Synthesis and cytotoxicity of racemic isodeoxypodophyllotoxin analogues with isoprene-derived side chains

Article abstract of DOI:10.1021/np050547x

A series of isodeoxypodophyllotoxin (5) analogues, 26-38, with various isoprene-derived side chains at the E-ring were designed and synthesized. For comparison, compound 39, with a benzyloxy group on the E-ring, and six D-ring opened analogues, 40-45, were also prepared. All the synthetic compounds were evaluated for their cytotoxic activities in vitro against seven cultured human tumor cell lines. Compounds 27, 43, and 44 were more cytotoxic than etoposide on BEL-7404, A549, and HL-60 cell lines, respectively. However, none of the synthetic isodeoxypodophyllotoxins were more cytotoxic than podophyllotoxin (1).

Full text of DOI:10.1021/np050547x

J. Nat. Prod. 2006, 69, 1145-1152
1145
Synthesis and Cytotoxicity of Racemic Isodeoxypodophyllotoxin Analogues with
Isoprene-Derived Side Chains
Yu Zhao,*,† Ju Hong Feng,† Hong Xia Ding,† Yi Xiong,‡ Christopher H. K. Cheng,†,§ Xiao Jiang Hao, Yong Min Zhang,‡
Yuan Jiang Pan,‡ Franc¸oise Gue´ritte,| Xiu Mei Wu,∇ Hua Bai,∇ and Joachim Sto¨ckigt†,#
Department of Traditional Chinese Medicine and Natural Drug Research, College of Pharmaceutical Sciences, Zhejiang UniVersity,
Yan An Road 353, Hangzhou 310031, People’s Republic of China, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang UniVersity,
Hangzhou 310031, People’s Republic of China, Department of Biochemistry, The Chinese UniVersity of Hong Kong, Shatin, N.T., Hong Kong,
People’s Republic of China, The Key Laboratory of Chemistry of Natural Products of Guizhou ProVince and Chinese Academy of Sciences,
Guiyang 550022, People’s Republic of China, Institut de Chimie des Substances Naturelles, CNRS, AVenue De la Terrasse,
F-91198 Gif-sur-YVette, France, Zhejiang Hisun Naturelite Pharmaceutical R&D Co., Ltd., 19-G, Huazhe Plaza,
Hangzhou 310006, People’s Republic of China, and Lehrstuhl fu¨r Pharmazeutische Biologie, Institut fu¨r Pharmazie, Johannes-Gutenberg
UniVersita¨t Mainz, Staudinger Weg 5, D-55099 Mainz, Germany
ReceiVed December 26, 2005
A series of isodeoxypodophyllotoxin (5) analogues, 26-38, with various isoprene-derived side chains at the E-ring
were designed and synthesized. For comparison, compound 39, with a benzyloxy group on the E-ring, and six D-ring
opened analogues, 40-45, were also prepared. All the synthetic compounds were evaluated for their cytotoxic activities
in vitro against seven cultured human tumor cell lines. Compounds 27, 43, and 44 were more cytotoxic than etoposide
on BEL-7404, A549, and HL-60 cell lines, respectively. However, none of the synthetic isodeoxypodophyllotoxins
were more cytotoxic than podophyllotoxin (1).
Lignans are a well-known class of natural products. Among them,
the best known cytotoxic lignan is podophyllotoxin (1) (Figure 1),
which can be found in Berberidaceae plants such as Podophyllum
peltatum Linnaeus, P. emodi Wall, and P. pleianthum Hance.1,2
Although the therapeutic application of podophyllotoxin via oral
administration has failed due to unacceptable gastrointestinal
toxicity, two of its semisynthetic glucosidic acetals, etoposide (2)
and teniposide (3), are currently used in clinical practice for the
treatment of small-cell lung cancer, testicular carcinoma, lymphoma,
and Kaposi’s sarcoma.3 The antitumor potency and clinical efficacy
of compounds 2 and 3 has prompted intensive interest in the
synthesis of new podophyllotoxin analogues.
The podophyllotoxin family includes podophyllotoxin (3a,9a-
trans-9a,9-cis) (1), picropodophyllotoxin (3a,9a-cis-9a,9-trans) (4),
and isodeoxypodophyllotoxin (3a,9a-trans-9a,9-trans) (5). It has
been established by structure-activity relationship (SAR) studies
that the 3a,9a-trans configuration is an important factor for high
cytotoxic activity.4 However, very little work has been done to
address the significance of the 9a,9-configuration for cytotoxicity.
Moreover, Zavala reported that racemic isodeoxypodophyllotoxin
has inhibitory activity against microtubule assembly comparable
to that of (-)-podophyllotoxin, while (-)-isodeoxypodophyllotoxin
is totally inactive. These observations have prompted our interest
and led to the current study.5
and some of them, such as compound 7, were cytotoxic to KB and
A-549 cell lines.9 Thus, it would be of interest to study the cytotoxic
action of the isoprenyl-like podophyllotoxin derivatives.
Thus, a series of racemic isodeoxypodophyllotoxin derivatives
(26-38) containing various isoprene-derived side chains on the
E-ring were designed and synthesized. Compound 39, which
possesses a benzyloxy group on the E-ring at the same position,
was also prepared for SAR comparison. Six D-ring opened
analogues of isodeoxypodophyllotoxin lignans (40-45) were also
synthesized by hydrolysis of the olide rings of compounds 23-39.
All the synthetic compounds were evaluated for their cytotoxic
activities in vitro against seven cultured human tumor cell lines,
viz., KB, BEL-7404, A549, HeLa, PC-3, CNE, and HL-60, and
the results are reported herein.
Results and Discussion
Synthesis. As illustrated in Scheme 1, the synthesis of a series
of racemic isodeoxypodophyllotoxin analogues was started using
benzaldehydes 8 and 9. The Stobbe´ condensation of compound 8
or 9 with dimethylsuccinate in the presence of sodium methoxide
gave the unsaturated hemiesters 10 and 11, which were subjected
to a catalytic hydrogenation with palladium charcoal to furnish the
saturated hemiesters 12 and 13, respectively. The overall yield of
the two reactive steps was 62%. Butyrolactones 14 and 15 were
obtained by the reaction of 12 and 13 with potassium hydroxide,
followed by reduction with sodium borohydride and calcium
chloride in 75% yield.10
The prenylated arylnaphthalene lignan, 7-O-(3-methyl-2-butenyl)-
isodaurinol (6), was isolated from Haplophyllum myrtifolium by
Go¨zler and co-workers.6 Only a few lignans have been reported to
possess such an isoprene-derived side chain.7,8 We have also
reported several sinapyl alcohol derivatives with such side chains,
Subsequent R-hydroxyalkylation of the butyrolactones 14 and
15 with benzaldehydes 16 and 17 (Scheme 2), at low temperature
in the presence of lithium diisopropylamide, afforded alcohols 18-
21 in 76-92% yields.11 Each of the compounds (18-21) was an
approximately equimolar mixture of the erythro (18a-21a) and
threo isomers (18b-21b), as indicated by the proton signals of
CHOH around δ 4.81 (d, J ) 8.0 Hz, CHOH) for the erythro isomer
* To whom correspondence should be addressed. Tel: (86)-571-
87217313. Fax: (86)-571-85270026. E-mail: dryuzhao@zju.edu.cn;
dryuzhao@hotmail.com.
† College of Pharmaceutical Sciences, Zhejiang University.
‡ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Univer-
sity.
1
and around δ 5.29 (br s, CHOH) for the threo isomer in their H
§ The Chinese University of Hong Kong.
The Key Laboratory of Guizhou Province and Chinese Academy of
Sciences.
NMR spectra. However, in the next cyclization in the presence of
trifluoroacetic acid (TFA), each mixture of erythro and threo
alcohols, of compounds 18-21, could be used as starting materials
without separation, resulting in the same cyclized products 22-25
in 63-72% yields. As usually described for such a cyclization
| ICSN, CNRS.
∇ Zhejiang Hisun Naturelite Pharmaceutical R&D Co., Ltd.
# Johannes-Gutenberg Universita¨t Mainz.
10.1021/np050547x CCC: $33.50
© 2006 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/20/2006

1146 Journal of Natural Products, 2006, Vol. 69, No. 8
Zhao et al.
Figure 1.
Scheme 1a
found that compounds 27, 39, 43, and 44 showed satisfactory
cytotoxicity against at least one tested cell line.
Among the series of target compounds (26-38) with a 3a,9a-
trans-9a,9-trans stereochemistry and a closed D-ring, compound
27 displayed significant cytotoxicity against KB and BEL-7407 cell
lines, and its IC50 values were 3.76 and 5.63 µM, respectively.
Except compound 27, most of the compounds with isoprene-derived
side chains exhibited poor cytotoxicities against the seven tumor
cell lines. Compounds 32-38, with the unsaturated chains on the
4′ position of the E-ring, also exhibited almost no cytotoxicity.
However, some interesting observations were made. Compound 27
was 10 times more cytotoxic against KB and BEL-7407 cell lines
than compound 26, and although compound 31 displayed weak
cytotoxicity against KB and HeLa cell lines, it was more potent
than compounds 28-30. These facts suggest that elongation of the
isoprene-derived chain could enhance the cytotoxic potency of the
compounds. An additional methoxy group at C-8 of the B-ring
resulted in a significant decrease of cytotoxicity of compound 31
compared to that of compound 27, and this may be attributable to
the spatial arrangement of the farnesoxyl group at C-3′ and the
methoxy group at C-8. By comparing the four isodeoxypodophyl-
lotoxin intermediates 22-25, it was found that compounds 22 and
24, bearing a hydroxy group at C-3′ of the E-ring, were more
cytotoxic than compounds 23 and 25 with hydroxyl at the C-4′
position of the E-ring.
Lactone 39, with a benzyloxy group at C-4′ on the E-ring,
exhibited cytotoxicity as potent as compound 27 on KB and BEL-
7407 cell lines, with IC50 values of 2.65 and 14.8 µM, respectively.
