Synthesis, anti-virus and anti-tumour activities of dibenzylbutyrolactone lignans and their analogues

Article abstract of DOI:10.3184/030823409X12506792542747

An efficient synthesis of dibenzylbutyrolactone lignans and their analogues has been developed. Based on a Stobbe condensation of piperonal or veratraldehyde with diethylsuccinate and alkylation with 3,4- methylenedioxybenzyl bromide to give the skeleton

Full text of DOI:10.3184/030823409X12506792542747

JOURNAL OF CHEMICAL RESEARCH 2009
SEPTEMBER, 565–569
RESEARCH PAPER 565
Synthesis, anti-virus and anti-tumour activities of dibenzylbutyrolactone
lignans and their analogues
Yamu Xia*, Jia You, Yuanyuan Zhang and Zhongliang Su
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, P.R. China
An efficient synthesis of dibenzylbutyrolactone lignans and their analogues has been developed. Based on a Stobbe
condensation of piperonal or veratraldehyde with diethylsuccinate and alkylation with 3,4-methylenedioxybenzyl
bromide to give the skeleton of the lignan. The ( )-diacid was resolved with quinine and the functional groups were
transformed to obtain three benzylbutyrolactone lignans and seven analogues. Four natural lignans were prepared
by this method, and five lignans were synthesised for the first time. The synthesised compounds were evaluated
for anti-HIV, anti-HSV, and anti-tumour activities. Results showed that the dibenzylbutyrolactone lignans and
their analogues were inactive against HIV Tat transactivation and HSV-1 in vitro, but some compounds displayed
significant activity against MDA-MB-435 human breast cancer cell.
Keywords: dibenzylbutyrolactone lignan, biological activity
Lignans are a class of secondary plant metabolites produced
by the oxidative dimerisation of two phenylpropanoid units.
They are widely distributed in the plant kingdom. Lignans
are found in all parts of the plants, including the roots, stems,
leaves, fruit, and seeds and they exhibit a wide range of
biological activities.1-3 Different families of lignans include
dibenzylbutanes, dibenzocyclooctadienes and a diverse family
of dibenzylbutyrolactone.4
Many dibenzylbutyrolactone lignans and their analogues
have interesting antitubercular, anti-inflammatory and
insecticidal activities.5-7 More particularly some, such as
retrojusticidin B, exhibit differential inhibition of HIV-1 RT
and human DNA polymerase-a.8 Some display strong activity
as potent anti-HIV agents.9,10 Other dibenzylbutyrolactone
lignans and their analogues have been shown to have a
beneficial anti-tumour effect throughout the early promotional
phase of carcinogenesis, and useful drugs have been
developed from the well-known lignan podophyllotoxin for
the treatment of cancer and other ailments. Their activities are
greatly reduced when the lignan skeleton or ester and lactone
groups are not present.11-13
The synthesis of dibenzylbutyrolactone lignans and their
analogues continue to play a central role in the asymmetric
synthesis of lignans. Fischer has reported total syntheses of
(–)-arctigenin, (-)-matairesinol and (-)-a-conidendrin, by
way of a highly stereoselective domino radical sequence.14
Ferrie et al. have developed a short synthetic route of lactonic
lignans. This method exploited a three-component coupling
strategy using a novel Lewis acid catalysed ring-opening/
cyclisation reaction of 2-methoxytetrahydrofuran derivatives
leading to g–butyrolactones as a key step.15 The asymmetric
synthesis of a series of (7'S,8R,8'R)-7'-hydroxylignano-
9,9'-lactones was described by Raffaelli, among them the
mammalian lignan (7'S)-hydroxyenterolactone and (7'S)-
parabenzlactone, allowing the stereochemistry of natural
occurring (-)-parabenzlactone to be re-assigned.16
In order to elucidate further the structural specificity of
dibenzylbutyrolactone lignans and analogues underlying
HIV, HSV and tumour cell suppression, we now describe
an efficient approach to the asymmetric synthesis of
dibenzylbutyrolactone lignans and analogues. Furthermore,
we report the first synthesis of five lignans. The effect of 10
dibenzylbutyrolactone lignans and analogues in their pure
form was examined on HIV Tat transactivation in human
epithelial cells, HSV-1 gene and human leukaemia, liver,
prostate, stomach, and breast cancer cell.
Results and discussion
Synthesis of compounds
In order to construct the skeleton of dibenzylbutyrolactone
lignans and their analogues, we report a route involving a
Stobbe condensation and alkylation. As shown in Scheme 1,
we first used cheap piperonal (heliotropin) (1a) and
veratraldehyde (1b) as raw materials, to obtain the trans-
(E)-unsaturated diester 2a or 2b by a Stobbe condensation
and esterification reaction. The trans-(E)-configuration of
the olefinic double bond was evident from the appearance of
1
the deshielded vinylic proton at d7.76/7.84 in the H NMR
spectrum.17,18 When ester 2a or 2b was treated with LDA
at –78°C, it was alkylated with 3,4-methylenedioxybenzyl
bromide to produce the compounds 3a or 3b. Saponification
of 3a or 3b gave the diacid 4a or 4b. Then, the diacids were
resolved via their quinine salts. The quinine salt of diacid
(–)-4a or (–)-4b crystallised first. Concentration of the
mother liquors gave a solid which yielded the quinine salt
of (+)-diacid 4a' or 4b'. The diacid (–)-4a or (–)-4b was
esterified with EtOH to produce diester (–)-5a or (–)-5b.
Treatment of (–)-5b with LiAlH4/AlCl3 afforded the
unsaturated diol, followed by oxidation with MnO2 to give
(–)-Kaerophyllin 8. Compounds (–)-5a or (–)-5b were
hydrogenated using a 10% palladium on charcoal catalyst,
following by reduction with LiAlH4 in THF to produce a
readilyseparablemixture(approximate1:1)ofthethreo-(–)-6a
and erythro-7a or threo-(–)-6b and erythro-7b. diols Threo-
6a and 6b had consistently larger Rf values than those of the
corresponding erythro-7a and 7b, and each pair was easily
separated by flash column chromatography over silica gel.
The absolute configuration of threo-(–)-6a and erythro-7a
or threo-(–)-6b and erythro-7b were agreement with those
reported in the literature. Subjecting the diol 6a to Ag2CO3/
celite oxidation afforded (–)-hinokinin 9 in 92% yield.
