Tandem pericyclic reactions in a new FeCl3-promoted synthesis of catechol analogues of restrytisol C

Article abstract of DOI:10.1016/S0040-4020(02)00798-6

The uncommon stilbene, 3,4-dimethoxy-12-acetoxy stilbene, has been synthesised by Heck coupling methodology in three steps. Treatment of this stilbene with ferric chloride in dichloromethane (room temperature) gave the unnatural stilbenoid dimers; 8,8′-(12,12′-bisacetoxyphenyl)-7′-(3′,4′- dimethoxyphenyl)-3,4-dimethoxy-7′,8′-dihydro-naphthalene and 8-(12-acetoxyphenyl)-8′-(12′-hydroxyphenyl)-7′-(3′, 4′-dimethoxyphenyl)-3,4-dimethoxy-7′,8′-dihydro- naphthalene. The structures of both stilbene dimers were unambiguously confirmed by 1D (¹H, ¹³C) and 2D NMR experiments (COSY, HMQC, HMBC and NOESY). This is the first report of a FeCl₃-promoted sequential pericyclic pathway leading to a highly oxygenated oligostilbenoid dimer (incorporating two asymmetric centres). The NMR spectroscopic evidence and a mechanistic interpretation consistent with these structures are discussed.

Full text of DOI:10.1016/S0040-4020(02)00798-6

Tetrahedron 58 (2002) 7201–7206
Tandem pericyclic reactions in a new FeCl3-promoted synthesis of
catechol analogues of restrytisol C
b
b
b
c
d
N. F. Thomas,a K. C. Lee, Thomas Paraidathathu, J. F. F. Weber, K. Awang, D. Rondeau
,
*
and P. Richommed
aDepartment of Pharmacy, Faculty of Health, Science and Applied Science, Sedaya International College, Taman Segar, Cheras,
56100 Kuala Lumpur, Malaysia
bDepartment of Pharmacy, Faculty of Allied Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz,
50300 Kuala Lumpur, Malaysia
cDepartment of Chemistry, Faculty of Sciences, Universiti Malaya, 59100 Kuala Lumpur, Malaysia
´
SCRMN, Faculte des Sciences, 2, Bd. Lavoisier, 49045 Angers Cedex, France
d
Received 10 May 2002; revised 12 June 2002; accepted 4 July 2002
Abstract—The uncommon stilbene, 3,4-dimethoxy-12-acetoxy stilbene, has been synthesised by Heck coupling methodology in three steps.
Treatment of this stilbene with ferric chloride in dichloromethane (room temperature) gave the unnatural stilbenoid dimers; 8,80-(12,120-
bisacetoxyphenyl)-70-(30,40-dimethoxyphenyl)-3,4-dimethoxy-70,80-dihydro-naphthalene and 8-(12-acetoxyphenyl)-80-(120-hydroxy-
phenyl)-70-(30,40-dimethoxyphenyl)-3,4-dimethoxy-70,80-dihydro-naphthalene. The structures of both stilbene dimers were unambiguously
confirmed by 1D (1H, 13C) and 2D NMR experiments (COSY, HMQC, HMBC and NOESY). This is the first report of a FeCl3-promoted
sequential pericyclic pathway leading to a highly oxygenated oligostilbenoid dimer (incorporating two asymmetric centres). The NMR
spectroscopic evidence and a mechanistic interpretation consistent with these structures are discussed. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
It is by now well established that resveratrol 1, a stilbene,
has significant antiplatelet1 and antioxidant2 properties. It is
also the biosynthetic progenitor of the oligostilbenoid
polyphenols3 such as 1-viniferin 2, balanocarpol 3, heimiol
A 4 and hopeaphenol 5 (Scheme 1). Some of these are
known to have interesting biological activities. Oligo-
stilbenoid polyphenols are generated from resveratrol by
oxidative phenolic coupling, and like resveratrol, possess
the typical resorcinol arrangement. Stilbene monomer
building blocks with the catechol arrangement are relatively
infrequently used in oligostilbenoid biosynthesis. One can
of course speculate on the reasons for this. Specific enzyme
systems capable of binding efficiently to catechol stilbenes
may be less common. The ortho dihydroxy substituents in
such stilbenes tend to be protected for example as dimethyl
ethers or as methylenedioxyethers.3 We have noticed that a
significant proportion of these stilbenes lack the all
important trans olefinic bond between the two benzene
rings which must surely severely limit the options for
complex phenol biosynthesis. Our previous work in the
oligostilbenoids has included the isolation and structure
Keywords: stilbene; ferric chloride; pericyclic; dihydronaphthalene;
restrytisol.