This indicates that, to enhance cytotoxic potency, an aromatic group
is more preferable than an aliphatic chain connected to the 4′-OH
of the E-ring.
The trans-lactone D-ring is generally considered to be an
important feature for the bioactivity of podophyllotoxin analogues.
Among the series of compounds (40-45) with an opened D-ring,
compound 44 was also found to possess significant cytotoxicity
against six tumor cell lines at around 10 µM, especially against
the HL-60 cell line, with an IC50 of 4.54 µM. In addition,
compounds 40-45 were more selectively cytotoxic against the HL-
60 cell line than compounds 22-39, which possess an intact D-ring.
It should be noted that compound 44 exhibited an IC50 value of
4.54 µM against HL-60 cells, with a potency superior to the
a Reagents and conditions: (i) (CH2CO2CH3)2, NaOCH3, CH3OH, reflux 5
h, 65%; (ii) H2, Pd/C, rt, 3 h, 95%; (iii) KOH, CaCl2, NaBH4, EtOH, rt, 5 h,
75%.
reaction, the products 22-25 were racemic isodeoxypodophyllo-
toxin-type compounds with 3a,9a-trans-9a,9-trans stereochemistry.
This was confirmed by the signals (J3a,9a ) 13.2 Hz, J9a,9 ) 11.2
Hz) of vicinal protons at the 3a, 9a, and 9 positions.12 Furthermore,
under the acidic conditions of TFA, the methoxymethyl protecting
group could be removed simultaneously, as expected.
Four unsaturated aliphatic groups were chosen in order to obtain
compounds with different isoprene-derived side chains. These were
allyl, 3-methyl-2-butenyl, geranyl, and farnesyl, consisting of 3, 5,
10, and 15 carbons, respectively. Thirteen compounds (26-38) were
prepared by reacting 22-25 with the bromides of the four
unsaturated aliphatic groups under basic conditions, and the yields
were 63-77%. Compound 39, possessing a benzyloxy group on
the E-ring, was also prepared from compound 24. In addition, six
D-ring opened derivatives (40-45) were synthesized by acid-
catalyzed transesterification13 of compounds 22-25, 37, and 38
(see Scheme 3 and Table 1).
Cytotoxic Evaluation. Synthetic compounds 26-45, as well as
the isodeoxypodophylltoxin intermediates 22-25, were evaluated
for their cytotoxicity against seven human cultured tumor cell lines,
viz., KB, BEL-7404, A549, HeLa, PC-3, CNE, and HL-60. It was

Racemic Isodeoxypodophyllotoxin Analogues
Journal of Natural Products, 2006, Vol. 69, No. 8 1147
Scheme 2a
a Reagents and conditions: (i) n-BuLi, (i-Pr)2NH, THF, -80 °C, 2 h, 76-92%; (ii) TFA, CH2Cl2, 0 °C, 2 h, 63-72%.
13C NMR spectra were measured on a Bruker AM-400 FT-NMR
Scheme 3a
instrument with TMS as the internal standard. ESIMS data were
performed on a Bruker Esquire 3000+ spectrometer. HRFABMS
spectra were recorded on a VG ZABHS spectrometer. Solvents and
reagents were purified according to standard laboratory techniques. TLC
was performed on silica gel 60 GF-254 plates (Merck). Column
chromatography was performed on silica gel (200-300 mesh, Qingdao
Marine) if not otherwise specified. n-Butyllithium, diisopropylamine,
and trifluoroacetic acid were purchased from Acros Chemical Company
and MTT from Sigma, St. Louis, MO. Other chemicals were mainly
purchased from Tianjin Chemical Manufactory and Beijing Chemical
Manufactory.
4-(3,4-Dimethoxyphenyl)-3-methoxycarbonyl-3-butenoic Acid (10).
Under argon atmosphere, a solution of 3,4-dimethoxybenzaldehyde (8)
(10 g, 0.06 mol) and dimethylsuccinate (9.5 mL, 0.072 mol) in 20 mL
of MeOH was added to a stirred refluxing solution, which was prepared
by dissolving sodium (2.0 g, 0.087 mol) in MeOH (10 mL). The flask
was kept under reflux for 5 h and then concentrated under vacuum.
The residue was partitioned between H2O and ether, and the aqueous
phase was acidified with 10% HCl at 0 °C. The resulting oil was
extracted into EtOAc, washed successively with H2O and brine, and
then dried (MgSO4). Evaporation and recrystallization from EtOAc/
hexane gave the hemiester as an off-white powder (10.9 g, 65%
yield): mp 148-150 °C (lit.11 mp 149-150 °C).
a Each structure depicted represents the relative stereochemistry of a racemic
compound. Reagents and conditions: (i) K2CO3, acetone, reflux 8 h, 63-78%;
(ii) MeOH, HCl, rt, 2 h, 58-77%.
4-(3,4,5-Trimethoxyphenyl)-3-methoxycarbonyl-3-butenoic Acid
(11). The preceding reaction was repeated with 3,4,5-trimethoxyben-
zaldehyde (9) (10 g, 0.051 mol) to give the crude product, which was
purified by column chromatography on silica gel (hexane/EtOAc/
HCOOH, 50:50:0.1) to give the title compound 11 (9.9 g, 62.6% yield)
as a yellow oil.
(()-4-(3,4-Dimethoxyphenyl)-3-methoxycarbonyl Butanoic Acid
(12). A mixture of compound 10 (10.9 g, 0.039 mol) and palladium-
charcoal (10%, 1.1 g) was stirred at room temperature under H2 for 3
h. The catalyst was filtered off, and the solvent was evaporated under
reduced pressure to afford the pure saturated hemiester 12 (10.1 g,
92.0% yield) as a yellowish solid: mp 107-108 °C (ether) (lit.11 mp
108-109 °C).
(()-4-(3,4,5-Trimethoxyphenyl)-3-methoxycarbonylbutanoic Acid
(13). By the same procedure used to obtain compound 12, hemiester
11 (9.9 g, 0.032 mol) was converted to the saturated hemiester 13 (9.5
g, 95.2% yield) as a yellowish solid: mp 126-127 °C (ether) (lit.14
mp 128-129 °C).
(()-4-(3,4-Dimethoxyphenyl)-4,5-dihydro-2(3H)-furanone (14).
To a stirred solution of 8 g (0.028 mol) of compound 12 in 150 mL of
absolute EtOH was added 2 g (0.036 mol) of KOH. After dissolution,
cytotoxicity of the front-line antitumor drug etoposide (IC50 ) 10.5
µM). Moreover, compound 27 demonstrated notable cytotoxicity
against the BEL-7404 cell line, with an IC50 value at 5.63 µM,
while compound 43 showed impressive cytotoxicity against the
A549 cell line, with an IC50 of 14.5 µM. Both compounds were
more cytotoxic on the corresponding human tumor cell lines than
the positive control etoposide. However, none of the synthesized
compounds were more cytotoxic than podophyllotoxin, although
this natural toxin is strictly confined in clinical utilization due to
its unbearable side-effects on patients.
It is expected that isodeoxypodophyllotoxin lignans might offer
potential for further development into therapeutic agents. Design
and synthesis of additional isodeoxypodophyllotoxin derivatives
containing a 3a,9a-trans-9a,9-cis configuration and studies of their
structure-cytotoxicity relationships are in progress.
Experimental Section
General Experimental Procedures. Melting points were measured
1
on a Perkin-Taike X-4 apparatus and were uncorrected. H NMR and

1148 Journal of Natural Products, 2006, Vol. 69, No. 8
Zhao et al.
Table 1. Two Series of Isodeoxypodophyllotoxin Derivatives (()-26-45
6 g (0.054 mol) of powdered CaCl2 was also added. A solution of 4.0
g (0.108 mol) of NaBH4 in 30 mL of 1 M KOH was then introduced
dropwise at 20 °C. The white suspension was stirred at room
temperature for 5 h, then cooled to 0 °C and acidified with 10% HCl.
Water was added until the solution became clear, and EtOH was
removed in vacuo. The aqueous layer was extracted with EtOAc, and
the combined organic layer was washed with brine, dried (MgSO4),
and evaporated. The crude product was purified by column chroma-
tography on silica gel (hexane/EtOAc, 4:1) to give compound 14 (4.9
g, 74.7% yield) as a colorless oil.
(()-4-(3,4,5-Trimethoxyphenyl)-4,5-dihydro-2(3H)-furanone (15).
The experimental procedure as noted above for compound 14 was
repeated with compound 13 (8 g, 0.026 mol) to yield compound 15
(5.2 g, 75.7% yield) as a white solid: mp 81-83 °C (ether) (lit.14 mp
79-82 °C).
dropwise, and the mixture was further stirred for 2 h. The reaction
was quenched by a saturated NH4Cl solution, and the whole reaction
mixture was extracted with EtOAc. The combined organic phase was
dried (MgSO4) and concentrated, and then the residue was chromato-
graphed on silica gel (hexane/EtOAc, 3:1) to give a mixture (1.61 g,
88.7%) of the erythro isomer (18a) and the threo isomer (18b) as a
yellow gum, whose HPLC analysis and 1H NMR spectrum all showed
an 18a to 18b ratio of approximately 1:1.