Similarly, oxidation of the diol 7a withAg2CO3/celite produced
(±)-isohinokinin 10 in 94% yield. Compounds (–)-6a and
(–)-6b or 7a and 7b were allowed to react with excess Ac2O,
which after usual work-up gave the diacetate (–)-12a and
(–)-12b or 11a and 11b. When (–)-6a reacted with equimolar
Ac2O, compound 13 was obtained.
In summary, we have developed an efficient stereoselective
synthetic route to the dibenzylbutyrolactone lignans and
their analogues. By this method, three dibenzylbutyrolactone
lignans 8, 9 and 10 and seven analogues 5a, 5b, 11a, 11b,
12a, 12b and 13 were prepared. Compounds 8, 9, 10 and 12b
were natural products and their spectroscopic data were in
agreement with those reported in the literature. Compounds
11a, 11b, 12a, 12b and 13 were synthesised for the first time.
* Correspondent. E-mail: xiaym@qust.edu.cn

566 JOURNAL OF CHEMICAL RESEARCH 2009
R1
R2
COOH
COOH
R1
R2
COOH
COOH
R1
R2
COOEt
R1
R2
COOEt
COOEt
R1
R2
CHO
COOEt iv) NaOH/H2O, reflux,
then H+
i) diethylsuccinate,
EtONa, reflux
iii) 3,4-methylenedioxybenzyl bromide
LDA, -78°C
+
ii) EtOH/C6H6, H+, reflux
v) (-)-quinine resolution
O
2a, 2b
O
1a, 1b
O
O
4a', 4b' O
4a, 4b
O
3a,3b
R1
1
R1
R2
COOEt
COOEt
2'
5'
7'
R1
R2
1'
6'
CH2OH
CH2OH
2
3
3'
4'
vi) EtOH/C6H6, H+
7''
R2
CH2OH
O
CH2OH
4
vii) H2, Pd/C (10%)
viii) LiAlH4
4a, 4b
1''
a: R1, R2: OCH2O
b: R1=R2: OCH3
+
6''
5''
2''
3''
O
O
4''
O
7a,7b
O
5a, 5b
O
6a,6b
O
R1
R2
O
OAc
OAc
O
O
H3CO
H3CO
O
O
xii) Ac2O, CH2Cl2, rt
xi) Ag2CO3/celite, C6H6
reflux
ix) LiAlH4/AlCl3
6a
5b
x) MnO2, acetone, rt
O
O
O
9
12a, 12bO
O
6a,6b
8
O
1
2'
R1
R2
7'
2
3
1'
6'
3'
4'
O
2
O 1
O
O
OAc
OAc
2'
7'
OAc
OH
3
4
1'
6'
3'
O
O
xii) Ac2O, CH2Cl2, rt
7''
xii) Ac2O, CH2Cl2, rt
5'
7''
4
xi) Ag2CO3/celite, C6H6
7a,7b
1''
4'
7a
2''
5'
5
6''
5''
11a, 11b
1''
reflux
6''
5''
3''
O
2''
3''
O
O
O
4''
13
O
10
O
Scheme 1 Synthetic route for the compounds 2–13.
Biological activity
cancer cell, MDA-MB-435 human breast cancer cell.
The results are shown in Table 1.
Inhibition of HIV Tat transactivation: The HIV Tat protein,
a potent transactivator of HIV proviral transcription, is
required for HIV replication. The synthetic compounds were
evaluated for anti-HIV activity by determining their ability to
inhibit the HIV Tat transactivation in vitro. The assay has been
described previously.19 This test for anti-HIV activity indicated
the dibenzylbutyrolactone lignans and their analogues showed
no obvious inhibition of HIV Tat transactivation in vitro.
Inhibition of HSV-1 gene promoter activity: The activity
of the HSV-1 gene inhibitor was examined by measuring
the extent of Vero cells transfected with HSV-1 in vitro.
The assays for all the dibenzylbutyrolactone lignans and
their analogues reported here were in agreement with the
methods previously reported.20 We examined the effect of
the dibenzylbutyrolactone lignans and their analogues, and
compared this effect with that of Acyclovir. Results showed
that the dibenzylbutyrolactone lignans and their analogues
were inactive against HSV-1 in vitro.
We observed that all of the compounds at 10-5M, 10-6M
and 10-7M concentrations inhibited HL-60 cell, PC-3MIE8
cell, BGC-823 cell and Bel-7402 cell lines to below 30%.
The most interesting activities, however, were displayed
against MDA-MB-435 human breast cancer cell. In a screen
against MDA-MB-435 human breast cancer cell we observed
that the pair of 11a, 11b, 12b and 13 having an acetyl group
possessed good activity. Furthermore, 11a the 13 having two
methylenedioxy units showed inhibition ratio above 55% at
10-5M. Compounds 11a and 13 were not regioisomers, and
had a different configuration. Thus we concluded that the
acetyl group and methyleneoxy unit significantly influenced
the biological activity for dibenzylbutyrolactone lignans and
related analogues.
Experimental
Melting points were measured on a Kofler apparatus and were
uncorrected. Optical rotations were determined on a Perkin-Elmer
341 polarimeter. IR spectra were recorded on a Nicolet NEXUS 670
Inhibition of tumor cell: The assays of the some lignans
containing the ester function have been previously published.21
All dibenzylbutyrolactone lignans and their analogues
reported here were tested in the same assay. A series of our
dibenzylbutyrolactone lignans and related analogues were
evaluated against HL-60 human leukemic cell, PC-3MIE8
human prostatic carcinoma cell, BGC-823 human stomach
FT−IR and NicoletAVATAR 360 FT−IR spectrometer. The 1H and 13
C
NMR spectra were recorded on a Brucker AM−400 MHz, Mercury
Plus−300 MHz and Avance–200 MHz spectrometers. The chemical
shifts are reported in ppm relative to TMS as internal standard. Mass
spectra were recorded on a ZAB−HS spectrometer. HRMS were
Table 1 Anti-tumour activities of compounds
HL-60
(inhibitory rate %)
PC-3MIE8
(inhibitory rate %)
BGC-823
(inhibitory rate %)
MDA-MB-435
(inhibitory rate %)
10-5M
10-6M
10-7M
10-5M
10-6M
10-7M
10-5M
10-6M
10-7M
10-5M
10-6M
10-7M
5a
5b
8
9
10
11a
11b
12a
12b
13
–
16.0
5.4
7.3
10.4
1.8
8.4
8.2
7.3
–
–
5.9
–
3.3
9.0
1.9
7.3
7.4
2.7
–
–
–
14.3
13.8
–
–
–
–
–
–
–
–
–
–
–
–
–
14.2
14.5
–
4.2
–
4.2
–
–
14.9
–
–
3.0
–
–
–
35.9
27.9
–
27.6
17.4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4.3
–
13.1
3.4
25.9
6.6
11.0
–
2.0
–
3.4
–
1.6
–
–
–
2.5
–
1.4
–
–
–
59.5
30.8
–
–
–
–
–
–
12.4
–
14.0
–
–
–
–
–
–
–
36.1
55.9
14.1
14.2
–
–
–
–

JOURNAL OF CHEMICAL RESEARCH 2009 567
obtained on a Bruker Daltonics APEXII47e spectrometer. Elemental
analysis was performed by an Elementar Vario EL analyser. Flash
column chromatography was performed on silica gel (200–300 mesh)
and TLC inspections on silica gel GF254 plates, unless noted specially
below.
