Synthesis of anti-HIV lithospermic acid by two diverse strategies

Article abstract of DOI:10.1039/c2ob25575h

An efficient and convergent route for the synthesis of the natural product (+)-lithospermic acid, which possesses anti-HIV activity, was accomplished. The (±)-trans-dihydrobenzo[b]furan core therein was prepared by two different strategies. The first strategy involved the use of a palladium-catalyzed annulation to generate an appropriately substituted benzo[b]furan ester followed by a stereoselective reduction of a carbon-carbon double bond with Mg-HgCl ₂-MeOH. The second strategy relied on an aldol condensation between a suitably substituted methyl arylacetate and 3,4-dimethoxybenzaldehyde, followed by cyclization. Finally, a total synthesis of (+)-lithospermic acid was completed via coupling of a trans-dihydrobenzo[b]furan cinnamic acid with an enantiomerically pure methyl lactate.

Full text of DOI:10.1039/c2ob25575h

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Organic &
Biomolecular
Chemistry
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Volume 10 | Number 28 | 28 July 2012 | Pages 5317–5472
ISSN 1477-0520
PAPER
Jih Ru Hwu
1477-0520(2012)10:28;1-9
Synthesis of anti-HIV lithospermic acid by two diverse strategies

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PAPER
Synthesis of anti-HIV lithospermic acid by two diverse strategies†
Tirumala G. Varadarajua and Jih Ru Hwu*a,b
Received 17th March 2012, Accepted 11th May 2012
DOI: 10.1039/c2ob25575h
An efficient and convergent route for the synthesis of the natural product (+)-lithospermic acid, which
possesses anti-HIVactivity, was accomplished. The ( )-trans-dihydrobenzo[b]furan core therein was
prepared by two different strategies. The first strategy involved the use of a palladium-catalyzed
annulation to generate an appropriately substituted benzo[b]furan ester followed by a stereoselective
reduction of a carbon–carbon double bond with Mg–HgCl2–MeOH. The second strategy relied on an
aldol condensation between a suitably substituted methyl arylacetate and 3,4-dimethoxybenzaldehyde,
followed by cyclization. Finally, a total synthesis of (+)-lithospermic acid was completed via coupling of
a trans-dihydrobenzo[b]furan cinnamic acid with an enantiomerically pure methyl lactate.
Introduction
In 1963, Johnson and co-workers1 reported the first isolation of
lithospermic acid (1) from the roots of Lithospermum ruderale.
In 1975, Carmack and co-workers2 isolated the same acid, 1,
from the Lithospermum ruderale Dougl. ex Lehm (Boragina-
ceae). They proposed a new structure through the possession of
a trans relationship between the C(20)/C(21) substituents
attached to the dihydrobenzo[b]furan moiety, on the basis of
1H NMR coupling constants associated with similar com-
pounds.2 In the same year, Wagner and co-workers3 isolated the
same compound from Lithospermum officinale and confirmed
the structure of 1. Moreover, they prepared its derivative
(+)-heptamethyllithospermate. Though the structure of
(+)-lithospermic acid (1) has been established independently by
the groups of Carmack and Wagner, the absolute configuration
remained unassigned.
synthesis of racemic heptamethyllithospermate. After two
decades, Bergman, Ellman and co-workers9 accomplished the
first asymmetric total synthesis of (+)-lithospermic acid (1) and
established its absolute configuration as (+)-(10R,20S,21S)-1.
Very recently, Wang and Yu10 have also reported a total synthesis
of (+)-lithospermic acid. Meanwhile, Coster and co-workers11
disclosed the formal total synthesis of (+)-lithospermic acid (1)
by using a late stage separation of the diastereomeric mixture. In
these published works, Bergman, Ellman and Yu utilized natu-
rally-occurring (R)-rosmarinic acid to generate the C(10R)
stereogenic center in the natural product 1. To the best of our
knowledge, no general synthetic route to establish the C(10R)
chiral center from achiral starting material has been reported to
date. Here, we report the first asymmetric synthesis of (+)-(R)-
methyl 3-(3,4-dimethoxyphenyl)-2-hydroxypropanoate (3) as
well as the establishment of the C(10R) stereogenic center of 1
by a chemical method. In addition, we demonstrate two synthetic
sequences leading to the trans-dihydrobenzo[b]furan core of the
natural product 1 from different starting materials. Furthermore,
our success on the synthesis of (+)-lithospermic acid (1) via the
intermediate 2 is described.
In 2002, Huang and co-workers4 reported their isolation of
(+)-lithospermic acid (1) from Salvia miltiorrhiza and its non-
toxic HIV-1 integrase inhibitory activity. In addition, this caffeic
acid trimer (1)5 was found to possess inhibition properties of
adenylatecyclase by Kohda et al.6 and an antioxidizing low-
density lipoprotein by Lin et al.7
Given these remarkable biological properties, the total syn-
thesis of (+)-lithospermic acid (1) and its analogues has attracted
much attention. In 1979, Jacobson and Raths8 completed the
aDepartment of Chemistry and Frontier Research Center on
Fundamental and Applied Sciences of Matters, National Tsing Hua
University, Hsinchu, Taiwan 30013, R.O.C.
bDepartment of Chemistry, National Central University, Jhongli,
Taoyuan, Taiwan 32001, R.O.C. E-mail: jrhwu@mx.nthu.edu.tw
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra as well as HPLC chromatograms for compounds
11, ( )-12, ( )-13, ( )-5, 16, 8, ( )-17, ( )-18, ( )-19, 20, and 21. See
DOI: 10.1039/c2ob25575h
A retrosynthetic plan for (+)-lithospermic acid (1) is depicted
in Scheme 1. We decided to synthesize the enantiomerically-
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enriched heptamethyllithospermate 2, in which demethylation of
all seven methyl groups to give lithospermic acid had already
been reported.9 Esterification of cinnamic acid 5 with (+)-(R)-
methyl lactate 3 would give the intermediate 2. The (+)-lactate 3
could be synthesized from commercially available 3,4-dimethoxy-
benzaldehyde (4). Moreover, we planned to obtain the desired
trans-dihydrobenzo[b]furan cinnamic acid 5 through two differ-
ent strategies: namely palladium-catalyzed annulation and an
aldol condensation.
(+)-3 from its racemates by kinetic resolution with the enzyme
Lipase PS. In comparison with their results, we successfully
developed a simple approach for the enantioselective synthesis
of (+)-(R)-3 and it can be regarded as a general route for the
syntheses of other lactates.
Next, our goal was to synthesize the key intermediate trans-
dihydrobenzo[b]furan cinnamic acid 5. Recently, our group has
utilized palladium-catalyzed annulation16 in the syntheses of
functionalized benzo[b]furans and indoles for organic light-emit-
ting diodes.17 We envisioned that similar chemistry could be
applied to the synthesis of the dihydrobenzo[b]furan segment of
(+)-lithospermic acid (1). Accordingly, we coupled 2-iodoisova-
nillin (6)18 with the activated alkyne 79 by using (PPh3)2PdCl2
(0.060 equiv) with LiCl and NaHCO3 in DMF at 110 °C to give
the benzo[b]furan ester 11 as pale yellow needles
(mp 166–167 °C, see Scheme 3). Subsequently, the chemo- and
stereoselective reduction of 11 to the corresponding trans-
dihydrobenzo[b]furan 13 was attempted. Application of the
reduction conditions, including H2/Pd–C19 and Et3SiH/TFA,20
led to the recovery of the starting material or undesired products.