*
Corresponding author. Fax: þ60-3-2698-3271;
e-mail: noelthomas@sedaya.edu.my
Scheme 1. Examples of oligostilbenoid polyphenols.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00798-6

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N. F. Thomas et al. / Tetrahedron 58 (2002) 7201–7206
Scheme 2. Synthesis of stilbene 8 and transformation of 8 to dihydronaphthalene stilbene dimers.
elucidation of a new oligostilbenoid heimiol A 4.4 Further
investigation has resulted in our recent report of the regio
controlled oxidative lactonisation of stilbenes using
manganese triacetate.5–7 Since nature is able to construct
complex polyphenols from unprotected stilbenes like
resveratrol, we were keen to study oxidative coupling of
our stilbenes with one electron oxidants such as manganese
triacetate, vanadium oxytrichloride8 and FeCl3. This type of
study has not received much attention.
rings B and D. These are 7.32 ppm, doublet J¼8.7 Hz
integrating for two protons (H-10, H-14); 6.94 ppm,
doublet, J¼8.7 Hz, integrating for two protons (H-11,
H-13), 7.27 ppm doublet, J¼8.6 Hz, corresponding to two
protons (H-100, H-140) and 6.950ppm, doublet J¼8.6 Hz
integrating for two protons (H-11 , H-130). Further exami-
1
nation of the H spectrum reveals an ABM system for the
catechol ring C (ortho and meta coupled protons with
coupling constants of 8.3 and 1.9 Hz, respectively). The
three singlets in the aromatic region (6.87, 6.52, 7.09 ppm)
were identified as the isolated protons in rings A and E (H-2,
H-5 and H-7, respectively) after examination of the HMBC
2. Results and discussion
1
spectrum. Apart from the aromatic region, the H NMR
Stilbene 8 was prepared (Heck coupling),9,10 by heating a
mixture of 4-iodoacetoxybenzene 6 and 3,4-dimethoxy-
styrene 7 in the presence of palladium dichloride,
triphenylphosphine, potassium acetate and silver nitrate in
DMF for 7 days. We obtained the stilbene 8 in 32% yield
(Scheme 2). Treatment of 8 with FeCl3 in dichoromethane
produced the 0two stilbene dimers; 8,80-(12,120-bisacetoxy-
phenyl)-70-(3 ,40-dimethoxyphenyl)-3,4-dimethoxy-70,80-
dihydro-na0phthalene 9 in 17% yield and 8-(12-acetoxy-
phenyl)-8 -(120-hydroxyphenyl)-70-(30,40-di-methoxy-
phenyl)-3,4-dimethoxy-70,80-dihydro-naphthalene 10 in 7%
yield. Both structures (9 and 10) were unambiguosly
assigned by means of 1D (1H and 13C) NMR, and extensive
2D NMR experiments (COSY, HMQC, HMBC and
NOESY) and also high resolution mass spectral data.
spectrum also showed two broad singlets at 4.15 and
4.11 ppm corresponding to H-70 and H-80, four methoxy and
two acetoxy singlets. The connection between protons and
their corresponding carbons was established by HMQC.
Correlations from 2D long distance heteronuclear NMR
spectrum (HMBC, Fig. 1) allowed the assignment of all
proton and carbon signals. Observation of a cross peak with
2J and 3J (two 0and three bond correlations) shown by H-700/
C-80, H-70/C-2 , H-70/C-5, H-70/C-90, H-70/C-8, H-80/C-7 ,
8,80-(12,120-Bisacetoxyphenyl)-70-(30,40-dimethoxy-phenyl)-
3,4-dimethoxy-70,80-dihydro-naphthalene 9 was obtained as
a yellow oil. The spot on the TLC plate exhibited a strong
blue fluorescence under UV (254 nm) which suggests that
the trans stilbene chromophore has been retained. This is
consistent with a structure in which the olefinic bond is at
C7–C8 and not C8–C80 as in some natural analogues (see
below). High resolution EI mass spectrum gave a molecular
ion peak with accurate mass 594.2273 compatible with the
molecular formula C36H34O8 (calcd mass 594.2254, D
1.9 mmu) corresponding to two stilbene units 8 minus two
protons. The H NMR and H–1H COSY spectra sho0 wed
two sets of ortho-coupled aromatic protons in AA0BB spin
systems assignable to two independent 4-acetoxyphenyl
1
1
Figure 1. Main HMBC correlations in 9 (400 MHz, CDCl3).