145.7 (C-4'), 147.2 (C-4''), 148.6 (C-3'), 149.1 (C-3''), 166.7 (C=O),
172.7 (C=O). Anal. Calcd for C25H28O8: C, 65.78; H, 6.18. Found:
C, 65.61; H, 6.29%. HRMS Calcd for C25H29O8 (M + H+): 457.1857.
Found: 457.1856. EI−MS (m/z,%): 456 (M+, 3), 411 (1), 382 (1), 322
(4), 247 (51), 137 (100).
Diethyl 2-(3',4'-methylenedioxybenzylidene) succinate (2a):
Piperonal 1a (15.0 g, 100 mmol) and diethylsuccinate (17.4 g,
100 mmol) were added to a solution of NaOEt (13.6 g, 200 mmol)
in EtOH (200 mL). After heating under reflux for 4 h, ethanol was
removed. The residue was cooled and acidified with HCl (5 N). The
mixture was extracted with EtOAc (3 ¥ 80 mL). The EtOAc layer
was then washed with a saturated solution of NaHCO3 (100 mL).
Acidification of the NaHCO3 extract with HCl (2 N) provided an
oily layer, which was again extracted with EtOAc (3 ¥ 100 mL).
ThecombinedorganiclayerwasdriedoverMgSO4 andconcentratedin
vacuo. This residue was then added to the mixture of EtOH (250 mL),
benzene(100mL), andH2SO4 (2mL), thenheatedatrefluxwithaDean
and Stark apparatus for 24 h to remove water. The reaction mixture
was concentrated in vacuo and extracted with EtOAc (200 mL),
then washed with a NaHCO3 saturated solution (3 ¥ 50 mL).
The extract was dried over MgSO4 and concentrated in vacuo. Flash
column chromatography of the residue afforded compound 2a as a
yellow oil (28.2 g, 92%). 1H NMR (200 MHz, CDCl3) d: 1.22 (t,
J = 7.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H), 3.51 (s, 2H), 4.16 (q, J = 7.3 Hz,
2H), 4.27 (q, J = 7.3 Hz, 2H), 5.96 (s, 2H), 6.76−6.87 (m, 3H), 7.76
(s, 1H). Anal. Calcd for C16H18O6: C, 62.74; H, 5.92. Found: C,
62.55; H, 5.78%. EI−MS (m/z,%): 306 (M+, 70), 261 (20), 232 (34),
203 (52), 175 (59), 159 (100).
(–)-2-(3',4'-Methylenedioxybenzylidene)-3-(3'',4''-methylenedioxy-
benzyl) succinic acid (4a): Diester 3a (26.4 g, 60 mmol) was
added to a solution of 20% aqueous NaOH (250 mL) and heated at
reflux for 3 h. After cooling to room temperature, the mixture was
washed with EtOAc (3 ¥ 30 mL). After being discoloured with
activated carbon, the mixture was acidified with HCl (2 N), and a
white solid was obtained. The crude product was crystallised from
HOAc to give the (±)-diacid 4a. The (±)-diacid 4a and (–)-quinine
(38.9 g, 120 mmol) in ethanol (120 mL) was heated at reflux for 1 h.
The reaction mixture was allowed to cool to room temperature slowly
and fine white crystals were obtained. After two recrystallisations
from ethanol it was added to a solution of HCl (2 N, 100 mL) and
stirred for 1 h. The mixture was extracted with EtOAc (3 ¥ 80 mL),
and the extract was dried over MgSO4 and evaporated. The white
solids were recrystallised in EtOAc to yield the (–)-diacid 4a as white
crystals (10.1 g, 44%). M.p. 98–99°C. [a]D16 –95.3 (c 1.0, EtOH). IR
(KBr, cm-1) vmax: 3385, 2898, 1703, 1498, 1242, 1040, 928, 813, 620.
1H NMR (200 MHz, DMSO-d6) d: 2.85 (dd, J = 10.2 Hz, J = 13.8 Hz,
1H, H-7''a), 3.25 (dd, J = 4.4 Hz, J = 13.8 Hz, 1H, H-7''b), 3.93 (dd,
J = 4.4 Hz, J = 10.2 Hz, 1H, H-3), 5.92 (d, J = 7.6 Hz, 2H, OCH2O),
6.04 (s, 2H, OCH2O), 6.37−6.90 (m, 6H, ArH), 7.53 (s, 1H, H-7').
Anal. Calcd for C20H16O8: C, 62.50; H, 4.20. Found: C, 65.39; H,
4.33%. EI−MS (m/z,%): 384 (M+, 1), 366 (1), 244 (1), 203 (3), 159
(2), 135 (100). The white solids from evaporated solution were
recrystallised twice in methanol and water to yield the (+)-diacid 4a'
Diethyl 2-(3',4'-dimethoxybenzylidene) succinate (2b): Following
the procedure described for the preparation of 2a, and starting
with the veratraldehyde 1b (16.6 g, 100 mmol), compound 2b was
obtained as a yellow oil (29.6 g, 92%). 1H NMR (200 MHz, CDCl3)
d: 1.33 (t, J = 7.3 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 3.58 (s, 2H),
3.87 (s, 3H), 3.90 (s, 3H), 4.21 (q, J = 7.3 Hz, 2H), 4.27 (q, J = 7.3
Hz, 2H), 6.86−7.00 (m, 3H), 7.84 (s, 1H). Anal. Calcd for C17H22O6:
C, 63.34; H, 6.88. Found: C, 63.21; H, 6.64%. EI−MS (m/z,%): 322
(M+, 42), 276 (14), 249 (16), 175 (100).
