Synthesis and bioactivity of erythro-nordihydroguaiaretic acid, threo-(-)-saururenin and their analogues

Article abstract of DOI:10.2298/JSC090410108X

Full details of the total syntheses of erythro-nordihydroguaiaretic acid, threo-(-)-saururenin and their analogues are presented. The syntheses were based on a unified synthetic strategy involving the Stobbe reaction, alkylation to construct the skeleton

Full text of DOI:10.2298/JSC090410108X

J. Serb. Chem. Soc. 75 (10) 1325–1335 (2010)
UDC 542.913+57–188:547.474.4
JSCS–4055
Original scientific paper
Synthesis and bioactivity of erythro-nordihydroguaiaretic acid,
threo-(–)-saururenin and their analogues
1
1
1
1
2
*
YAMU XIA , YUANYUAN ZHANG , WEI WANG , YINING DING and RUI HE
1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao
266042 and 2College of Mathematics and Physics, Qingdao University of Science
and Technology, Qingdao 266042, P. R. China
(Received 10 April, revised 11 June 2010)
Abstract: Full details of the total syntheses of erythro-nordihydroguaiaretic acid,
threo-(–)-saururenin and their analogues are presented. The syntheses were based
on a unified synthetic strategy involving the Stobbe reaction, alkylation to
construct the skeleton of lignans and resolution of the threo- and erythro-iso-
mers. The syntheses were achieved in eight to nine steps from simple aromatic
precursors, and by this route 13 lignans were obtained. Among the synthesized
lignans, seven lignans were natural products; moreover three of the seven natu-
ral products were synthesized for the first time. The effect of 13 lignans was
examined on HIV Tat transactivation in human epithelial cells, HSV-1 gene and
human leukemic, liver, prostate, stomach and breast cancer cell. Bioactivity re-
sults indicated that one product showed activity against the HIV gene and five
compounds exhibited anti-HSV activity.
Keywords: synthesis; bioactivity; NDGA; saururenin.
INTRODUCTION
Lignans are a class of naturally occurring plant phenols that formally arise
biosynthetically from two cinnamic acid (phenylpropanoid) residues, as defined
1
originally by Howarth in 1936. Lignans are found in all parts of plants, inc-
luding the roots, stems, leaves, fruit and seeds, and they exhibit a wide range of
biological activities, including antitumor, anti-inflammatory, immunosuppres-
sive, cardiovascular, neuroprotective, neurotrophic, antioxidant and antiviral ac-
2
tions. There is a growing interest in lignans and their synthetic derivatives due
3,4
to applications in cancer chemotherapy and anti-virus therapy.
Nordihydroguaiaretic acid (NDGA) is a naturally occurring lignan from the
creosote bush (Larrea tridentata). NDGA has been utilized in traditional healing
practices for a wide range of ailments and was licensed for use as a topical
*Corresponding author. E-mail: xiaym@qust.edu.cn
doi: 10.2298/JSC090410108X
1325
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1326
XIA et al.
treatment for actinic keratosis (Actinex, Chemex Pharmaceuticals, Denver,
5,6
CO). NDGA is a known antioxidant, a lipoxygenase inhibitor, and has also
7–9
been shown to inhibit P450.
(–)-Saururenin is a threo-alkene, but different
from erythro-NDGA, and was isolated from Saururus cernuus L., an aquatic
10
weed commonly found in the eastern United States. Saururus cernuus L. has
11
been used in folk medicine as a sedative and as poultice for tumors. More re-
cently, much of the interest in NDGA, (–)-saururenin and their analogues cen-
tered on their role in anti-virus and anti-tumor activity. Hwu reported that NDGA
and its analogues exhibited activity against HIV, and tetramethyl NDGA was a
12
stronger anti-HIV agent. Cheng et al. showed that in Vero cells, NDGA and its
analogues inhibited the expression of the herpes immediate early gene, which is
13
essential for HSV replication. NDGA, (–)-saururenin and their analogues have
14–16
also been shown to have cancer chemopreventive properties.
