrated synthesis that realizes mul-
tiple transformations in one-pot.25 Furthermore, we succeeded in
the first total syntheses of hericenone J and hericene A using 1a as
a common intermediate. We believe that the present investigation
will become an important guideline for developing new efficient
routes to polyfunctionalized bioactive polyphenols. Further studies
to synthesize the natural hericenones and their analogs are cur-
rently underway in our laboratory.
4. Experimental section
4.1. General remarks
All reactions utilizing air- or moisture-sensitive reagents were
performed under an atmosphere of argon. Commercially available
dry solvents were used for DMF, CHCl3, CH2Cl2, MeOH, and THF.
Triethylamine and i-Pr2NEt were distilled from CaH2. DMAP was
recrystallized from AcOEt. The commercially available LiCl was
dried at 140 ꢀC under vacuum overnight before use. Me2BBr was
prepared from BBr3 and Me4Sn23 and stored as a 1.76 M dichloro-
methane solution in a refrigerator (ꢁ30 ꢀC). Reactions were mon-
itored by thin-layer chromatography (TLC) carried out on 0.25 mm
silica gel plates (60-F254) that were analyzed by fluorescence upon
254 nm irradiation or by staining with p-anisaldeyde/AcOH/H2SO4/
EtOH, 12MoO3$H3PO4/EtOH, or (NH4)6Mo7O24$4H2O/H2SO4. The
products were purified by flash chromatography on silica gel
(spherical, neutral, 40e50 mm) and, if necessary, were further pu-
rified by HPLC equipped with a pre-packed column using hexane/
EtOAc as the eluent. NMR spectra were recorded with a 500 MHz
(1H: 500 MHz, 13C: 125 MHz), a 400 MHz (1H: 400 MHz, 13C:
100 MHz), or a 300 MHz (1H: 300 MHz, 13C: 75 MHz) spectrometer
and referenced to the solvent peak at 7.26 ppm (1H) and 77.16 ppm
Scheme 3. Synthesis of hericenone J (10).
(
13C) for CDCl3. Splitting patterns are indicated as follows: br, broad;
Synthesis of hericene A (15) was achieved as follows (Scheme 4).
LiAlH4 reduction of lactone 9 followed by acylation with palmitoyl
chloride under precise conditions provided a mixture of acylation
products 12e14, all of which will be useful for SAR studies. After
separation by silica gel chromatography, isomer 12 was subjected
to DesseMartin oxidation22 and deprotection23 to furnish hericene
A (15).4 In this case, Me2BBr was superior to CSA for deprotection.24
The biological activities of 15 and its analogs will be investigated in
due course.
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Infrared
spectra were recorded with an FT/IR spectrometer and reported as
wavenumber (cmꢁ1). Low- and high-resolution mass spectra were
measured by EI or FAB method.
4.1.1. (E)-Ethyl 4-(methoxymethoxy)-2-butenoate (3). To a solution
of monoethyl fumarate (2) (25.0 g, 174 mmol) in THF (87 mL) was
added a solution of BH3$Me2S (16.5 mL, 174 mmol) in THF (130 mL)
dropwise over 2 h at ꢁ10 ꢀC. The reaction mixture was gradually
allowed to warm to room temperature and stirred for 18 h. The
reaction was quenched by the dropwise addition of AcOH/H2O (1:1,
v/v, 5 mL) with stirring until no more gas evolution occurred. The
mixture was concentrated and the residual slurry was treated with
ice-cold saturated aqueous NaHCO3 solution (80 mL). The resulting
mixture was extracted with EtOAc (2ꢂ). The combined organic
layer was washed with saturated aqueous NaHCO3 solution, dried
over anhydrous MgSO4 and concentrated to give (E)-ethyl 4-
hydroxy-2-butenoate11 (15.1 g, 116 mmol, 67%). To a solution of
(E)-ethyl 4-hydroxy-2-butenoate (15.1 g, 116 mmol) in 1,2-
dichloroethane (116 mL) were added i-Pr2NEt (60.7 mL,
389 mmol) and MOMCl (10.6 mL, 140 mmol) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 70 h and quenched by
the addition of saturated aqueous NaHCO3 solution. The mixture
was concentrated and the residue was extracted with hexane (2ꢂ).
The combined organic layer was washed with 1 M aqueous HCl
Scheme 4. Synthesis of hericene A.