16
as white crystals (9.0 g, 39%). M.p. 96–97°C. [a] D + 94.8 (c 0.8,
EtOH). 1H NMR, IR, and MS of 4a' are in agreement with 4a.
(–)-2-(3',4'-Dimethoxybenzylidene)-3-(3'',4''-methylenedioxybenzyl)
succinic acid (4b): Following the procedure described for the
preparation of 4a, and starting with the diester 3b (27.4 g, 60 mmol),
(–)-diacid 4b was obtained as white crystals (10.8 g, 45%). M.p.
16
90−91°C. [a]D –143.2 (c 0.7, EtOH). IR (KBr, cm-1) vmax: 3522,
Diethyl 2-(3',4'-methylenedioxybenzylidene)-3- (3'',4''-methylene-
dioxybenzyl)succinate (3a):Asolution of LDA(80 mmol, 2 M in THF)
in THF at –78°C was added dropwise under nitrogen atmosphere to
a well-stirred solution of compound 2a (24.5 g, 80 mmol) in THF
(100 mL). The mixture was stirred at this temperature for 20 min,
then 3,4- methylenedioxybenzyl bromide (17.2 g, 80 mmol) in
THF (50 mL) was added. The mixture was stirred at –78°C for
2 h. The mixture was quenched with NH4Cl saturated solution
(100 mL). After warming to room temperature, the mixture was
extracted with CH2Cl2 (3 ¥ 80 mL) and the organic layer was dried
over MgSO4 and concentrated in vacuo. Flash chromatography
of the residue over silica gel gave compound 3a as a white solid
(31.6 g, 90%). M.p. 58–59°C. IR (KBr, cm-1) vmax: 3410, 2981, 1736,
1490, 1246, 1039, 930, 809, 770. 1H NMR (200 MHz, CDCl3) d:
1.26 (t, J = 7.2 Hz, 3H, CH3), 1.34 (t, J = 7.2 Hz, 3H, CH3), 2.85
(dd, J = 10.0 Hz, J = 14.2 Hz, 1H, H-7''a), 3.34 (dd, J = 5.0 Hz,
J = 14.2 Hz, 1H, H-7''b), 3.98 (dd, J = 5.0 Hz, J = 10.0 Hz, 1H, H-3),
4.15−4.32 (m, 4H, 2 ¥ CH2CH3), 5.88 (s, 2H, OCH2O), 5.97 (s, 2H,
OCH2O), 6.35−6.73 (m, 6H, ArH), 7.66 (s, 1H, H-7'). 13C NMR (50
MHz, CDCl3) d: 14.4 (2 ¥ CH2CH3), 36.0 (C-3), 45.8 (C-7''), 61.2 (2
¥ OCH2CH3), 100.9 (OCH2O), 101.4 (OCH2O), 108.1 (C-5'), 108.4
(C-5''), 108.7 (C-2'), 109.7 (C-2''), 122.4 (C-6'), 122.7 (C-6''), 129.3
(C-1'), 130.1 (C-1''), 133.2 (C-2), 142.5 (C-7'), 146.1(C-4'), 147.5
(C-4''), 147.8 (C-3', C-3''), 166.9 (C=O), 172.9 (C=O). Anal. Calcd
for C24H24O8: C, 65.45; H, 5.49. Found: C, 65.21; H, 5.68%. HRMS
Calcd for C24H25O8 (M + H+): 441.1544. Found: 441.1538. EI-MS
(m/z,%): 440 (M+, 4), 395 (1), 306 (5), 231 (40), 137 (100).
2943, 1714, 1516, 1255, 1142, 925. 1H NMR (200 MHz, DMSO-
d6) d: 2.83 (dd, J = 10.2 Hz, J = 14.0 Hz, 1H, H-7''a), 3.18 (dd,
J = 4.8 Hz, J = 14.0 Hz, 1H, H-7''b), 3.64 (s, 3H, OCH3), 3.73 (s,
3H, OCH3), 3.95 (dd, J = 4.8 Hz, J = 10.2 Hz, 1H, H-3), 5.87 (d,
J = 8.2 Hz, 2H, OCH2O), 6.35−6.89 (m, 6H, ArH), 7.52 (s, 1H,
H-7'). Anal. Calcd for C21H20O8: C, 63.00; H, 5.03. Found: C, 62.91;
H, 5.18%. HRMS Calcd for C21H21O8 (M + H+): 401.1231. Found:
401.1239. EI-MS (m/z,%): 400 (M+, 1), 382 (17), 260 (5), 219 (12),
175 (26), 135 (100). (+)-diacid 4b' was obtained as white crystals
(9.2 g, 38%). M.p. 89–91°C. [a] D16 + 142.6 (c 0.6, EtOH). 1H NMR,
IR, MS and HRMS of 4b' are in agreement with 4b.
(–)-Diethyl2-(3',4'-methylenedioxybenzylidene)-3-(3'',4''-methylene-
dioxybenzyl)succinate (5a): 4a (7.7 g, 20 mmol) was added to a
100 mL mixture of EtOH: benzene: H2SO4 (100: 50: 1). The mixture
was heated under reflux with a Dean and Stark apparatus to remove
water for 36 h. The reaction mixture was concentrated in vacuo and
extracted with EtOAc (100 mL), and then neutralised with a NaHCO3
saturated solution (3 ¥ 30 mL). The extract was dried over MgSO4
and concentrated in vacuo. Flash column chromatography of the
16
residue gave (R)-(–)-diester 5a as colourless oil (8.0 g, 91%). [a]D
–68.4 (c 1.0, CHCl3). 1H NMR, IR, MS and HRMS of 5a are in
agreement with 3a.
(–)-Diethyl2-(3',4'-dimethoxybenzylidene)-3-(3'',4''-methylenedioxy-
benzyl) succinate (5b): Following the procedure described for the
preparation of 5a, and starting with the diester 4b (8.0 g, 20 mmol),
diacid 5b was obtained as a colourless oil (8.2 g, 90%). [a]D16 –170.1
(c 1.0, CHCl3). 1H NMR, IR, MS and HRMS of 5b are in agreement
with 3b.
(–)-Dihydrocubebin (6a) and meso-2,3-bis(3',4'-methylenedioxy-
benzyl)butane-1,4-diol (7a): (R)-(–)-Diester 5a (7.1 g, 16 mmol)
in ethyl acetate (200 mL) was stirred under hydrogen atmosphere
for 12 h in the presence of 10% Pd/C (0.7 g). The reaction mixture
was filtered through a pad of celite, and the solvent was removed
in vacuo to give a white solid. The solid was dissolved in dry THF
(80 mL) and added to a stirred suspension of LiAlH4 (1.4 g, 36 mmol).