NDGA, (–)-saururenin and their analogues have stimulated substantial syn-
thetic efforts due to their biological activity. Lieberman et al. used the coupling
of two molecules of 1-piperonyl-1-bromoethane as the key step to give the ske-
17
leton of NDGA. Son et al. developed a modified procedure for the synthesis of
18
NDGA and related lignans. Gezginci and Timmermann reported the synthesis
of meso-nordihydroguaiaretic acid from (3,4-dimethoxyphenyl)acetone using the
19
low-valent Ti-induced carbonyl-coupling reaction of the ketone as the key step.
Rao et al. described the synthesis of analogues of (–)-saururenin from Saururus
cernuus, together with (–)-austrobailignan-5 by regioselective cleavage of the
20
methylenedioxyphenyl groups. A synthetic route to NDGA and machilin A in-
21
volving two Stobbe condensations to give the skeleton of lignan was reported.
In this paper, an efficient approach for the chiral synthesis of NDGA, (–)-sa-
ururenin and their analogues is presented. By this method, 13 lignans were syn-
thesized, among them, seven lignans were natural products and moreover three of
the seven natural products were synthesized for the first time. The biological ef-
fect of the 13 lignans in their pure form was examined on HIV Tat transactivation
in human epithelial cells, the HSV-1 gene and human leukemic, liver, prostate,
stomach, and breast cancer cells. The bioactivity results indicated that some com-
pounds exhibited better activities against the HIV and herpes virus. Finally, it
should be emphasized that the bioactivity is affected by the skeleton configu-
ration and functional groups.
RESULTS AND DISCUSSION
Synthesis of compounds
The starting materials were piperonal 1a and veratraldehyde 1b. Condensa-
tion of 1a or 1b with diethyl succinate in EtONa/EtOH solution afforded the ben-
zylidene half-ester, which was followed by esterification to produce the diester
2a or 2b. Treatment of 2a or 2b in THF with LDA and 3,4-methylenedioxyben-
zyl bromide at –78 °C afforded the diester 3a or 3b. Then the compound 3a or 3b
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SYNTHESIS AND BIOACTIVITY OF LIGNANS
1327
was hydrolyzed to form the diacid. At this stage, the diacids were resolved via
the quinine salt. The quinine salt of diacid (–)-4a or (–)-4b crystallized first. Con-
centration of the mother liquors gave a solid, which yielded the quinine salt of
(+)-4a’ or (+)-4b’. The diacid 4a or 4b was esterified to produce the diester (–)-
-5a or (–)-5b. The diester 5a or 5b was hydrogenated under a H atmosphere,
2
following by reduction with LiAlH in THF to produce a readily separable mix-
4
ture (approximately 1:1) of diols threo-(–)-6a and erythro-7a or threo-(–)-6b and
erythro-(–)-7b. 7a was a meso-compound and did not have optical rotation (Sche-
me 1). The spectral data were in agreement with those found in the literature.
Scheme 1. Synthesis route of the compounds 2–7. The starting materials were piperonal (1a)
and veratraldehyde (1b). Condensation of 1a or 1b with diethyl succinate in EtONa/EtOH
solution afforded the benzylidene half-ester, which was followed by esterification to produce
the diester 2a or 2b. Treatment of 2a or 2b in THF with LDA and 3,4-methylenedioxybenzyl
bromide at –78 °C afforded the diester 3a or 3b. Then compound 3a or 3b was hydrolyzed to
form the diacid. At this stage, the diacids were resolved via the quinine salt. The quinine salt
of diacid (–)-4a or (–)-4b crystallized first. Concentration of the mother liquors gave a solid,
which yielded the quinine salt of (+)-4a’ or (+)-4b’. The diacid 4a or 4b was esterified to
produce diester (–)-5a or (–)-5b. The diester 5a or 5b was hydrogenated under an H2 at-
mosphere, followed by reduction with LiAlH4 in THF to produce a readily separable mixture
(approximately 1:1) of diols threo-(–)-6a and erythro-7a or threo-(–)-6b and erythro-(–)-7b.