9090
S. Kobayashi et al. / Tetrahedron 67 (2011) 9087e9092
solution, saturated aqueous NaHCO3 solution, brine, dried over
anhydrous MgSO4, and concentrated to give MOM ether 3 (18.3 g,
105 mmol, 91%) as a brownish oil, which was used for the next
reaction without further purification: 1H NMR (400 MHz, CDCl3)
vacuo to give analytically pure MOM ether 8 (1.03 g, 3.38 mmol,
92%) as a tan solid: 1H NMR (400 MHz, CDCl3)
6.71 (s,1H, H4), 5.52
(s, 2H, MOM), 5.19 (s, 2H, H3), 4.00 (s, 3H, MOM), 3.67 (s, 3H, OMe);
13C NMR (75 MHz, CDCl3)
168.0, 162.4, 154.8, 149.6, 110.6, 108.0,
d
d
d
6.97 (dt, 1H, J¼16, 4.0 Hz), 6.09 (dt, 1H, J¼16, 2.0 Hz), 4.66 (s, 2H),
101.2, 99.9, 68.7, 58.5, 57.2; FT-IR (KBr) 3023, 2967, 2947, 1750, 1599,
1459, 1432 cmꢁ1; MS (EI, 70 eV) m/z (%) 304 (Mþ, 22), 302 (Mþ, 21),
273 (64), 271 (76), 244 (100), 242 (94); HRMS (EI): m/z calcd for
C11H1179BrO5: 301.9790, C11H1181BrO5: 303.9771, found: 301.9788,
303.9765, respectively. Anal. Calcd for C11H11BrO5: C, 43.59; H, 3.66.
Found: C, 43.80; H, 3.69.
4.22 (dd, 2H, J¼4.0, 2.0 Hz), 4.20 (q, 2H, J¼7.2 Hz), 3.38 (s, 3H), 1.29
(t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 166.4, 144.0, 121.4,
96.2, 65.9, 60.5, 55.6, 14.4.
4.1.2. Ethyl 2-((methoxymethoxy)methyl)-4,6-dioxocyclohexane
carboxylate (6). To a solution of MOM ether 3 (4.01 g, 23.0 mmol)
and ethyl acetoacetate 4 (4.36 mL, 34.5 mmol) in EtOH (58 mL) was
added NaOEt (1.0 M solution in EtOH, 23.0 mL, 23.0 mmol). The
mixture was stirred at room temperature for 24 h. Upon addition of
NaOEt (1 M solution in EtOH, 4.6 mL, 4.6 mmol), the reaction
mixture was slowly poured into refluxing EtOH (518 mL) containing
4.1.5. Geranyl bromide. To a solution of geraniol (5.00 g, 32.4 mmol)
and CBr4 (21.5 g, 64.8 mmol) in benzene (100 mL) was added PPh3
(17.0 g, 64.8 mmol) by portions over 15 min at 0 ꢀC. The mixture
was stirred at 0 ꢀC for 3 h before it was diluted with hexane
(150 mL). The precipitate was removed by filtration through a pad
of Celite and the filtrate was concentrated. Hexane (50 mL) was
added to the residue and the precipitate was again removed by
filtration. After the filtrate was concentrated, the residue was dis-
tilled under reduced pressure to give geranyl bromide (6.71 g,
ꢀ
molecular sieves 3 A (15 g) over a period of 12 h through a dropping
funnel. After being stirred at reflux for 34 h, the reaction mixture
was filtered through a pad of Celite. The filtrate was concentrated
and treated with 1 M aqueous H2SO4 solution. The resulting mix-
ture was extracted with EtOAc (2ꢂ). The combined organic layer
was washed with brine, dried over anhydrous MgSO4, and con-
centrated. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc¼2/1/1/1/1/2) to give diketone 6 (2.37 g,
9.17 mmol, 40%) as an amber solid. Data for 6 (diastereomeric
30.9 mmol, 95%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
(m, 1H), 5.07 (m, 1H), 4.02 (d, 2H, J¼8.4 Hz), 2.06e2.11 (m, 4H), 1.73
(s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3)
143.5,
d 5.53
d
131.9, 123.5, 120.5, 39.5, 29.6, 26.2, 25.7, 17.7, 16.0. This product is
commercially available and the 1H and 13C NMR spectra are con-
sistent with those of the authentic sample.
mixture): 1H NMR (400 MHz, CDCl3)
d 4.47 (s, 2H, MOM), 4.26 (q,
1H, J¼7.0 Hz, OEt), 4.26 (q, 1H, J¼7.0 Hz, OEt), 3.64e3.55 (m, 4H, H1,
H5, H8), 3.39 (dt, 1H, J¼18, 1.8 Hz, H5), 3.27 (s, 3H, MOM), 2.86 (br
dd, 1H, J¼16, 6.0 Hz, H3), 2.79 (m, 1H, H2), 2.62 (ddt, 1H, J¼16, 4.0,
1.6 Hz, H3), 1.30 (t, 3H, J¼7.0 Hz, OEt); FT-IR (KBr) 2981, 2828, 1742,
1599, 1467, 1447, 1408, 1371, 1316, 1259, 1182 cmꢁ1; MS (EI, 70 eV)
m/z (%) 227 (MþꢁOMe, 17), 213 (7), 183 (100), 137 (55), 113 (19), 95
(22), 85 (13); HRMS (EI): m/z calcd for C11H15O5 [MꢁOMe]þ
227.0919, found: 227.0919.
