Synthesis of 4-O-Methylcedrusin. Selective protection of catechols with diphenyl carbonate

Article abstract of DOI:10.3390/50200153

4-O-Methylcedrusin, a minor component in 'sangre de drago', has been synthesized using a strategy of successive protection and deprotection reactions under very mild conditions. The key step of this synthesis is a selective protection of a catechol group

Full text of DOI:10.3390/50200153

Molecules 2000, 5, 153-161
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of 4-O-Methylcedrusin. Selective Protection of
Catechols with Diphenyl Carbonate
Stefaan M. O. Van Dyck, Guy L. F. Lemière*, Tim H. M. Jonckers and Roger Dommisse
Department of Chemistry, Laboratory of Natural Product Synthesis for Chemotherapy, University of
Antwerp (RUCA), Groenenborgerlaan 171, 2020 Antwerpen, Belgium
Tel.: ++32 3 2180226, Fax: ++32 3 2180233, E-mail: lemiere@ruca.ua.ac.be
*Author to whom correspondence should be addressed.
Received: 1 November 1999 / Accepted: 19 January 2000 / Published: 18 February 2000
Abstract: 4-O-Methylcedrusin, a minor component in ‘sangre de drago’, has been synthe-
sized using a strategy of successive protection and deprotection reactions under very mild
conditions. The key step of this synthesis is a selective protection of a catechol group as a
cyclic carbonate in the presence of an isolated phenol group.
Keywords: Carbonates, lignans, phenolics, protecting groups, natural products.
Introduction
The red viscous latex ‘sangre de drago’ or dragon’s blood, obtained by slashing the bark of various
Croton species (Euphorbiaceae), is used in South-American popular medicine for several purposes in-
cluding wound healing [1]. Recently the anticancer activity of the dihydrobenzofuran-type neolignan
extracted from this latex and of some analogues has been demonstrated [2]. 4-O-Methylcedrusin is a
minor component found in sangre de drago [3]. We now wish to report the first synthesis of racemic
[4] 4-O-methylcedrusin from caffeic acid (Scheme 1).
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

154
Molecules 2000, 5
OMe
OH
OMe
OH
OH
OH
OH
OH
O
O
HO
HO
MeO
OH
OMe
O
O
O
4-O-methylcedrusin
1
2
caffeic acid
3
Scheme 1.
Results and Discussion
The dihydrobenzofuran skeleton of this type of neolignan is often obtained by an oxidative coupling
of cinnamate esters using silver oxide [5] or horseradish peroxidase [6]. Therefore caffeic acid was
esterified in methanol using Dowex 50w-X-8® as a heterogenous acidic catalyst giving methyl caffeate
in quantitative yield. The ester was then oxidized with silver oxide in benzene/THF at room tempera-
ture resulting in the formation of (2).
Since only the two catecholic hydroxyl groups in product (2) have to be methylated we looked for a
method to selectively protect a catechol in the presence of an isolated phenol group. After the protec-
tion of the phenol group and deprotection of the catechol moiety the methylation can be performed. In
this strategy one should also consider that product (2) is base as well as acid sensitive. Since some
widely used catechol protecting groups such as acetals, cyclic boronates and cyclic sulfates [7] some-
times require rather drastic conditions for their formation or removal they did not appear to be useful
for our synthesis. We preferred the cyclic carbonate protecting group because it can easily be intro-
duced and removed. Although this group is often used in sugar chemistry [8], it has been used only to
a very limited extent for catechols since these carbonates are very sensitive to hydrolysis [7]. Also no
information about the selectivity of this group towards catechols could be found in the literature.
Therefore the protection conditions were examined in a test reaction on a mixture of the model com-
pounds 4-cyanophenol and catechol. The reaction products were analyzed by GC and showed a selec-
tivity of over 95% towards the catechol indicating the usefulness of the cyclic carbonate as a selective
protecting group.
The procedure described in the literature for the introduction of a cyclic carbonate was greatly sim-
plified [9]. Product (2) and diphenyl carbonate, both dissolved in diethyl ether, were stirred at room
temperature with a catalytic amount of triethylamine. The carbonate (5) precipitated from the solution
allowing an easy work-up. The formation of the cyclic carbonate was clearly visible in the IR spectra.