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XIA et al.
Reaction of diol threo-(–)-6a or threo-(–)-6b with equimolar amounts of
TsCl in a dilute solution at room temperature gave the corresponding 8a and 8b,
while diol threo-(–)-6a or threo-(–)-6b with TsCl in concentrated solution at 0 °C
gave the ditoluenesulfonyl esters, which were reduced with LiAlH in THF to
4
provide 10a and 10b. On the other hand, etherification of 6a or 6b gave the
compounds 9a and 9b. The compounds 11a, 11b, 12a, 12b, 13a and 13b were
prepared in a similar manner. Compound 13a was refluxed with PCl in anhyd-
5
rous CCl , followed by hydrolysis of the resulting dichloromethylene derivative
4
with water to provide meso-nordihydroguaiaretic acid 14 (Schemes 2 and 3).
Scheme 2. Synthesis route of the compounds 8–10. Reaction of diol threo-(–)-6a or
threo-(–)-6b with an equimolar amount of TsCl in dilute solution at room temperature
gave the corresponding 8a and 8b, while diol threo-(–)-6a or threo-(–)-6b with TsCl
in concentrated solution at 0 °C gave the ditoluenesulfonyl esters, which were
reduced with LiAlH4 in THF to provide 10a or 10b. Etherification of
6a or 6b gave the compounds 9a or 9b.
The compounds 6a, 6b, 7b, 10a, 10b, 13a and 14 are natural products while
compounds 7b, 10b and 13a were synthesized for the first time.
Spectroscopic data of the synthesized compounds
The spectral data (Supplementary material) are in agreement with those
19
already reported.
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SYNTHESIS AND BIOACTIVITY OF LIGNANS
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Scheme 3. Synthesis route of the compounds 11–14. Etherification of 6a or 6b gave the com-
pounds 9a or 9b. Compounds 11a, 11b, 12a, 12b, 13a and 13b were prepared similarly.
Compound 13a was refluxed with PCl5 in anhydrous CCl4, followed by hydrolysis
of the resulting dichloromethylene derivative with water to provide
meso-nordihydroguaiaretic acid (14).
Bioactivity
Antitumor activity. NDGA (14), (–)-saururenin (10b) and their analogues 8a,
8b, 9a, 9b, 10a, 11a, 11b, 12a, 12b, 13a and 13b were evaluated in vitro against
HL-60 human leukemic cells, PC-3MIE8 human prostatic carcinoma cells, BGC-
-823 human stomach cancer cells and MDA-MB-435 human breast cancer cell,
27
and the assays of the lignans have been previously published. The antitumor
test indicated the inhibitory rates of tumor cell were less than 30 %, and the syn-
thesized compounds showed no obvious antitumor activity.
Anti-HIV activity. The synthesized compounds were evaluated for their anti-
-HIV activity by determining their ability to inhibit the HIV Tat transactivation in
28
vitro. The assay method was described previously.
The compounds 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b and
14 were tested for their activities against the HIV and herpes viruses. The results
–1
showed that 9a has activity against HIV-RT (IC = 160 μg ml ), while the
50
other tested compounds exhibited no obvious activity.
Anti-HSV activity. The activity of the HSV-1 gene inhibitor was examined
by measuring the extent of the process of Vero cells transfected with HSV-1 in
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XIA et al.
vitro. The assays of the compounds NDGA, (–)-saururenin and their analogues
29
reported here were in agreement with those previously reported. The results are
given in Table I.