4.1.6. Geranyl tributyltin. To
a solution of geraniol (5.03 g,
32.6 mmol) in THF (60 mL) was added n-BuLi (1.6 M solution in
hexane, 20.0 mL, 32.4 mmol) at ꢁ78 ꢀC. The mixture was stirred for
20 min followed by the addition of MsCl (2.56 mL, 32.4 mmol). The
mixture was stirred at ꢁ78 ꢀC for 40 min followed by the addition
of n-Bu3SnLi (0.54 M solution in THF) [prepared from i-Pr2NH
(5.01 mL, 35.7 mmol), n-BuLi (1.6 M solution in hexane, 20.0 mL,
32.4 mmol), and Bu3SnH (9.44 g, 32.4 mmol) in THF (60 mL) at 0 ꢀC].
The resulting mixture was stirred at ꢁ78 ꢀC for 2.5 h and allowed to
warm to room temperature. The stirring was continued for 20 h
before the mixture was quenched with H2O. The resulting mixture
was extracted with hexane (3ꢂ), and the organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated. The
residue was purified by flash chromatography on silica gel (hexane/
Et3N¼100/1) to give geranyl tributyltin (8.97 g, 21.0 mmol, 64%) as
4.1.3. 6-Bromo-7-hydroxy-5-methoxyisobenzofuran-1(3H)-one
(1a). To a refluxing suspension of CuBr2 (3.46 g, 15.5 mmol) in
CHCl3 (24 mL) was added dropwise a solution of diketone 6
(930 mg, 3.60 mmol) in MeOH (12 mL). The mixture was stirred at
reflux for 37 h and the precipitate formed was removed by filtration
through a pad of Celite. The filtrate was concentrated and treated
with hexane/EtOAc (1:2) and 1 M aqueous HCl solution. The organic
layer was separated and the aqueous layer was extracted with
hexane/EtOAc (1:2) (3ꢂ). The combined organic layer was washed
with H2O, dried over anhydrous MgSO4, and concentrated. The
residue was purified by flash chromatography on silica gel (hexane/
EtOAc¼2/1/1/1) to give phthalide 1a (650 mg, 2.51 mmol, 70%) as
a colorless oil: 1H NMR (400 MHz, CDCl3)
d
5.32 (br td, 1H, J¼8.8,
1.2 Hz), 5.10 (br tt, J¼7.2, 1.4 Hz, 1H), 2.08e1.95 (m, 4H), 1.68 (s, 3H),
1.66 (d, 2H, J¼9.2 Hz), 1.60 (s, 3H), 1.57 (s, 3H), 1.53e1.44 (m, 6H),
1.34e1.25 (m, 6H), 0.89 (t, 9H, J¼7.6 Hz), 0.85e0.81 (m, 6H); 13C
NMR (75 MHz, CDCl3)
d 131.3, 129.3, 124.8, 123.0, 40.0, 29.4, 27.6,
a tan solid: 1H NMR (400 MHz, CDCl3)
H3), 3.98 (s, 3H, OMe); 13C NMR (100 MHz, CDCl3)
d
6.55 (s, 1H, H4), 5.26 (s, 2H,
171.7, 163.2,
27.2, 25.9, 17.8, 15.8, 13.9, 10.7, 9.5; FT-IR (neat) 2957, 2924, 2871,
2854, 1455, 1376 cmꢁ1; MS (FAB): m/z calcd for C22H44Sn [MꢁnBu]þ
371, found: 371.
d
154.3,147.4,105.3, 98.8, 97.2, 70.5, 57.2; FT-IR (KBr) 3395,1751,1618,
1480, 1467, 1458, 1438 cmꢁ1; MS (EI, 70 eV) m/z (%) 260 (Mþ, 89),
258 (Mþ, 94), 231 (96), 229 (100); HRMS (EI): m/z calcd for
C9H779BrO4: 257.9528, C9H781BrO4: 259.9508, found: 257.9530,
259.9503, respectively. Anal. Calcd for C9H7BrO4: C, 41.73; H, 2.72.
Found: C, 41.52; H, 2.72.