In order to circumvent this problem, we considered metallic
Mg in methanol (Mg–MeOH)21 as an ideal reducing system,
which has been used in the reduction of α,β-unsaturated esters.21
Accordingly, benzo[b]furan ester 11 was produced up to a 30%
yield (see entry 1 of Table 1). Furthermore, we treated compound
11 with Mg (40.0 equiv) in the presence of a catalytic amount of
HgCl2 (0.10 equiv) by following the procedure reported by Lee
et al. (entry 5 of Table 1).21a ( )-trans-Dihydrobenzo[b]furan 12
was generated as a pale yellow liquid in a 82% yield. Separation
of this racemate to give the desired compound 12 in its enantio-
merically pure form met with failure when a reported procedure
was used.22 This racemic compound exhibited four singlets
Results
At the outset, our approach towards obtaining the optically
active lactate (R)-3 was to reduce the enol ester 9 (see
Scheme 2). It can be prepared from 3,4-dimethoxybenzaldehyde
(4) and N-acetylglycine in three steps by the Dalla’s procedure.12
Although we were able to reduce 9 with NaBH4 to give the
racemic lactate 3, use of chiral reducing agents including NB-
Enantride, K-Glucoride and (R,R)-(−)-trans-4,5-bis[(diphenyl-
phosphino)methyl]-2,2-di-methyl-1,3-dioxolane (i.e., DIOP–
Rh(I)) did not lead to (+)-3 with a high % ee. Alternatively, we
dehydroxylated the optically active diol 1013 selectively at the
benzylic position14 by Et3SiH in the presence of CF3COOH at
0 °C. The desired (+)-methyl lactate 3 was generated in a 75%
yield with a >99% ee. These mild conditions did not cause epi-
merization of the hydroxyl group at the α position. Its enantio-
meric excess was determined by HPLC analysis with a Chiralcel
OD column. Bergman, Ellman and co-workers9 reported a
method for generating this optically active lactate (R)-3 by penta-
methylation of commercially available rosmarinic acid followed
by saponification. On the other hand, Eicher et al.15 obtained
Scheme 1 Retrosynthetic analysis of (+)-lithospermic acid (1) via its heptamethyl derivative 2.
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Scheme 2 Syntheses of racemic and optically active (+)-(R)-methyl lactate 3.
Scheme 3 A palladium-catalyzed annulation strategy in the synthesis of ( )-trans-dihydrobenzofuran cinnamic acid 5.
Table 1 Reduction of benzo[b]furan ester 11 with Mg–HgCl2–MeOH
C(2)-protons of dihydrobenzo[b]furan moiety, respectively, as
well as a doublet at 4.49 ppm with J = 12.4 Hz for the C(8)H2
protons attached to a free hydroxyl group. Furthermore, in its
13C NMR spectrum, the resonance occurred at 55.94 and
87.08 ppm for the C(3)- and the C(2)-carbons, respectively, as
well as at 62.66 ppm for the C(8) carbon. In its IR spectrum, one
strong stretching absorption band appeared at 1736 cm−1 for the
O(CvO) group and at 3516 cm−1 for the OH group. Moreover,
its exact mass was detected as 374.1366, which agreed well with
the theoretical value of 374.1360 for C20H22O7. These spectro-
scopic data clearly confirm the structure of trans-dihydro-
benzo[b]furan 12.
Entry Mg (equiv) HgCl2 (equiv) Temp (°C) Time (h) Yield (%)
1
2
3
4
5
40.0
40.0
5.0
40.0
40.0
—
—
0.10
0.10
0.10
25
65
25
25
25
48
12
3.0
3.0
20
30
0
35
60
82
1
between 3.69 and 3.84 ppm in its H NMR spectrum for the 12
protons resulting from three unequivalent methoxy groups and
one methyl ester. In addition, we observed two characteristic
doublets with J = 6.0 Hz at 4.24 and 5.93 ppm for the C(3)- and
We oxidized alcohol 12 to the corresponding aldehyde 13,8,9
known to possess
a trans configuration, by manganese
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dioxide.23 Finally, the Knoevenagel condensation of aldehyde
( )-13 with malonic acid under basic conditions was performed
by use of the Ellman’s procedure to give the desired ( )-trans-
dihydrobenzo[b]furan cinnamic acid 5.8,9
Subsequent cyclization of compound 17 with iodotrimethylsi-
lane (2.2 equiv)28 in dichloromethane led to the desired bromo-
dihydrobenzo[b]furan 18 as a gummy oil in a 75% yield.
In the IR spectrum of the new dihydrobenzo[b]furan 18,
strong absorptions resulting from stretching vibrations appeared
At this stage, we planned a completely different approach for
the synthesis of dihydrobenzo[b]furan 5, commencing with
o-vanillin (14). This was converted to 2-benzyloxy-6-bromo-
3-methoxybenzaldehyde (15) in four steps by the procedure
reported by Nakanishi (Scheme 4).24 Condensation of aldehyde
1
at 1736 cm−1 for the ester CvO group. Its H NMR spectrum
displayed two doublets at 5.82 and 4.30 ppm with J = 7.2 Hz for
the H(2) and H(3) protons, respectively, and one singlet at
3.73 ppm for the CO2CH3 protons. Although the JH(2)–H(3) value
is not diagnostic to distinguish the cis and trans isomers, the
anisotropic effect of the C(2) aryl group causes a chemical shift
of the H(3) proton upfield and the CO2CH3 protons downfield in
the trans isomers than those of the corresponding cis isomers.11
The trans compounds often display the H(3) protons around
4.3 ppm and the CO2CH3 protons around 3.8–3.9 ppm, yet the
cis compounds display the H(3) protons around 4.9 ppm and the
CO2CH3 protons around 3.3 ppm. Our experimental data clearly
indicate the trans configuration of the dihydrobenzofuran moiety
in compound 18.
25
15 with CH3SCH2SOCH3 in the presence of benzyltrimethyl-
ammonium hydroxide (Triton B) at 100 °C gave the ketene-
thioacetal 16. Upon acid-catalyzed hydrolysis in dry methanol,
the desired methyl arylacetate 8 was formed in an 86% yield. We
then performed an aldol condensation26 between
8 and
3,4-dimethoxybenzaldehyde (4) in the presence of lithium diiso-
propylamide (LDA) at −78 °C to exclusively give a coupled
( )-β-hydroxy ester as white solids (mp 95–96 °C) in a 65%
yield . At this time, the relative stereochemistry of the product
was not important and was tentatively assigned as 17. The
hydroxyl group therein could be removed to form a carbocationic
intermediate for cyclization, after which the required trans
configuration of the dihydrofuran product must be ensured.27
Afterwards, we performed a Heck coupling29 between furan
18 and tert-butyl ester, using Pd(OAc)2 (0.10 equiv) and PPh3
(0.30 equiv) in Et3N, to produce an α,β-unsaturated tert-butyl
Scheme 4 An alternative strategy to construct the dihydrobenzo[b]furan cinnamic acid 5 by use of an aldol condensation.