N. F. Thomas et al. / Tetrahedron 58 (2002) 7201–7206
7203
Figure 4. Main NOESY correlations in 10 (500 MHz, CDCl3).
Figure 2. Main NOESY correlations in 9 (500 MHz, CDCl3).
1
dimer. The H and 13C NMR spectra of 10 were similar to
compound 9 except for the replacement of an acetoxy group
with a free hydroxy group at C-120. The increased shielding
of H-110,130 in 10 (6.69 ppm) compared to 9 (6.95 ppm) and
increased deshielding of the C-120, 154.69 ppm (10)
compared to 149.42 ppm (9) is0consistent with the presence
of a free hydroxy group at C-12 , as opposed to an acetoxy in
the case of 9. This 0reflects the much greater ‘carbonyl’
character of the C-12 in 10 compared to 9. The structure of
10 was further confirmed by 2D NMR HMQC, HMBC
(Fig. 3) and NOESY (Fig. 4) spectral data. In the HMBC
H-80/C-10, H-80/C-90, H-80/C-7, H-7/C-6, H-7/C-80, H-7/C-2
and H-7/C-9 allowed us to establish the naphthalene
structure of 9. The relative configuration of 9 was deduced
from the NOESY spectrum0. The distinct correlation (Fig. 2)
between H-80 with H-2 /600 and H-700 with H-100/140
confirmed that protons H-7 and H-8 are in an anti
configuration, a correlation not seen in compound 10 and
confirming the latter’s syn configuration (see Section 3.2.2).
8-(12-Acetoxyphenyl)-80-(120-hydroxyphenyl)-70-(30,40-
dimethoxyphenyl)-3,4-dimethoxy-70,80-dihydro-naphtha-
lene 10 was also obtained as a yellow oil. The appearance of
a strong blue fluorescence spot under UV (254 nm) again
suggested the retention of a trans stilbene chromophore in
structure 10. The high resolution mass spectrum (CI) gave
an exact mass 553.2241 for the pseudomolecular ion
[MþH]þ, compatible with the molecular formula
C34H32O7 (calcd mass 553.2226, D 1.5 mmu) of a stilbene
2
3
spectrum, observation of a cross peak with J and J (two
and0three bonds correlation) shown by H-70/C-80, H-70/C-20,
H-7 /C-5, H-70/C-90, H-70/C-8, H-80/C-70, H-80/C-10, H-80/C-
90, H-80/C-7, H-7/C-6, H-7/C-80, H-7/C-2 and H-7/C-9 led
us to establish the structure of 10. The NOESY spectrum
confirms the syn configuration of H-70 and H-80 (Fig. 4).
The formation of compounds 9 and 10 can be explained by
thermally allowed pericyclic transformations.11 The
mechanistic pathway is initiated by removal of an electron
by Fe3þ (the oxidizing agent) from the olefinic system 11
(or 8) to form a radical cation 12. This is followed by
coupling of two radical cationic species to produce 13.
Rapid deprotonation of 13 would yield the dienes 14A and
14B the Z,Z- and Z,E-isomers, respectively. 6p electrocyclic
ring closure of 14A and 14B would give 15A and 15B,
respectively. This is followed by sigmatropic rearrange-
ments to provide 9 and 10 as shown in Scheme 3. Both syn
and anti isomers were isolated from the reaction mixture.