4.1.7. (E)-6-(3,7-Dimethylocta-2,6-dienyl)-5-methoxy-7-(methox-
ymethoxy)isobenzofuran-1(3H)-one (9). Conditions A: To a solution
of aryl bromide 8 (50.0 mg, 0.165 mmol) in THF (1 mL) was added t-
BuLi (1.59 M in pentane, 218
m
L, 0.347 mmol) at ꢁ78 ꢀC. The mixture
was stirred at ꢁ78 ꢀC for 20 min followed by the addition of
CuCN$2LiCl in THF (1 mL) [prepared by vigorously stirring CuCN
(44.3 mg, 0.495 mmol) and LiCl (42.0 mg, 0.990 mmol) in THF for
18 h]. The suspension was gradually warmed to ꢁ35 ꢀC, at which
point copper reagent almost dissolved. The reaction mixture was
again cooled to ꢁ78 ꢀC followed by the addition of geranyl bromide
4.1.4. 6-Bromo-5-methoxy-7-(methoxymethoxy)isobenzofuran-
1(3H)-one (8). To a solution of phthalide 1a (954 mg, 3.68 mmol) in
1,2-dichloroethane (10 mL) were added i-Pr2NEt (1.92 mL,
11.0 mmol) and MOMCl (419 mL, 5.52 mmol) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 13 h before it was
quenched by the addition of saturated aqueous NaHCO3 solution.
The mixture was extracted with hexane/EtOAc (1:1) (3ꢂ), and the
combined organic layer was washed with saturated aqueous NH4Cl
solution, brine, dried over anhydrous MgSO4, and concentrated. The
residue was washed with hexane (3ꢂ) by decantation and dried in
(107 mg, 0.495 mmol) and HMPA (144
mL, 0.825 mmol) in THF
(1 mL). The resulting dark purple solution was gradually warmed to
room temperature over a period of 10 h before it was quenched by
the addition of saturated aqueous NH4Cl solution. The mixture was
extracted with EtOAc (2ꢂ), and the combined organic layer was

S. Kobayashi et al. / Tetrahedron 67 (2011) 9087e9092
9091
washed with brine, dried over anhydrous MgSO4, and concentrated.
The residue was purified by flash chromatography on silica gel
(hexane/EtOAc¼4/1/1/1) to give 9 (9.0 mg, 0.025 mmol, 15%).
Conditions B: Aryl bromide 8 (358 mg, 1.18 mmol), geranyl
tributyltin (1.00 g, 2.36 mmol), (Ph3P)2PdCl2 (84.0 mg, 0.120 mmol),
and CsF (359 mg, 2.36 mmol) were dissolved in DMF (5.9 mL). The
solution was warmed to 80 ꢀC and stirred for 13 h. The insoluble
materials were removed by filtration through a pad of Celite and
successively washed with diethyl ether. The filtrate was treated
with saturated aqueous KF solution and stirred at room tempera-
ture for 1 h. The mixture was extracted with diethyl ether (3ꢂ), and
the combined organic layer was dried over anhydrous MgSO4 and
concentrated. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc¼3/1) to give the coupling product 9
(370 mg, 1.03 mmol, 87%) as a colorless solid: 1H NMR (400 MHz,
43% for two steps), 13 (4.1 mg, 0.0068 mmol, 10% for two steps), 14
(22.5 mg, 0.0267 mmol, 37% in two steps), and the recovery of diol
11 (2.7 mg, 0.0074 mmol, 10%). Data for 11: colorless oil; 1H NMR
(400 MHz, CDCl3)
d 6.77 (s, 1H), 5.10e5.13 (m, 2H), 5.03e5.06 (m,
2H), 4.93 (s, 2H), 4.71 (d, 4H, J¼8.8 Hz), 3.84 (s, 3H), 3.62 (s, 3H),
3.33 (d, 2H, J¼6.4 Hz), 1.94e2.08 (m, 4H), 1.75 (s, 3H), 1.64 (s, 3H),
1.57 (s, 3H); 13C NMR (400 MHz, CDCl3)
d 158.3, 156.1, 140.1, 135.2,