Product (5) had a characteristic (C=O) absorption at 1831 cm-1. Further, the very broad hydroxyl ab-
sorption band of product (2) changes into a much sharper signal at 3358 cm-1 after the carbonate for-
mation.
Protection of the remaining phenol group was achieved through the reaction of (5) with tert-
butyldimethylchlorosilane (TBDMSCl) and imidazole in dry DMF. The cyclic carbonate protecting

155
Molecules 2000, 5
group could immediately be removed by addition of a small amount of water to this reaction mixture.
Hydrolysis was complete within 3 hours [10] giving deprotected product (7). Subsequently the cate-
chol unit is methylated with methyl iodide and K2CO3 in acetone giving product (8). The TBDMS
protecting group was then removed by refluxing (8) with an excess of ammonium fluoride in metha-
nol. The use of a polar protic solvent for the fluoride ions was decisive for the success of the deprotec-
tion. In non-polar solvents the fluoride ion is too basic to be compatible with our products. The double
bond in the side chain was reduced with H2 on Pd/C (10) and the ester functions were reduced with
LiAlH4 leading to the desired 4-O-methylcedrusin (1).
OH
OH
OH
OH
OH
MeOH
Ag2O
O
3
MeO
benzene/THF
Dowex 50w-x8
O
Me
OMe
O
O
O
4
2
O
O
O
O
O
O
diphenyl-
carbonate
OH
OTBDMS
O
TBDMSCl
O
ether
Et3N
imidazole
DMF
O
Me
O
Me
OMe
OH
OMe
O
O
O
O
5
6
OMe
OH
OMe
OTBDMS
O
OTBDMS
O
H2O
MeI
K2CO3
acetone
MeO
O
Me
OMe
OMe
O
O
O
O
7
8
1
OMe
OMe
OH
O
H2
LiAlH4
ether
NH4F
10
Pd/C
MeOH
O
Me
OMe
O
O
9
Scheme 2.

156
Molecules 2000, 5
Conclusion
Summarising we can say that 4-O-methylcedrusin has been synthesized in a straightforward way
from caffeic acid using a strategy of successive selective protection and deprotection reactions. A new
synthetic method for the selective protection of a catechol as a cyclic carbonate was introduced. The
low stability of the catechol carbonates towards hydrolysis was turned into an advantage by incorpo-
rating the deprotection of the catechol in a convenient one-pot synthesis. The incorporation of this cy-
clic carbonate as a protective group is expected to be useful in the syntheses of other sensitive poly-
phenolic natural products.
Acknowledgements: We wish to thank Joos Verreydt and Jos Aerts for their technical assistance. Tim
Jonckers would like to thank the ‘Vlaams instituut ter bevordering van het wetenschappelijk technolo-
gisch onderzoek in de industrie (IWT)’ for a scholarship.
Experimental
General
Melting points were determined on a Büchi B-545 melting point apparatus. 1H NMR and 13C NMR
spectra were measured on a Varian Unity 400 spectrometer. Additional HETCOR and long-range
HETCOR measurements to verrify the proposed assignments were performed on the same spectrome-
ter. DCI mass spectra were obtained on a Ribermag R-10-10B mass spectrometer. Infrared spectra
were obtained from a Bruker Vector 22 infrared spectrometer. Column chromatography was performed
on Merck silicagel 60, 0.040-0.063 mm, 230-400 mesh ASTM. Precoated silica gel plates (kieselgel
60, F254, 0.2 mm) were used for TLC analysis. All products and reagents were purchased from Acros.
Methyl caffeate (4)
It was prepared from a mixture of caffeic acid (4 g) and Dowex 50 W x 8 200-400® (0.4 g) in 25
cm3 of absolute methanol. After heating under reflux for 1 night the mixture was filtered and evapo-
rated under reduced pressure to afford the product as a solid (100%) which was used without further
purification.
