Stereoselective cyclization of stilbene derived carbocations

Article abstract of DOI:10.1016/S0040-4020(03)00050-4

Cyclodimerization of 2,6-dimethoxy-4-methylstilbene under acidic conditions affords the rotationally restricted 1,3-bis-(2,6-dimethoxy-4-methylphenyl)-2-phenyl-1,2,3,4- tetrahydronaphthalene. Nucleophilic addition of this stilbene to 1,4-benzoquinone and maleic anhydride, respectively, followed by an intramolecular cyclization yields dihydrobenzofuran derivatives and a trisubstituted butanolide, respectively. These stereoselective cyclizations involving stilbene derived carbocations apparently biomimic the cyclization of naturally occurring stilbenes during oxidative oligomerization.

Full text of DOI:10.1016/S0040-4020(03)00050-4

Tetrahedron 59 (2003) 1501–1507
Stereoselective cyclization of stilbene derived carbocations
*
Xing-Cong Li and Daneel Ferreira
*
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy,
The University of Mississippi, University, MS 38677, USA
Received 15 October 2002; revised 7 January 2003; accepted 7 January 2003
Abstract—Cyclodimerization of 2,6-dimethoxy-4-methylstilbene under acidic conditions affords the rotationally restricted 1,3-bis-(2,6-
dimethoxy-4-methylphenyl)-2-phenyl-1,2,3,4-tetrahydronaphthalene. Nucleophilic addition of this stilbene to 1,4-benzoquinone and maleic
anhydride, respectively, followed by an intramolecular cyclization yields dihydrobenzofuran derivatives and a trisubstituted butanolide,
respectively. These stereoselective cyclizations involving stilbene derived carbocations apparently biomimic the cyclization of naturally
occurring stilbenes during oxidative oligomerization. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
boron tribromide in dichloromethane,4 yielded a sterically
congested cyclodimerization product, 1,3-bis-(2,6-di-
methoxy-4-methylphenyl)-2-phenyl-1,2,3,4-tetrahydro-
naphthalene (6). The non-symmetric nature of 5 renders this
reaction an ideal model to examine the stereochemical
course of the cyclodimerization of stilbenes. In addition, we
describe the reactions of a stilbene derived carbocation with
selected dienophiles.
Cyclodimerizations of stilbenes under acidic conditions
to form tetralins and/or indanes have been studied
extensively.1,2 Hiscock et al.1 suggested that the mechanism
for the Lewis acid (SbCl3) promoted formation of the
tetralin 3a and indane 4a from symmetric trans-stilbene
(1a) involved a dimeric stilbene carbocation (2) as the
key intermediate (Scheme 1). Recently, Aguirre et al.2,3
attempted to demonstrate the stereoselective nature of the
cyclodimerization of N-1,2-diarylethylamides where forma-
tion of the carbocationic intermediate related to stilbene
1b is catalyzed by ethyl polyphosphate (Scheme 1). In the
course of our synthesis of antifungal styryl 1,4-benzo-
quinones, attempted O-demethylation of the intermediate
2,6-dimethoxy-4-methylstilbene (5) using the Lewis acid,
2. Results and discussion
Reaction of 2,6-dimethoxy-4-methylstilbene (5), available
via n-butyllithium induced reaction of 3,5-dimethoxy-
toluene and phenylacetaldehyde followed by dehydration,
with BBr3 as Lewis acid in CH2Cl2 at 2788C for 50 min
gave compound 6 in 34% yield. The molecular formula of 6,
C34H36O4, which was established by a combination of high
resolution ESI-MS and 13C NMR spectral data indicated
that it is a dimerization product of 5. In the 1H NMR
spectrum of 6, an aromatic methoxy signal appeared at d
3.29 (3H, s), along with three other methoxyls at d 3.62,
3.75, and 3.77 (3H each, s) resonating in the normal range
of aromatic methoxy protons (d 3.6–4.0). The appearance
1
of four instead of two methoxy signals, in the H- and 13C
NMR spectra indicated that 6 was rotationally restricted.