(()-(3S,4R)-4-(3,4-Dimethoxybenzyl)-3-{(S)-hydroxy[4-methoxy-
3-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one (18a)
and (()-(3S,4R)-4-(3,4-Dimethoxybenzyl)-3-{(R)-hydroxy[4-meth-
oxy-3-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one
1
(18b). H NMR (400 MHz, CDCl3) δ 7.03 (1H, dd, J ) 8.0, 2.0 Hz,
H-6′′), 6.90 (1H, d, J ) 2.0 Hz, H-2′′), 6.81 (1H, d, J ) 8.0 Hz, H-5′′),
6.65 (1H, d, J ) 8.0 Hz, H-5′), 6.42 (1H, dd, J ) 8.0, 2.0 Hz, H-6′),
6.36 (1H, d, J ) 1.6 Hz, H-2′), 5.29 (0.5H, br s, CHOH for 18b), 4.81
(0.5H, d, J ) 8.0 Hz, CHOH for 18a), 5.22 (2H, s, OCH2O), 4.28
(1H, t, J ) 8.4 Hz, H-5), 4.13 (1H, br s, H-5), 3.87 (3H, s, OCH3),
3.82 (3H, s, OCH3), 3.69 (3H, s, OCH3), 3.50 (3H, s, OCH2OCH3),
2.97 (1H, br s, OH-7′′), 2.87-2.82 (1H, m, H-4), 2.63-2.66 (1H, m,
H-3), 2.41-2.30 (2H, m, H-7′); ESIMS m/z 450 [M + NH4]+.
General Procedure for Preparation of Compounds 18-21. To a
solution of LDA, prepared from diisopropylamine (0.45 mL, 3.1 mmol)
and n-butyllithium (1.6 M in hexane, 2.5 mL, 4.0 mmol) in dry THF
(20 mL), was added a solution of compound 14 (1.0 g, 4.2 mmol) in
5 mL of dry THF at -80 °C. After 15 min, a solution of the
benzaldehyde 16 (8.5 g, 4.3 mmol) in dry THF (8 mL) was added

Racemic Isodeoxypodophyllotoxin Analogues
Journal of Natural Products, 2006, Vol. 69, No. 8 1149
Table 2. 13C NMR Data [100 MHz, δ (ppm)] for Compounds 22-39 in CDCl3
C no.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
1
3
3a
175.5 175.8 176.0 175.9 175.5 175.5 175.9 175.9 175.9 176.0 175.9 175.8 175.8 175.9 175.8 175.8 175.9 175.9
71.0
40.5
32.6
70.4
40.6
32.5
70.7
39.9
33.6
70.5
39.8
33.5
71.0
40.5
32.5
71.1
40.5
32.6
70.7
39.9
33.6
70.7
39.9
33.6
70.7
39.9
33.6
70.7
39.9
33.6
70.4
40.6
32.5
70.4
40.5
32.5
70.4
40.6
32.5
70.5
39.8
33.5
70.5
39.8
33.5
70.5
39.8
33.4
70.6
39.8
33.4
70.4
40.6
32.5
4
4a
5
6
7
8
8a
126.8 126.9 131.2 131.1 126.8 126.8 131.2 131.2 131.2 131.2 126.9 126.9 126.8 131.1 131.1 131.1 131.1 126.9
108.1 108.1 107.2 107.0 108.1 108.2 107.1 107.1 107.1 107.1 108.1 108.1 108.1 107.0 107.0 107.0 107.0 108.1
147.6 147.8 152.3 152.2 147.5 147.5 152.3 152.3 152.4 152.3 147.8 147.8 147.8 152.2 152.2 152.2 152.2 147.8
146.2 146.5 141.2 141.1 146.2 146.2 141.3 141.2 141.2 141.2 146.5 146.4 146.4 141.1 141.1 141.1 141.1 146.4
112.9 113.0 152.3 152.5 112.9 112.9 152.6 152.6 152.7 152.7 113.0 113.0 113.0 152.5 152.6 152.5 152.6 113.0
131.4 131.7 125.6 125.5 131.5 131.5 125.6 125.6 125.7 125.7 131.7 131.7 131.7 125.5 125.5 125.4 125.4 131.7
9
9a
45.5
48.8
45.6
49.1
41.3
50.9
41.3
50.8
45.5
48.9
45.5
48.9
41.4
50.9
41.4
50.9
41.4
50.9
41.4
50.9
45.6
49.1
45.6
49.1
45.6
49.1
41.3
50.8
41.3
50.8
41.3
50.8
41.3
50.8
45.6
49.1
1′
2′
3′
4′
5′
6′
136.3 136.7 139.5 139.2 136.2 136.3 139.4 139.5 139.2 139.4 136.6 136.7 136.8 138.8 138.7 139.1 139.0 136.6
113.0 112.5 110.1 110.3 112.9 113.0 110.4 110.5 110.5 110.5 112.4 112.5 112.5 110.6 110.8 111.3 111.2 112.5
145.5 148.5 144.8 146.7 147.7 147.7 147.5 147.6 147.6 147.6 147.8 148.0 148.0 147.3 147.5 148.8 148.6 147.8
148.7 144.9 145.2 144.6 147.4 147.4 147.3 147.3 147.5 147.5 147.5 147.4 147.5 147.0 147.4 146.1 146.0 147.5
110.2 110.9 113.3 113.8 110.2 110.2 113.6 113.6 113.6 113.6 111.0 110.9 110.9 113.5 113.4 112.9 112.9 110.9
121.5 121.6 120.6 120.4 121.4 121.4 120.0 120.0 119.9 120.0 121.5 121.5 121.5 120.1 120.1 120.0 120.0 121.6
OMe-6
OMe-7
OMe-8
OMe-3′
OMe-4′
55.8
55.8
55.9
55.9
55.8
59.3
60.4
55.8
59.2
60.4
55.8
55.8
55.8
55.8
55.8
55.8
59.3
60.4
55.8
59.3
60.4
55.8
59.4
60.4
55.8
59.4
60.4
55.8
55.9
55.8
55.8
55.9
55.9
55.7
59.2
60.2
55.7
55.7
59.2
60.2
55.6
55.8
59.2
60.2
55.7
55.8
59.2
60.2
55.6
55.9
55.9
56.3
56.4
56.3
56.3
56.4
56.2
55.8
56.2
56.2
55.8
55.8
55.8
55.8
(()-(3S,4R)-4-(3,4-Dimethoxybenzyl)-3-{(S)-hydroxy[3-methoxy-
4-(methoxymethoxy)phenyl]methyl}-dihydrofuran-2(3H)-one (19a)
and (()-(3S,4R)-4-(3,4-dimethoxybenzyl)-3-{(R)-hydroxy[3-meth-
oxy-4-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one
(19b). Compounds 19a and 19b were obtained from compound 14 (0.6
g, 2.5 mmol) and compound 17 (0.49 g, 2.5 mmol) as a mixture of
erythro and threo isomers by the same procedure as for the preparation
of alcohol 18. Yield 75.9% as a yellow gum: 1H NMR (400 MHz,
CDCl3) δ 7.08 (1H, d, J ) 8.0 Hz, H-6′′), 6.80 (2H, d, J ) 8.0 Hz,
H-2′′, 5′′), 6.65 (1H, d, J ) 8.0 Hz, H-5′), 6.42 (1H, s, H-2′), 6.36
(1H, d, J ) 8.0 Hz, H-6′), 5.28 (0.5H, d, J ) 2.0 Hz, CHOH for 19b),
5.22 (2H, s, OCH2O), 4.84 (0.5H, d, J ) 8.0 Hz, CHOH for 19a), 4.31
(1H, t, J ) 8.4 Hz, H-5), 4.07 (1H, br s, H-5), 3.83 (3H, s, OCH3),
3.80 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.48 (3H, s, OCH2OCH3),
3.03 (1H, br s, OH-7′′), 2.85-2.80 (1H, m, H-4), 2.64 (1H, dd, J )
12.4, 3.6 Hz, H-3), 2.44 (1H, dd, J ) 14.4, 8.8 Hz, H-7′), 2.30 (1H,
dd, J ) 10.4, 7.2 Hz, H-7′); ESIMS m/z 450 [M + NH4]+.
(()-(3S,4R)-4-(3,4,5-Trimethoxybenzyl)-3-{(S)-hydroxy[4-meth-
oxy-3-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one (20a)
and (()-(3S,4R)-4-(3,4,5-trimethoxybenzyl)-3-{(R)-hydroxy[4-meth-
oxy-3-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one
(20b). Compounds 20a and 20b were obtained from compound 15 (0.53
g, 2.0 mmol) and compound 16 (0.39 g, 2.0 mmol) as a mixture of
erythro and threo isomers by the same procedure as for the preparation
of alcohol 18. Yield 92.0% as yellow gum: 1H NMR (400 MHz,
CDCl3) δ 7.09 (1H, d, J ) 8.0 Hz, H-6′′), 6.89 (1H, s, H-2′′), 6.80
(1H, d, J ) 8.0 Hz, H-5"), 6.07 (2H, s, H-2′, 6′), 5.31 (0.5H, br s,
CHOH for 20b), 5.21 (2H, s, OCH2O), 4.86 (0.5H, d, J ) 8.0 Hz,
CHOH for 20a), 4.33 (1H, t, J ) 8.8, 8.0 Hz, H-5), 4.10 (1H, t, J )
7.6 Hz, H-5), 3.85 (3H, s, OCH3), 3.77 (9H, s, OCH3 × 3), 3.48 (3H,
s, OCH2OCH3), 3.10 (1H, br s, OH-7′′), 2.86-2.82 (1H, m, H-4), 2.68
(1H, dd, J ) 6.8, 3.2 Hz, H-3), 2.40 (1H, dd, J ) 13.6, 8.4 Hz, H-7′),
2.29 (1H, dd, J ) 14.0, 7.2 Hz, H-7′); ESIMS m/z 480 [M + NH4]+.