Amorphous, mp 158°C; 1H NMR (acetone-d6) δ 8.3 (s, 2 H, 3-OH, 4-OH) 7.53 (d, J = 15.87 Hz, 1
H, H-7) 7.15 (d, J = 2.14 Hz, 1 H, H-2) 7.03 (dd, J = 8.09, 2.14 Hz, H-6) 6.86 (d, J = 8.09 Hz, 1 H, H-
5) 6.27 (d, J = 16.02 Hz, 1 H, H-8) 3.70 (s, 3 H, 9-OCH3); 13C NMR (acetone-d6) δ 167.82 (C-9)
148.75 (C-4) 146.33 (C-3) 145.68 (C-7) 127.75 (C-1) 122.51 (C-6) 116.43 (C-5) 115.28 (C-2) 115.21
(C-8) 51.45 (9-OCH3); DCI-MS (NH3): m/z = 195 (MH+).

157
Molecules 2000, 5
Methyl (E)–3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-
yl]prop-2-enoate (2)
It was prepared according to the method of Lemière et al. [11], using 1.905 g (9.8 mmol) of methyl
caffeate, 0.826 g (3.5 mmol) of silver(I)oxide, 40 cm3 of anhydrous benzene and 20 cm3 of anhydrous
acetone. The product was purified by column chromatography (column 30 cm x 3.8 cm, silica gel 60,
0.040-0.063 mm) with ethyl acetate/heptane 1/1 as the eluent. After evaporation and lyophilisation a
white foam is obtained (33%); amorphous mp 159°C.
1H NMR (acetone-d6) δ 8.05 (s, 2 H, 3-OH, 4-OH) 7.57 (d, J = 16.02 Hz, 1 H, H-7’) 7.14 (s, 1 H,
H-6’) 6.90 (d, J = 1.95 Hz, 1 H, H-2) 6.84 (d, J = 8.24 Hz, 1 H, H-5) 6.79 (dd, J = 8.24, 1.98 Hz, 1 H,
H-6) 6.33 (d, J = 16.02 Hz, 1 H, H-8’) 5.97 (d, J = 8.33 Hz, 1 H, H-7) 4.35 (d, J = 8.33 Hz, 1 H, H-8)
13
3.79 (s, 3 H, 9’-OCH3) 3.71 (s, 3 H, 9-OCH3) 3.38 (s, 1 H, 3’-OH); C NMR (acetone-d6) δ 171.69
(C-9) 167.79 (C-9’) 150.07 (C-3’) 146.33 (C-4) 146.09 (C-3) 145.42 (C-7’) 142.53 (C-4’) 132.70 (C-
1) 129.40 (C-1’) 127.33 (C-5’) 118.70 (C-6) 117.76 (C-2’) 117.33 (C-6’) 116.16 (C-5) 116.05 (C-8’)
113.93 (C-2) 87.88 (C-7) 56.29 (C-8) 52.95 (9-OCH3) 51.55 (9’-OCH3) [12]; DCI-MS (NH3): m/z =
387 (MH+); Anal. Calcd for C20H18O8: C, 62.17; H, 4.70. Found: C, 62.08; H, 4.64.
Methyl (E)-3-[2-(2-oxo-1,3-benzodioxol-5-yl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofu-
ran-5-yl]prop-2-enoate (5)
It was prepared by stirring 800 mg of coupling product (2), 440 mg of diphenyl carbonate and 3
drops of triethyl amine in 30 cm3 of diethyl ether for 2 days. The product precipitated from the mixture
and was filtered and washed with a minimal amount of diethyl ether. After lyophilisation the carbonate
was obtained in 60% yield as a white powder (mp 175°C). Product (2) could be recovered from the
filtrate in 30% yield.