The presence of five coupled aliphatic proton signals at d
4.91 (d, J¼10.7 Hz), 4.38 (dd, J¼10.7, 11.6 Hz), 4.27 (ddd,
J¼12.0, 11.6, 4.0 Hz), 3.82 (dd, J¼16.0, 12.0 Hz) and 2.87
1
(dd, J¼16.0, 4.0 Hz) in the H NMR spectrum, which was
Scheme 1. Proposed mechanism for the formation of tetralins 3a, b and
indanes 4a, b from stilbenes.
supported by a DQF-COSY, suggested that 6 possessed
a 1,2,3-trisubsititued tetrahydronaphthalene (tetralin) skele-
ton.1,2 The protonated carbon signals were further assigned
by an HMQC spectrum. Using an HMBC 0ex0pe0riment,5 the
long-range H/C correla0t0i0 ons, e.g. H-1/C-1 ,2 ,6 , H-2/C-100,
200,600, and H-3/C-1000,2 ,6000, were established. Thus, the
Keywords: stereoselective cyclization; stilbene; tetrahydronaphthalene;
dihydrobenzofuran; butanolide.
*
Corresponding authors. Tel.: þ1-662-915-1572; fax: þ1-662-915-7062;
e-mail: dferreir@olemiss.edu; xli@olemiss.edu.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00050-4

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X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
a conformation presumably being stabilized by attracting
p-alkyl interactions.6 The NOE correlation of MeO-20 with
H-30 further permitted complete NMR assignments of this
more rotationally restricted 2,6-dimethoxy-4-methylphenyl
moiety compared to the unit at C-3 (Table 1). The benzene
ring at C-2 should be able to rotate freely, as was evidenced
by the equivalent chemical shifts of H/C-200,600 and H/C-300,
500 as well as the NOE correlations of H-200,600 with both H-1
and H-3.
The cyclodimerization of 5 was optimized with different
acidic reagents and a remarkable yield (95%) was achieved
in trichloroacetic acid/MeOH at room temperature for 4
days. As could be anticipated only one pair of enantiomers
was obtained from the dimerization reaction, hence the
reaction being stereoselective.
Figure 1. Steric view of compound 6.
The mechanism for the formation of 6 (Scheme 2) shows
that in this type of reaction the carbocation 12 is exclusively
generated at the position a to the more electron-rich
aromatic ring. The dimeric carbocation 13 will then
intramolecularly alkylate the aromatic rings A and/or B,
depending on the nucleophilicity of the ortho-carbons of
each aromatic ring, to form indanes and/or tetralins (also
refer to Scheme 1), the latter compounds arising via
aromatization of intermediate 15. In the case of stilbene 5,
tetralin 6 is the only product since the ortho-positions of the
A-ring are blocked by the methoxy groups. The stereo-
selective control of this reaction is the key step forming the
relatively low-energy 2,3-trans intermediate 13. An alterna-
tive 2,3-cis intermediate 16 would impose a higher degree
of steric congestion than 13. Intermediate 13 will then
NMR data indicated that the structure of 6 is 1,3-bis-(2,6-
dimethoxy-4-methylphenyl)-2-phenyl-1,2,3,4-tetrahydro-
naphthalene. The coupling constants of the five aliphatic
protons as well as the NOE correlations (H-1/H-3; H-2/
H-4b) suggested that 6 possessed a 1,2-trans-2,3-trans
relative stereochemistry with a pseudo-chair conformation.