TABLE I. Anti-herpes virus activity of some of the synthesized compounds
Sample code
TC50 / μg ml-1
IC50 / μg ml-1
SI
10a
12a
12b
13a
143.17
231.12
192.45
111.11
12.35
68.71
143.10
53.42
111.10
4.12
2.08
1.61
3.6
1.0
3.0
14
Acyclovir
>250
1.66
>150.6
The compounds 10a, 12a, 12b, 13a and 14 showed activity against the
–1
herpes virus. The IC values of 10a and 12b were less than 100 μg ml , and
50
–1
compound 14 with an IC value of 4.12 μg ml exhibited better bioactivity
50
against the herpes virus. The results showed that the erythro-structure was good
for antiviral activity; however, the compounds with tetrahydrofuran ring did not
exhibit activity, which showed that the tetrahydrofuran ring appears suitable for
lowering the cytotoxicity. On the other hand, the results showed that the data of SI
was much lower. Thus, SI should be enhanced in a later study on structure–func-
tion relationships in order to increase the selectivity of the activity.
EXPERIMENTAL
The melting points were measured on a Gallenkamp melting point apparatus and are un-
corrected. The optical rotation values were determined on a Perkin-Elmer 341 polarimeter. In-
1
frared spectra were recorded on a Nicolet Nexus 670 FT−IR. The H-NMR and 13C-NMR
spectra were recorded on Brucker AM−400, Mercury Plus−300 and Avance–200 spectrome-
ters. The mass spectra were recorded on a ZAB−HS spectrometer. The HRMS were obtained
on a Bruker Daltonics APEXII47e spectrometer. Flash column chromatography was perfor-
med on silica gel (200–300 mesh) and TLC inspections on silica gel GF254 plates.
Diethyl 2-(3,4-methylenedioxybenzylidene)succinate (2a)
Piperonal (1a) (15.0 g, 100 mmol) and diethyl succinate (17.4 g, 100 mmol) were added
to a solution of NaOEt (13.6 g, 200 mmol) in EtOH (200 ml). After refluxing for 4 h, the
EtOH was removed. The residue was cooled and acidified with HCl (5 M). The mixture was
extracted with EtOAc (3×80 ml). The EtOAc layer was then re-extracted with a saturated
NaHCO3 solution (100 ml). The NaHCO3 extract was acidified with HCl and the pH value
was adjusted to 2. Then the obtained oily layer was again extracted with AcOEt (3×100 ml).
The combined organic layer was dried and concentrated in vacuo. This residue was then ad-
ded to a mixture of EtOH (250 ml), benzene (100 ml), and H2SO4 (2 ml), then refluxed in a
Dean Stark apparatus for 24 h. The mixture was concentrated in vacuo and extracted with
EtOAc (200 ml), then washed with a saturated NaHCO3 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). Yield: 92 %.
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SYNTHESIS AND BIOACTIVITY OF LIGNANS
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Diethyl 2-(3,4-dimethoxybenzylidene)succinate (2b)
Following the procedure described for the preparation of 2a but starting with veratral-
dehyde (1b) (16.6 g, 100 mmol), compound 2b was obtained as a yellow oil (29.6 g). Yield:
92 %.
Diethyl 2-(3,4-methylenedioxybenzyl)-3-(3,4-methylenedioxybenzylidene)succinate (3a)
To a well-stirred solution of 2a (24.5 g, 80 mmol) in THF (100 ml) was added dropwise
a solution of LDA (80 mmol, 2 M) in THF at –78 °C under a N2 atmosphere. 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 a saturated NH4Cl 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 com-
pound 3a as white crystals (31.6 g). Yield: 90 %.
Diethyl 2-(3,4-dimethoxybenzylidene)-3-(3,4-methylenedioxybenzyl)succinate (3b)
Following the procedure described for the preparation of 3a but starting with 2b (25.8 g,
80 mmol), compound 3b was obtained as a yellowish oil (31.7 g). Yield: 87 %.