1H NMR (1,4-dioxane-d8) δ 8.00 (s, 1 H, 3’-OH) 7.62 (d, J = 15.87 Hz, 1 H, H-7’) 7.52 (s, 1 H, H-
2) 7.36 (s, 2 H, H-5, H-6) 7.17 (s, 1 H, H-2’) 7.12 (s,1 H, H-6’) 6.38 (d, J = 15.87 Hz, 1 H, H-8’) 6.21
(d, J = 7.76 Hz, 1 H, H-7) 4.39 (d, J = 7.93 Hz, 1 H, H-8) 3.84 (s, 3 H, 9’-OCH3) 3.75 (s, 3 H, 9-
OCH3); 13C NMR (1,4-dioxane-d8) δ 171.91 (C-9) 168.28 (C-9’) 152.41 (C-4’) 150.00 (3-OCOO)
145.76 (C-7’) 145.66 (C-3) 145.36 (C-4) 143.16 (C-3’) 138.94 (C-1) 131.16 (C-1’) 127.14 (C-5’)
123.87 (C-6) 118.39 (C-6’) 118.10 (C-2’) 117.54 (C-8’) 111.52 (C-5) 119.62 (C-2) 87.81 (C-7) 57.35
+
(C-8) 53.76 (9-OCH3) 52.27 (9’-OCH3) [12]; DCI-MS (NH3): m/z = 413 (MH+), m/z = 430 (MNH4 );
IR (KBr) cm-1: 1831 (C=O), 3358 (OH); Anal. Calcd for C21H16O9: C, 61,17; H, 3.91. Found: C, 60.77;
H, 4.02.
Methyl (E)-3-[2-(2-oxo-1,3-benzodioxol-5-yl)-7-(tert-butyldimethylsilyloxy)-3-methoxycarbonyl-2,3-
dihydro-1-benzofuran-5-yl]prop-2-enoate (6)
It was prepared by stirring 570 mg of carbonate (5) with 230 mg TBDMSCl and 282 mg of imida-

158
Molecules 2000, 5
zole in 15 cm3 of anhydrous DMF for 8 hours. The reaction product was not isolated but the protecting
carbonate group was immediately hydrolyzed with a little water (see below).
+
DCI-MS (NH3) of the crude reaction mixture: m/z = 527 (MH+), m/z = 539 (MNH4 )
Methyl (E)-3-[2-(3,4-dihyroxyphenyl)-7-(tert-butyldimethylsilyloxy)-3-methoxycarbonyl-2,3-dihydro-
1-benzofuran-5-yl]prop-2-enoate (7)
It was prepared by adding 0.3 cm3 of water to the previous reaction mixture. This mixture was
stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (column 30 cm x 3.8 cm, silica gel 60, 0.040-
0.063 mm) with ethyl acetate/heptane 3/5 as the eluent. After evaporation and lyophilisation a slightly
brown tinted oil is obtained in 64% yield.
1H NMR (CDCl3) δ 7.58 (d, J = 15.87 Hz, 1H, H-7’) 7.12 (s, 1 H, H-6’) 6.95 (s, 1 H, H-2’) 6.89 (d,
J = 1.98 Hz, 1 H, H-2) 6.84 (d, J = 8.09 Hz, 1 H, H-5) 6.80 (dd, J = 8.09, 1.98 Hz, 1 H, H-6) 6.25 (d, J
= 15.87 Hz, 1 H, H-8’) 6.01 (d, J = 7.63 Hz, 1 H, H-7) 4.23 (d, J = 8.33 Hz, 1 H, H-8) 3.82 (s, 3 H, 9’-
OCH3) 3.79 (s, 3 H, 9-OCH3) 0.96 (s, 9 H, H-12) 0.18 (s, 3H, H-10a) 0.19 (s, 3H, H-10b); 13C NMR
(CDCl3) δ 170.98 (C-9) 168.01 (C-9’) 152.21 (C-4’) 144.94 (C-7’) 144.00 (C-3) 143.91 (C-4) 140.15
(C-3’) 133.03 (C-1) 128.48 (C-1’) 126.24 (C-5’) 121.68 (C-6) 118.64 (C-6’) 118.31 (C-2’) 115.53 (C-
8’) 115.32 (C-5) 113.02 (C-2) 86.37 (C-7) 55.84 (C-8) 52.84 (9-OCH3) 51.69 (9’-OCH3) 25.66 (C-12)
18.36 (C-11) –4.41 (C-10a)* –4.46 (C-10b)* (* may be reversed) [12]; DCI-MS (NH3): m/z = 501
+
(MH+), m/z = 518 (MNH4 ); Anal. Calcd for C26H32O8Si: C, 62.38; H, 6.44. Found: C, 62.48; H, 6.49.