(()-(3S,4R)-4-(3,4,5-Trimethoxybenzyl)-3-{(S)-hydroxy[3-meth-
oxy-4-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one (21a)
and (()-(3S,4R)-4-(3,4,5-trimethoxybenzyl)-3-{(R)-hydroxy[3-meth-
oxy-4-(methoxymethoxy)phenyl]methyl}dihydrofuran-2(3H)-one
(21b). Compounds 21a and 21b were obtained from compound 15 (1.33
g, 5.0 mmol) and compound 17 (0.98 g, 5.0 mmol) as a mixture of
erythro and threo isomers by the same procedure as for the preparation
of alcohol 18. Yield 86.6% as a yellow gum: 1H NMR (400 MHz,
CDCl3) δ 7.09 (1H, d, J ) 8.4 Hz, H-6′′), 6.90 (1H, s, H-2′′), 6.81
(1H, d, J ) 8.4 Hz, H-5′′), 6.08 (2H, s, H-2′, 6′), 5.31 (0.5H, br s,
CHOH for 21b), 5.20 (2H, s, OCH2O), 4.86 (0.5H, d, J ) 7.2 Hz,
CHOH for 21a), 4.32 (1H, t, J ) 8.0 Hz, H-5), 4.05 (1H, br s, H-5),
3.89 (3H, s, OCH3), 3.80 (9H, s, OCH3 × 3), 3.50 (3H, s, OCH2OCH3),
3.00 (1H, br s, OH-7′′), 2.87-2.82 (1H, m, H-4), 2.70 (1H, dd, J )
10.4, 4.8 Hz, H-3), 2.39 (1H, dd, J ) 13.2, 9.2 Hz, H-7′), 2.30 (1H,
dd, J ) 13.2, 6.0 Hz, H-7′); ESIMS m/z 480 [M + NH4]+.
General Procedure for the Preparation of Compounds 22-24
by Cyclization. (()-(3aR,9S,9aR)-9-(3-Hydroxy-4-methoxyphenyl)-
6,7-dimethoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-
one (22). A mixture of compounds 18a and 18b (0.2 g, 0.46 mmol)
was dissolved in dry CH2Cl2 (20 mL), and a solution of TFA (0.25
mL) in dry CH2Cl2 (2 mL) was added dropwise to it at 0 °C. The
mixture was stirred for 2 h and extracted with CH2Cl2. The combined
organic phase was washed with H2O and brine, dried (MgSO4), and
evaporated. The residue was purified by column chromatography on
silica gel (hexane/EtOAc, 2:1) to afford compound 22 (0.12 g, 71.3%
yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.83 (2H, dd, J ) 8.0,
1,2 Hz, H-5′, 6′), 6.66 (1H, d, J ) 1.2 Hz, H-2′), 6.60 (1H, s, H-5),
6.33 (1H, s, H-8), 5.57 (1H, s, OH), 4.52 (1H, dd, J ) 8.8, 6.4 Hz,
H-3R), 4.08 (1H, d, J ) 11.2 Hz, H-9), 3.97 (1H, dd, J ) 10.4, 8.4
Hz, H-3â), 3.89 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.61 (3H, s, OCH3),
2.98 (1H, dd, J ) 15.2, 5.2 Hz, H-4R), 2.93 (1H, dd, J ) 15.2, 11.6
Hz, H-4â), 2.63-2.58 (1H, m, H-3a), 2.51 (1H, dd, J ) 13.6, 11.2
Hz, H-9a); 13C NMR (100 MHz, CDCl3), see Table 2; ESIMS m/z 369
[M - H]-; HRFABMS m/z 370.1404 (calcd for C21H22O6, 370.1416).
(()-(3aR,9S,9aR)-9-(4-Hydroxy-3-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (23). The ex-
perimental procedure as noted above for compound 22 was repeated
with compound 19 (0.12 g, 0.27 mmol) to yield compound 23 (66 mg,
66.8% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.85 (1H, d, J
) 8.4 Hz, H-5′), 6.76 (1H, d, J ) 1.6 Hz, H-2′), 6.71 (1H, dd, J ) 8.0,
1.6 Hz, H-6′), 6.61 (1H, s, H-5), 6.34 (1H, s, H-8), 5.57 (1H, s, OH),
4.52 (1H, dd, J ) 8.4, 6.4 Hz, H-3R), 4.09 (1H, d, J ) 11.2 Hz, H-9),
3.99 (1H, dd, J ) 10.8, 8.4 Hz, H-3â), 3.87 (3H, s, OCH3), 3.85 (3H,
s, OCH3),3.61 (3H, s, OCH3), 2.99 (1H, dd, J ) 11.6, 4.2 Hz, H-4R),
2.93 (1H, dd, J ) 14.0, 10.8 Hz, H-4â), 2.64-2.59 (1H, m, H-3a),
2.48 (1H, dd, J ) 13.6, 11.2 Hz, H-9a); 13C NMR (100 MHz, CDCl3),
see Table 2; ESIMS m/z 369 [M - H]-; HRFABMS m/z 370.1409
(calcd for C21H22O6, 370.1416).
(()-(3aR,9S,9aR)-9-(3-Hydroxy-4-methoxyphenyl)-6,7,8-trimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (24). The ex-
perimental procedure as noted above for compound 22 was repeated
with compound 20 (0.25 g, 0.54 mmol) to yield compound 24 (136
mg, 63.0% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.91 (1H,
dd, J ) 8.0, 0.8 Hz, H-6′), 6.78 (1H, d, J ) 8.4 Hz, H-5′), 6.61 (1H,
d, J ) 0.8 Hz, H-2′), 6.46 (1H, s, H-5), 4.45 (1H, dd, J ) 8.4, 6.0 Hz,
H-3R), 4.27 (1H, d, J ) 9.6 Hz, H-9), 3.90 (1H, dd, J ) 8.8, 7.2 Hz,
H-3â), 3.85 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.73 (3H, s, OCH3),
3.13 (3H, s, OCH3), 2.93-2.88 (2H, m, H-4), 2.46-2.42 (1H, m, H-3a),
2.38 (1H, dd, J ) 13.6, 10.4 Hz, H-9a); 13C NMR (100 MHz, CDCl3),
see Table 2; ESIMS m/z 399 [M - H]-; HRFABMS m/z 400.1513
(calcd for C22H24O7, 400.1522).
(()-(3aR,9S,9aR)-9-(4-Hydroxy-3-methoxyphenyl)-6,7,8-trimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (25). The ex-
perimental procedure as noted above for compound 22 was repeated

1150 Journal of Natural Products, 2006, Vol. 69, No. 8
Zhao et al.
with compound 21 (0.2 g, 0.43 mmol) to yield compound 25 (119 mg,
69.2% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.97 (1H, d, J
) 1.6 Hz, H-2′), 6.76 (1H, d, J ) 8.0 Hz, H-5′), 6.50 (1H, dd, J ) 8.0,
1.6 Hz, H-6′), 6.46 (1H, s, H-5), 4.45 (1H, dd, J ) 8.4, 6.4 Hz, H-3R),
4.29 (1H, d, J ) 10.0 Hz, H-9), 3.93 (1H, dd, J ) 10.4, 8.4 Hz, H-3â),
3.88 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.13
(3H, s, OCH3), 2.92-2.87 (2H, m, H-4), 2.49-2.45 (1H, m, H-3a),
2.38 (1H, dd, J ) 13.2, 10.4 Hz, H-9a); 13C NMR (100 MHz, CDCl3),
see Table 2; ESIMS m/z 399 [M - H]-; HRFABMS m/z 400.1512
(calcd for C22H24O7, 400.1522).
General Procedure for the Preparation of Compounds 26-39.
(()-(3aR,9S,9aR)-9-(3-Geranoxy-4-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (26). Compound
22 (0.1 g 0.27 mmol) was dissolved in dry Me2CO3 (10 mL) and stirred
for 15 min with K2CO3 (0.18 g, 1.3 mmol) and KI (0.1 g, 0.60 mmol).
Geranyl bromide (about 0.25 g), prepared by the reaction of geranol
with PBr3, was added to the flask, and the mixture was refluxed for 8
h. The reaction product was chromatographed on silica gel (hexane/
EtOAc, 4:1) to give compound 26 (98 mg, 71.7% yield) as a yellow
gum: 1H NMR (400 MHz, CDCl3) δ 6.83 (2H, s, H-5′, 6′), 6.67 (1H,
s, H-2′), 6.61 (1H, s, H-5), 6.32 (1H, s, H-8), 5.47 (1H, t, J ) 6.4 Hz,
H-8′), 5.07 (1H, t, J ) 6.4 Hz, H-12′), 4.54-4.52 (3H, m, H-3R, 7′),
4.10 (1H, d, J ) 11.2 Hz, H-9), 3.96 (1H, dd, J ) 10.0, 9.6 Hz, H-3â),
3.86 (6H, s, OCH3 × 2), 3.59 (3H, s, OCH3), 3.02 (1H, dd, J ) 14.8,
4.8 Hz, H-4R), 2.92 (1H, dd, J ) 14.4, 12.0 Hz, H-4â), 2.64-2.58
(1H, m, H-3a), 2.49 (1H, dd, J ) 13.2, 11.6 Hz, H-9a), 2.04-1.99
(4H, m, H-10′, 11′), 1.59, 1.63, 1.67 (CH3 × 3); 13C NMR (100 MHz,
CDCl3) δ 131.7 (C, C-9′), 129.6 (C, C-13′), 124.0 (CH, C-12′), 120.1
(CH, C-8′), 69.7 (CH2, C-7′), 39.6 (CH2, C-10′), 26.4 (CH2, C-11′),
25.7 (CH3, C-14′), 17.7 (CH3, C-16′), 16.4 (CH3, C-15′), other data
see Table 2; ESIMS m/z 524 [M + NH4]+; HRFABMS m/z 506.2660
(calcd for C31H38O6, 506.2668).