The mixture was stirred for 10 h. Then the reaction was quenched
by ice water and filtered. The filtrate was dried over MgSO4 and
concentrated in vacuo. Flash column chromatography of the residue
gave threo-(–)-6a (2.7 g) and erythro-7a (2.6 g).
Diethyl 2-(3',4'-dimethoxybenzylidene)-3-(3'',4''-methylenedioxy-
benzyl)succinate (3b): Following the procedure described for the
preparation of 3a, and starting with 2b (25.8 g, 80 mmol), compound
3b was obtained as a yellowish oil (31.7 g, 87%). IR (KBr, cm-1)
1
vmax: 2958, 2839, 1741, 1517, 918, 810, 760. H NMR (200 MHz,
CDCl3) d: 1.26 (t, J = 7.2 Hz, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3),
2.91 (dd, J = 9.8 Hz, J = 14.2 Hz, 1H, H-7''a), 3.34 (dd, J = 5.0 Hz,
J = 14.2 Hz, 1H, H-7''b), 3.78 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
4.10 (dd, J = 5.0 Hz, J = 9.8 Hz, 1H, H-3), 4.18 (q, J = 7.2 Hz, 2H,
CH2CH3), 4.30 (q, J = 7.2 Hz, 2H, CH2CH3), 5.85 (s, 2H, OCH2O),
6.35−6.80 (m, 6H, ArH), 7.71 (s, 1H, H-7'). 13C NMR (50 MHz,
CDCl3) d: 14.1 (CH2CH3), 14.2 (CH2CH3), 35.7 (C-3), 45.5 (C-7''),
55.7 (OCH3), 55.8 (OCH3), 60.9 (2 ¥ CH2CH3), 100.7 (OCH2O),
107.7 (C-5'), 109.4 (C-5''), 110.7 (C-2'), 111.4 (C-2''), 121.1 (C-6'),
122.0 (C-6''), 127.9 (C-1'), 129.5 (C-1''), 132.9 (C-2), 142.3 (C-7'),
(–)-Dihydrocubebin (6a). Yield 47%. White crystals. M.p. 112–
16
113°C. [a]D –41.9 (c 0.8, CHCl3). (Lit.22 m.p. 112°C. [a]D –42).
IR (KBr, cm-1) vmax: 3382, 2921, 1514, 1242, 1032, 928, 809, 764. 1H

568 JOURNAL OF CHEMICAL RESEARCH 2009
NMR (200 MHz, CDCl3) d: 1.80−1.84 (m, 2H, H-2, H-3), 2.55−2.81
(m, 4H, 2 ¥ ArCH2), 3.48 (d, J = 11.2 Hz, 2H, CH2OH), 3.72 (s, 2H, 2
¥ OH), 3.74 (d, J = 11.2 Hz, 2H, CH2OH), 5.91 (s, 4H, 2 ¥ OCH2O),
6.58−6.73 (m, 6H,ArH). 13C NMR (100 MHz, CDCl3) d: 35.8 (C-2, C-
3), 44.2 (C-7', C-7''), 59.9 (C-1, C-4), 100.7 (2 ¥ OCH2O), 108.1 (C-5',
C-5''), 109.2 (C-2', C-2''), 121.8 (C-6', C-6''), 134.3 (C-1', C-1''), 145.6
(C-4', C-4''), 147.5 (C-3', C-3''). Anal. Calcd for C20H22O6: C, 67.03;
H, 6.19. Found: C, 67.21; H, 6.33%. HRMS Calcd for C20H26NO6
(M + NH4+): 376.1755. Found: 376.1760. EI−MS (m/z,%): 358 (M+,
2), 340 (0.1), 204 (0.3), 161 (3), 135 (100).
(–)-Hinokinin (9): Freshly-prepared Ag2CO3/Celite (2 mmol) and
compound 6a (0.36 g, 1 mmol) was added to 30 mL of anhydrous
benzene. The solution was heated at reflux for 16 h, cooled and
filtered. The filtrate was concentrated in vacuo. Flash column
chromatography of the residue gave compound 9 as a colourless solid
20
(0.33 g, 93%). M.p. 63–64°C. [a]D –34.2 (c 1.3, CHCl3). (Lit.26
[a]D –36). IR (KBr, cm-1) vmax: 2916, 1767, 1494, 1430, 1247, 1037,
928. 1H NMR (200 MHz, CDCl3) d: 2.42−2.60 (m, 4H, 2 ¥ ArCH2),
2.83 (dd, J = 7.2 Hz, J = 14.1 Hz, 1H, H-4), 2.98 (dd, J = 4.5 Hz,
J = 14.1 Hz, 1H, H-3), 3.86 (dd, J = 7.2 Hz, J = 9.3 Hz, 1H, H-5a),
4.13 (dd, J = 6.9 Hz, J = 9.3 Hz, 1H, H-5b), 5.93 (s, 2H, OCH2O),
5.94 (s, 2H, OCH2O), 6.50−6.75 (m, 6H, ArH). 13C NMR (75 MHz,
CDCl3) d: 34.7 (C-6'), 38.3 (C-6), 41.2 (C-4), 46.4 (C-3), 71.1 (C-5),
101.0 (2 ¥ OCH2O), 108.2, 108.3, 108.7, 109.3, 121.5, 122.2, 131.2,
131.5, 146.2, 146.4, 147.8 (C-a, C-a'), 178.4 (C-2). Anal. Calcd for
C20H18O6: C, 67.79; H, 5.12. Found: C, 67.93; H, 5.31%. EI-MS
(m/z,%): 354 (M+, 14), 218 (4), 192 (3), 135 (100).
(±)-Isohinokinin (10): Freshly-prepared Ag2CO3/Celite (2 mmol)
and compound 7a (0.36 g, 1 mmol) was added to 30 mL of anhydrous
benzene. The solution was heated at reflux for 16 h, cooled and filtered.
The filtrate was concentrated in vacuo. Flash column chromatography
of the residue gave (±)-Isohinokinin 10 as a colourless solid (0.33 g,
93%). M.p. 115–116°C. (Lit.27 m.p. 115°C). [a]D20 0 (c 1.0, CHCl3).
IR (KBr, cm-1) vmax: 2902, 1771, 1490, 1443, 1248, 1038, 927, 809.