The 3D-structure of 6, which was generated by Chem3D
Proe 5.0 and energy-minimized by MM2, showed that the
MeO-20 was located directly above the plane of the aromatic
ring of the tetrahydronaphthalene moiety, explaining the
significant shielding of the methoxy protons (Fig. 1), such
Table 1. NMR data for compound 6 in CDCl3 (d, ppm; J, Hz)
C/H
dC
dH
NOESY
1
2
3
4
44.4
47.6
36.7
35.4
4.91 d (10.7)
4.38 dd (10.7, 11.6)
4.27 ddd (16, 11.6, 4.0)
3.82 dd (16, 12.0)…4b
H-3,8,200,600
H-4b,200,600
H-1,4a,200,600
H-2
2.87 dd (16, 4.0)…4a
7.12 d (7.4)
7.06 t (7.4)
6.98 t (7.4)
6.80 d (7.7)
–
–
H-3,5
H-4a
–
–
H-1
–
5
6
7
8
128.2
124.7
125.5
127.8
142.2
138.2
120.3
158.9
105.8
137.2
107.0
159.0
56.4
9
10
–
–
–
10
–
20
–
6.17 s
–
6.35 s
–
3.29 s
3.62 s
2.29 s
–
6.93 br d (8.8)
6.91 br t (7.6)
6.85 br t (7.0)
30
MeO-20, Me-40
40
–
50
MeO-60, Me-40
60
–
MeO-200
MeO-6
Me-40
100
H-300
56.1
22.3
H-5
H-30,50
145.6
128.6
126.8
125.1
118.4
159.4a
105.3b
136.9
105.6b
158.1a
55.4b
56.3b
22.1
–
H-1,2,3
–
–
–
200,600
300,500
400
1000
–
–
2000
–
3000
6.19 sa
–
MeO-2000
4000
–
5000
6.20 sa
–
MeO-6000
–
6000
3.78 sb
3.75 sb
2.21 s
H-3
H-5
000
000
000
000
MeO-2
MeO-6
Me-4000
H-3000,5000
a,b
Signals may be interchangeable within each column.

X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
1503
Scheme 2. Stereoselective formation of 6.
Scheme 3. Proposed [5þ2]-cycloaddition of stilbenes with benzoquinones.7
determine a 1,2-trans conformation for the carbocation 14
in the final intramolecular cyclization step, since a 1,2-cis
conformation 17 would impose considerable steric hin-
drance between the 2,6-dimethoxy-4-methylphenyl moiety
at C-1 and the two benzene rings.
reactions of stilbenes with 2-substituted 1,4-benzoquinone
derivatives under Lewis acid catalysis have been
reported7–9 and the stereoselective formation of 2,3-trans-
dihydrobenzofuran was proposed to proceed via an initial
[5þ2]-cycloaddition of the styrene with the pentadienyl
carbocation moiety of the Lewis acid-quinone complex
followed by rearrangement of intermediate 18 into dienone
19 (Scheme 3).7 However, this mechanism seems inapplic-
able to our case since the 1,4-benzoquinone (9) would not be
able to stabilize the carbocation formed as indicated in
intermediate 18 (Scheme 3). We assume that the mechanism
for the formation of 7 is simply via generation of the
stablized carbocation 21 that originates by addition of 5
to the ‘activated’ benzoquinone 20 (Scheme 4). Stereo-
selective formation of 2,3-trans stereochemistry of the
Reaction of 5 with 1,4-benzoquinone (9) under acid
catalysis (HCl/MeOH or Cl3CCOOH/MeOH) afforded
products 7 and 8. The structure of 7 was established as
2,3-trans-2-(2,6-dimethoxy-4-methylphenyl)-5-methoxy-3-
phenyl-2,3-dihydrobenzofuran by ESI-MS and NMR
including COSY, HMQC, and HMBC. The trans-stereo-
chemistry of the dihydrobenzofuran was confirmed by a
NOESY experiment, which showed NOE correlations
between H-2 and H-200/-600 of the benzene ring. Similar
Scheme 4. Stereoselective formation of 7 and 8.

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X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
Scheme 5. Stereoselective formation of 11.
dihydrobenzofuran ring is then determined by the lower
degree of steric hindrance of the aromatic rings in
intermediates 21 and 22, compared to 24 and 25,
respectively. Compound 7 is susceptible to further acid-
catalyzed reaction with intermediate 20 to give compound 8
via cyclization of intermediate 23.
oxy-1-phenyl-1,2-dihydro-3,9-dioxacyclopenta[b]fluorene.
The mechanism for the formation of this product (Scheme
4) is supported by previously reported reactions of
resorcinol with 1,4-benzoquinone.10 It is interesting to
note that the ESI-MS of 8 exhibited a strong fragmentation
ion peak of [M2COMe2CO], characteristic for 2-methoxy-
dibenzofuran derivatives as shown in their EI-MS spectra,11
without giving the molecular ion peak. Both compounds 7
and 8 were again obtained as the 2,3-trans racemates.