131.4, 125.4, 124.3, 122.9, 122.6, 108.5, 100.4, 64.5, 57.5, 56.6, 55.7,
39.7, 26.7, 25.7, 23.6, 17.7, 16.3; FT-IR (KBr) 3311, 3235, 2926, 2855,
1604, 1577, 1458, 1400 cmꢁ1; MS (EI, 70 eV) m/z (%) 364 (Mþ, 2), 302
(49), 259 (30), 233 (100), 219 (65), 197 (96), 162 (26); HRMS (EI): m/
z calcd for C21H32O5: 364.2250, found: 364.2252. Data for 12: col-
orless oil; 1H NMR (400 MHz, CDCl3)
d 6.75 (s, 1H), 5.25 (s, 2H), 5.11
(m, 1H), 5.04 (m, 1H), 4.98 (s, 2H), 4.65 (d, 2H, J¼6.8 Hz), 3.83 (s,
3H), 3.63 (s, 3H), 3.33 (d, 2H, J¼6.4 Hz), 3.07 (t, 1H, J¼6.8 Hz, OH),
2.34 (t, 2H, J¼7.2 Hz), 2.08e1.95 (m, 4H), 1.75 (s, 3H), 1.64 (s, 3H),
1.60 (m, 2H), 1.57 (s, 3H), 1.25 (m, 24H), 0.88 (t, 3H, J¼6.4 Hz); 13C
CDCl3) d 6.65 (s, 1H, H4), 5.39 (s, 2H, MOM), 5.17 (s, 2H, H3), 5.15 (m,
1H, H20), 5.05 (m, 1H, H60), 3.90 (s, 3H, MOM), 3.58 (s, 3H, OMe),
3.45 (d, 2H, J¼6.8 Hz, H10), 2.04 (m, 2H, H50), 1.95 (m, 2H, H40), 1.77
(s, 3H, C30-Me), 1.64 (s, 3H, C70-Me), 1.57 (s, 3H, C70-Me); 13C NMR
NMR (100 MHz, CDCl3)
d 173.8, 158.3, 156.4, 135.4, 134.3, 131.5,
126.4, 124.3, 123.9, 122.6, 108.9, 100.4, 64.2, 57.6, 56.2, 55.8, 39.8,
34.5, 32.1, 29.8, 29.6, 29.5, 29.4, 29.3, 29.2, 26.7, 25.8, 25.1, 24.9, 23.8,
22.8, 17.8, 16.4, 14.3; FT-IR (KBr) 3460, 2954, 2917, 2849, 1740, 1604,
1578, 1467, 1395 cmꢁ1. Data for 13: colorless oil; 1H NMR (400 MHz,
(100 MHz, CDCl3)
d 169.3, 164.3, 155.0, 148.7, 135.7, 131.4, 124.6,
124.4, 121.9, 109.3, 101.1, 99.1, 68.8, 57.9, 56.2, 39.8, 26.7, 25.8, 23.0,
17.8, 16.3; FT-IR (KBr) 3124, 2925, 2844,1736,1698,1607,1467,1432,
1403, 1376 cmꢁ1; MS (EI, 70 eV) m/z (%) 360 (Mþ, 5), 315 (54), 261
(40), 259 (20), 247 (28); HRMS (EI): m/z calcd for C21H28O5:
360.1937, found: 360.1935.
CDCl3) d 6.85 (s, 1H), 5.27 (s, 2H), 5.13 (m, 1H), 5.04 (m, 1H), 4.94 (s,
2H), 4.71 (d, 2H, J¼6.4 Hz), 3.85 (s, 3H), 3.58 (s, 3H), 3.36 (d, 2H,
J¼6.4 Hz), 2.29 (t, 2H, J¼7.6 Hz), 2.08e1.94 (m, 4H), 1.75 (s, 3H), 1.64
(s, 3H), 1.60 (m, 2H), 1.57 (s, 3H), 1.26 (m, 24H), 0.88 (t, 3H,
4.1.8. (E)-6-(3,7-Dimethylocta-2,6-dienyl)-7-hydroxy-5-methoxyisob-
enzofuran-1(3H)-one (hericenone J, 10). To a solution of 9 (10.6 mg,
0.0294 mmol) in MeOH (1 mL) was added CSA (1.4 mg,
0.0059 mmol). The mixture was stirred at room temperature for 6
days before it was quenched by the addition of Et3N (1 mL). The re-
action mixture was concentrated and the residue was purified by
flash column chromatography on silica gel (hexane/EtOAc¼5/1) to
give hercenone J (10) (9.2 mg, 0.029 mmol, 99%) as a colorless solid;
J¼6.4 Hz); 13C NMR (75 MHz, CDCl3)
d 174.1, 159.2, 156.4, 140.2,
135.4, 131.5, 124.4, 123.5, 122.7, 119.3, 107.5, 100.9, 63.2, 59.1, 57.8,
55.8, 39.8, 34.5, 32.1, 29.83, 29.79, 29.7, 29.6, 29.5, 29.4, 29.3, 26.7,
25.8, 25.0, 23.7, 22.8, 17.8, 16.3, 14.3; FT-IR (KBr) 3444, 2917, 2848,
1739, 1708, 1604, 1578, 1463, 1427, 1403, 1384 cmꢁ1. Data for 14:
colorless oil; 1H NMR (400 MHz, CDCl3)
d 6.75 (s, 1H), 5.23 (s, 2H),
5.14 (s, 2H), 5.14 (m, 1H), 5.04 (m, 1H), 4.93 (s, 2H), 3.83 (s, 3H), 3.57
(s, 3H), 3.36 (d, 2H, J¼6.8 Hz), 2.37e2.26 (m, 4H), 2.05e1.95 (m, 4H),