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ester 19 in 81% yield. Finally, treatment of ester 19 with trifluoro-
acetic acid gave the desired ( )-trans-dihydrobenzo[b]furancin-
namic acid 5 as a pale yellow solid in a 92% yield.8,9 The phys-
ical properties and spectroscopic characteristics obtained by us
for compound 5 are consistent with the reported data.8,9
the single electron transfer took place in benzo[b]furan ester 11
to chemo- and stereoselectively afford the hydroxymethyl trans-
dihydrobenzo[b]furan 12 in a 30% yield (see Scheme 3 and
entry 1 of Table 1). The yield was improved to 82% by the
addition of a catalytic amount of HgCl2. Lee21a reported that the
use of HgCl2 can activate the Mg and thus accelerate the
reduction. Moreover, generation of magnesium methoxide in situ
was responsible for the base-promoted epimerization at the C(3)
carbonyl ester to the trans-diastereomer 12. In this regard, met-
allic Mg in a protic solvent acted not only as a single electron
transfer reducing reagent but also the source of a base for
epimerization.21
During the preparation of this manuscript, we noted that
Coster and co-workers11 obtained a similar key intermediate as
( )-trans-dihydrobenzo[b]furan 13 for the synthesis of lithosper-
mic acid (1). It includes the Sonogashira coupling, protection of
the C(4)-formyl group, Pd(II)-catalyzed carbonylative annulation,
Mg-mediated reduction and finally deprotection. Through a
different pathway, we were able to obtain the desired ( )-trans-
13 in three steps, including the palladium-catalyzed annulation,16
Mg/HgCl2-mediated reduction, and oxidation with a 48% overall
yield.
Finally, to obtain heptamethyllithospermate 2, we esterified9
( )-5 with (+)-R-methyl lactate 3 in the presence of 4-dimethyl-
aminopyridine (DMAP), 1-ethyl-3-(3′-dimethylaminopropyl)-
carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt,
Scheme 4). A 1 : 1 mixture of (10R, 20S, 21S)-2 and the corres-
ponding diastereomeric counterpart (10R,20R,21R)-2 was
produced as a yellow foam in a 85% overall yield. Their physical
properties and spectroscopic characteristics are consistent with
those of the reported compounds.8,11 For example, a new charac-
1
teristic peak at δ 5.26–5.35 ppm in the H NMR spectrum for
the proton in –O(CvO)CHCOO– indicates the formation of a
new ester bond. Further conversion of (10R,20S,21S)-2 to the
final target (+)-1 through multi-demethylation has been reported
by Coster,11 Bergman and Ellman.9
Discussion
Antus,19 Rupprecht,30 and their co-workers reported that hydro-
genation of 2,3-disubstituted benzo[b]furans with hydrogen gas
in the presence of 10% palladium on carbon (Pd/C) affords the
corresponding 2,3-dihydrobenzo[b]furans with a cis configur-
ation. Isomerization of this cis isomer occurs under alkaline con-
ditions at an elevated temperature to give the thermodynamically
more stable trans diastereomer.30 Using this method, we
hydrogenated benzo[b]furan ester 11 in methanol19 for 3 h.
4-(Hydroxymethyl)benzo[b]furan 20 was obtained, in which the
C(2)vC(3) double bond remained intact (see Scheme 5).
Elongation of the hydrogenation time to 24 h produced
4-methylbenzo[b]furan 21 through deoxygenation of the benzyl
alcohol moiety in 20. Our results reveal that the formyl group in
11 was problematic and converted to an undesired methyl group
before the conjugated C(2)vC(3) bond in the benzo[b]furan
nucleus was hydrogenated.
Conclusion
The first asymmetric syntheses of (+)-(R)-methyl lactate 3
(>99%ee) was completed in four steps with an overall yield of
75% from commercially available 3,4-dimethoxybenzaldehyde.
Two different synthetic routes were also developed for the dia-
stereoselective synthesis of the trans-dihydrobenzo[b]furan
segment of lithospermic acid (1). The first strategy involved the
chemo- and stereoselective reduction of benzo[b]furan ester 11
with metallic Mg and catalytic HgCl2 in methanol. The second
strategy involved an aldol condensation and subsequent intra-
molecular cyclization of β-hydroxy ester 17 to give the desired
trans-dihydrobenzo[b]furan core of compound 1. These two
strategies demonstrate expedient and concise routes for the
synthesis of heptamethyllithospermate 2 from readily available
starting materials in five and seven steps, respectively. Moreover,
these two strategies were applied successfully in a total synthesis
of (+)-lithospermic acid (1).
On the other hand, we endeavoured to circumvent the diffi-
culty of the diastereoselective reduction of 2,3-disubstituted-
benzo[b]furan by using metallic Mg in methanol.21 Accordingly,
Scheme 5 Hydrogenation of benzo[b]furan ester 11 containing a formyl group.
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q = quartet; m = multiplet; J = coupling constant (hertz). High-
resolution mass spectra were obtained by means of a JEOL
JMS-700 mass spectrometer. A Perkin-Elmer 241 polarimeter
with a sodium lamp was used for the determination of specific
rotations at room temperature. Melting points were obtained with
a Fargo MP-2D melting point apparatus.
Experimental section
General methods
All reactions were carried out in oven-dried glassware (120 °C)
under an atmosphere of nitrogen unless as indicated otherwise.
Ethyl acetate and hexane from Mallinckrodt Chemical Co. were
dried and distilled from CaH2. Diethyl ether and THF from Mal-
linckrodt Chemicals Co. were dried by distillation from sodium
and benzophenone under an atmosphere of nitrogen. Aceto-
nitrile, acetone, dichloromethane and methanol were purchased
from Mallinckrodt Chemical Co. Acetic anhydride, tert-butanol
and pyridine were purchased from Echo Chemical Co. AD-mix-
α, benzyltrimethylammonium hydroxide (Triton B), tert-butyl
acrylate, bromine, n-butyllithium, carbon tetrabromide (CBr4),
4-dimethylaminopyridine (DMAP), 2,2-dimethyl-1,3-propane-
diol, 3,4-dimethoxybenzaldehyde, p-dioxane, 1,2-ethanediol,
1-hydroxybenzotriazole (HOBt), iodine monochloride, iodo-
trimethylsilane, isovanillin, magnesium, manganese dioxide,
mercuric chloride, methanesulfonamide, palladium acetate, pot-
assium bromide, potassium iodide, p-toluenesulfonic acid
(PTSA), triethylsilane, trifluoroacetic acid, triphenylphosphine,
and o-vanillin were purchased from Aldrich Chemical Co.
Benzyl bromide (BnBr), bis(triphenylphosphine)palladium(II)-
chloride, diisopropylamine, 1-ethyl-3-(3′-dimethylaminopropyl)-
carbodiimide hydrochloride (EDCI), methyl chloroformate,
methyl (methylthio)methyl sulfoxide (CH3SCH2SOCH3) and
1,3-propanedithiol were purchased from Fluka Chemical Co.