The NMR spectra of compound 8 showed close resem-
blance with those of 7 except for an additional aromatic
ring. Using an HMBC spectrum, the structure of 8 was
established as 2-(2,6-dimethoxy-4-methylphenyl)-6-meth-
Reaction of stilbene 5 with maleic anhydride (10) in
Scheme 6. Possible biosynthetic pathways of resveratrol dimers.

X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
1505
BBr3/CH2Cl2 at 2788C for 30 min followed by work-up in
the presence of MeOH afforded, in addition to the
cyclodimerization product 6, a novel butanolide 11. The
molecular formula of 11 was determined as C22H24O6 by a
combination of HRESI-MS and 13C NMR spectral data. The
presence of a phenyl group and a 2,6-dimethoxyl-4-
methylphenyl moiety was readily confirmed by the 1H-
and 13C NMR spectra. DQF-COSY of 11 showed five
coupled aliphatic protons of one spin-network at d 6.06
(1H, d, J¼9.4 Hz), 3.96 (1H, dd, J¼11.5, 9.4 Hz), 3.43 (1H,
ddd, J¼11.5, 7.4, 6.0 Hz), 2.94 (1H, dd, J¼15.6, 5.9 Hz),
and 2.58 (1H, dd, J¼15.6, 7.5 Hz). These protons were
correlated with respective carbons by an HMQC spectrum.
Additionally, two carbonyl groups at d177.1 and 171.8 and
one methoxy group at d 52.2 appeared in the 13C NMR
spectrum. In conjunction with the HMBC analysis, the
structure of 11 was established as methyl [5-(2,6-di-
methoxy-4-methylphenyl)-2-oxo-4-phenyltetrahydrofuran-
3-yl]-acetate. Since the coupling constants between
protons of the g-lactone ring may not be reliable for
assigning their relative stereochemistry,7,12 a NOESY
experiment was performed. The key NOE correlations
between H-200/600 of the benzene ring and both H-3 and H-5
indicated a trans,trans-relative stereochemistry of H-3, H-4,
and H-5. Such assignments were further supported by the
weak NOE correlation between H-3 and H-5.
used as an additional tool in characterizing complex
naturally occurring stilbene oligomers.22–24
3. Experimental
3.1. General
Melting points were measured on a Thomas Hoover
capillary melting point apparatus and are uncorrected. UV
spectra were measured on a Hewlett Packard 8453
spectrometer. IR spectra were recorded on an ATI Mattson
Genesis Series FTIR Spectrometer. NMR spectra were
recorded on Bruker Avance DPX-300 (300 MHz), DRX-
400 (400 MHz) or DRX-500 (500 MHz) NMR spectro-
meters. Chemical shifts are expressed relative to the
deuterated solvent (CDCl3: dH/dC, 7.26/77.4). COSY,
HMQC, HMBC (J, 10 Hz), NOESY (mixing time,
800 ms) spectra were performed with standard pulse
programs. GC–MS was run on an Hewlett–Packard (HP)
5890 Series II Plus Gas Chromatograph interfaced to a HP
5970B Mass Selective Detector: DB-1 minibore capillary
column (0.18 mm ID, 20 m), column temperature
100!2808C (108C/min!25 min), He (45 psi). ESI-FTMS
were measured on a Bruker-Magnex BioAPEX 30es ion
cyclotron high-resolution HPLC-FT spectrometer by direct
injection into an electrospray interface. Column chroma-
tography was run on silica gel (40 mm, J. T. Baker). TLC
The mechanism for the formation of racemic 11 is similar to
the aforementioned genesis of dihydrobenzofurans 7 and 8.
Nucleophilic addition of 5 to the BBr3 activated maleic
anhydride complex generates the stilbene derived carbo-
cation 26, which undergoes an intramolecular cyclization
to form the bicyclic intermediate 27/28 (Scheme 5).
Methanolysis of the intermediate gives the final product
11. The stereoselectivity of this reaction is also similar to
that depicted in Scheme 4. Formation of the 3,4-trans
configured heterocyclic ring is determined by steric control
of the benzene ring and the C-3 side chain.
was performed on silica gel sheets (Alugramw Sil G/UV254
,
Macherey-Nagel, Germany). All the reagents were pur-
chased from Aldrich (Milwaukee, WI).