1.74 (s, 3H), 1.64 (s, 3H), 1.60 (m, 4H), 1.57 (s, 3H), 1.26 (m, 48H), 0.88
1H NMR (400 MHz, CDCl3)
d 7.71 (s, 1H), 6.48 (s, 1H), 5.21 (s, 1H) 5.17
(t, 1H, J¼7.2 Hz), 5.04 (t, 1H, J¼6.8 Hz), 3.88 (s, 3H), 3.34 (d, 2H,
(t, 6H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d 174.0, 173.7, 159.1,
J¼7.2 Hz), 2.03 (m, 2H), 1.95 (t, 2H, J¼7.6 Hz), 1.76 (s, 3H), 1.63 (s, 3H),
156.5, 135.4, 131.5, 124.5, 124.4, 122.7, 120.6, 108.6, 101.0, 64.1, 58.9,
57.8, 55.9, 39.9, 34.6, 34.6, 32.2, 29.9, 29.7, 29.6, 29.5, 29.4, 26.8,
25.9, 25.2, 23.8, 22.9, 17.9, 16.4, 14.4; FT-IR (KBr) 2955, 2917, 2849,
1.56 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 172.9 (C1), 164.9 (C5), 154.5
(C7), 146.1 (C3a), 135.9 (C30), 131.3 (C70), 124.4 (C60), 121.3 (C20), 116.9
(C6), 104.2 (C7a), 96.2 (C4), 70.5 (C3), 56.2 (OMe), 39.9 (C40), 26.7
(C50), 25.7 (C80), 21.6 (C10), 17.7 (C70-Me), 16.2 (C30-Me); FT-IR (KBr)
3427, 3002, 2979, 2920, 2859, 1736, 1698, 1619, 1492, 1467, 1449,
1349 cmꢁ1; MS (EI, 70 eV) m/z (%) 316 (Mþ, 8), 236 (28), 194 (57), 193
(100), 176 (24), 145 (24); HRMS (EI): m/z calcd for C19H24O4: 316.1675,
found: 316.1676.
1734, 1604, 1578, 1467, 1403 cmꢁ1
.
4.1.10. (E)-4-(3,7-Dimethylocta-2,6-dienyl)-2-formyl-3-hydroxy-5-
methoxybenzyl palmitate (hericene A, 15). To a solution of alcohol 12
(25.6 mg, 0.0425 mmol) in CH2Cl2 (3.2 mL) were added pyridine
(17.0
mL, 0.210 mmol) and DesseMartin periodinane (26.7 mg,
0.0630 mmol). The reaction mixture was stirred at room tempera-
ture for 3 h before it was quenched by the addition of saturated
aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution.
The mixture was stirred for 30 min and extracted with EtOAc (2ꢂ).
Thecombined organiclayerwas washed brine, driedoveranhydrous
MgSO4, and concentrated. The residue was purified by flash chro-
matography on silica gel (hexane/EtOAc¼10/1) to give aldehyde
(21.6 mg, 0.0360 mmol, 85%) as a colorless oil: 1H NMR (400 MHz,
4.1.9. (E)-4-(3,7-Dimethylocta-2,6-dienyl)-2-(hydroxymethyl)-5-
methoxy-3-(methoxymethoxy)benzyl palmitate (11). To a solution of
phthalide 9 (50.0 mg, 0.139 mmol) in THF (2.8 mL) was added
LiAlH4 (16.6 mg, 0.437 mmol) at 0 ꢀC. The mixture was stirred at
0 ꢀC for 30 min before it was quenched by the addition of H2O and
1 M aqueous NaOH solution. The resulting mixture was extracted
with EtOAc (3ꢂ), and the combined organic layer was washed with
1 M aqueous HCl solution, brine, dried over anhydrous MgSO4, and
concentrated to give diol 11 (53.8 mg). The diol 11 (26.0 mg,
0.0713 mmol) was dissolved in CH2Cl2 (1.5 mL) followed by the
CDCl3) d 10.35 (s, 1H), 6.83 (s, 1H), 5.52 (s, 2H), 5.11 (m, 1H), 5.03 (m,
1H), 5.02 (s, 2H), 3.90 (s, 3H), 3.56 (s, 3H), 3.36 (d, 2H, J¼6.4 Hz), 2.41
(t, 2H, J¼7.6 Hz), 2.07e1.97 (m, 4H), 1.76 (s, 3H), 1.68 (m, 2H), 1.64 (s,
3H), 1.57 (s, 3H), 1.25 (m, 24H), 0.88 (t, 3H, J¼7.6 Hz); 13C NMR
addition of pyridine (27
0.007 mmol), and palmitoyl chloride (11
The mixture was stirred at 0 ꢀC for 1 h and 11
m
L, 0.33 mmol), DMAP (0.8 mg,
L, 0.036 mmol) at 0 ꢀC.