(()-(3aR,9S,9aR)-9-(3-Farnesoxy-4-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (27). By the
same procedure used to obtain compound 26, compound 22 (0.1 g,
0.27 mmol) was reacted with farnesyl bromide to give compound 27
(113 mg, 73.0% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3)
δ 6.83 (2H, s, H-5′, 6′), 6.68 (1H, s, H-2′), 6.61 (1H, s, H-5), 6.32
(1H, s, H-8), 5.47 (1H, t, J ) 6.4 Hz, H-8′), 5.10-5.09 (2H, m, H-12′,
16′), 4.54-4.51 (3H, m, H-3R, 7′), 4.10 (1H, d, J ) 11.2 Hz, H-9),
3.96 (1H, dd, J ) 11.6, 9.2 Hz, H-3â), 3.86 (6H, s, OCH3 × 2), 3.59
(3H, s, OCH3), 3.00 (1H, dd, J ) 15.2, 4.8 Hz, H-4R), 2.92 (1H, dd,
J ) 15.6, 11.6 Hz, H-4â), 2.65-2.60 (1H, m, H-3a), 2.48 (1H, dd, J
) 13.2, 11.6 Hz, H-9a), 2.08-1.98 (8H, m, H-10′, 11′, 14′, 15′), 1.59,
1.63, 1.67, 1.71 (CH3 × 4); 13C NMR (100 MHz, CDCl3) δ 135.4 (C,
C-9′), 132.2 (C, C-13′), 131.5 (C, C-17′), 124.6 (CH, C-16′), 123.7
(CH, C-12′), 120.5 (CH, C-8′), 69.4 (CH2, C-7′), 39.6 (CH2, C-10′,
C-14′), 26.5 (CH2, C-15′), 26.3 (CH2, C-11′), 25.5 (CH3, C-18′), 17.5
(CH3, C-21′), 16.4 (CH3, C-20′), 15.8 (CH3, C-19′), other data see Table
2; ESIMS m/z 592 [M + NH4]+; HRFABMS m/z 574.3284 (calcd for
C36H46O6, 574.3294).
(()-(3aR,9S,9aR)-9-(3-Allyloxy-4-methoxyphenyl)-6,7,8-trimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (28). By the
same procedure used to obtain compound 26, compound 24 (0.1 g,
0.25 mmol) was reacted with allyl bromide to give compound 28 (86
mg, 78.1% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.85 (1H,
s, H-2′), 6.76 (1H, d, J ) 8.0 Hz, H-5′), 6.71 (1H, d, J ) 7.6 Hz,
H-6′), 6.46 (1H, s, H-5), 6.06 (1H, ddd, J ) 22.4, 10.8, 5.6 Hz, H-8′),
5.33 (1H, dd, J ) 17.2, 1.6 Hz, H-9′), 5.23 (1H, dd, J ) 10.4, 1.2 Hz,
H-9′), 4.57 (1H, d, J ) 5.2 Hz, H-7′), 4.46 (1H, dd, J ) 8.0, 6.4 Hz,
H-3R), 4.30 (1H, d, J ) 10.4 Hz, H-9), 3.95 (1H, dd, J ) 10.4, 8.8
Hz, H-3â), 3.86 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.73 (3H, s, OCH3),
3.10 (3H, s, OCH3), 2.94-2.86 (2H, m, H-4), 2.44-2.42 (1H, m, H-3a),
2.37 (1H, dd, J ) 14.4, 10.0 Hz, H-9a); 13C NMR (100 MHz, CDCl3)
δ 134.6 (CH, C-8′), 116.8 (CH, C-9′), 69.5 (CH2, C-7′), other data see
Table 2; ESIMS m/z 458 [M + NH4]+; HRFABMS m/z 440.1828 (calcd
for C25H28O7, 440.1835).
3.92 (1H, dd, J ) 10.4, 8.8 Hz, H-3â), 3.87 (3H, s, OCH3), 3.82 (3H,
s, OCH3), 3.73 (3H, s, OCH3), 3.08 (3H, s, OCH3), 2.92-2.87 (2H, m,
H-4), 2.46-2.42 (1H, m, H-3a), 2.39 (1H, dd, J ) 14.0, 10.4 Hz, H-9a),
1.64, 1.71 (CH3 × 2); 13C NMR (100 MHz, CDCl3) δ 137.7 (C, C-9′),
119.6 (CH, C-8′), 65.8 (CH2, C-7′), 25.8 (CH3, C-11′), 18.2 (CH3,
C-10′), other data see Table 2; ESIMS m/z 486 [M + NH4]+;
HRFABMS m/z 468.2170 (calcd for C27H32O7, 468.2184).
(()-(3aR,9S,9aR)-9-[3-Geranoxy-4-methoxyphenyl]-6,7,8-tri-
methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (30).
By the same procedure used to obtain compound 26, compound 24
(0.1 g, 0.25 mmol) was reacted with geranyl bromide to give compound
30 (95 mg, 70.9% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ
6.80-6.75 (3H, m, H-2′, 5′, 6′), 6.46 (1H, s, H-5), 5.53 (1H, t, J ) 6.4
Hz, H-8′), 5.07 (1H, t, J ) 6.4 Hz, H-12′), 4.57 (2H, d, J ) 6.4 Hz,
H-7′), 4.47 (1H, dd, J ) 8.4, 6.4 Hz, H-3R), 4.30 (1H, d, J ) 10.8 Hz,
H-9), 3.93 (1H, dd, J ) 10.0, 9.2 Hz, H-3â), 3.86 (3H, s, OCH3), 3.82
(3H, s, OCH3), 3.73 (3H, s, OCH3), 3.08 (3H, s, OCH3), 2.94-2.88
(2H, m, H-4), 2.46-2.42 (1H, m, H-3a), 2.38 (1H, dd, J ) 14.0, 10.4
Hz, H-9a), 2.08-1.98 (4H, m, H-10′, 11′), 1.59, 1.65, 1.67 (CH3 × 3);
13C NMR (100 MHz, CDCl3) δ 131.6 (C, C-9′), 129.7 (C, C-13′), 124.0
(CH, C-12′), 120.0 (CH, C-8′), 69.6 (CH2, C-7′), 39.6 (CH2, C-10′),
26.4 (CH2, C-11′), 25.7 (CH3, C-14′), 17.7 (CH3, C-16′), 16.4 (CH3,
C-15′), other data see Table 2; ESIMS m/z 554 [M + NH4]+;
HRFABMS m/z 536.2764 (calcd for C27H32O7, 536.2774).
(()-(3aR,9S,9aR)-9-[3-Farnesoxy-4-methoxyphenyl]-6,7,8-tri-
methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (31).
By the same procedure used to obtain compound 26, compound 24
(0.1 g, 0.25 mmol) was reacted with farnesyl bromide to give compound
31 (112 mg, 74.2% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ
6.82-6.66 (3H, m, H-2′, 5′, 6′), 6.46 (1H, s, H-5), 5.47 (1H, t, J ) 6.4
Hz, H-8′), 5.10 (2H, t, J ) 6.4 Hz, H-12′, 16′), 4.57 (2H, d, J ) 6.4
Hz, H-7′), 4.46 (1H, dd, J ) 8.4, 6.4 Hz, H-3R), 4.30 (1H, d, J ) 10.0
Hz, H-9), 3.92 (1H, dd, J ) 10.0, 9.2 Hz, H-3â), 3.86 (3H, s, OCH3),
3.82 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.09 (3H, s, OCH3), 2.95-
2.91 (2H, m, H-4), 2.47-2.41 (1H, m, H-3a), 2.38 (1H, dd, J ) 14.0,
10.4 Hz, H-9a), 2.10-1.98 (8H, m, H-10′, 11′, 14′, 15′), 1.64, 1.66,
1.67, 1.71 (CH3 × 4); 13C NMR (100 MHz, CDCl3) δ 135.5 (C, C-9′),
132.1 (C, C-13′), 131.5 (C, C-17′), 124.7 (CH, C-16′), 123.9 (CH,
C-12′), 120.2 (CH, C-8′), 69.9 (CH2, C-7′), 39.5 (CH2, C-10′, C-14′),
26.6 (CH2, C-15′), 26.3 (CH2, C-11′), 25.5 (CH3, C-18′), 17.5 (CH3,
C-21′), 16.4 (CH3, C-20′), 15.9 (CH3, C-19′), other data see Table 2;
ESIMS m/z 622 [M + NH4]+; HRFABMS m/z 604.3392 (calcd for
C37H48O7, 604.3400).
(()-(3aR,9S,9aR)-9-[4-Allyloxy-3-methoxyphenyl]-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (32). By the
same procedure used to obtain compound 26, compound 23 (0.1 g,
0.27 mmol) was reacted with allyl bromide to give compound 32 (79
mg, 71.4% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.83 (1H,
d, J ) 8.0 Hz, H-5′), 6.75 (1H, d, J ) 8.0 Hz, H-6′), 6.72 (1H, s,
H-2′), 6.61 (1H, s, H-5), 6.32 (1H, s, H-8), 6.10 (1H, ddd, J ) 23.2,
11.2, 5.6 Hz, H-8′), 5.40 (1H, d, J ) 15.6 Hz, H-9′), 5.28 (1H, d, J )
10.4 Hz, H-9′), 4.60 (2H, d, J ) 5.6 Hz, H-7′), 4.53 (1H, dd, J ) 8.0,
6.8 Hz, H-3R), 4.11 (1H, d, J ) 11.2 Hz, H-9), 3.99 (1H, dd, J )
10.0, 8.8 Hz, H-3â), 3.87 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.60
(3H, s, OCH3), 3.00 (1H, dd, J ) 14.8, 4.4 Hz, H-4R), 2.97 (1H, dd,
J ) 15.2, 13.2 Hz, H-4â), 2.65-2.57 (1H, m, H-3a), 2.51 (1H, dd, J
) 13.2, 11.2 Hz, H-9a); 13C NMR (100 MHz, CDCl3) δ 134.5 (CH,
C-8′), 116.8 (CH, C-9′), 69.4 (CH2, C-7′), other data see Table 2;
ESIMS m/z 428 [M + NH4]+; HRFABMS m/z 410.1718 (calcd for
C24H26O6, 410.1729).