(+)-(R)-Methyl 3-(3,4-dimethoxyphenyl)-2-hydroxypropanoate
((+)-3)
To a solution containing (2R,3S)-methyl 3-(3,4-dimethoxyphe-
nyl)-2,3-dihydroxypropanoate13 (10, 542.1 mg, 2.117 mmol, 1.0
equiv) and triethylsilane (270.4 mg, 2.326 mmol, 1.1 equiv) in
CH2Cl2 (20 mL) at 0 °C, trifluoroacetic acid (3.671 g,
32.17 mmol, 15.0 equiv) was added via a syringe and stirring
was continued for 30 min. The reaction was quenched with satu-
rated aqueous NaHCO3 (20 mL) and the resultant solution was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with a saturated aqueous NaCl solution
(20 mL), dried over MgSO4(s), filtered and concentrated under
reduced pressure to afford a residue. Purification of the residue
by chromatography with a silica gel column (40% EtOAc in
hexane as the eluent) gave (+)-3 (381.1 mg, 1.587 mmol) as a
white solid in a 75% yield with >99%ee, as determined by
HPLC with a Chiralcel OD column and isopropyl alcohol (10%)
in hexane as the eluent. The major fraction showed up at tr =
18.94 min and the minor fraction at tr = 16.02 min by use of a
UV detector with λ = 279 nm. For (+)-3: mp (recrystallized from
Methyl
2-oxo-3-(3,4-dimethoxyphenyl)propionate
(9),12
toluene) 56–57 °C, lit.9 (53–54 °C); [α]D +9.9° (c = 0.77 in
23
(2R,3S)-methyl 3-(3,4-dimethoxyphenyl)-2,3-dihydroxypropano-
CH2Cl2), lit.9 +10.6° (c = 0.67 in CH2Cl2); TLC Rf: 0.56 (60%
ate
(10),13
4-formyl-2-hydroxy-3-iodoanisole
(6),18
1
EtOAc in hexane as the eluent); H NMR (CDCl3; 400 MHz)
(3,4-dimethoxyphenyl)propynoic acid methyl ester (7)9 and
2-benzyloxy-6-bromo-3-methoxybenzaldehyde (15)24 were pre-
pared by literature methods.
δ 2.92 (dd, J = 14.0, 5.6 Hz, 1 H, ArCH), 3.07 (dd, J = 14.0,
5.6 Hz, 1 H, ArCH), 3.76 (s, 3 H, CO2CH3), 3.83 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 4.40–4.43 (m, 1 H, CHO),
6.71–6.79 (m, 3 H, 3 × ArH); 13C NMR (CDCl3; 100 MHz)
δ 39.91, 52.18, 55.62, 55.65, 71.24, 111.00, 112.54, 121.31,
128.65, 147.81, 148.59, 174.35 (CvO). Its physical properties
and spectroscopic characteristics are consistent with those
previously reported.9 The corresponding racemate ( )-3 was
Analytical thin layer chromatography (TLC) was performed
on precoated plates (silica gel 60 F-254), which were purchased
from Merck Inc. Purification by gravity column chromatography
was carried out by use of Silicycle ultra pure silica gel (particle
size 40–63 μm, 230–400 mesh). The enantiomeric excess was
determined by an HPLC (Waters 515) with Chiralcel OD
(250 × 4.6 mm) column at 25 °C. The results were compared
with racemic isomers with a flow rate of 1.0 mL min−1 and with
isopropyl alcohol in hexane as the mobile phase. Purity of all the
products was >98.0%, as checked by an HPLC (Waters 515)
with a Lichrosorb Si-100 (200 × 4.6 mm, 5 μm) column at
25 °C.
1
prepared through an established method12 and its H NMR and
13C NMR characteristics are consistent with those of (+)-3.
Methyl 2-(3,4-dimethoxyphenyl)-4-formyl-7-methoxybenzo[b]-
furan-3-carboxylate (11)
Infrared (IR) spectra were measured on a Perkin–Elmer model
spectrum one B spectrophotometer. Absorption intensities are
recorded by the following abbreviations: s = strong; m =
medium and w = weak. Proton NMR spectra were obtained on a
Varian Mercury-400 (400 MHz) spectrometer, using chloroform-
d (CDCl3) and acetone-d6 (CD3COCD3) as solvents. Proton
NMR chemical shifts were referenced to residual protonated sol-
vents (δ 7.24 and 2.05 ppm for chloroform and acetone, respect-
ively). Carbon-13 NMR spectra were obtained on a Varian
Mercury-400 (100 MHz) spectrometer using chloroform-d as the
solvent. Carbon-13 chemical shifts are referenced to the center
of the CDCl3 triplet (δ 77.0 ppm). Multiplicities are recorded by
the following abbreviations: s = singlet; d = doublet; t = triplet;
To a solution containing 4-formyl-2-hydroxy-3-iodoanisole18
(6, 152.6 mg, 0.5488 mmol, 1.0 equiv), (Ph3P)2PdCl2
(23.11 mg, 0.0329 mmol, 0.060 equiv), LiCl (23.26 mg,
0.5488 mmol, 1.0 equiv) and NaHCO3 (230.5 mg, 2.744 mmol,
5.0 equiv) in DMF (20 mL) (3,4-dimethoxyphenyl)propynoic
acid methyl ester9 (7, 145.0 mg, 0.6584 mmol, 1.2 equiv) was
added. After the reaction mixture was stirred under nitrogen at
110 °C for 6 h, it was quenched with saturated aqueous NH4Cl
(50 mL) and extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with a saturated aqueous NaCl solu-
tion (10 mL), dried over MgSO4(s), filtered and concentrated
under reduced pressure to afford a residue. Purification of the
residue by chromatography with a silica gel column (30%
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EtOAc in hexane as the eluent) gave 11 (125.9 mg,
0.3402 mmol) as pale yellow crystalline solids in a 62% yield:
mp (recrystallized from EtOAc) 166–167 °C; TLC Rf 0.36 (40%
48–49 °C; TLC Rf 0.47 (40% EtOAc in hexane as the eluent);
1H NMR (CDCl3; 400 MHz) δ 3.75 (s, 3 H, OCH3), 3.83 (s,
6 H, 2 × OCH3), 3.96 (s, 3 H, CO2CH3), 4.69 (d, J = 7.0 Hz, 1
H, ArCHCO2), 5.85 (d, J = 7.0 Hz, 1 H, ArOCHAr), 6.82 (d,
J = 8.0 Hz, 1 H, ArH), 6.90–6.97 (m, 3 H, 3 × ArH), 7.40 (d,
J = 8.4 Hz, 1 H, ArH), 9.81 (s, 1 H, CHO); 13C NMR (CDCl3;
100 MHz) δ 52.57, 55.85, 55.86, 56.16, 56.52, 88.73, 108.71,
110.96, 111.60, 118.17, 124.49, 126.50, 128.52, 132.01, 149.13,
149.23, 149.47, 149.54, 171.82 (CvO), 190.56 (CvO); MS
(EI) m/z (relative intensity) 372 (M+, 100), 313 (68), 272 (11),
155 (13), HRMS (EI) calcd for C20H20O7: 372.1209, found
372.1176. Its spectroscopic characteristics are consistent with
those previously reported.8
1
EtOAc in hexane as the eluent); H NMR (CDCl3; 400 MHz)
δ 3.92 (s, 3 H, CO2CH3), 3.95 (s, 3 H, OCH3), 3.97 (s, 3 H,
OCH3), 4.10 (s, 3 H, OCH3), 6.92 (d, J = 8.4 Hz, 1 H, ArH),
6.94 (d, J = 8.4 Hz, 1 H, ArH), 7.49–7.54 (m, 2 H, 2 × ArH),
7.75 (d, J = 8.4 Hz, 1 H, ArH), 10.03 (s, 1 H, CHO); 13C NMR
(CDCl3; 100 MHz) δ 52.44, 55.85, 55.90, 56.26, 106.19,
110.10, 110.42, 111.00, 120.94, 121.40, 122.88, 126.79, 131.64,
142.85, 148.86, 149.61, 150.69, 157.10, 166.18 (CvO), 189.63
(CvO); IR (KBr) 3010 (w), 2031 (w), 1722 (s, CvO), 1677
(s), 1617 (m), 1575 (s), 1516 (s), 1499 (s), 1399 (m), 1300 (s),
803 cm−1 (m); MS (FAB) m/z 370 (M+, 75), 339 (100), 311 (9),
221 (15), 165 (8); HRMS (FAB) calcd for C20H18O7: 370.1053,
found 370.1050.