L (0.036 mmol) each
m
(75 MHz, CDCl3) d 191.5, 173.4, 162.9, 161.3, 139.2, 136.0, 131.6, 124.3,
m
123.3,122.0,121.1,106.0,101.7, 64.4, 58.2, 55.9, 39.8, 34.6, 32.1, 29.83,
29.80, 29.76, 29.6, 29.5, 29.5, 29.4, 26.7, 25.8, 25.2, 23.1, 22.8, 17.8,
16.4,14.3; FT-IR (KBr) 2925, 2854,1742,1680,1598,1566,1465,1377,
1289, 1218, 1160, 1116, 1048 cmꢁ1; HRMS (FAB): m/z calcd for
C37H61O6 [MþH]þ 601.4468, found 601.4476.
of palmitoyl chloride was added twice at the intervals of 1 h with
stirring at 0 ꢀC. The reaction mixture was quenched with saturated
aqueous NaHCO3 solution and extracted with EtOAc (3ꢂ). The
combined organic layer was washed with brine, dried over anhy-
drous MgSO4, and concentrated. The residue was purified by flash
chromatography on silica gel (hexane/EtOAc¼15/1/6/1/3/1/1/
2 containing 5% MeOH) to give esters 12 (18.3 mg, 0.0304 mmol,
To a solution of the above aldehyde (7.0 mg, 0.012 mmol) in
CH2Cl2 (2 mL) was added Me2BBr (1.76 M in CH2Cl2, 11
mL,
0.019 mmol) at ꢁ78 ꢀC. The mixture was stirred at ꢁ78 ꢀC for 1.2 h

9092
S. Kobayashi et al. / Tetrahedron 67 (2011) 9087e9092
3. Kimura, Y.; Nishibe, M.; Nakajima, H.; Hamasaki, T.; Shimada, A.; Tuneda, A.;
Shigematsu, N. Agric. Biol. Chem. 1991, 55, 2673e2674.
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before it was quenched by the addition of saturated aqueous
NaHCO3. The mixture was extracted with EtOAc (3ꢂ), and the
combined organic layer was washed with brine, dried over anhy-
drous MgSO4, and concentrated. The residue was purified by flash
chromatography on silica gel (hexane/EtOAc¼20/1/10/1) to give
5. For
a review on mycophenolic acid: Bentley, R. Chem. Rev. 2000, 100,
3801e3825.
6. (a) Kobayashi, K.; Shimizu, H.; Itoh, M.; Suginome, H. Bull. Chem. Soc. Jpn. 1990,
63, 2435e2437; (b) Makara, G. M.; Anderson, W. K. J. Org. Chem. 1995, 60,
5717e5718; (c) Lee, Y.; Fujiwara, Y.; Ujita, K.; Nagatomo, M.; Ohta, H.; Shimizu,
I. Bull. Chem. Soc. Jpn. 2001, 74, 1437e1443; (d) Patterson, J. W. J. Org. Chem.
1995, 60, 4542e4548.
hericene A (15) (4.7 mg, 8.4
m
mol, 70%) and the recovery of alde-
mol, 26%). Data for 15: colorless oil; 1H NMR
12.37 (s, 1H, OH), 10.10 (s, 1H, CHO), 6.52 (s, 1H,
hyde (1.9 mg, 3.2
(300 MHz, CDCl3)
m
d
H6), 5.32 (s, 2H, C1eCH2), 5.16 (br t,1H, J¼7.2 Hz, H20), 5.05 (br t,1H,
J¼7.0 Hz, H60), 3.91 (s, 3H, OMe), 3.33 (br d, 2H, J¼7.2 Hz, H10), 2.33
(t, 2H, J¼7.2 Hz, H200), 2.03 (m, 1H, H50), 1.96 (m, 1H, H40), 1.76 (br s,
3H, H100), 1.63 (br s, 3H, H80), 1.61 (m, 2H, H300), 1.57 (br s, 3H, H90),
1.25 (m, 26H), 0.88 (t, 3H, J¼7.2 Hz, H1600). 13C NMR (75 MHz, CDCl3)
7. (a) Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. Tetrahedron 1972, 28,
ꢁ
4395e4404; (b) Ple, P. A.; Hamon, A.; Jones, G. Tetrahedron 1997, 53,
3395e3400.
