Effect of benzylic oxygen on the antioxidant activity of phenolic lignans

Article abstract of DOI:10.1021/np050089s

It has been clarified in the present investigation that a high degree of oxidation at the benzylic position of phenolic lignans bearing a 4-hydroxy-3-methoxybenzyl group reduces their antioxidant activity and that the antioxidant activity of the bis(4-hydroxy-3-methoxybenzyl)tetrahydrofuran lignan 2 is higher than that of the corresponding y-butyrolactone lignan 1. This was demonstrated by comparing the antioxidant activities of compounds 1 and 2 with those of the (benzyl)(hydroxybenzyl)tetrahydrofurans 3 and 4, the bis(hydroxybenzyl)tetrahydrofurans 7 and 8, the (benzoyl)(benzyl)tetrahydrofuran 6, and the dibenzoyltetrahydrofuran 9. The activity level of compound 2 was approximately the same potency as that of the tetrahydronaphthalene- tetrahydrofuran 5. These compounds possess either a 4-hydroxy-3-methoxybenzyl group or a 4-hydroxy-3-methoxybenzoyl group as the benzyl or benzoyl group. An examination of radical scavenging activity showed differences of activity between diastereomers. To make this comparison possible, compounds 1-9 were synthesized using new synthetic routes for several of these lignans. In this investigation, stereoisomers of the (benzyl)(hydroxybenzyl)tetrahydrofurans 3 and 4 and liovils 7 and 8 were synthesized for the first time.

Full text of DOI:10.1021/np050089s

J. Nat. Prod. 2005, 68, 1459-1470
1459
Effect of Benzylic Oxygen on the Antioxidant Activity of Phenolic Lignans
Satoshi Yamauchi,*,† Yoshimasa Hayashi,† Yuki Nakashima,† Takuya Kirikihira,‡ Kazuki Yamada,‡ and
Toshiya Masuda‡
Faculty of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime 790-8566, Japan, and Faculty of Integrated Arts
and Sciences, University of Tokushima, Tokushima 770-8502, Japan
Received March 15, 2005
It has been clarified in the present investigation that a high degree of oxidation at the benzylic position
of phenolic lignans bearing a 4-hydroxy-3-methoxybenzyl group reduces their antioxidant activity and
that the antioxidant activity of the bis(4-hydroxy-3-methoxybenzyl)tetrahydrofuran lignan 2 is higher
than that of the corresponding γ-butyrolactone lignan 1. This was demonstrated by comparing the
antioxidant activities of compounds 1 and 2 with those of the (benzyl)(hydroxybenzyl)tetrahydrofurans
3 and 4, the bis(hydroxybenzyl)tetrahydrofurans 7 and 8, the (benzoyl)(benzyl)tetrahydrofuran 6, and
the dibenzoyltetrahydrofuran 9. The activity level of compound 2 was approximately the same potency
as that of the tetrahydronaphthalene-tetrahydrofuran 5. These compounds possess either a 4-hydroxy-
3-methoxybenzyl group or a 4-hydroxy-3-methoxybenzoyl group as the benzyl or benzoyl group. An
examination of radical scavenging activity showed differences of activity between diastereomers. To make
this comparison possible, compounds 1-9 were synthesized using new synthetic routes for several of
these lignans. In this investigation, stereoisomers of the (benzyl)(hydroxybenzyl)tetrahydrofurans 3 and
4 and liovils 7 and 8 were synthesized for the first time.
Phenolic lignans are found in a wide variety of dietary
and other plants. The relationship between antioxidant
activity and protection against the effects of various
diseases in adults has recently become a topic of consider-
able interest.1 Mechanistic studies of the antioxidant
activity of phenolic lignans are therefore an important
subject for research into the effects of dietary plants on
health. Although the catechol structure is known to be
important in terms of high antioxidant activity, there have
been no reports concerning the relationship between plant
lignan structures and their antioxidant activity. It has been
reported recently that the presence of a tertiary hydroxy
group on the main lignan structure decreases antioxidant
activity.2,3 Eklund and co-workers have shown that the
treatment of dibenzylbutyrolactone lignans with a radical
initiator yielded compounds that were oxidized at the
benzylic position.4
Figure 1. Structures of compounds 1-9.
The aim of the present investigation is to clarify the
effect of the degree of benzylic oxidation on the resultant
antioxidant activity using plant lignans. To achieve this,
it was considered necessary to synthesize lignans 1-9
(Figure 1) and to evaluate their antioxidant activity. As a
phenyl moiety, the 4-hydroxy-3-methoxyphenyl group was
selected, since this is one of the most common groups
among lignans. The assay systems used were not enzymatic
Results and Discussion
The syntheses of 1-4 and 6-9 began with γ-butyrolac-
tone 107 (Schemes 1 and 2). Benzylation on the R-position
of γ-butyrolactone 10 using LDA yielded 11. On the other
hand, the aldol condensation of 10 with 4-benzyloxy-3-
methoxybenzaldehyde using LDA yielded aldol products 12
and 13, which could then be separated (1:1). The hydroxy
in character, so the use of racemic 1-9 would be sufficient
groups of these aldol products were protected as triisopro-
for this project. However, we assumed that optically active
pylsilyl (TIPS) ethers. After the LiAlH4 reductions of 11,
compounds could be obtained from less expensive starting
14, and 15, the corresponding diols were subjected to
materials, and, for this reason, optically active compounds
cleavage of the trityl ether under acidic conditions to give
of 1-9 were synthesized in the present work. To achieve
triols 16-18, respectively. In this detritylation, partial
effective syntheses, synthetic routes that yielded several
epimerization was observed at the benzylic position of 17,
of lignans 1-9 were selected. During this synthetic process,
giving a 4:1 mixture of 17/18 from 14. Oxidative cleav-
two stereoisomers of a (benzyl)(hydroxybenzyl)tetrahy-
age of the glycol portions on the triols 16-18, followed by
drofuran lignan5 (3 and 4) and of liovil6 (7 and 8) were
PCC oxidation, gave lactones 19-21, respectively. The
synthesized for the first time.
erythro selective aldol condensation of lactones 19-21 with
4-benzyloxy-3-methoxybenzadehyde was observed by em-
ploying potassium hexamethyldisilazane (KHMDS).8 The
* To whom correspondence should be addressed. Tel: +81 89 946 9846.
Fax: +81 89 977 4364. E-mail: syamauch@agr.ehime-u.ac.jp.
aldol products 22 and 23, which were separated (9:1), were
obtained from 19. In the case of the aldol condensations of
† Ehime University.
‡ Tokushima University.
10.1021/np050089s CCC: $30.25
© 2005 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/03/2005