( )-(2E)-3-[2-(3,4-Dimethoxyphenyl)-7-methoxy-3-
methoxycarbonyl-2,3-dihydro benzo[b]furan-4-yl]prop-2-enoic
acid (5): method 1
( )-Methyl trans-2-(3,4-dimethoxyphenyl)-4-hydroxymethyl-7-
methoxy-2,3-dihydrobenzo[b]furan-3-carboxylate (12)
To
a solution containing aldehyde ( )-13 (51.20 mg,
0.1375 mmol, 1.0 equiv) and malonic acid (43.21 mg,
0.4152 mmol, 3.0 equiv) in pyridine (10 mL) piperidine
(68.79 mg, 0.6875 mmol, 5.0 equiv) was added. After the reac-
tion mixture was stirred under nitrogen at 100 °C for 8 h, it was
quenched with saturated aqueous NH4Cl (50 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic layers were
washed with HCl(aq) (1.0 N, 30 mL), dried over MgSO4(s),
filtered and concentrated under reduced pressure to afford a
residue. Purification of the residue by chromatography with a
silica gel column (85% EtOAc in hexane as the eluent) gave
( )-5 (48.20 mg, 0.1169 mmol) as a light yellow solid in a 85%
yield: mp (recrystallized from EtOAc) 65–66 °C; TLC Rf 0.47
(40% EtOAc in hexane as the eluent); 1H NMR (CDCl3;
400 MHz) δ 3.81 (s, 3 H, OCH3), 3.87 (s, 6 H, 2 × OCH3), 3.93
(s, 3 H, CO2CH3), 4.52 (d, J = 5.6 Hz, 1 H, ArCHCO2), 6.07 (d,
J = 5.6 Hz, 1 H, ArOCHAr), 6.31 (d, J = 15.8 Hz, 1 H,
Ph–CvCH–CO2), 6.85–6.92 (m, 4 H, 4 × ArH), 7.26 (d, J = 8.8
Hz, 1 H, ArH), 7.84 (d, J = 15.8 Hz, 1 H, Ph–CHvC–CO2);
13C NMR (CDCl3; 100 MHz) δ 52.80, 55.81, 55.82, 55.83,
56.07, 87.36, 108.69, 111.09, 112.91, 116.61, 117.96, 120.77,
124.04, 125.14, 132.15, 143.12, 146.44, 148.36, 149.15, 149.21,
171.68 (CvO), 172.20 (CvO). Its spectroscopic characteristics
are consistent with those previously reported.9,11
To a solution containing aldehyde 11 (150.1 mg, 0.4055 mmol,
1.0 equiv) and Mg (394.3 mg, 16.22 mmol, 40.0 equiv) in tetra-
hydrofuran (10 mL) and methanol (10 mL) HgCl2 (11.01 mg,
0.0405 mmol, 0.10 equiv) was added. After the reaction mixture
was stirred at room temperature for 48 h, it was quenched with
HCl(aq) (5.0 N, 20 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were washed with a saturated
aqueous NaCl solution (15 mL), dried over MgSO4(s), filtered
and concentrated under reduced pressure to afford a residue.
Purification of the residue by chromatography with a silica gel
column (35% EtOAc in hexane as the eluent) gave ( )-12
(124.4 mg, 0.3325 mmol) as a pale yellow liquid in a 82% yield:
1
TLC Rf 0.37 (40% EtOAc in hexane as the eluent); H NMR
(CDCl3; 400 MHz) δ 3.74 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3),
3.79 (s, 3 H, OCH3), 3.84 (s, 3 H, CO2CH3), 4.24 (d, J = 6.0
Hz, 1 H, ArCHCO2), 4.49 (d, J = 12.4 Hz, 2 H, CH2O), 5.93 (d,
J = 6.0 Hz, 1 H, ArOCHAr), 6.75–6.87 (m, 5 H, 5 × ArH);
13C NMR (CDCl3; 100 MHz) δ 52.82, 55.71, 55.76, 55.77,
55.94, 62.66, 87.08, 108.72, 110.96, 112.54, 118.01, 121.48,
121.49, 123.10, 130.20, 132.47, 144.12, 148.26, 149.00, 172.58
(CvO); IR (neat) 3516 (br, OH), 2952 (m), 2834 (w), 1736 (s,
CvO), 1593 (m), 1515 (s), 1438 (s), 1160 (s), 1024 (s), 808 (m)
cm−1; MS (FAB) m/z 374 (M+, 9), 297 (37), 154 (55), 136 (70),
55 (100); HRMS (FAB) calcd for C20H22O7: 374.1366, found
374.1360.
( )-(2E)-3-[2-(3,4-Dimethoxyphenyl)-7-methoxy-3-
methoxycarbonyl-2,3-dihydro benzo[b]furan-4-yl]prop-2-enoic
Acid (5): method 2
( )-Methyl trans-2-(3,4-dimethoxyphenyl)-4-formyl-7-methoxy-
2,3-dihydrobenzo[b]-furan-3-carboxylate (13)
To a solution containing tert-butyl ester( )-19 (21.20 mg,
0.045 mmol, 1.0 equiv) in CH2Cl2 (15 mL) trifluoroacetic acid
(5.41 mg, 0.4509 mmol, 10.0 equiv) was added via a syringe at
0 °C. After stirring at room temperature for 2 h, it was quenched
with saturated aqueous NaHCO3 (5.0 mL) and the resultant solu-
tion was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with a saturated aqueous NaCl solu-
tion (10 mL), dried over MgSO4(s), filtered and concentrated
under reduced pressure to afford a residue. Purification of the
residue by chromatography with a silica gel column (90%
EtOAc in hexane as the eluent) gave ( )-5 (17.14 mg,
To
a
solution containing alcohol ( )-12 (112.6 mg,
0.3009 mmol, 1.0 equiv) in dichloromethane (10 mL) manga-
nese dioxide (130.7 mg, 1.504 mmol, 5.0 equiv) was added.