3.1.1. 2,6-Dimethoxy-4-methylstilbene (5). According to
the procedure for preparation of similar compounds,25,26
n-butyllithiuim (10.3 mL of a 2.5 M solution in hexane,
25.75 mmol) was slowly added to a cold (08C) solution of
3,5-dimethoxytoluene (2.61 g, 17.17 mmol) in dry Et2O
(50 mL) under an argon blanket. After 30 min stirring at
08C, the formation of a white precipitate was observed.
The mixture was further stirred at room temperature for
24 h. The resulting suspension was cooled again to 08C and
phenylacetylaldehyde (3 mL, 25.75 mmol) was added
dropwise over 10 min. After 1 h stirring at 08C, the cloudy
reaction mixture was quenched by the addition of
ammonium chloride solution (15 mL). The Et2O layer was
separated, and the aqueous layer was extracted with Et2O
(15 mL£3). The organic layers were combined and washed
with brine, dried (MgSO4), and concentrated to give an oily
residue. To this oil was added 250 mL of MeOH and 4 mL
of concentrated HCl. After stirring at room temperature
for 24 h, the solution was neutralized with 6% NaOH,
concentrated to half volume, and extracted with Et2O
(100 mL£4). The Et2O layer was washed with brine, dried
(MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (200 g) eluting with a mixture of
hexane and CH2Cl2 (3:1, 1.5 L, 1:2, 500 mL) and CH2Cl2
(500 mL) to yield compound 5 (1.2 g, 28%) as a viscous
oil, UV (MeOH) lmax (log 1) 208 (4.33), 230 (sh, 4.04),
320 (4.16), 338 (sh, 3.98) nm; IR (KBr) nmax 3077–2836
(multiple peaks), 1609, 1584, 1474, 1417, 1197, 1120, 971,
It is interesting to note that the aforementioned reactions
seem to mimic the oligocyclizations of naturally occurring
stilbenes, e.g. resveratrol (29), which is widely distributed in
the plant kingdom and well-known for its important
biological activities.13,14 The difference is, however, that
dimerizations or oligomerizations of resveratrol catalyzed
by enzymes in organisms presumably involve phenol
oxidative coupling via stilbene derived radicals (29a–e).
The possible biosynthetic routes for the formations of a few
representative resveratrol dimers (30–36)15–20 are pro-
posed as shown in Scheme 6. This may explain the natural
occurrence of ampelopsin D (33),18 the structure of which
had been questioned19 but was later confirmed by chemical
and spectral evidence.21
In conclusion, the formation of stilbene-derived carbo-
cations in the reactions of stilbene derivatives with acidic
reagents has been clearly defined. Similar to the intra-
molecular cyclizations of naturally occurring stilbenes
which contribute to their fascinating oligomerization
chemistry, the susceptibility of the stilbene-derived carbo-
cations to stereoselective cyclizations may be useful for
preparation of stilbene derivatives. The proposed bio-
synthetic routes of resveratrol dimers (Scheme 6) can be
1
950, 748, 699 cm21; H NMR (CDCl3, 400 MHz) d: 7.64
(1H, d, J¼17.0 Hz), 7.63 (2H, d, J¼7.0 Hz), 7.55 (1H, d,
J¼17.0 Hz), 7.41 (2H, t, J¼7.5 Hz), 7.28 (1H, t, J¼7.3 Hz),

1506
X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
6.48 (2H, s), 3.94 (6H, s), 2.43 (3H, s); 13C NMR (CDCl3,
100 MHz) d: 158.6 (2C), 139.7, 138.6, 131.4, 128.6 (2C),
126.9, 126.4 (2C), 120.2, 112.2, 105.1 (2C), 55.8 (2C), 22.3;
GC–MS (tR¼13.26 min) m/z 254 [M, base beak]þ.