The anti isomer was the major compound. This may be due
to its greater thermodynamic stability. Its predominance
probably also reflects the fact that it is formed from the more
abundant diene 14A
The transformation of 14A to 9 and 14B to 10 can be
explained by frontier orbital considerations, as shown in
Schemes 4 and 5. Considering the Highest Occupied
Molecular Orbital (HOMO) for both 6p system (hexatriene)
14A and 14B, disrotatory ring closure of 14A would provide
the anti disposed hydrogen at the two new asymmetric
centers 15A and then followed by [1,5] suprafacial hydride
Figure 3. Main HMBC correlations in 10 (400 MHz, CDCl3).

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N. F. Thomas et al. / Tetrahedron 58 (2002) 7201–7206
Scheme 3. Proposed mechanism for the formation of 9 and 10.
shifts to 9 (Scheme 4). By contrast disrotatory ring closure
of 14B would produce the syn configuration shown in 15B.
This is then followed by symmetry allowed [1,5] suprafacial
hydride shifts and deprotection of the acetate leading to 10
as shown in Scheme 5.
diene isomer related to our 14B (see Scheme 3). Our
compounds (and 16) are structurally related to the natural
product cyphostemmin A 17 which incorporates the cis
(rather than the trans) stilbene chromophore (Scheme 6).
From a biosynthetic standpoint, it would appear that for 17
formation, the 1,5 sigmatropic rearrangement 15A to 9
(Scheme 3) is prohibited, and that a prototropic shift (non-
concerted) involving the proton at C-6 is the favoured
pathway. It is also noteworthy that the reported biomimetic
synthesis of 16 by Kouzi et al. also describes a number of
other compounds presumably arising from oxidative
phenolic coupling (excluding we believe 16). In our FeCl3
reactions these oxidative phenolic compounds seem to be
precluded, and pericyclic pathways leading to 9 and 10
predominate. The results of further synthetic and bio-
synthetic investigations from our group will be reported in
due course.
In conclusion, we would like to point out that we are aware
of recent reports regarding the isolation of cyphostemmins12
and the Botrytis cinerea catalysed dimerisation of resvera-
trol13 to produce a mixture of compounds from which
restrytisol C 16 was isolated as the diastereisomer shown. In
the light of our mechanistic rationale, the biosynthesis of 16
could well involve pericyclic reactions (see Scheme 3), but
intriguingly, the fact that the cis (syn ) isomer is not formed
in the B. cinerea catalysed transformation of resveratrol,
could suggest that stereospecific requirements for these
fungal pathogen enzymes, preclude formation of the Z,E-

N. F. Thomas et al. / Tetrahedron 58 (2002) 7201–7206
7205
Scheme 4. Thermally allowed 6p electron electro-cyclization leading to 9.
Scheme 5. Thermally allowed 6p electron electro-cyclization leading to 10.
in dry DMF (50 mL). To this stirring solution palladium(II)
chloride (0.238 g, 1.34 mmol), triphenylphosphine (0.703 g,
2.68 mmol), silver nitrate (2.28 g, 0.0134 mol), potassium
acetate (1.63 g, 0.0166 mol) and 3,4-dimethoxy styrene 7
(2.20 g, 0.0134 mol) was added. The mixture was refluxed
under nitrogen for a week. The reaction mixture was filtered
and extracted with ethyl acetate and water. The combined
ethyl acetate extracts were dried over anhydrous Na2SO4.
The crude was purified by column chromatography (ethyl
acetate/hexane; 1:10) to gave 1.28 g (32% yield) of
colourless crystals 8.
Scheme 6. Natural dihydronapthalenic stilbenoid dimmers.
3.1.1. 3,4-Dimethoxy-12-acetoxystilbene 8. IR (film) nmax
:
3007, 2963, 2938, 1756 (acetate CvO), 1600, 1580, 1238,
1212, 1191, 1163, 1137, 1024; 1H NMR (400 MHz, CDCl3)
d ppm: 7.49 (d; J¼8.6 Hz; 2H; H-10,14), 7.07 (d; J¼8.6 Hz;
2H; H-11,13), 7.06 (d; J¼2.2 Hz; 1H; H-2), 7.04 (dd; J¼8.0,
2.2 Hz; 1H; H-6), 7.00 (d; J¼16.4 Hz; 1H; H-7), 6.97 (d;
3. Experimental
3.1. Synthesis of 3,4-dimethoxy-12-acetoxy stilbene 8
4-Iodoacetoxybenzene 6 (3.59 g, 0.0134 mol) was dissolved

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N. F. Thomas et al. / Tetrahedron 58 (2002) 7201–7206
J¼16.4 Hz; 1H; H-8), 6.86 (d; J¼8.0 Hz; 1H; H-5), 3.95 (s;
3H; 3-OCH3), 3.90 (s; 3H; 4-OCH3), 2.31 (s; 3H; 12-OAc).