After stirring at room temperature for 48 h, the reaction mixture
was filtered through Celite and concentrated under reduced
pressure to afford a residue. Purification of the residue by chrom-
atography with a silica gel column (30% EtOAc in hexane as the
eluent) gave ( )-13 (106.3 mg, 0.2856 mmol) as pale yellow
crystals in a 95% yield: mp (recrystallized from EtOAc)
5462 | Org. Biomol. Chem., 2012, 10, 5456–5465
This journal is © The Royal Society of Chemistry 2012

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1
0.0416 mmol) as a pale yellow solid in a 92% yield. Its spectro-
scopic characteristics are consistent with those previously
reported.9
0.51 (25% EtOAc in hexane as the eluent); H NMR (CDCl3;
400 MHz) δ 2.11 (s, 3 H, SMe), 2.60 (s, 3 H, SOMe), 3.85 (s, 3
H, OCH3), 4.95 (dd, J = 11.2, 10.8 Hz, 2 H, PhCH2), 6.82 (d, J
= 8.8 Hz, 1 H, ArH), 7.24–7.35 (m, 6 H, 6 × ArH), 7.44 (s, 1 H,
CvC–H); 13C NMR (CDCl3; 100 MHz) δ 16.75, 40.14, 55.63,
74.77, 113.01, 113.04, 127.32, 127.73, 127.74, 127.75, 127.82,
128.00, 129.95, 132.11, 136.66, 145.70, 146.66, 151.87; IR
(neat) 3391 (w), 3003 (m), 2838 (m), 1567 (s), 1528 (s), 1436
(s), 1350 (s), 1293 (s), 1063 (s), 979 (s), 883 (m), 802 (s), 733
(s), 698 (s) cm−1; MS (FAB) m/z 427 (M+ + 2, 9), 425 (M+, 9),
347 (16), 287 (40), 147 (55), 91 (100); HRMS (FAB) calcd for
C18H19BrO3S2: 425.9959, found 425.9956.
(10R,20S,21S)-Methyl 2-(3,4-dimethoxyphenyl)-4-([3-(3,4-
dimethoxyphenyl)-1-methoxy-1-oxopropan-2-yloxy]-3-oxoprop-
1-enyl)-7-methoxy-2,3-dihydrobenzo[b]furan-3-carboxylate (2)
and its (10R,20R,21R)-diastereomer (2)
To a solution containing cinnamic acid ( )-5 (55.21 mg,
0.1333 mmol, 1.0 equiv), EDCI (28.11 mg, 0.1466 mmol, 1.1
equiv), DMAP (17.92 mg, 0.1466 mmol, 1.1 equiv) and HOBt
(19.80 mg, 0.1466 mmol, 1.1 equiv) in CHCl3 (10 mL)
(+)-methyl lactate (3, 38.40 mg, 0.1596 mmol, 1.2 equiv) was
added at 0 °C. After the reaction mixture was stirred under nitro-
gen at room temperature for 48 h, it was quenched with saturated
aqueous NH4Cl (20 mL) and extracted with CH2Cl2 (3 ×
15 mL). The combined organic layers were washed with a satu-
rated aqueous NaCl solution (15 mL), dried over MgSO4(s),
filtered and concentrated under reduced pressure to afford a
residue. Purification of the residue by chromatography with
silica gel column (40% EtOAc in hexane as the eluent) gave a
1 : 1 mixture of the title compound (10R,20S,21S)-2 and the
corresponding diastereomeric counterpart (10R,20R,21R)-2
(72.19 mg, 0.1135 mmol) as a yellow foam in a 85% overall
yield: TLC Rf 0.43 (40% EtOAc in hexane as the eluent);
1H NMR (CDCl3; 400 MHz) δ 3.15–3.16 (m, 2 H, ArCH2), 3.70
(s, 6 H, 2 × CO2CH3), 3.71 (s, 3 H, OCH3), 3.80 (s, 6 H, 2 ×
OCH3), 3.81 (s, 3 H, OCH3), 3.82 (s, 6 H, 2 × OCH3), 3.91 (s, 3
H, OCH3), 4.40 (d, J = 5.6 Hz, 1 H, ArCHCO2), 5.26–5.35 (m,
1 H, OCHCOO), 5.99–6.00 (m, 1 H, ArOCHAr), 6.30 (dd, dia-
stereomers, J = 16.0, 4.2 Hz, 1 H), 6.73–6.87 (m, 7 H, 7 × ArH),
7.19 (m, 1 H, ArH), 7.73 (dd, diastereomers, J = 16.0, 4.2 Hz, 1
H); 13C NMR (CDCl3; 100 MHz) δ 37.09, 37.12, 52.27, 52.78,
52.74, 55.78, 55.81, 55.82, 55.90, 55.92, 56.07, 56.14, 73.07,
87.41, 108.77, 108.79, 110.55, 111.13, 111.16, 112.44, 112.48,
112.93, 112.96, 116.37, 116.42, 117.98, 118.01, 120.54, 120.81,
121.40, 121.45, 124.25, 124.34, 124.95, 125.14, 128.30, 132.27,
132.30, 135.26, 142.28, 142.41, 146.35, 148.04, 148.06, 148.40,
148.45, 148.78, 149.23, 149.30, 166.03, 170.23, 171.62, 171.70.
The spectral data are consistent with those previously
reported.8,11
Methyl 2-(2-benzyloxy-6-bromo-3-methoxyphenyl)ethanoate (8)
To
a solution containing ketenethioacetal 16 (1.256 g,
2.948 mmol, 1.0 equiv) in dry MeOH (25 mL) HCl (g) was
added at room temperature for 2 h. After the reaction mixture
was stirred for 2 h, the solvent therein was evaporated under
reduced pressure and the resultant solution was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with a saturated aqueous NaCl solution (20 mL), dried over
MgSO4(s), filtered and concentrated under reduced pressure to
afford a residue. Purification of the residue by chromatography
with a silica gel column (20% EtOAc in hexane as the eluent)
gave 8 (927.1 mg, 2.546 mmol) as a yellow liquid in a 86%
yield: TLC Rf 0.38 (30% EtOAc in hexane as the eluent);
1H NMR (CDCl3; 400 MHz) δ 3.62 (s, 3 H, OCH3), 3.82 (s, 2
H, CH2CO2), 3.85 (s, 3 H, CO2CH3), 5.01 (s, 2 H, PhCH2) 6.78
(d, J = 9.2 Hz, 1 H, ArH), 7.26–7.42 (m, 6 H, 6 × ArH); 13C
NMR (CDCl3; 100 MHz) δ 35.85, 51.92, 55.88, 74.89, 112.69,
112.70, 115.89, 127.55, 127.98, 128.09, 123.33, 128.35, 129.14,
137.28, 147.37, 152.09, 171.05 (CvO); IR (neat) 2074 (w),
1736 (m, CvO), 1635 (s), 1470 (m), 1273 (m), 1078 (m), 1004
(w), 747 (s) cm−1; MS (EI) m/z (relative intensity) 366 (M+ + 2,
65), 364 (M+, 65), 242 (4), 213 (20), 91 (100), 65 (10); HRMS
(EI) calcd for C17H17BrO4: 364.0310, found 364.0307.