1H NMR (300 MHz, CDCl3) d: 2.29 (t, J = 13.5 Hz, 1H, H-6'a),
2.53−2.75 (m, 1H, H-4), 2.73 (dd, J = 10.5 Hz, J = 14.7 Hz, 1H, H-
6a), 2.88 (dd, J = 3.0 Hz, J = 13.5 Hz, 1H, H-6'b), 3.01−3.15 (m, 1H,
H-3), 3.22 (dd, J = 4.2 Hz, J = 14.7 Hz, 1H, H-6b), 4.01−4.11 (m,
2H, 2 ¥ H-5), 5.92 (s, 2H, OCH2O), 5.96 (s, 2H, OCH2O), 6.51−6.54
(m, 2H, ArH), 6.71−6.81 (m, 4H, ArH). 13C NMR (75 MHz, CDCl3)
d: 30.5 (C-6'), 32.5 (C-6), 39.9 (C-4), 45.2 (C-3), 69.3 (C-5), 101.0
(2 ¥ OCH2O), 108.4 (C-g, C-g'), 108.6, 109.0, 121.2, 121.9, 132.0,
132.1, 146.2 (C-b, C-b'), 147.9 (C-a, C-a'), 177.8 (C-2). Anal. Calcd
for C20H18O6: C, 67.79; H, 5.12. Found: C, 67.63; H, 5.39%. EI-MS
(m/z,%): 354 (M+, 12), 218 (7), 192 (5), 135 (100).
Meso-2,3-Bis(3',4'-methylenedioxybenzyl) butane-1,4-diol (7a):
Yield 46%. Colourless oil. [a]D16 0 (c 0.7, CHCl3). IR (KBr, cm-1) vmax
:
1
3293, 2920, 1488, 1246, 1037, 928, 811, 731. H NMR (200 MHz,
CDCl3) d: 1.99−2.05 (m, 2H, H-2, H-3), 2.49−2.63 (m, 4H, 2 ¥ArCH2),
3.45−3.61 (m, 4H, 2 ¥ CH2OH), 3.71 (s, 2H, 2 ¥ OH), 5.92 (s, 4H,
2 ¥ OCH2O), 6.61−6.76 (m, 6H, ArH). 13C NMR (50 MHz, CDCl3) d:
33.4 (C-2, C-3), 45.2 (C-7', C-7''), 62.9 (C-1, C-4), 100.8 (2 ¥ OCH2O),
108.1 (C-5', C-5''), 109.2 (C-2', C-2''), 121.8 (C-6', C-6''), 134.1
(C-1', C-1''), 145.8 (C-4', C-4''), 147.6 (C-3', C-3''). Anal. Calcd for
C20H22O6: C, 67.03; H, 6.19. Found: C, 67.16; H, 6.41%. HRMS
Calcd for C20H26NO6 (M + NH4+): 376.1755. Found: 376.1760.
EI-MS (m/z,%): 358 (M+, 3), 340 (0.3), 204 (0.8), 161 (4), 135 (100).
(–)-Dihydro-3',4'-dimethoxy-3'',4''-demethylenedioxycubebin (6b)
and (–)-2,3-Desmethoxy seco-isolintetralin (7b): Following the
procedure described for the preparation of 6a and 7a, and starting
with the diester 5b (7.3 g, 16 mmol), 3b (2.6 g) and 7b (2.9 g) were
obtained.
(–)-Dihydro-3',4'-dimethoxy-3'',4''-demethylenedioxycubebin (6b):
16
Yield 44%. Colourless oil. [a]D –36.8 (c 0.5, CHCl3). (Lit.23 [a]D
1
–9.9) IR (KBr, cm-1) vmax: 3374, 1593, 1515, 1488, 1442, 928. H
NMR (200 MHz, CDCl3) d: 1.85−1.87 (m, 2H, H-2, H-3), 2.60−2.80
(m, 4H, 2 ¥ H-7', 2 ¥ H-7''), 3.50 (d, J = 11.6 Hz, 2H, CH2OH),
3.56 (s, 2H, 2 ¥ OH), 3.80 (d, J = 11.6 Hz, 2H, CH2OH), 3.82 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 5.90 (s, 2H, OCH2O), 6.57−6.80
(m, 6H, ArH). 13C NMR (100 MHz, CDCl3) d: 35.7 (C-2), 35.9 (C-
3), 43.9 (C-7'), 44.1 (C-7''), 55.8 (OCH3), 55.9 (OCH3), 60.2 (C-1),
60.3 (C-4), 100.7 (OCH2O), 108.0 (C-5'), 109.3 (C-5''), 111.2 (C-2'),
112.1 (C-2''), 121.0 (C-6'), 121.8 (C-6''), 133.1 (C-1'), 134.3 (C-1''),
145.7 (C-4'), 147.3 (C-4''), 147.5 (C-3'), 148.8 (C-3''). Anal. Calcd
for C21H26O6: C, 67.36; H, 7.00. Found: C, 67.19; H, 6.79%. HRMS
Calcd for C21H30NO6 (M + NH4+): 392.2068. Found: 392.2063. EI-
MS (m/z,%): 374 (M+, 4), 356 (0.4), 220 (3), 203 (3), 151 (100).
(–)-2,3-Desmethoxy seco-isolintetralin (7b): Yield 48%. Colourless
Meso-2,3-bis(3',4'-methylenedioxybenzyl)-1,4-butanediol diacetates
(11a): The minimum amount of pyridine was added to a mixture of 7a
(0.36 g, 1 mmol) in CH2Cl2 (30 mL). Then Ac2O was added dropwise.
The mixture was stirred at room temperature for 10 h. The solution
was concentrated. Flash column chromatography of the residue gave
20
11a as a colourless oil (0.40 g, 90%). [a]D 0 (c 0.4, CHCl3). IR
(KBr, cm-1) vmax: 3450, 2899, 1737, 1494, 1245, 1038, 930, 812, 775.
1H NMR (300 MHz,CDCl3) d: 2.04 (s, 6H, 2 ¥ COCH3), 2.14−2.17
(m, 2H, H-2, H-3), 2.53 (dd, J = 7.2 Hz, J = 14.1 Hz, 2H, ArCH2),
2.70 (dd, J = 9.0 Hz, J = 13.8 Hz, 2H, ArCH2), 4.01−4.13 (m, 4H,
2 ¥ CH2OMe), 5.93 (s, 4H, 2 ¥ OCH2O), 6.54−6.75 (m, 6H, ArH).