Methyl (E)-3-[2-(3,4-dimethoxyphenyl)-7-(tert-butyldimethylsilyloxy)-3-methoxycarbonyl-2,3-dihydro-
1-benzofuran-5-yl]prop-2-enoate (8)
It was prepared by heating a solution of 100 mg of product (7), 6 cm3 of methyl iodide and 1 g of
potassium carbonate in 20 cm3 acetone under reflux for 16 h. The solvent was removed under reduced
pressure and the crude product was purified by column chromatography (column 30 cm x 3.8 cm, sil-
ica gel 60, 0.040-0.063 mm) with ethyl acetate/heptane 3/5 as the eluent. After evaporation and ly-
ophilisation a colourless oil is obtained in 68% yield.
1H NMR (CDCl3) δ 7.59 (d, J = 15.87 Hz, 1H, H-7’) 7.18 (s, 1 H, H-6’) 6.99 (s, 1 H, H-2’) 6.94
(dd, J = 8.24, 1.98 Hz, 1 H, H-6) 6.91 (d, J = 1.83 Hz, 1 H, H-2) 6.85 (d, J = 8.24 Hz, 1 H, H-5) 6.26
(d, J = 15.87 Hz, 1 H, H-8’) 6.09 (d, J = 8.09 Hz, 1 H, H-7) 4.28 (d, J = 8.09 Hz, 1 H, H-8) 3.87 (s, 3
H, 3-OCH3)* 3.85 (s, 3 H, 4-OCH3)* 3.83 (s, 3H, 9-OCH3) 3.78 (s, 3H, 9’-OCH3) 0.98 (s, 9 H, H-12)
0.19 (s, 6H, H-10); 13C NMR (CDCl3) δ 170.87 (C-9) 167.65 (C-9’) 152.12 (C-3) 149.43 (C-4) 149.36
(C-4’) 144.67 (C-7’) 140.16 (C-3’) 132.62 (C-1) 128.61 (C-1’) 126.34 (C-5’) 121.67 (C-6) 118.36 (C-
6’) 118.20 (C-2’) 115.53 (C-8’) 111.39 (C-5) 109.10 (C-2) 86.61 (C-7) 56.03 (3-OCH3) 56.00 (4-
OCH3) 55.83 (C-8) 52.82 (9-OCH3) 51.56 (9’-OCH3) 25.67 (C-12) 18.37 (C-11) –4.39 (C-10) (* may

159
Molecules 2000, 5
+
be reversed) [12]; DCI-MS (NH3): m/z = 529 (MH+) m/z = 546 (MNH4 ); Anal. Calcd for C28H36O8Si:
C, 63.61; H, 6.86. Found: C, 63.86; H, 6.94.
Methyl (E)–3-[2-(3,4-dimethoxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-
yl]prop-2-enoate (9)
It was prepared by heating a reaction tube filled with a solution of 50 mg of product (8) and 20 mg
of ammonium fluoride in 3 cm3 of methanol for 45 minutes at 60°C. The solvent was removed under
reduced pressure and the crude product was purified by column chromatography (column 30 cm x 3.8
cm, silica gel 60, 0.040-0.063 mm) with ethyl acetate/heptane 3/5 as the eluent. After evaporation and
lyophilisation a white solid (amorphous mp 143°C) is obtained in 82% yield.