(CDCl3, 300 MHz) d: 7.30 (2H, br t, J¼7.3 Hz, H-300,500),
7.24 (1H, br t, J¼7.3 Hz, H-400), 7.20 (2H, br d, J¼7.3 Hz,
H-200,600), 6.77 (1H, d, J¼7.0 Hz, H-7), 6.73 (1H, d0d, 0J¼7.0,
2.2 Hz, H-6), 6.59 (1H, br s, H-4), 6.40 (2H, s, H-3 ,5 ), 6.16
(1H, d, J¼9.4 Hz, H-2), 5.05 (1H0, d, J¼9.0 Hz, H-3), 3.74
(3H, s, MeO-5), 3.63 (6H, s, H-2 ,60), 2.35 (3H,0 s,0 Me-40);
13C NMR (CDCl3, 75 MHz) d: 159.7 (2C, s, C-2 ,6 ), 155.2
3.1.2. 1,2-trans-2,3-trans-1,3-Bis-(2,6-dimethoxy-4-methyl-
phenyl)-2-phenyl-1,2,3,4-tetrahydronaphthalene (6). To
a stirred solution of 5 (67 mg, 0.264 mmol) in dry CH2Cl2
(5 mL) at 2788C under argon, BBr3 in CH2Cl2 (1 M,
0.53 mL, 0.53 mmol) was added dropwise. After stirring
at 2788C for 50 min, the mixture was warmed to room
temperature and quenched with saturated aqueous ammo-
nium chloride (2 mL) and H2O (10 mL). The mixture was
stirred for 1 h, the organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (10 mL£3). The
combined organic layers were concentrated to dryness, and
the residue was chromatographed on silica gel eluting with a
mixture of hexane and CHCl3 to give recovered 5 (22 mg)
and compound 6 (31 mg, 34%) as colorless needles, mp
2148C, UV (MeOH) lmax (log 1) 210 (4.45), 238 (sh, 3.76),
270 (2.86) nm; IR (KBr) nmax 3077–2835 (multiple peaks),
1608, 1584, 1465, 1417, 1237, 1206, 1124, 972, 816, 742,
00
(s, C-8), 154.2 (s, C-5), 143.3 (s, C-1 ), 140.7 (s, C-40),
00
132.8 (s, C-9), 128.9 00 (2C, d, C-300,5 ), 128.8 (2C, d,
C-200,600), 127.1 (s, C-4 ), 113.50 (d, C-6), 113.3 (s, C-10),
111.2 (d, C-4), 106.2 (2C, C-30,5 ), 85.3 (d, C-2), 56.4 (2C,
q, MeO-20,60), 54.4 (2C, C-3 and MeO-5), 22.6 (q, Me-40);
ESI-MS m/z 399 [M(C24H26O5)þNa]þ, 377 [MþH]þ; GC–
MS (tR¼18.89 min) m/z 376 [M]þ, 345 [3762OMe]þ.
Compound 8: white powder, mp 170–1728C, UV (MeOH)
lmax (log 1) 210 (4.90), 238 (sh, 4.12), 310 (3.93) nm; IR
(KBr) nmax 3070–2838 (multiple peaks), 1608, 1585, 1477,
;
1419, 1216, 1121, 955, 815, 738, 699 cm21 1H NMR
(CDCl3, 500 MHz) d: 7.31 (2H, br t, J¼7.6 Hz, H-30,50),
7.25 (1H, br t, J¼7.6 Hz, H-40), 7.19 (2H, br d, J¼7.6 Hz,
H-20,60), 6.96 (1H, d, J¼7.8 Hz, H-8), 6.91 (1H, d, J¼
2.9 Hz, H-5), 6.82 (s, H-4), 6.78 (1H, dd, J¼8.9, 2.9 Hz,
H-7), 6.68 (1H, d, J¼0.6 Hz, H-10), 6.41 (2H, s, H-300,500),
6.19 (1H, d, J¼8.7 Hz, H-2), 4.98 (1H, d, J¼8.7 Hz, H-1),
3.78 (3H, s, MeO-6), 3.65 (6H, s, H-200,600), 2.37 (3H, s,
Me-400); 13C NMR (CDCl3, 125 MHz) d: 159.6 (2C, s,
C-200,600), 154.9 (s, C-3a), 154.1 (s, C-6), 145.9 (s, C-8a),
145.6 (s, C-9a), 143.0 (s,0 C-10), 141.0 (s, C-400), 132.7 (s,
C-10a), 128.9 (2C, d, C-3 ,50), 128.6 (2C, d, C-20,60), 127.2
(d, C-40), 120.3 (s, C-5a), 118.5 (s, C-4a), 117.0 (d, C-8),
114.9 (d, C-7), 114.5 (d, C-5), 113.0 (s, C-100), 112.8 (d,
C-10), 109.1 (d, C-4), 106.1 (2C, d, C-300,500), 85.7 (d, C-2),
56.4 (2C, q, MeO-200,600), 56.3 (q, MeO-6), 54.1 (d, C-1),
22.5 (q, Me-400); ESI-MS m/z 397 [M(C30H26O5)2COMe2
COþ2H]þ; GC–MS (tR¼20.69 min) m/z 466 [M]þ, 396
[M2COMe2COþH]þ, 365 [3962OMe]þ.