13C NMR (100 MHz, CDCl3) d: 20.8 (2 ¥ CH3), 34.1 (C-2, C-3),
39.8 (C-7', C-7''), 64.5 (C-1, C-4), 100.8 (2 ¥ OCH2O), 108.2 (C-
5', C-5''), 108.9 (C-2', C-2''), 121.7 (C-6', C-6''), 133.3 (C-1', C-1''),
145.9 (C-4', C-4''), 147.7 (C-3', C-3''), 170.8 (2 ¥ C=O). Anal. Calcd
for C24H26O8: C, 65.15; H, 5.92. Found: C, 65.31; H, 5.67%. HRMS
Calcd for C24H30NO8 (M + NH4+): 460.1966. Found 460.1964. EI-
MS (m/z,%): 442 (M+, 5), 322 (1), 281 (1), 187 (13), 135 (100).
Erythro-(–)-2-(3',4'-methylenedioxybenzyl)-3-(3'',4''-dimethoxy-
benzyl)-1,4-butanediol diacetates (11b): Following the procedure
described for the preparation of 11a, and starting with 7b (0.37 g,
1 mmol), compound (–)-11b was obtained as a colourless oil (0.43 g,
16
oil. [a]D –1.7 (c 0.3, CHCl3). (Lit.24 [a]D –1.6). IR (KBr, cm-1)
1
vmax: 3365, 2919, 1514, 1241, 1032, 727, 643. H NMR (200 MHz,
CDCl3) d: 1.84−1.86 (m, 2H, H-2, H-3), 2.56−2.82 (m, 4H, 2 ¥ H-7',
2 ¥ H-7''), 3.50 (d, J = 11.0 Hz, 2H, CH2OH), 3.75 (d, J = 11.0 Hz,
2H, CH2OH), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.95 (s, 2H,
2 ¥ OH), 5.89 (s, 2H, OCH2O), 6.56−6.78 (m, 6H, ArH). 13C NMR
(100 MHz, CDCl3) d: 33.1 (C-2), 33.4 (C-3), 45.0 (C-7'), 45.2 (C-7''),
55.8 (OCH3), 55.9 (OCH3), 62.9 (C-1), 63.0 (C-4), 100.8 (OCH2O),
108.1 (C-5'), 109.3 (C-5''), 111.2 (C-2'), 112.1 (C-2''), 121.0 (C-6'),
121.8 (C-6''), 133.0 (C-1'), 134.2 (C-1''), 145.8 (C-4'), 147.3 (C-4''),
147.6 (C-3'), 148.8 (C-3''). Anal. Calcd for C21H26O6: C, 67.36; H,
7.00. Found: C, 67.11; H, 6.84%. HRMS Calcd for C21H30NO6 (M +
NH4+): 392.2068. Found: 392.2063. EI-MS (m/z,%): 374 (M+, 4.7),
356 (0.23), 220 (1.8), 203 (2.5), 151 (100).
20
(–)-Kaerophyllin (8): LiAlH4 (0.076 g, 2 mmol) was added to dry
THF at 0°C and the mixture was stirred at this temperature for 10 min,
then anhydr-AlCl3 (0.082 g, 0.6 mmol) was added. After stirring for
20 min compound 5b (0.90 g, 2 mmol) was added. The mixture was
stirred for 10 h. Then the reaction was quenched by water and filtered.
The filtrate was concentrated in vacuo. The residue was dissolved in
acetone. Then freshly-prepared MnO2 (0.54 g, 6 mmol) was added.
After stirring for 36 h, the mixture was filtered and the filtrate was
concentrated in vacuo. Flash column chromatography of the residue
93%). [a]D –1.3 (c 0.8, CHCl3). IR (KBr, cm-1) vmax: 2926, 1717,
1511, 1243, 1036, 913. 1H NMR (300 MHz, CDCl3) d: 2.00 (s, 6H, 2 ¥
COCH3), 2.05−2.25 (m, 2H, H-2, H-3), 2.50−2.74 (m, 4H, 2 ¥ArCH2),
3.82 (s, 6H, 2 ¥ OCH3), 3.96−4.10 (m, 4H, H-1, H-4), 5.89 (s, 2H,
OCH2O), 6.55−6.78 (m, 6H, ArH). 13C NMR (100 MHz, CDCl3) d:
20.8 (2 ¥ CH3), 33.7 (C-3), 34.1 (C-2), 39.7 (C-7', C-7''), 55.6 (OCH3),
55.7 (OCH3), 64.6 (C-4), 64.7 (C-1), 100.8 (OCH2O), 108.1 (C-5''),
108.9 (C-5''), 111.1 (C-2''), 111.7 (C-2'), 120.8 (C-6''), 121.7 (C-6'),
132.1 (C-1''), 133.3 (C-1'), 145.9 (C-4''), 147.3 (C-4'), 147.6 (C-3''),
148.8 (C-3'), 170.9 (2 ¥ C=O). Anal. Calcd for C25H30O8: C, 65.49;
H, 6.59. Found: C, 65.33; H, 6.67%. HRMS Calcd for C25H34NO8 (M
+ NH4+): 476.2279. Found 476.2279. EI-MS (m/z,%): 458 (M+, 19),
398 (1), 203 (13), 187 (8), 151 (100), 135 (64).
20
gave 8 as a colourless solid (0.60 g, 82%). M.p. 146–147°C. [a]D
–67.7 (c 1.2, CHCl3). (Lit.25 m.p. 148°C. [a]D –66.9). IR (KBr, cm-1)
vmax: 2913, 1745, 1644, 1596, 1515, 1249, 1185, 1035, 927, 807.
1H NMR (200 MHz, CDCl3) d: 2.61 (dd, J = 10.4 Hz, J = 14.4 Hz,
1H, H-6'a), 3.04 (dd, J = 4.2 Hz, J = 14.4 Hz, 1H, H-6'b), 3.75−3.92
(m, 1H, H-4), 3.92 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.27 (d,
J = 4.0 Hz, 2H, 2 ¥ H-5), 5.94 (s, 2H, OCH2O), 6.61−7.25 (m, 6H,
ArH), 7.54 (d, J = 1.8 Hz, 1H, H-6). 13C NMR (50 MHz, CDCl3) d:
37.4 (C-6'), 39.6 (C-4), 55.9 (2 ¥ OCH3), 69.4 (C-5), 101.1 (OCH2O),
108.4, 109.0, 111.2, 112.9, 121.9, 123.5, 125.6, 126.8, 131.4 (C-3),
137.4 (C-6), 146.5, 147.9, 149.0, 150.6, 172.6 (C-2). Anal. Calcd
for C21H20O6: C, 68.47; H, 5.47. Found: C, 68.25; H, 5.26%. EI-MS
(m/z,%): 368 (M+, 9), 306 (0.3), 233 (69), 135 (100).