(()-(3aR,9S,9aR)-9-(4-Geranoxy-3-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (33). By the
same procedure used to obtain compound 26, compound 23 (0.1 g,
0.27 mmol) was reacted with geranyl bromide to give compound 33
(91 mg, 66.6% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.83
(1H, d, J ) 7.6 Hz, H-5′), 6.76 (1H, dd, J ) 7.2, 0.8 Hz, H-6′), 6.70
(1H, d, J ) 0.8 Hz, H-2′), 6.61 (1H, s, H-5), 6.33 (1H, s, H-8), 5.53
(1H, t, J ) 6.4 Hz, H-8′), 5.09 (1H, t, J ) 6.4 Hz, H-12′), 4.60 (2H,
d, J ) 6.8 Hz, H-7′), 4.55 (1H, dd, J ) 7.6, 7.2 Hz, H-3R), 4.12 (1H,
d, J ) 10.8 Hz, H-9), 3.99 (1H, dd, J ) 10.0, 9.2 Hz, H-3â), 3.87 (3H,
s, OCH3), 3.81 (3H, s, OCH3), 3.60 (3H, s, OCH3), 3.02-2.95 (2H, m,
H-4), 2.66-2.58 (1H, m, H-3a), 2.51 (1H, dd, J ) 13.2, 11.6 Hz, H-9a),
2.08-2.06 (4H, m, H-10′, 11′), 1.60, 1.67, 1.72 (CH3 × 3); 13C NMR
(100 MHz, CDCl3) δ 131.7 (C, C-9′), 129.9 (C, C-13′), 124.1 (CH,
C-12′), 120.0 (CH, C-8′), 69.7 (CH2, C-7′), 39.6 (CH2, C-10′), 26.4
(()-(3aR,9S,9aR)-9-[3-(3-Methylbut-2-enyloxy)-4-methoxyphenyl]-
6,7,8-trimethoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-
one (29). By the same procedure used to obtain compound 26,
compound 24 (0.1 g, 0.25 mmol) was reacted with 3-methyl-2-butenyl
bromide to give compound 29 (91 mg, 77.7% yield) as a gum: 1H
NMR (400 MHz, CDCl3) δ 6.79-6.76 (3H, m, H-2′, 5′, 6′), 6.46 (1H,
s, H-5), 5.42 (1H, t, J ) 6.4 Hz, H-8′), 4.55 (1H, d, J ) 6.4 Hz, H-7′),
4.47 (1H, dd, J ) 8.4, 6.4 Hz, H-3R), 4.30 (1H, d, J ) 10.4 Hz, H-9),

Racemic Isodeoxypodophyllotoxin Analogues
Journal of Natural Products, 2006, Vol. 69, No. 8 1151
(CH2, C-11′), 25.7 (CH3, C-14′), 17.8 (CH3, C-16′), 16.4 (CH3, C-15′),
other data see Table 2; ESIMS m/z 524 [M + NH4]+; HRFABMS m/z
506.2674 (calcd for C31H38O6, 506.2668).
(0.1 g, 0.25 mmol) was reacted with farnesyl bromide to give compound
38 (97 mg, 64.2% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ
6.88 (1H, br s, H-2′), 6.76 (1H, d, J ) 8.4 Hz, H-5′), 6.63 (1H, d, J )
8.4 Hz, H-6′), 6.46 (1H, s, H-5), 5.49 (1H, t, J ) 6.4 Hz, H-8′), 5.09
(2H, m, H-12′, H-16′), 4.56 (2H, d, J ) 6.4 Hz, H-7′), 4.49 (1H, dd,
J ) 8.8, 8.4 Hz, H-3R), 4.30 (1H, d, J ) 10.0 Hz, H-9), 3.96 (1H, dd,
J ) 11.2, 9.2 Hz, H-3â), 3.86 (3H, s, OCH3), 3.83 (3H, s, OCH3),
3.76 (3H, s, OCH3), 3.08 (3H, s, OCH3), 2.95-2.89 (2H, m, H-4),
2.46-2.42 (1H, m, H-3a), 2.41 (1H, dd, J ) 10.0, 9.6 Hz, H-9a), 2.04-
1.98 (8H, m, H-10′, 11′, 14′, 15′), 1.59, 1.67, 1.69, 1.76 (CH3 × 4);
13C NMR (100 MHz, CDCl3) δ 135.6 (C, C-9′), 132.1 (C, C-13′), 131.5
(C, C-17′), 124.6 (CH, C-16′), 123.8 (CH, C-12′), 120.4 (CH, C-8′),
69.9 (CH2, C-7′), 39.8 (CH2, C-10′), 39.7 (CH2, C-14′), 26.5 (CH2,
C-15′), 26.2 (CH2, C-11′), 25.5 (CH3, C-18′), 17.6 (CH3, C-21′), 16.5
(CH3, C-20′), 16.0 (CH3, C-19′), other data see Table 2; ESIMS m/z
622 [M + NH4]+; HRFABMS m/z 604.3388 (calcd for C37H48O7,
604.3400).
(()-(3aR,9S,9aR)-9-(4-Farnesoxy-3-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (34). By the
same procedure used to obtain compound 26, compound 23 (0.1 g,
0.27 mmol) was reacted with farensyl bromide to give compound 34
(98 mg, 63.2% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.83
(1H, d, J ) 8.4 Hz, H-5′), 6.76 (1H, d, J ) 8.0 Hz, H-6′), 6.70 (1H,
s, H-2′), 6.61 (1H, s, H-5), 6.33 (1H, s, H-8), 5.54 (1H, t, J ) 6.4 Hz,
H-8′), 5.10 (2H, t, J ) 6.4 Hz, H-12′, 16′), 4.60 (2H, d, J ) 6.4 Hz,
H-7′), 4.53 (1H, dd, J ) 8.0, 7.6 Hz, H-3R), 4.12 (1H, d, J ) 10.8 Hz,
H-9), 4.00 (1H, dd, J ) 10.0, 9.6 Hz, H-3â), 3.86 (3H, s, OCH3), 3.81
(3H, s, OCH3), 3.70 (3H, s, OCH3), 2.96-2.90 (2H, m, H-4), 2.68-
2.60 (1H, m, H-3a), 2.48 (1H, dd, J ) 13.2, 11.6 Hz, H-9a), 2.08-
2.03 (8H, m, H-10′, 11′, 14′, 15′), 1.60, 1.67, 1.72, 1.74 (CH3 × 4);
13C NMR (100 MHz, CDCl3) δ 135.6 (C, C-9′), 132.0 (C, C-13′), 131.5
(C, C-17′), 124.7 (CH, C-16′), 123.7 (CH, C-12′), 120.2 (CH, C-8′),
69.9 (CH2, C-7′), 39.8 (CH2, C-10′), 39.6 (CH2, C-14′), 26.7 (CH2,
C-15′), 26.5 (CH2, C-11′), 25.5 (CH3, C-18′), 17.5 (CH3, C-21′), 16.4
(CH3, C-20′), 15.9 (CH3, C-19′), other data see Table 2; ESIMS m/z
592 [M + NH4]+; HRFABMS m/z 574.3280 (calcd for C36H46O6,
574.3294).
(()-(3aR,9S,9aR)-9-[4-Allyloxy-3-methoxyphenyl]-6,7,8-trimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (35). By the
same procedure used to obtain compound 26, compound 25 (0.1 g,
0.25 mmol) was reacted with allyl bromide to give compound 35 (84
mg, 76.5% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 6.84 (1H,
s, H-2′), 6.76 (1H, d, J ) 8.0 Hz, H-5′), 6.71 (1H, d, J ) 8.0 Hz,
H-6′), 6.46 (1H, s, H-5), 6.04 (1H, ddd, J ) 22.8, 10.4, 5.6 Hz, H-8′),
5.33 (1H, dd, J ) 17.2, 1.6 Hz, H-9′), 5.23 (1H, dd, J ) 10.4, 1.2 Hz,
H-9′), 4.55 (1H, dd, J ) 13.2, 6.0 Hz, H-7′), 4.46 (1H, dd, J ) 8.4, 6.4
Hz, H-3R), 4.29 (1H, d, J ) 10.0 Hz, H-9), 3.92 (1H, dd, J ) 10.0,
8.8 Hz, H-3â), 3.86 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.73 (3H, s,
OCH3), 3.09 (3H, s, OCH3), 2.96-2.90 (2H, m, H-4), 2.47-2.42 (1H,
m, H-3a), 2.37 (1H, dd, J ) 13.6, 11.6 Hz, H-9a); 13C NMR (100
MHz, CDCl3) δ 134.5 (CH, C-8′), 116.7 (CH, C-9′), 69.5 (CH2, C-7′),
other data see Table 2; ESIMS m/z 458 [M + NH4]+; HRFABMS m/z
440.1827 (calcd for C25H28O7, 440.1835).
(()-(3aR,9S,9aR)-9-[4-(3-Methylbut-2-enyloxy)-3-methoxyphenyl]-
6,7,8-trimethoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-
one (36). By the same procedure used to obtain compound 26,
compound 25 (0.1 g, 0.25 mmol) was reacted with 3-methyl-2-butenyl
bromide to give compound 36 (83 mg, 70.9% yield) as a gum: 1H
NMR (400 MHz, CDCl3) δ 6.77-6.74 (3H, m, H-2′, 5′, 6′), 6.47 (1H,
s, H-5), 5.43 (1H, t, J ) 6.4 Hz, H-8′), 4.56 (1H, d, J ) 6.0 Hz, H-7′),
4.47 (1H, dd, J ) 8.4, 6.4 Hz, H-3R), 4.29 (1H, d, J ) 10.0 Hz, H-9),
3.92 (1H, dd, J ) 10.4, 9.2 Hz, H-3â), 3.88 (3H, s, OCH3), 3.87 (3H,
s, OCH3), 3.73 (3H, s, OCH3), 3.08 (3H, s, OCH3), 2.94-2.88 (2H, m,
H-4), 2.49-2.44 (1H, m, H-3a), 2.37 (1H, dd, J ) 14.0, 10.4 Hz, H-9a),
1.63, 1.70 (CH3 × 2); 13C NMR (100 MHz, CDCl3) δ 137.0 (C, C-9′),
120.0 (CH, C-8′), 65.5 (CH2, C-7′), 25.8 (CH3, C-11′), 17.9 (CH3,
C-10′), other data see Table 2; ESIMS m/z 486 [M + NH4]+;
HRFABMS m/z 468.2172 (calcd for C27H32O7, 468.2184).