(–)-2-(3,4-Methylenedioxybenzyl)-3-(3,4-methylenedioxybenzylidene)succi-nic acid (4a)
Diester 3a (26.4 g, 60 mmol) was added to a 20 % aqueous solution of NaOH (250 ml)
and refluxed for 3 h. After cooling to room temperature, the mixture was washed with EtOAc
(3×30 ml). After decolorizing with active carbon, the mixture was acidified with HCl (2 M)
whereby white solids were obtained. The crude product was crystallized from HOAc to give
the (±)-diacid 4a. The (±)-diacid 4a and (–)-quinine (38.9 g, 120 mmol) in ethanol (120 ml)
were refluxed for 1 h. The reaction mixture was allowed to cool slowly to room temperature,
whereby fine white crystals were obtained. After two recrystallizations from ethanol, the solid
was added to a solution of HCl (2 M, 100 ml) and stirred for 1 h. The mixture was extracted
with EtOAc (3×80 ml) and the extract was dried over MgSO4 and the solvent evaporated. The
white solid was recrystallized from EtOAc to yield the (–)-diacid 4a as white crystals (10.1 g).
Yield: 44 %.
The white solids obtained by concentrating the mother liquors were recrystallized twice
from methanol and water to yield the (+)-diacid 4a’ as white crystals (9.0 g). Yield: 39 %.
(–)-2-(3,4-Dimethoxybenzylidene)-3-(3,4-methylenedioxybenzyl)succinic acid (4b)
Following the procedure described for the preparation of 4a but starting with the diester
3b (27.4 g, 60 mmol), the (–)-diacid 4b was obtained as white crystals (10.8 g). Yield: 45%.
The (+)-diacid 4b’ was obtained as white crystals (9.2 g). Yield: 38 %.
(–)-Diethyl 2-(3,4-methylenedioxybenzyl)-3-(3,4-methylenedioxybenzylidene)succinate (5a)
To 151 ml of a mixture of EtOH:benzene:H2SO4 (100:50:1) was added 4a (7.7 g, 20
mmol). The mixture was refluxed in a Dean–Stark apparatus for 36 h to remove the water.
The reaction mixture was concentrated in vacuo, extracted with EtOAc (100 ml) and then
neutralized with a saturated NaHCO3 solution (3×30 ml). The extract was dried over MgSO4
and concentrated in vacuo. Flash column chromatography of the residue gave the (–)-diester
5a as a colorless oil (8. 0 g). Yield: 91 %.
(–)-Diethyl 2-(3,4-methylenedioxybenzyl)-3-(3,4-dimethoxybenzylidene)succinate (5b)
Following the procedure described for the preparation of 5a but starting with the diester
4b (8.0 g, 20 mmol), the diacid 5b was obtained as a colorless oil (8.2 g). Yield: 90 %.
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XIA et al.
(–)-Dihydrocubebin (6a) and meso-2,3-Bis(3,4-methylenedioxybenzyl)butane-1,4-diol (7a)
The (–)-diester 5a (7.1 g, 16 mmol) in ethyl acetate (200 ml) was stirred under a hydro-
gen atmosphere for 12 h in the presence of 10 % Pd/C (0.7 g). The reaction mixture was fil-
tered 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 chroma-
tography of the residue gave threo-(–)-6a (2.7 g, yield: 47 %) as white crystals and erythro-7a
(2.6 g, yield: 46 %) as a colorless oil.
(2R,3R)-2-(3,4-Dimethoxybenzyl)-3-(3,4-methylenedioxybenzyl)-1,4-butanediol (6b) and
(2R,3S)-2-(3,4-Dimethoxybenzyl)-3-(3,4-methylenedioxybenzyl)-1,4-butanediol (7b)
Following the procedure described for the preparation of 6a and 7a but starting with the
diester 5b (7.3 g, 16 mmol), 6b (2.6 g, yield: 44 %) and 7b (2.9 g, yield: 48 %) were obtained
as colorless oils.
(–)-Dehydroxycubebin (8a)
To a solution of (–)-diol 6a (0.36 g, 1 mmol) and pyridine (0.08 g, 1 mmol) in CH2Cl2
(25 ml) was added TsCl (0.19 g, 1 mmol) in CH2Cl2 (20 ml) at room temperature. The mix-
ture was stirred for 24 h, quenched with HCl (2 M) and extracted with CH2Cl2 (3×20 ml). The
organic layer was dried over MgSO4 and concentrated in vacuo. Flash column chromategra-
phy of the residue gave (–)-dehydroxycubebin (8a) as a colorless oil (0.26 g). Yield: 76 %.