13C NMR (100.4 MHz, CDCl3) d ppm: 130.08 (C-1),
108.57 (C-2), 148.93 (C-3), 148.80 (C-4), 111.04 (C-5),
119.75 (C-6), 128.51 (C-7), 125.53 (C-8), 135.15 (C-9),
126.95 (C-10,14), 121.57 (C-11, 13), 149.61 (C-12), 169.28
(CvO), 55.71 (3-OCH3), 55.65 (4-OCH3), 20.91 (COC H3).
H-20), 6.72 (d; J¼8.3 Hz; 1H; H-50), 6.68 (dd; J¼8.6 Hz,
1.9 Hz; 1H; H-60), 06.52 (s; 1H; H-5), 4.09 (br s; 1H; H-80),
4.07(br s; 1H; H-7 ), 4.70 (br s; 1H; 120-OH), 3.96 (s; 3H;
3-OCH3), 3.82 (s; 3H; 40-OCH3), 3.78 (s; 3H; 30-OCH3)p,
3.77 (s; 3H; 4-OCH3)p, 2.24 (s; 3H; 12-OAc); 13C NMR
(100.4 MHz, CDCl3) d ppm: 126.96 (C-1), 137.88 (C-10),
110.04 (C-2), 110.83 (C-200), 147.83 (C-3), 148.71 (C-300),
148.69 (C-4), 147.57 (C-4 0), 112.58 (C-5), 111.24 (C-50),
127.45 (C-6), 119.32 (C-60 ), 124.99 (C-7), 53.07 (C-70),
135.47 (C-8), 50.99 (C-8 ), 138.48 (C-9), 134.30 (C-9 ),
126.45 (C-10,14), 128.60 (C-100,140), 121.30 (C-11,13),
115.54 (C-110,130), 149.61 (C-12), 154.69 (C-120), 55.73
(30-OCH3), 55.79 (30-OCH3)p, 55.78 (4-OCH3)p, 55.91
(4 -OCH3), 21.04 (12-COC H3), 169.61 (CvO) (p—inter-
changeable).
3.2. Synthesis of stilbene dimer 9 and 10
To a stirring solution of stilbene 8 (0.4 g, 1.34 mmol) in
dichloromethane (40 mL), FeCl3·6H2O (2 mL, 13.4 mmol)
was added. The reaction was monitored by TLC. After 3 h,
reaction mixture was worked up with MeOH. The crude
product was purified by column chromatography (100%
CHCl3) and centrifugal chromatography (100% CHCl3).
Two pure compounds were isolated.
Acknowledgments
3.2.1. 8,80-(12,120-Bisacetoxyphenyl)-70-(30,40-dimethoxy-
phenyl)-3,4-dimethoxy-70,80-dihydro-naphthalene 9. The
compound was isolated as yellow oil, 0.14 g (17% yield).