(()-(3aR,9S,9aR)-9-(4-Geranoxy-3-methoxyphenyl)-6,7,8-tri-
methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (37).
By the same procedure used to obtain compound 26, compound 25
(0.1 g, 0.25 mmol) was reacted with geranyl bromide to give compound
37 (91 mg, 68.0% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ
6.88 (1H, br s, H-2′), 6.76 (1H, d, J ) 8.4 Hz, H-5′), 6.62 (1H, d, J )
8.4 Hz, H-6′), 6.46 (1H, s, H-5), 5.48 (1H, J ) 6.4 Hz, H-8′), 5.07
(1H, t, J ) 6.0 Hz, H-12′), 4.57 (2H, d, J ) 6.4 Hz, H-7′), 4.49 (1H,
dd, J ) 8.4, 6.4 Hz, H-3R), 4.31 (1H, d, J ) 9.6 Hz, H-9), 3.95 (1H,
dd, J ) 10.0, 8.8 Hz, H-3â), 3.86 (3H, s, OCH3), 3.84 (3H, s, OCH3),
3.73 (3H, s, OCH3), 3.08 (3H, s, OCH3), 2.93-2.87 (2H, m, H-4),
2.46-2.40 (1H, m, H-3a), 2.40 (1H, dd, J ) 14.0, 10.0 Hz, H-9a),
2.08-1.99 (4H, m, H-10′, 11′), 1.58, 1.66, 1.69 (CH3 × 3); 13C NMR
(100 MHz, CDCl3) δ 131.4 (C, C-9′), 129.9 (C, C-13′), 123.7 (CH,
C-12′), 120.1 (CH, C-8′), 69.5 (CH2, C-7′), 39.6 (CH2, C-10′), 26.4
(CH2, C-11′), 25.7 (CH3, C-14′), 17.6 (CH3, C-16′), 16.4 (CH3, C-15′),
other data see Table 2; ESIMS m/z 554 [M + NH4]+; HRFABMS m/z
536.2758 (calcd for C27H32O7, 536.2774).
(()-(3aR,9S,9aR)-9-(4-Benzyloxy-3-methoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (39). By the
same procedure used to obtain compound 26, compound 23 (0.1 g,
0.27 mmol) was reacted with benzyl bromide to give compound 39
(97 mg, 78.4% yield) as a gum: 1H NMR (400 MHz, CDCl3) δ 7.45-
7.29 (5H, m, OCH2Ph-H), 6.84 (1H, d, J ) 8.4 Hz, H-5′), 6.72-6.70
(2H, m, H-2′, 6′), 6.60 (1H, s, H-5), 6.30 (1H, s, H-8), 5.14 (2H, s,
OCH2Ph), 4.53 (1H, dd, J ) 8.0, 7.2 Hz, H-3R), 4.11 (1H, d, J ) 12.0
Hz, H-9), 3.99 (1H, dd, J ) 10.4, 9.6 Hz, H-3â), 3.87 (3H, s, OCH3),
3.83 (3H, s, OCH3), 3.59 (3H, s, OCH3), 2.98-2.92 (2H, m, H-4),
2.65-2.60 (1H, m, H-3a), 2.50 (1H, dd, J ) 13.2, 11.2 Hz, H-9a); 13
C
NMR (100 MHz, CDCl3) δ 128.5 (CH, C-9′, C-13′), 128.3 (CH, C-10′,
C-12′), 128.1 (CH, C-11′), 125.4 (C, C-8′), 75.0 (CH2, C-7′), other
data see Table 2; ESIMS m/z 478 [M + NH4]+; HRFABMS m/z
460.1878 (calcd for C37H48O7, 460.1886).
General Procedure for the Preparation of Compounds 40-45.
(()-(1S,2R,3R)-Methyl 1-(3-hydroxy-4-methoxyphenyl)-3-(hydroxy-
methyl)-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate
(40). To a solution of compound 22 (74 mg, 0.2 mmol) in 5 mL of
MeOH was added 1 M H2SO4 (1 mL) at room temperature. After
stirring for 2 h, the solvent was removed under reduced pressure, and
the residue was redissolved in EtOAc (10 mL). The organic phase was
washed with H2O and brine, dried (MgSO4), and concentrated in vacuo
to afford a crude product, which was purified by column chromatog-
raphy on silica gel with hexane/EtOAc, 1:1, as eluent to give the pure
product 40 (62 mg, 77.1% yield) as a gum: 1H NMR (400 MHz,
CDCl3) δ 6.84 (1H, d, J ) 8.0 Hz, H-5′), 6.65 (1H, d, J ) 8.0 Hz,
H-6′), 4.24 (1H, d, J ) 10.8 Hz, H-1), 3.86 (3H, s, OCH3), 6.61 (1H,
s, H-2′), 6.56 (1H, s, H-5), 6.22 (1H, s, H-8), 5.57 (1H, s, OH-3′), 3.80
(3H, s, OCH3), 3.66 (2H, d, J ) 4.0 Hz, H-9), 3.59 (3H, s, OCH3),
3.54 (3H, s, OCH3), 2.92-2.88 (2H, m, H-4), 2.74 (1H, dd, J ) 12.4,
11.2 Hz, H-2), 2.34-2.26 (1H, m, H-3); 13C NMR (100 MHz, CDCl3),
see Table 3; ESIMS m/z 401 [M - H]-; HRFABMS m/z 402.1668
(calcd for C22H26O7, 402.1679).
(()-(1S,2R,3R)-Methyl 1-(4-Hydroxy-3-methoxyphenyl)-3-(hy-
droxymethyl)-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene-2-car-
boxylate (41). The experimental procedure as noted above for
compound 40 was repeated with compound 23 (74 mg, 0.2 mmol) to
yield compound 41 (58 mg, 72.6% yield) as a gum: 1H NMR (400
MHz, CDCl3) δ 6.84 (1H, d, J ) 8.0 Hz, H-5′), 6.65 (1H, dd, J ) 8.0,
2.0 Hz, H-6′), 6.61 (1H, s, H-5), 6.55 (1H, d, J ) 2.0 Hz, H-2′), 6.22
(1H, s, H-8), 5.58 (1H, br s, OH-4′), 4.24 (1H, d, J ) 11.2 Hz, H-1),
3.86 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.66 (2H, d, J ) 4.4 Hz,
H-9), 3.59 (3H, s, OCH3), 3.54 (3H, s, OCH3), 2.90-2.88 (2H, m,
H-4), 2.73 (1H, dd, J ) 11.6, 10.8 Hz, H-2), 2.34-2.28 (1H, m, H-3);
13C NMR (100 MHz, CDCl3), see Table 3; ESIMS m/z 401 [M - H]-;
HRFABMS m/z 402.1664 (calcd for C22H26O7, 402.1679).
(()-(1S,2R,3R)-Methyl 1-(3-Hydroxy-4-methoxyphenyl)-3-(hy-
droxymethyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (42). The experimental procedure as noted above for
compound 40 was repeated with compound 24 (80 mg, 0.2 mmol) to
yield compound 42 (60 mg, 69.3% yield) as a gum: 1H NMR (400
MHz, CDCl3) δ 6.71 (1H, d, J ) 8.4 Hz, H-5′), 6.59 (1H, s, H-2′),
6.56 (1H, dd, J ) 8.4, 1.2 Hz, H-6′), 6.46 (1H, s, H-5), 5.53 (1H, s,
OH-3′), 4.46 (1H, d, J ) 9.2 Hz, H-1), 3.86 (3H, s, OCH3), 3.84 (3H,
s, OCH3), 3.75 (3H, s, OCH3), 3.66 (3H, s, OCH3), 3.61 (2H, d, J )
3.6 Hz, H-9), 3.28 (3H, s, OCH3), 2.80-2.75 (2H, m, H-4), 2.66 (1H,
dd, J ) 11.2, 9.6 Hz, H-2), 2.14-2.05 (1H, m, H-3); 13C NMR (100
(()-(3aR,9S,9aR)-9-(4-Farnesoxy-3-methoxyphenyl)-6,7,8-tri-
methoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (38).
By the same procedure used to obtain compound 26, compound 25

1152 Journal of Natural Products, 2006, Vol. 69, No. 8
Zhao et al.
Table 3. 13C NMR Data [100 MHz, δ (ppm)] for Compounds
40-45 in CDCl3
(1H, t, J ) 6.4 Hz, H-8′), 5.10-5.08 (2H, m, H-12′, H-16′), 4.54 (2H,
d, J ) 6.8 Hz, H-7′), 4.47 (1H, d, J ) 9.6 Hz, H-9), 3.85 (3H, s, OCH3),
3.78 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.63 (3H, s, OCH3), 3.61
(2H, d, J ) 4.2 Hz, H-9), 3.12 (3H, s, OCH3), 2.83 (1H, dd, J ) 15.6,
11.2 Hz, H-4â), 2.77 (1H, dd, J ) 16.0, 4.4 Hz, H-4R), 2.66 (1H, dd,
J ) 14.0, 12.8 Hz, H-2), 2.19-2.14 (9H, m, H-3, 10′, 11′, 14′, 15′),
1.60, 1.66, 1.68, 1.70 (CH3 × 4); 13C NMR (100 MHz, CDCl3) δ 135.5
(C, C-9′), 132.1 (C, C-13′), 131.5 (C, C-17′), 124.5 (CH, C-16′), 123.7
(CH, C-12′), 120.2 (CH, C-8′), 69.9 (CH2, C-7′), 39.5 (CH2, C-10′,
C-14′), 26.6 (CH2, C-15′), 26.3 (CH2, C-11′), 25.5 (CH3, C-18′), 17.5
(CH3, C-21′), 16.4 (CH3, C-20′), 15.9 (CH3, C-19′), other data see Table
3; ESIMS m/z 654 [M + NH4]+; HRFABMS m/z 604.3654 (calcd for
C38H52O8, 636.3662).