1
697, 584 cm21; H (500 MHz) and 13C (125 MHz) NMR
data in CDCl3, see Table 1; HRESI-MS m/z 509.2696
(calcd for [M(C34H36O4)þH]þ, 509.2686); GC–MS (tR¼
26.02 min) m/z 508 [M]þ, 417, 356, 265, 223 (base peak),
165, 91.
Cyclodimerization of 5 was performed under different
conditions: (a) HCl/MeOH, rt/2 days; (b) Cl3CCOOH/CH2-
Cl2, rt/4 days; (c) Cl3CCOOH/EtOH, rt/2 days; and (d)
Cl3CCOOH/MeOH, rt/4 days. The formation of 6 with a
95% isolated yield was achieved under the conditions in d
with complete consumption of 5.
3.1.3. 2,3-trans-2-(2,6-Dimethoxy-4-methylphenyl)-5-
methoxy-3-phenyl-2,3-dihydrobenzofuran (7) and 2-
(2,6-dimethoxy-4-methylphenyl)-6-methoxy-1-phenyl-
1,2-dihydro-3,9-dioxacyclopenta[b]fluorene (8). A solu-
tion of 5 (36 mg, 0.142 mmol), 9 (36 mg, 0.333 mmol) and
concentrated HCl (0.5 mL) in MeOH (5 mL) was stirred at
room temperature for 2 days. The mixture was neutralized
with NaHCO3. After adding H2O (10 mL), the mixture was
extracted with CH2Cl2 (10 mL£3). The combined organic
layers were washed with brine (20 mL), dried (MgSO4), and
concentrated. The residue was chromatographed on silica
gel eluting with a mixture of hexane and CH2Cl2 to give
compounds 6 (5 mg, 10%), 7 (8 mg, 23%) and 8 (6 mg,
14%) with a recovery of 5 (12 mg).
3.1.4. Methyl [5-(2,6-dimethoxy-4-methylphenyl)-2-oxo-
4-phenyltetrahydrofuran-3-yl]-acetate (11). To a stirred
solution of 5 (57 mg, 0.224 mmol) and 10 (31 mg,
0.316 mmol) in dry CH2Cl2 (5 mL) at 2788C under argon
BBr3 in CH2Cl2 (1 M, 0.3 mL, 0.3 mmol) was added
dropwise. After stirring at 2788C for 30 min, the mixture
was warmed to room temperature and quenched with
saturated aqueous ammonium chloride (5 mL) and 50%
aqueous MeOH (10 mL). The organic layer was separated,
the aqueous layer was diluted with H2O and then extracted
with CH2Cl2 (10 mL£3). The combined organic layers were
concentrated to dryness. The residue was chromatographed
on silica gel eluting with a mixture of hexane and CHCl3 to
give compounds 11 (14 mg, 20%) and 6 (6 mg, 7%) with a
recovery of 5 (11 mg). 11: colorless needles, 1438C, UV
(MeOH) lmax (log 1) 210 (4.88), 238 (sh, 4.19), 284
(2.57) nm; IR (KBr) nmax 3080–2840 (multiple peaks),
1766 (lactone), 1730 (ester), 1611, 1585, 1463, 1420, 1245,
Similarly, a solution of 5 (36 mg, 0.142 mmol), 9 (28 mg,
0.259 mmol) and Cl3CCOOH (35 mg, 0.214 mmol) in
MeOH (5 mL) was stirred at room temperature for 4 days.