HRMS-EI 594.2273; IR (film) nmax: 3020, 2937, 2835, 1760
(acetate CvO), 1604, 1505, 1296, 1238, 1199, 1167, 1019,
755; 1H NMR (400 MHz, CDCl3) d ppm: 7.32 (d;
J¼8.7 Hz; 2H; H-10,14), 7.27 (d; J¼8.6 Hz; 2H;
H-1000,1400), 7.09 (s; 1H; H-7), 6.95 (d; J¼8.6 Hz; 2H;
H-11 ,13 ), 6.94 (d; J¼8.7 Hz; 2H; H-11,13), 6.87 (s; 1H;
H-2), 6.75 (d; J¼1.9 Hz; 1H; H-20), 6.703 (d; J¼8.3 Hz; 1H;
H-50), 6.69 (dd; J¼8.3, 1.9 Hz; 1H; H-6 ), 6.52 (s; 1H; H-5),
4.15 (br s; 1H; H-80), 4.11 (br s; 1H; H-70), 3.960 (s; 3H;
3-OCH3), 3.82 (s; 3H; 40-OCH3), 3.78 (s; 6H; 3 -OCH3,
4-OCH3), 2.27 (s; 6H; 12-OAc, 120-OAc). 13C NMR
(100.4 MHz, CDCl3) d ppm: 126.77 (C-1), 137.69 (C-10),
110.14 (C-2), 110.81 (C-200), 147.97 (C-3), 147.70 (C-300),
148.89 (C-4), 148.80 (C-4 0), 112.62 (C-5), 111.29 (C-50),
127.20 (C-6), 119.31 (C-6 ), 125.35 (C-7), 52.74 (C-70),
134.95 (C-8), 51.17 (C-80), 138.023 (C-9), 139.94 (C-9 ),
126.45 (C-10,14), 128.48 (C-10 ,140), 121.66 (C-11,13),
121.42 (C-110,130), 149.74 (C-12), 149.42 (C-120), 55.74
(3-OCH3), 55.81 (30-OCH3, 40-OCH3), 55.94 (40-OCH3),
21.05 (12-COC H3)p, 21.00 (12 -COC H3)p, 169.40 (CvO)
(p—interchangeable).
This work was supported by a grant from the Malaysian
Government (IRPA No 09-02-02-0061).
References
1. Pace-Asciak, C. R.; Hahn, S.; Diamandis, E. P.; Soleas, G.;
Goldberg, M. D. Clin. Chim. Acta 1995, 235, 207–219.
2. Frankel, E. N.; Kanner, J.; German, J. B.; Parks, E.; Kinsella,
J. E. Lancet 1993, 341, 454–457.
3. Gorham, J. The Biochemistry of the Stilbenoids. Chapman and
Hall: London, 1995.
4. Weber, J. F. F.; Wahab, I. A.; Marzuki, A.; Thomas, N. F.;
Kadir, A. A.; Hadi, A. H. A.; Awang, K.; Latiff, A.;
Richomme, P.; Delaunay, J. Tetrahedron Lett. 2001, 42,
4895–4897.
5. Thomas, N. F.; Lee, K. C.; Thomas, P.; Weber, J. F. F.;
Awang, K. Tetrahedron Lett. 2002, 43, 3151–3155.
6. Snider, B. B.; Buckman, B. O. Tetrahedron 1989, 45, 6969.
7. Melikyan, G. G. Aldrichim. Acta 1998, 31, 50–64.
8. Kende, A. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1976, 98,
267.
9. Grigg, R.; Dorrity, M. J.; Malone, J. F.; Sridharan, V.;
Sukirthalingam, S. Tetrahedron Lett. 1990, 31, 1343–1346.
10. Meijere, A. D.; Meyer, F. E. Angew. Chem., Int. Ed. Engl.
1994, 33, 2379–2411.
3.2.2. 8-(12-Acetoxyphenyl)-80-(120-hydroxyphenyl)-70-
(30,40-dimethoxyphenyl)-3,4-dimethoxy-70,80-dihydro-
naphthalene 10. The compound was isolated as yellow oil,
0.052 g (7% yield); IR (film) nmax: 3439, 3020, 2935, 2837,
1756 (acetate CvO), 1607, 1512, 1241, 1200, 1167, 1026,
11. Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl.
1969, 8, 781–932.
1
756; HRMS-CI [MþH]þ 553.2241; H NMR (400 MHz,
12. Ducrot, P. H.; Kollmann, A.; Bala, A. E.; Majira, A.; Kerhoas,
L.; Delorme, R.; Einhorn, J. Tetrahedron Lett. 1998, 39,
9655–9658.
CDCl3) d ppm: 7.33 (d; J¼8.8 Hz; 2H; H-10,14), 7.13 (d;
J¼8.6 Hz; 2H; H-100,140), 7.07 (s; 1H; H-7), 6.93 (d;
J¼8.8 Hz;; 2H; H-11,13), 6.69 (d; J¼8.6 Hz; 2H;
H-110,130), 6.87 (s; 1H; H-2), 6.74 (d; J¼1.9 Hz; 1H;
13. Cichewicz, R. H.; Kouzi, S. A.; Hamann, M. T. J. Nat. Prod.
2000, 63, 29–33.