1H NMR (CDCl3) δ 7.61 (d, J = 15.87 Hz, 1H, H-7’) 7.13 (s, 1 H, H-6’) 7.07 (s, 1 H, H-2’) 6.96
(dd, J = 8.24, 1.98 Hz, 1 H, H-6) 6.89 (d, J = 1.98 Hz, 1 H, H-2) 6.86 (d, J = 8.24 Hz, 1 H, H-5) 6.29
(d, J = 16.02 Hz, 1 H, H-8’) 6.13 (d, J = 8.09 Hz, 1 H, H-7) 4.36 (d, J = 8.04 Hz, 1 H, H-8) 3.87 (s, 3
H, 3-OCH3)* 3.86 (s, 3 H, 4-OCH3)* 3.83 (s, 3H, 9-OCH3) 3.79 (s, 3H, 9’-OCH3); 13C NMR (CDCl3) δ
170.62 (C-9) 167.64 (C-9’) 149.77 (C-3) 149.58 (C-4) 148.33 (C-4’) 144.57 (C-7’) 140.53 (C-3’)
131.84 (C-1) 129.21 (C-1’) 125.59 (C-5’) 118.81 (C-6) 117.51 (C-2’) 116.03 (C-8’) 116.13 (C-6’)
111.53 (C-5) 109.36 (C-2) 87.73 (C-7) 56.12 (3-OCH3)* 56.07 (4-OCH3)* 55.77 (C-8) 52.91 (9-OCH3)
+
51.68 (9’-OCH3) (* may be reversed) [12]; DCI-MS (NH3): m/z = 415 (MH+) m/z = 432 (MNH4 );
Anal. Calcd for C22H22O8: C, 63.76; H, 5.35. Found: C, 63.53; H, 5.36
Methyl 3-[2-(3,4-dimethoxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]pro-
panoate) (10)
It was prepared from a mixture of 80 mg of product (9) and 100 mg of 5% Pd/C in 25 cm3 of ethyl
acetate. This mixture was shaken in a Parr apparatus for 30 minutes with hydrogen at 60 psi. After-
wards the catalyst was filtered off and the solvent was removed under reduced pressure giving a col-
ourless oil in 90% yield.
1H NMR (CDCl3) δ6.92 (d, J = 1.98 Hz, 1 H, H-2) 6.86 (d, J = 8.08 Hz, 1 H, H-5), 6.80 (dd, J =
8.08, 1.98 Hz, 1 H, H-6) 6.68 (s, 1 H, H-2’) 6.62 (s,1 H, H-6’) 5.97 (d, J = 7.48 Hz, 1 H, H-7) 4.36 (d,
J = 7.48 Hz, 1 H, H-8) 3.87 (s, 3 H, 3-OCH3)* 3.85 (s, 3 H, 4-OCH3)* 3.83 (s, 3H, 9-OCH3) 3.79 (s,
3H, 9’-OCH3); 13C NMR (CDCl3) δ 173.31 (C-9) 170.02 (C-9’) 149.22 (C-3) 146.21 (C-4) 142.63 (C-
3’) 140.78 (C-4’) 134.74 (C-1’) 131.68 (C-1) 128.13 (C-5’) 119.59 (C-6’) 118.65 (C-2’) 117.81 (C-6’)
113.11 (C-5) 111.46 (C-2) 87.09 (C-7) 56.11 (3-OCH3)* 56.06 (4-OCH3)* 55.42 (C-8) 52.88 (9-OCH3)
51.67 (9’-OCH3) 34.88 (C-8’) 31.44 (C-7’) (* may be reversed) [12]; DCI-MS (NH3): m/z = 417
+
(MH+) m/z = 434 (MNH4 ); Anal. Calcd for C22H24O8: C, 63.45; H, 5.81. Found: C, 63.37; H, 5.77

160
Molecules 2000, 5
3-[2-(3,4-Dimethoxyphenyl)-3-hydroxymethyl-7-hydroxy-2,3-dihydro-1-benzofuran-5-yl]propan-1-ol
(1)
It was slowly prepared by adding a solution of 40 mg of product (10) in 5 cm3 of anhydrous THF to
a stirring suspension of 20 mg of LiAlH4 in 15 cm3 of anhydrous diethyl ether. After 2 hours concen-
trated HCl was added until a clear solution was obtained. This solution was extracted with ethyl acetate
and the combined fractions were washed with water. The organic layer was dried on MgSO4, filtered
and the solvent was evaporated under reduced pressure. The crude product was purified by column
chromatography (column 30 cm x 3.8 cm, silica gel 60, 0.040-0.063 mm) ethyl acetate as the eluent.