(–)-5-{[(3R,4R)-4-(3,4-Dimethoxybenzyl)-tetrahydro-3-furanyl]methyl}-1,3-benzodioxole (8b)
Following the procedure described for the preparation of (–)-dehydroxycubebin (8a) but
starting with 6b (0.37 g, 1.0 mmol), compound 8b was obtained as a colorless oil (0.27 g).
Yield: 75 %.
(+)-5.5’-[(2R,3R)-2,3-Bis(methoxymethyl)-1,4-butanediyl]bis(1,3-dioxole) (9a)
To a mixture of NaH (1 mmol) and 6a (0.36g, 1 mmol) in THF (30 ml) was added CH3I
(2 mmol). The mixture was stirred for 7 h at room temperature, quenched with a saturated
NH4Cl solution (20 ml) and then extracted with CH2Cl2 (3×20 ml). The organic layer was
dried over MgSO4 and concentrated in vacuo. Flash column chromatography of the residue
gave 9a as a colorless oil (0.33 g). Yield: 85 %;
(+)-5-[(2-(2R,3R)-4-(3,4-Dimethoxybenzyl)-2,3-bis(methoxymethyl)-butyl]-1,3-benzodioxole (9b)
Following the procedure described for the preparation of 9a but starting with 6b (0.37 g,
1 mmol), compound 9b was obtained as a colorless oil (0.35 g). Yield: 88 %.
(–)-Austrobailignan-5 (10a)
To a solution of (–)-diol 6a (0.72 g, 2.0 mmol) in pyridine (2.5 ml) was added TsCl (0.76
g, 4 mmol) at 0 °C The mixture was stirred at this temperature for 4 h, acidified with HCl (2
M, 20 ml) and extracted with EtOAc (3×20 ml). The organic layer was washed with a satu-
rated NaCl solution (20 ml), dried over MgSO4 and concentrated in vacuo to give the crude
ditoluenesulfonyl ester. A mixture of this ditoluenesulfonyl ester and LiAlH4 (0.20 g, 5.0 mmol)
in dry THF (30 ml) was refluxed for 6 h, the mixture quenched with ice-water, filtered and
then concentrated in vacuo. Flash column chromatography of the residue gave 10a as white
crystals (0.56 g). Yield: 86 %.
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SYNTHESIS AND BIOACTIVITY OF LIGNANS
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(–)-Saururenin (10b)
Following the procedure described for the preparation of 10a but starting with the diester
6b (0.75 g, 2 mmol), compound 10b was obtained as a colorless oil (0.6 g). Yield: 87 %.
meso-5,5’-[(Tetrahydro-3,4-furandiyl)bis(methylene)]bis(1,3-benzodioxole) (11a)
Following the procedure described for the preparation of 8a, compound 7a (0.36 g, 1
mmol) was used as the starting material to give compound 11a as a colorless oil (0.25 g).
Yield: 74 %.
(+)-5-{[(3S,4R)-4-[(3,4-Dimethoxyphenyl)methyl]tetrahydro-3-furanyl]methyl}-1,3-
-benzodioxole (11b)
Following the procedure described for the preparation of 8a but starting with 7b (0.37 g,
1 mmol), compound 11b was obtained as a colorless oil (0.26 g). Yield: 72 %
meso-5,5’-[Bis(methoxymethyl)-1,4-butanediyl]bis(1,3-benzodioxole) (12a)
Following the procedure described for the preparation of 9a but starting with 7a (0.36 g,
1 mmol), compound 12a was obtained as a colorless oil (0.32 g). Yield: 82 %.