Work-up and chromatography on silica gel eluting with a
mixture of hexane and CH2Cl2 gave compounds 7 (22 mg,
50%) and trace amount of 8 (,1 mg) with a recovery of 5
(6 mg). Cyclodimerization of 5 to form 6 was not detected
under these conditions.
1
1179, 1115, 989, 827, 755, 705 cm21; H NMR (CDCl3,
500 MHz) d: 7.30 (2H, br t, J¼7.2 Hz, H-300,500), 7.2400(1H,
br t, J¼7.2 Hz, H-400), 7.20 (2H, br d, J¼7.2 Hz, H-2 ,600),
6.36 (2H, s, H-3000,5000), 6.06 (1H, d, J¼9.4 Hz, H-5), 3.96
(1H, dd, J¼11.5, 9.4 Hz, H-4), 3.70 (6H, s, MeO-2000,6000),
3.47 (3H, s, MeO-20), 3.43 (1H, ddd, J¼11.5, 7.4, 6.0 Hz,
H-3), 2.94 (1H, dd, J¼15.6, 5.9 Hz, H-10a), 2.58 (1H, dd,
Compound 7: colorless needles, mp 1408C, UV (MeOH)
lmax (log 1) 210 (4.88), 238 (sh, 4.18), 302 (2.79) nm; IR
(KBr) nmax 3080–2823 (multiple peaks), 1609, 1586, 1486,
1465, 1204, 1118, 1033, 952, 814, 740, 702 cm21; 1H NMR

X.-C. Li, D. Ferreira / Tetrahedron 59 (2003) 1501–1507
1507
J¼15.6, 7.5 Hz, H-10b), 2.33 (3H, s, Me-4000); 13C NMR
(CDCl3, 125 MHz) d: 177.1 (s, C-2), 171.8 (s, C-20), 159.4
7. Engler, T. A.; Draney, B. W.; Gfesser, G. A. Tetrahedron Lett.
1994, 35, 1661–1664.
000
(2C, s, C-2 ,6000), 141.5 (s, C-4000), 138.8 (s, C-100), 129.0
8. Engler, T. A.; Letavic, M. A.; Combrink, K. D.; Takusagawa,
F. J. Org. Chem. 1990, 55, 5810–5812.
00
00
(2C, d, C-3 ,500), 128.2 (2C, d, C-2 ,600), 127.9 (d, C-400),
000
110.7 (s, C-1000), 106.1 (2C, d, C-3000,5 ), 78.7 (d, C-5), 56.5
9. Engler, T. A.; Combrink, K. D.; Ray, J. E. J. Am. Chem. Soc.
1988, 110, 7931–7933.
(2C, s, MeO-2000,6000), 52.2 (s, MeO-2 ), 52.1 (d, C-4), 22.6
0
(s, Me-4000); HRESI-MS m/z 385.1661 (calcd for
[M(C22H24O6)þH], 385.1646), 407.1439 (calcd for
[M(C22H24O6)þNa], 407.1465).
10. Hoegberg, H. E.; Komlos, P. Acta Chem. Scand. 1979, 33,
271–276.
¨
11. Pring, B. G.; Stjernstrom, N. E. Acta Chem. Scand. 1968, 22,
549–561.
12. Nakajima, K.; Taguchi, H.; Endo, T.; Yosioka, I. Chem.
Pharm. Bull. 1978, 26, 3050–3057.
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C. F.; Beecher, C. W. W.; Fong, H. H. S.; Farnsworth, N. R.;
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Science 1997, 275, 218–220.
The authors wish to thank Mr Frank M. Wiggers for NMR
spectra, Dr D. Chuck Dunbar and Ms Rangavalli Manyam
for measuring ESI-MS, and Dr Baogen Wu for helpful
discussion. This work was supported by the United States
Department of Agriculture, Agricultural Research Service
Specific Cooperative Agreement No. 58-6408-2-0009.
15. Ducrot, P.-H.; Kollmann, A.; Bala, A. E.; Majira, A.; Kerhoas,
L.; Delorme, R.; Einhorn, J. Tetrahedron Lett. 1998, 39,
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16. Breuil, A.-C.; Adrian, M.; Pirio, N.; Meunier, P.; Bessis, R.;
Jeandet, P. Tetrahedron Lett. 1998, 39, 537–540.
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