Threo-(–)-2,3-bis(3',4'-methylenedioxybenzyl)-1,4-butanediol
diacetates (12a): Following the procedure described for the
preparation of 11a, and starting with 6a (0.36 g, 1 mmol), compound
20
(–)-12a was obtained as a colourless oil (0.41 g, 92%). [a]D –37.2
(c 0.5, CHCl3). IR (KBr, cm-1) vmax: 2898, 1737, 1494, 1245, 1037,
930, 811, 775. 1H NMR (300 MHz, CDCl3) d: 2.07 (s, 6H, 2 ¥ COCH3),
2.07−2.17 (m, 2H, H-2, H-3), 2.56 (dd, J = 7.2 Hz, J = 14.1 Hz, 2H,
ArCH2), 2.66 (dd, J = 7.2 Hz, J = 14.1 Hz, 2H, ArCH2), 4.00 (dd,
J = 5.1 Hz, J = 11.1 Hz, 2H, CH2OMe), 4.10 (dd, J = 5.1 Hz,

JOURNAL OF CHEMICAL RESEARCH 2009 569
J = 11.1 Hz, 2H, CH2OMe), 5.93 (s, 4H, 2 ¥ OCH2O), 6.51−6.72
(m, 6H, ArH). 13C NMR (100 MHz, CDCl3) d: 20.9 (2 ¥ CH3), 34.8
(C-2, C-3), 39.9 (C-7', C-7''), 64.1 (C-1, C-4), 100.8 (2 ¥ OCH2O),
108.1 (C-5', C-5''), 109.1 (C-2', C-2''), 121.8 (C-6', C-6''), 133.3 (C-1',
C-1''), 145.9 (C-4', C-4''), 147.6 (C-3', C-3''), 170.9 (2 ¥ C=O). Anal.
Calcd for C24H26O8: C, 65.15; H, 5.92. Found: C, 65.37; H, 5.77%.
EI-MS (m/z,%): 442 (M+, 6), 322 (2), 281 (1), 187 (19), 135 (100).
Threo-(–)-2-(3',4'-methylenedioxybenzyl)-3-(3'',4''-dimethoxy-
benzyl)-1,4-butanediol diacetates (12b): Following the procedure
described for the preparation of 11a, and starting with 6b (0.37 g,
1 mmol), compound (–)-12b was obtained as a colourless oil
(0.42 g, 92%). [a]D20 –32.6 (c 0.6, CHCl3). IR (KBr, cm-1) vmax: 2937,
1736, 1512, 1240, 1034, 929. 1H NMR (300 MHz, CDCl3) d: 2.07 (s,
6H, 2 ¥ COCH3), 2.07−2.13 (m, 2H, H-2, H-3), 2.56−2.70 (m, 4H,
2 ¥ ArCH2), 3.82 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.00−4.11 (m,
2H, H-1), 4.05−4.15 (m, 2H, H-4), 5.93 (s, 2H, OCH2O), 6.51−6.79
(m, 6H, ArH). 13C NMR (100 MHz, CDCl3) d: 20.9 (2 ¥ CH3),
34.8 (C-3), 34.9 (C-2), 39.7 (C-7''), 39.8 (C-7'), 55.7 (OCH3), 55.9
(OCH3), 64.2 (C-4), 64.3 (C-1), 100.8 (OCH2O), 108.1 (C-5''), 109.1
(C-5''), 111.1 (C-2''), 111.7 (C-2'), 120.9 (C-6''), 121.8 (C-6'), 132.1
(C-1''), 133.3 (C-1'), 145.9 (C-4''), 147.4 (C-4'), 147.6 (C-3''), 148.8
(C-3'), 170.9 (2 ¥ C=O). Anal. Calcd for C25H30O8: C, 65.49; H, 6.59.
Found: C, 65.66; H, 6.37%. EI-MS (m/z,%): 458 (M+, 19), 398 (1),
203 (13), 187 (8), 151 (100), 135 (64).
Received 19 June 2009; accepted 10 August 2009
Paper 09/0648 doi: 10.3184/030823409X12506792542747
Published online: 8 September 2009
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Threo-(–)-2,3-bis(3',4'-methylenedioxybenzyl)-1,4-butanediol
monoacetate (13): Starting with 6a (0.36 g, 1 mmol) andAc2O (0.06 g,
1 mmol), and following the procedure described for the preparation
of 11a, 13 was obtained as a colourless oil (0.29 g, 72%). [a]D20 –44.6
(c 0.1, CHCl3). IR (KBr, cm-1) vmax: 3453, 2894, 1733, 1495, 1247,
1
1038, 929, 811, 732. H NMR (300 MHz, CDCl3) d: 1.79−1.89 (m,
1H, H-3), 2.07 (s, 3H, COCH3), 2.06−2.26 (m, 1H, H-2), 2.50−2.73
(m, 4H, 2 ¥ ArCH2), 3.60 (s, 2H, H-4), 4.01−4.14 (m, 2H, H-1), 5.91
(s, 4H, 2 ¥ OCH2O), 6.53−6.71 (m, 6H, ArH). 13C NMR (100 MHz,
CDCl3) d: 21.2 (CH3), 34.9 (C-3), 35.2 (C-2), 40.2 (C-7''), 43.4 (C-
7'), 62.4 (C-4), 64.9 (C-1), 101.1 (2 ¥ OCH2O), 108.3 (C-5', C-5''),
109.5 (C-2', C-2''), 122.1 (C-6', C-6''), 134.1 (C-1''), 134.4 (C-1'),
146.0 (C-4', C-4''), 147.9 (C-3', C-3''), 171.4 (C=O). Anal. Calcd for
C22H24O7: C, 65.99; H, 6.04. Found: C, 65.73; H, 6.26%. EI-MS (m/z,
%): 400 (M+, 5), 382 (1), 340 (2), 187 (6), 135 (100).
This work was financially supported by the Open Foundation
of Chemical Engineering Subject, Qingdao University of
Science and Technology, China and the National Natural
Science Foundation of Shandong (No. 2006Q02). Peking
University School of Pharmaceutical Sciences is kindly
acknowledged for evaluation of our compounds in their human
tumor cell line screening panel and The National Centre for
Drug Screening is acknowledged for the anti-HIV, ant-HSV
assay of our compound.
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