( )-Methyl 2-[(2-benzyloxy-6-bromo-3-methoxyphenyl)]-3-
hydroxy-3-(3,4-dimethoxy-phenyl)propanoate (17)
To
a
solution containing diisopropylamine (649.6 mg,
6.416 mmol, 1.1 equiv) in tetrahydrofuran (50 mL) n-butyl-
lithium (397.9 mg, 6.416 mmol, 1.1 equiv) was added at 0 °C.
After stirring for 30 min, the resultant mixture was cooled to
−78 °C. Methyl phenyl acetate 8 (2.125 g, 5.837 mmol, 1.0
equiv) was then added to the reaction mixture, which was stirred
at the same temperature for an additional 30 min. Finally, 3,4-
dimethoxybenzaldehyde (4, 969.6 mg, 5.835 mmol, 1.0 equiv)
was added to the reaction mixture and stirring was continued for
1 h. The reaction mixture was quenched with saturated aqueous
NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with a saturated aqueous
NaCl solution (30 mL), dried over MgSO4(s), filtered and con-
centrated under reduced pressure to afford a residue. Purification
of the residue by chromatography with a silica gel column (30%
EtOAc in hexane as the eluent) gave ( )-17 (2.010 g,
3.792 mmol) as a white solid in a 65% yield: mp (recrystallized
2-Benzyloxy-6-bromo-3-methoxy-2-[2-(methylsulfinyl)-2-
(methylthio)vinyl] benzene (16)
To a solution containing aldehyde24 15 (2.125 g, 6.617 mmol,
1.0 equiv) and Triton
B (4.0 ml) in THF (10 mL)
CH3SCH2SOCH3 (986.2 mg, 7.939 mmol, 1.2 equiv) was added
via a syringe at 0 °C. After the reaction mixture was refluxed at
100 °C for 12 h, it was quenched with saturated aqueous NH4Cl
(20 mL) and the resultant solution was extracted with CH2Cl2 (3
× 50 mL). The combined organic layers were washed with a
saturated aqueous NaCl solution (50 mL), dried over MgSO4(s),
filtered and concentrated under reduced pressure to afford a
residue. Purification of the residue by chromatography with a
silica gel column (20% EtOAc in hexane as the eluent) gave 16
(2.260 g, 5.305 mmol) as a yellow gum in a 80% yield: TLC Rf
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5456–5465 | 5463

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from EtOAc) 95–96 °C; TLC Rf 0.56 (30% EtOAc in hexane as
the eluent); 1H NMR ((CD3)2CO; 400 MHz) δ 3.56 (s, 3 H,
OCH3), 3.66 (s, 6 H, 2 × OCH3), 3.92 (s, 3 H, CO2CH3), 4.56
(br, 1 H), 4.72 (s, 2 H, PhCH2), 5.59 (d, 1 H, CHO), 6.20–6.69
(m, 3 H, 3 × ArH), 6.75 (s, 1 H, ArH), 6.86 (d, J = 8.4 Hz, 1 H,
ArH), 7.15 (d, J = 8.4 Hz, 1 H, ArH), 7.37–7.44 (m, 3 H, 3 ×
ArH), 7.53–7.55 (d, J = 7.2 Hz, 1 H, ArH); 13C NMR
((CD3)2CO; 100 MHz) δ 52.45, 55.56, 55.78, 56.27, 56.28,
73.01, 74.31, 111.31, 111.42, 114.08, 119.88, 128.53, 128.54,
128.55, 128.58, 129.05, 129.06, 129.07, 132.02, 134.57, 134.58,
138.68, 149.18, 149.30, 151.95, 174.42 (CvO); IR (neat)
3478 (br, OH), 2934 (s), 2829 (w), 1718 (s, CvO), 1514 (m),
1465 (s), 1432 (m), 1027 (m), 805 (m) cm−1; MS (FAB) m/z
532 (M+ + 2, 9), 364 (20), 285 (35), 273 (25), 136 (30), 91
(100); HRMS (FAB) calcd for C26H27BrO7: 530.0940, found
530.0947.
saturated aqueous NaCl solution (20 mL), dried over MgSO4(s),
filtered and concentrated under reduced pressure to afford
a residue. Purification of the residue by chromatography with a
silica gel column (20% EtOAc in hexane as the eluent) gave
( )-19 (136.4 mg, 0.2901 mmol) as a yellow foam in a 81%
yield: mp (recrystallized from EtOAc) 101–102 °C; TLC Rf 0.50
(30% EtOAc in hexane as the eluent); 1H NMR (CDCl3;
400 MHz) δ 1.53 (s, 9 H, C(CH3)3), 3.84 (s, 3 H, OCH3), 3.89
(s, 6 H, 2 × OCH3), 3.97 (s, 3 H, CO2CH3), 4.52 (d, J = 5.8 Hz,
1 H, ArCHCO2), 6.05 (d, J = 5.8 Hz, 1 H, ArOCHAr), 6.27 (d,
J = 16.0 Hz, 1 H, Ph–CvCH–CO2), 6.86–6.96 (m, 4 H, 4 ×
ArH), 7.24 (d, J = 8.4 Hz, 1 H, ArH), 7.66 (d, J = 16.0 Hz, 1 H,
Ph–CHvC–CO2); 13C NMR (CDCl3; 100 MHz) δ 28.07, 28.08,
28.09, 52.70, 55.83, 55.84, 56.01, 56.02, 80.25, 87.44, 108.69,
111.04, 112.84, 117.98, 119.78, 120.24, 124.68, 124.75, 132.27,
139.59, 145.77, 148.26, 149.12, 149.18, 166.11 (CvO), 171.84
(CvO); IR (neat) 2972 (w), 2936 (w), 1702 (s, CvO), 1627 (m,
CvO), 1589 (s), 1483 (s), 1276 (s), 1146 (s), 1084 (m), 971
(m), 805 (s) cm−1; MS (EI) m/z (relative intensity) 470 (M+, 64),
440 (8), 414 (52), 382 (32), 337 (100), 309 (23), 239 (16),
231 (23); HRMS (EI) calcd for C26H30O8: 470.1941, found
470.1944.