Cytotoxicity Assays. Cytotoxicities of the test compounds against
cultured human KB, BEL-7404, A549, HeLa, PC-3, CNE, and HL-60
cell lines were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl-2H-tetrazolium bromide (MTT) assay.15 This was performed
by assessment of the remaining number of viable cells after exposure
of a given number of cells in culture to a particular concentration of
the test compounds. Cell viability was assessed using 3-(4,5-dimeth-
ylthiazol-2-yl)-2,5- diphenyl-2H-tetrazolium bromide (MTT).15 Briefly,
a fresh solution was prepared in phosphate-buffered saline immediately
before use. The different cell lines were diluted in fresh complete
medium and seeded in 96-well plates, applying 104 cells/well. After
24 h of incubation, the cells were treated with the synthetic compounds
at various concentrations during 72 h. Then, MTT solution (10 µL)
was added to each well. The plates were placed in a CO2 incubator
(Shellab) for 4 h and then lysed and incubated with DMSO. The plates
were analyzed in a multiwell plate reader (Bio-Tek ELX800) at 570
nm. The 50% inhibitory concentration (IC50) was calculated as the
compound concentration required to reduce the MTT signal by 50%
compared with untreated control cultures, which was determined
graphically from the dose-response curves.
C no.
40
41
42
43
44
45
1
2
3
4
48.8
53.0
40.0
48.8
53.0
40.0
44.0
54.2
40.0
44.0
54.1
40.0
44.0
54.2
40.0
44.0
54.2
40.0
31.9
32.0
33.0
33.0
33.0
33.0
4a
5
6
7
8
8a
9
127.4
110.7
147.5
147.3
112.1
130.2
65.4
127.4
110.9
147.5
147.2
112.0
130.2
65.4
124.0
106.6
151.9
140.8
152.0
132.1
65.4
124.1
106.5
151.9
141.0
152.0
132.1
65.4
124.1
106.5
151.9
140.9
152.1
132.1
65.4
124.0
106.5
151.9
141.0
152.0
152.1
65.4
10
1′
2′
3′
4′
5′
6′
OMe-6
OMe-7
OMe-8
OMe-10
OMe-3′
OMe-4′
175.1
135.4
114.0
144.6
145.5
110.3
122.5
55.8
175.1
135.5
114.1
146.6
144.4
111.0
122.2
55.8
175.6
140.3
113.4
144.7
145.3
110.3
124.0
55.8
175.5
140.2
113.6
146.0
144.5
110.4
124.1
55.7
175.5
140.1
113.5
147.3
146.5
110.8
124.3
55.8
175.6
140.2
113.5
147.1
146.6
110.7
124.3
55.8
55.9
55.9
59.4
60.5
51.8
59.4
60.5
51.8
59.4
60.5
51.8
59.4
60.5
51.8
53.0
55.8
53.0
55.8
55.8
55.7
55.8
55.8
MHz, CDCl3), see Table 3; ESIMS m/z 431 [M - H]-; HRFABMS
m/z 432.1772 (calcd for C23H28O8, 432.1784).
(()-(1S,2R,3R)-Methyl 1-(4-Hydroxy-3-methoxyphenyl)-3-(hy-
droxymethyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (43). The experimental procedure noted above for
compound 40 was repeated with compound 25 (80 mg, 0.2 mmol) to
yield compound 43 (65 mg, 75.7% yield) as a gum: 1H NMR (400
MHz, CDCl3) δ 6.76 (1H, d, J ) 8.0 Hz, H-5′), 6.55 (1H, d, J ) 2.0
Hz, H-2′), 6.51 (1H, dd, J ) 8.0, 2.0 Hz, H-6′), 6.46 (1H, s, H-5), 5.53
(1H, s, OH-4′), 4.45 (1H, d, J ) 9.2 Hz, H-1), 3.84 (3H, s, OCH3),
3.78 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.63 (3H, s, OCH3), 3.60
(2H, d, J ) 4.8 Hz, H-9), 3.15 (3H, s, OCH3), 2.78 (2H, dd, J ) 14.0,
10.0 Hz, H-4), 2.65 (1H, dd, J ) 11.2, 9.6 Hz, H-2), 2.14-2.06 (1H,
m, H-3); 13C NMR (100 MHz, CDCl3), see Table 3; ESIMS m/z 431
[M - H]-; HRFABMS m/z 432.1788 (calcd for C23H28O8, 432.1784).
(()-(1S,2R,3R)-Methyl 1-(4-Geranoxy-3-methoxyphenyl)-3-(hy-
droxymethyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (44). The experimental procedure as noted above for
compound 40 was repeated with compound 37 (54 mg, 0.1 mmol) to
yield compound 44 (35 mg, 62.2% yield) as a gum: 1H NMR (400
MHz, CDCl3) δ 6.73 (1H, d, J ) 8.4 Hz, H-5′), 6.59 (1H, s, H-2′),
6.52 (1H, d, J ) 8.4 Hz, H-6′), 6.46 (1H, s, H-5), 5.49 (1H, J ) 6.4
Hz, H-8′), 5.07 (1H, t, J ) 6.8 Hz, H-12′), 4.55 (2H, d, J ) 6.4 Hz,
H-7′), 4.47 (1H, d, J ) 9.6 Hz, H-1), 3.85 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.73 (3H, s, OCH3), 3.63 (3H, s, OCH3), 3.61 (2H, d, J ) 7.2
Hz, H-9), 3.12 (3H, s, OCH3), 2.83 (1H, dd, J ) 16.0, 11.6 Hz, H-4â),
2.76 (1H, dd, J ) 16.0, 4.0 Hz, H-4R), 2.67 (1H, dd, J ) 16.0, 7.2 Hz,
H-2), 2.14-2.06 (5H, m, H-3, 10′, 11′), 1.59, 1.66, 1.68 (CH3 × 3);
13C NMR (100 MHz, CDCl3) δ 131.6 (C, C-9′), 129.7 (C, C-13′), 124.0
(CH, C-12′), 120.1 (CH, C-8′), 69.6 (CH2, C-7′), 39.6 (CH2, C-10′),
26.4 (CH2, C-11′), 25.7 (CH3, C-14′), 17.6 (CH3, C-16′), 16.4 (CH3,
C-15′), other data see Table 3; ESIMS m/z 586 [M + NH4]+;
HRFABMS m/z 568.3026 (calcd for C33H44O8, 568.3036).
Acknowledgment. This work is in part financially supported by
the China-France PRA BT-01-02, the DAAD-CSC PPP project (CSC
[2004] 3067), and the Special 985 Fund from Zhejiang University. One
of the authors (Y.Z.) would also like to express his thanks to the Chinese
Ministry of Education as well as to Mr. K.-S. Li for the Cheung Kong
Scholar Chair Professorship at Zhejiang University.
References and Notes
(1) Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. ReV. 2003, 2, 201-
207.
(2) Gordaliza, M.; Garc´ıa, P. A.; Miguel del Corral, J. M.; Castro, M.
A.; Go´mez-Zurita, M. A. Toxicon 2004, 44, 441-459.
(3) Hande, K. R. Eur. J. Cancer 1998, 34, 1514-1521.
(4) Gordaliza, M.; Miguel del Corral, J. M.; Castro, M. A.; Lo´pez-
Va´zquez, M. L.; Garc´ıa, P. A.; Feliciano, A. S.; Garc´ıa-Gra´valos,
M. D. Bioorg. Med. Chem. Lett. 1995, 5, 2465-2468.
(5) Zavala, F.; Gue´nard, D.; Robin, J. P.; Brown, E. J. Med. Chem. 1980,
23, 546-549.
(6) Sagˇlam, H.; Go¨zler, T.; Go¨zler, B. Fitoterapia 2003, 74, 564-569.
(7) Ulubelen, A.; Gil, R. R.; Cordell, G. A.; Mericli, A. H.; Mericli, F.
Phytochemistry 1995, 39, 417-422.
(8) Chen, I. S.; Chen, T. L.; Chang, Y. L.; Teng, C. M.; Lin, W. Y. J.
Nat. Prod. 1999, 62, 833-837.
(9) Zhao, Y.; Hao, X. J.; Lu, W.; Cai, J. C.; Yu, H.; Seve´net. T.; Gue´ritte.
F. J. Nat. Prod. 2002, 65, 902-908.
(10) Robin, J. P.; Landais, Y. Tetrahedron 1992, 48, 819-830.
(11) Cambie, R. C.; Craw, P. A.; Rutledge, P. S.; Woodgate, P. D. Aust.
J. Chem. 1988, 41, 897-918.
(12) Mitra, J.; Mitra, A. K. Indian J. Chem., Sect. B 1992, 31, 452-455.
(13) Reynolds, A, J.; Scott, A. J.; Turner, C. I.; Sherburn, M. S. J. Am.
Chem. Soc. 2003, 125, 12108-12109.
(()-(1S,2R,3R)-Methyl 1-(4-Farnesoxy-3-methoxyphenyl)-3-(hy-
droxymethyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (45). The experimental procedure as noted above for
compound 40 was repeated with compound 38 (60 mg, 0.1 mmol) to
yield compound 45 (37 mg, 58.2% yield) as a gum: 1H NMR (400
MHz, CDCl3) δ 6.73 (1H, d, J ) 8.0 Hz, H-5′), 6.59 (1H, d, J ) 2.0
Hz, H-2′), 6.51 (1H, dd, J ) 8.0, 2.0 Hz, H-6′), 6.46 (1H, s, H-5), 5.49
(14) Brown, E.; Robin, J. P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579.
(15) Araki, T.; Enokido, Y.; Inamura. N.; Aizawa, S.; Reed, J. C.;
Hatanaka, H. Brain Res. 1998, 794, 239-247.
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