After lyofilisation a white foam is obtained in 58% yield. The foam liquified quickly to a colourless oil
under normal pressure.
1H NMR (CDCl3) δ6.95 (dd, J = 8.08, 1.98 Hz, 1 H, H-6) 6.92 (d, J = 1.98 Hz, 1 H, H-2) 6.85 (d, J
= 8.08 Hz, 1 H, H-5) 6.68 (s, 1 H, H-2’) 6.62 (s, 1 H, H-6’) 5.55 (d, J = 7.47 Hz, 1 H, H-7) 3.90 (m,
2H, H-9a, H-9b) 3.87 (s, 3 H, 3-OCH3)* 3.85 (s, 3 H, 4-OCH3)* 3.67 (t, J = 6.41 Hz, 1 H, H-9’) 3.60
(m, 1 H, H-8) 2.62 (t, J = 7.63 Hz, 1 H, H-7’) 1.85 (m, J = 7.63, 6.41 Hz, 1 H, H-8’); 13C NMR
(CDCl3) δ 149.47 (C-3) 149.36 (C-4) 145.06 (C-3’) 139.99 (C-4’) 135.92 (C-1’) 133.54 (C-5‘) 127.48
(C-1) 118.72 (C-6) 115.92 (C-6’) 115.71 (C-2’) 111.41 (C-5) 109.46 (C-2) 88.18 (C-7) 63.80 (C-9)
62.31 (C-9’) 56.05 (3-OCH3, 4-OCH3) 54.11 (C-8) 34.48 (C-7’) 31.73 (C-8’) [12]; DCI-MS (NH3):
m/z = 343 (MH+-H2O); Anal. Calcd for C20H24O6: C, 66.65; H, 6.71. Found: C, 66.68; H, 6.67
References and Notes
1. Pieters, L.; De Bruyne, T.; Van Poel, B.; Vingerhoets, B.; Totté, J; Vanden Berghe, D.; Vlietinck,
A. Phytomed. 1995, 2, 17-22.
2. Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemière G., accepted for
publication in J. Med. Chem.
3. Pieters, L.; De Bruyne, T.; Claeys, M.; Vlietinck, A. J. Nat. Prod. 1993, 56, 6, 899-906.
4. The relative configurations in schemes 1 and 2 are depicted according to a proposal of Maerhr, H.
J. Chem. Ed. 1985, 62, 114-120.
5. Antus, S.; Bauer, R.; Gottsegen, A.; Seligmann, O.; Wagner, H. Liebigs Ann. Chem. 1987, 357-
360.
6. Bolzacchini, E.; Brunow, G.; Meinardi, S.; Orlandi, M.; Rindone, B.; Rumakko, P.; Setela, H.
Tetrahedron Lett. 1998, 39, 3291-3294.
7. For a broad review on these and other protective groups see: Greene, T. W.; Wuts, P. G. M. Pro-
tective Groups in Organic Chemistry; John Wiley: New York, 1974.
8. Raaijmakers, H.; Zwanenburg B.; Chittenden G. J. F. J. Carbohydrate Chemistry 1993, 12, 8,
1117-1125.
9. Einhorn, A.; Cobliner, J.; Pfeifer, H. Ber. 1904, 37, 100-128.

161
Molecules 2000, 5
10. The rate of hydrolysis is very dependent to the type of solvent. In acetone or dioxane the hydroly-
sis is significantly slower needing reaction times of about 18h.
11. Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V. J. Chem.
Soc. Perkin I 1995, 1775-1779.
13
12. The numbering used for the assignment of 1H and C-NMR signals is as shown in the following
structure. This numbering is used for easy comparison of the signals of the compounds (1)-(10)
with earlier work [11] and is in accordance with a recent IUPAC recommendation [13]
3
2
4
'
1
3
'
O
4
'
2
5
7
6
'
8
'
1
8
'
'
5
9
9
'
'
6
7
13. Provisional recommendation, IUBMB-IUPAC, Joint Commision on Biochemical Nomenclature
(JCBN), Nomenclature of lignans an neolignans, 30 June 1999.
Samples Availability: Available from the authors.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.