( )-Methyl trans-2-(3,4-dimethoxyphenyl)-4-bromo-7-methoxy-
2,3-dihydrobenzo[b]-furan-3-carboxylate (18)
To a solution containing ( )-17 (915.6 mg, 1.727 mmol, 1.0
equiv) in dry dichloromethane (30 mL) iodotrimethylsilane
(760.3 mg, 3.799 mmol, 2.2 equiv) was added via a syringe at
0 °C. After stirring at room temperature for 1 h, it was quenched
with saturated aqueous NH4Cl (20 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with a saturated aqueous NaCl solution (15 mL), dried over
MgSO4(s), filtered and concentrated under reduced pressure to
afford a residue. Purification of the residue by chromatography
with silica gel column (25% EtOAc in hexane as the eluent)
gave ( )-18 (546.8 mg, 1.295 mmol) as a yellow gummy oil in a
75% yield: TLC Rf 0.64 (20% EtOAc in hexane as the eluent);
1H NMR (CDCl3; 400 MHz) δ 3.73 (s, 3 H, OCH3), 3.81 (s, 9
H, CO2CH3 + 2 × OCH3), 4.30 (d, J = 7.2 Hz, 1 H, ArCHCO2),
5.82 (d, J = 7.2 Hz, 1 H, ArOCHAr), 6.70 (d, J = 8.8 Hz, 1 H,
ArH), 6.79 (d, J = 8.0 Hz, 1 H, ArH), 6.86–6.92 (m, 2 H, 2 ×
ArH), 6.95 (d, J = 8.8 Hz, 1 H, ArH); 13C NMR (CDCl3;
100 MHz) δ 52.74, 55.93, 55.95, 56.31, 58.09, 87.89, 108.90,
109.70, 111.18, 114.38, 118.29, 118.30, 124.49, 126.21, 131.78,
144.10, 149.29, 149.44, 171.43 (CvO); IR (neat) 2069 (w),
1736 (m, CvO), 1637 (s), 1517 (m), 1485 (m), 1263 (m),
1025 (s), 762 (w) cm−1; MS (EI) m/z (relative intensity)
424 (M+ + 2, 74), 422 (M+, 73), 392 (100), 390 (99), 343 (34),
311 (33), 284 (30), 84 (55); HRMS (EI) calcd for C19H19BrO6:
422.0365, found 422.0362.
Methyl 4-hydroxymethyl-7-methoxy-2-(3,4-dimethoxyphenyl)-
benzo[b]furan-3-carboxylate (20)
To a solution containing aldehyde 11 (51.20 mg, 0.1383 mmol,
1.0 equiv) in dry methanol (10 mL) 10% Pd/C (14.72 mg,
0.1383 mmol, 1.0 equiv) was added. The flask was evacuated
and back-filled with a H2 balloon three times and allowed to stir
under a H2(g) atmosphere at room temperature for 3 h. After-
wards, the reaction mixture was filtered through Celite (rinsing
several times with methanol) and concentrated under reduced
pressure to afford a residue. Purification of the residue by chrom-
atography with a silica gel column (40% EtOAc in hexane as the
eluent) gave 20 (46.12 mg, 0.1239 mmol) as white solids in a
90% yield: mp (recrystallized from CH2Cl2) 98–99 °C; TLC Rf
1
0.37 (35% EtOAc in hexane as the eluent); H NMR (CDCl3;
400 MHz) δ 3.82 (s, 3 H, OCH3), 3.90 (s, 6 H, 2 × OCH3), 3.95
(s, 3 H, CO2CH3), 4.72 (s, 2 H, CH2O), 6.74 (d, J = 8.0 Hz,
1 H, ArH), 6.90 (d, J = 8.4 Hz, 1 H, ArH), 7.11 (d, J = 8.0 Hz,
1 H, ArH), 7.28–7.32 (m, 2 H, 2 × ArH); 13C NMR (CDCl3;
100 MHz) δ 52.18, 55.84, 55.85, 55.92, 63.43, 106.51, 108.90,
110.62, 111.50, 121.98, 122.15, 125.58, 126.18, 126.62, 143.50,
144.94, 148.50, 150.48, 158.70, 166.74 (CvO); IR (neat) 3435
(br, OH), 2849 (w), 2056 (w), 1728 (s, CvO), 1630 (s),
1507 (m), 1464 (m), 1265 (m), 1096 (w), 1052 (w), 738 (s)
cm−1; MS (EI) m/z (relative intensity) 372 (M+, 77) 356 (100),
339 (43), 309 (31), 85 (29), 57 (66); HRMS (EI) calcd for
C20H20O7: 372.1209, found 372.1208.
( )-tert-Butyl (2E)-3-[2-(3,4-Dimethoxyphenyl)-7-methoxy-3-
methoxycarbonyl-2,3-dihydrobenzo[b]furan-4-yl]propenoate
(19)
To a solution containing ( )-18 (151.2 mg, 0.3582 mmol, 1.0
equiv), Pd(OAc)2 (8.043 mg, 0.0358 mmol, 0.10 equiv) and
PPh3 (28.17 mg, 0.1074 mmol, 0.30 equiv) in Et3N (362.1 mg,
3.582 mmol, 10.0 equiv) tert-butyl acrylate (229.5 mg,
1.791 mmol, 5.0 equiv) was added. After the reaction mixture
was stirred under nitrogen at 110 °C for 16 h, it was quenched
with saturated aqueous NH4Cl (20 mL) and extracted with Et2O
(3 × 30 mL). The combined organic layers were washed with a
Methyl 4-methyl-7-methoxy-2-(3,4-dimethoxyphenyl)benzo[b]-
furan-3-carboxylate (21)
To a solution containing aldehyde 11 (65.28 mg, 0.1763 mmol,
1.0 equiv) in dry methanol (10 mL) 10% Pd/C (18.73 mg,
0.1760 mmol, 1.0 equiv) was added. The flask was evacuated
and back-filled with a H2 balloon three times and allowed to stir
5464 | Org. Biomol. Chem., 2012, 10, 5456–5465
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under a H2(g) atmosphere at room temperature for 24 h. After-
wards, the reaction mixture was filtered through Celite (rinsing
several times with methanol) and concentrated under reduced
pressure to afford a residue. Purification of the residue by chrom-
atography with a silica gel column (40% EtOAc in hexane as the
eluent) gave 21 (53.36 mg, 0.1498 mmol) as a yellow foam in a
85% yield: mp (recrystallized from EtOAc) 88–89 °C; TLC Rf
1
12 V. Dalla, P. Cotelle and J. P. Catteau, Tetrahedron Lett., 1997, 38, 1577–
1580.
0.46 (20% EtOAc in hexane as the eluent); H NMR (CDCl3;
400 MHz) δ 2.47 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3), 3.91 (s, 3
H, OCH3), 3.93 (s, 3 H, OCH3), 3.97 (s, 3 H, CO2CH3), 6.72 (d,
J = 8.0 Hz, 1 H, ArH), 6.90–6.94 (m, 2 H, 2 × ArH), 7.39–7.42
(m, 2 H, 2 × ArH); 13C NMR (CDCl3; 100 MHz) δ 18.94,
52.10, 55.89, 55.96, 56.08, 106.94, 109.57, 110.80, 110.86,
121.13, 122.25, 123.13, 125.25, 127.28, 142.97, 143.41, 148.72,
150.28, 155.91, 166.40 (CvO); IR (neat) 2917 (m), 2848 (w),
1723 (s, CvO), 1629 (s), 1509 (s), 1463 (s), 1364 (w), 1262 (s),
1229 (s), 1123 (m), 1043 (m), 800 (m), 736 (m) cm−1; MS (EI)
m/z (relative intensity) 356 (M+, 100), 325 (13), 97 (11), 85 (38),
71 (55), 57 (93); HRMS (EI) calcd for C20H20O6: 356.1260,
found 356.1261.
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We thank the National Science Council (grant No. 99-2113-
M-007-008-MY3) and Ministry of Education of R.O.C. (grant
No. 100N2011E1) for financial support. Valuable suggestions
and information provided by Professor Ru Chih Huang of The
Johns Hopkins University is greatly appreciated.
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