(+)-5-{[(3S,4R)-4-[(3,4-Dimethoxyphenyl)-2,3-bis(methoxymetyl)butyl]-1,3-benzodioxole (12b)
Following the procedure described for the preparation of 9a but starting with 7b (0.37 g,
1 mmol), compound 12b was obtained as a colorless oil (0.34 g). Yield: 85 %.
meso-Machilin A (13a)
Following the procedure described for the preparation of 10a, compound 7a (1.07 g, 3
mmol) was used as starting material to give meso-machilin A (4) as white crystals (0.87 g).
Yield: 89 %.
(–)-Isosaururenin (13b)
Following the procedure described for the preparation of 10a but starting with 7b (0.75
g, 2 mmol), compound 13b was obtained as a colorless oil (0.55 g). Yield: 81 %.
meso-Nordihydroguaiaretic acid (14)
Compound 13a (0.65 g, 2 mmol) was dissolved in dry CCl4 (50 ml), PCl5 (2.50 g, 12
mmol) was then added. The mixture was refluxed for 10 h under a nitrogen atmosphere. The
amber-colored solution was concentrated in vacuo and then ice water (15 ml) was added
slowly into the residue and refluxed for 5 h under a nitrogen atmosphere. A white solid ap-
peared slowly in the solution, which was collected, washed with water and crystallized from
ethanol to give meso-nordihydroguaiaretic acid (14) as white crystals (0.51 g). Yield: 85 %.
CONCLUSIONS
In summary, an efficient chiral synthetic method was developed to give
NDGA, (–)-saururenin and their analogues. With cheap materials, short experi-
mental procedures, mild conditions and simple operations, the route will exhibit
more potential value in the future.
SUPPLEMENTARY MATERIAL
Spectroscopic data of the synthesized compounds are available electronically from http://
//www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. This work was financially supported by the foundation of State Key
Laboratory of Applied Organic Chemistry of China (No. 200708) and the National Natural
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1334
XIA et al.
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 Center for Drug Screening is acknowledged for the an-
ti-HIV and anti-HSV assay of the compounds.
И З В О Д
СИНТЕЗА И БИОЛОШКА АКТИВНОСТ erythro-НОРДИХИДРОГВАЈАРЕТИЧНЕ
КИСЕЛИНЕ, thrеo-САУРУРЕНИНА И ЊИХОВИХ АНАЛОГА
1
1
1
1
2
YAMU XIA , YUANYUAN ZHANG , WEI WANG , YINING DING и RUI HE
1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042 и 2College
of Mathematics and Physics, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
У раду је дат детаљан приказ тоталне синтезе erythro-нордихидрогвајаретичне кисе-
лине, threo-(–)-сауруренина и њихових аналога. Општа синтетичка стратегија која је
примењена заснива се на Stobbе-oвoj реакцији, алкиловању у циљу изградње лигнанског
скелета и раздвајању threo- и erythro-изомера. Синтеза 13 лигнана је остварена у 8–9
синтетичких фаза коришћењем једноставних ароматичних прекурсора. Од добијених
лигнана седам су природни производи од којих је за три урађена прва синтеза у овом раду.
Испитан је утицај свих добијених лигнана на HIV Tat трансактивацију у хуманим епителним
ћелијама, HSV-1 ген и ћелије хумане леукемије, рака јетре, простате, желуца и дојке. Резул-
тати биолошких испитивања указују да један производ показује активност према HIV-у а пет
једињења поседују анти-HSV активност.