ꢁ~
ꢁ
8. Covarrubias-Zuniga, A.; Gonzalez-Lucas, A. Tetrahedron Lett. 1998, 39,
2881e2882.
9. (a) Birch, A. J.; Wright, J. J. Aust. J. Chem. 1969, 22, 2635e2644; (b) Watanabe,
M.; Tsukazaki, M.; Hamada, Y.; Iwao, M.; Furukawa, S. Chem. Pharm. Bull. 1989,
d
193.3 (C8), 173.4 (C100), 163.6 (C5), 163.0 (C3), 138.5 (C1), 135.9
ꢁ
ꢁ
37, 2948e2951; (c) de la Cruz, R. A.; Talamas, F. X.; Vazquez, A.; Muchowski, J.
M. Can. J. Chem. 1997, 75, 641e645; (d) Nelson, P. H.; Carr, S. F.; Devens, B. H.;
Eugui, E. M.; Franco, F.; Gonzalez, C.; Hawley, R. C.; Loughhead, D. G.; Milan, D.
J.; Papp, E.; Patterson, J. W.; Rouhafza, S.; Sjogren, E. B.; Smith, D. B.; Ste-
phenson, R. A.; Talamas, F. X.; Waltos, A.-M.; Weikert, R. J.; Wu, J. C. J. Med.
Chem. 1996, 39, 4181e4196.
(C70), 131.4 (C30), 124.5 (C60), 121.3 (C20), 118.2 (C4), 113.0 (C2), 105.7
(C6), 63.1 (C7), 56.0 (C9), 39.9 (C40), 34.4 (C200), 32.1 (C300), 29.84,
29.81, 29.79, 29.73, 29.59, 29.51, 29.38, 29.26, 26.8 (C50), 25.8 (C80),
25.0, 22.8, 21.5 (C10), 17.8 (C90), 16.3 (C100), 14.3 (C1600); FT-IR (film)
2923, 2855,1741,1637,1622,1578,1498,1466,1410,1377,1344,1311,
1286, 1253, 1223, 1172, 1150, 1122, 1017 cmꢁ1; HRMS (FAB): m/z
calcd for C35H57O5 [MþH]þ 557.4206, found: 557.4244.
10. Danheiser, R. L.; Gee, S. K.; Perez, J. J. J. Am. Chem. Soc. 1986, 108, 806e810.
11. Kende, A. S.; Fludzinski, P. Org. Synth. 1986, 64, 221e223.
12. When a 0.3 M ethanol solution of 3 (1 equiv) and ethyl acetoacetate 4 (1 equiv)
was refluxed together in the presence of NaOEt (1 equiv), the expected cyclic
ketone 6 was obtained in only 18% yield. Careful analysis of the crude mixture
indicated that self-condensation of 3 took precedence over intermolecular
Michael addition. Thus, a mixture of 3 (1 equiv), 4 (1.5 equiv) and NaOEt
Acknowledgements
(1 equiv) was first stirred at room temperature for 24
h to induce in-
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105) from the MEXT and
KAKENHI (22550115) from the JSPS.
termolecular Michael addition. After addition of another aliquot of NaOEt (0.
2 equiv), the mixture was added to refluxing EtOH over a period of 12 h (final
concentration: 0.03 M) and stirred at reflux an additional 34 h. In this manner,
the yield of 6 was doubly improved.
13. Cleaver, L.; Croft, J. A.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1976, 29,
1989e2001.
Supplementary data
14. King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459e3461.
15. Related examples: (a) Saimoto, H.; Ohrai, S.; Sashiwa, H.; Shigemasa, Y.; Hir-
ama, T. Bull. Chem. Soc. Jpn. 1995, 68, 2727e2734; (b) Falck, J. R.; Reddy, K. K.;
Chandrasekhar, S. Tetrahedron Lett. 1997, 38, 5245e5248; (c) Treadwell, E. M.;
Cermak, S. C.; Wiemer, D. F. J. Org. Chem. 1999, 64, 8718e8723.
16. Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333e3336.
17. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508e524.
18. Related examples: (a) Takemura, S.; Hirayama, A.; Tokunaga, J.; Kawamura, F.;
Inagaki, K.; Hashimoto, K.; Nakata, M. Tetrahedron Lett. 1999, 40, 7501e7505;
(b) Jung, Y.-S.; Joe, B.-Y.; Seong, C.-M.; Park, N.-S. Bull. Korean Chem. Soc. 2000,
21, 463e464; (c) Takaoka, S.; Nakade, K.; Fukuyama, Y. Tetrahedron Lett. 2002,
43, 6919e6923.
1H and 13C NMR spectra for all new synthetic compounds and
comparisons of the NMR data for synthetic compounds and natural
products. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2011.09.104.
References and notes
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€
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