(Примљено 10. априла, ревидирано 11. јуна 2010)
REFERENCES
1. R. D. Howarth, Annu. Rep. Prog. Chem. 33 (1936) 266
2. M. Saleem, H. J. Kim, M. S. Ali, Y. S. Lee, Nat. Prod. Rep. 22 (2005) 696
3. N. Li, J. Wu, T. Hasegawa, J. Sakai, L. Bai, L. Wang, S. Kakuta, Y. Furuya, H. Ogura, T.
Kataoka, A. Tomida, T. M. Tsuruo, J. Nat. Prod. 70 (2007) 544
4. G. Zhang, N. Li, Y. Wang, Y. Zheng, Z. Zhang, M. Wang, J. Nat. Prod. 70 (2007) 662
5. S. Arteaga, A. Andrade-Cetto, R. Cardenas, J. Ethnopharmacol. 98 (2005) 231
6. J. D. Lambert, R. T. Dorr, B. N. Timmermann, Pharm. Biol. 42 (2004) 149
7. J. L. Billinsky, E. S. Krol, J. Nat. Prod. 71 (2008) 1612
8. W. Tong, X. Ding, T. E. Adrian, Biochem. Biophys. Res. Commun. 296 (2002) 942
9. R. Agarwal, Z. Y. Wang, D. P. Bik, H. Mukhtar, Drug Metab. Dispos. 19 (1991) 620
10. K. V. Rao, N. S. P. Rao, J. Nat. Prod. 53 (1990) 212
11. K. V. Rao, F. M. Alvarez, J. Nat. Prod. 45 (1982) 393
12. J. R. Hwu, W. N. Tseng, J. Gnabre, P. Giza, R. C. C. Huang, J. Med. Chem. 41 (1998)
2994
13. H. S. Cheng, L. Teng, J. N. Li, R. Park, D. E. Mold, J. Gnabre, J. R. Hwu, W. N. Tseng,
R. C. C. Huang, J. Med. Chem. 41 (1998) 3001
14. S. Whitman, M. Gezginci, B. N. Timmermann, T. R. Holman, J. Med. Chem. 45 (2002)
2659
15. T. W. Moody, J. Leyton, A. Martinez, S. Hong, A. Mallkinson, J. L. Mulshine, Exp. Lung
Res. 24 (1998) 617
16. J. Chang, J. Reiner, J. X. Xie, Chem. Rev. 105 (2005) 4581
Available online at www.shd.org.rs/JSCS/
_________________________________________________________________________________________________________________________
2010 Copyright (CC) SCS

SYNTHESIS AND BIOACTIVITY OF LIGNANS
1335
17. S. V. Lieberman, G. P. Mueller, E. T. Stiller, J. Am. Chem. Soc. 69 (1947) 1540
18. J. K. Son, S. H. Lee, L. Nagarapu, Y. Jahng, Bull. Korean Chem. Soc. 26 (2005) 1117
19. M. H. Gezginci, B. N. Timmermann, Tetrahedron Lett. 42 (2001) 6083
20. K. V. Rao, S. K. Chattopadhyay, J. Org. Chem. 55 (1990) 1427
21. Y. M. Xia, Q. Wang, Y. N. Din, F. K. Yang, X. P. Cao, Chin. J. Org. Chem. 28 (2008) 1040
22. A. S. R. Anjaneyulu, P. A. Ramaiah, L. R. Row, R. Venkateswarlu, A. Pelter, R. S. Ward,
Tetrahedron 37 (1981) 3641
23. M. J. Kato, M. Yoshida, O. R. Gottlieb, Phytochemistry 31 (1992) 283
24. P. Satyanarayana, S. Venkateswarlu, Tetrahedron 47 (1991) 8931
25. S. T. Murphy, E. Ritchie, W. C. Taylor, Aust. J. Chem. 28 (1975) 81
26. H. Shimomura, Y. Sashida, M. Oohara, Phytochemistry 26 (1987) 1513
27. J. L. Wu, N. Li, T. Hasegawa, J. Sakai, S. Kakuta, W. Tang, S. Oka, M. Kiuchi, H.
Ogura, T. Kataoka, A. Tomida, T. Tsuruo, M. Ando, J. Nat. Prod. 68 (2005) 1656
28. G. T. Tan, J. M. Pezzuto, A. D. Kinghorn, S. H. Hughes, J. Nat. Prod. 54 (1991) 143
29. R. Dulbeccok, Proc. Natl. Acad. Sci. U.S.A. 38 (1952) 747.
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