1460 Journal of Natural Products, 2005, Vol. 68, No. 10
Scheme 1. Syntheses of 1-4 and 6-9a
Yamauchi et al.
a Ar1 ) 4-benzyloxy-3-methoxyphenyl. (a) 11: LDA, 4-benzyloxy-3-methoxybenzyl bromide, THF, -70 °C, 1 h (41%); 12, 13: ArCHO, LDA, THF, -70 °C,
30 min, silica gel column (12: 46%, 13: 47%); (b) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 30 min (14: 85%, 15: 83%); (c) 16: (i) LiAlH4, THF, rt, 30 min; (ii)
concentrated HCl, EtOH, rt, 1.5 h (77%, 2 steps); 17, 18: (i) LiAlH4, THF, rt, 30 min; (ii) HCO2H, ether, -10 °C, 10 min (17: 44% as a 4:1 mixture with 18,
18: 46%, 2 steps); (d) (i) NaIO4, MeOH, rt, 3 h; (ii) PCC, CH2Cl2, rt, 16 h (19: 90%, 20: 77% as a 4:1 mixture with 21, 21:82%, 2 steps); (e) 22, 24, 25:
KHMDS, 4-benzyloxy-3-methoxybenzaldehyde, THF, -70 °C, 1 h (22: 88%, 24: 79%, 25: 81%); 23: LDA, 4-benzyloxy-3-methoxybenzaldehyde, THF, -70
°C, 1 h (41%); (f) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1.5 h (26: 87%, 27: 65%, 28: 84%, 29: 100%); (g) 30, 31: LiAlH4, THF, rt, 30 min (30: 72%, 31: 84%);
32: (i) DIBAL-H, CH2Cl2, -70 °C, 30 min; (ii) LiBH4, THF, rt, 20 h (58%, 2 steps); 33: LiBH4, THF, rt, 48 h (65%).
Scheme 2. Syntheses of 1-4 and 6-9a
a Ar1 ) 4-benzyloxy-3-methoxyphenyl, Ar2 ) 4-hydroxy-3-methoxyphenyl. (a) p-TsCl, pyridine, CH2Cl2, rt, 21 h (34: 77%, 35: 62%, 36: 50%, 37: 52%);
(b) (n-Bu)4NF, THF, rt, 1 h (38: 76%, 39: 87%, 40: 100%, 41: 70%); (c) H2, 5% Pd/C, EtOAc, rt, 2 h (3: 67%, 4: 92%, 7: 84%, 8: 80%, 6: 66%, 9: 100%);
(d) H2, Pd(OH)2, EtOAc, rt, 22 h (1: 63%, 2: 78%); (e) PCC, MS 4A, CH2Cl2, rt, 16 h (42: 94%, 43: 78%).
20 and 21, the production of threo isomers was not
observed, yielding 24 and 25 as single isomers, respectively.
Although lactone 20 contained 21 as an impurity, the pure
aldol product 24 was obtained by purification. In the aldol
condensation of 19 using LDA, the ratio of the produc-
tion of threo isomer 23 was increased (22/23 ) 1:1). The
benzylic hydroxy groups were protected as TIPS ethers, and
the resulting silyloxy lactones 26-29 were reduced to diols
30-33 using LiAlH4. The intramolecular etherification of
diols 30-33 was accomplished by treatment with p-TsCl,
leading to the tetrahydrofuran derivatives 34-37, re-
spectively. Cleavage of the silyl ether using (n-Bu)4NF,
followed by hydrogenolysis in the presence of Pd/C, yielded
3, 4, 7, and 8, respectively. Matairesinol (1) and the diben-
zyltetrahydrofuran lignan 2 were obtained from mixtures
of 22/23 and 38/39, respectively, by reduction of a hydroxy

Antioxidant Activity of Phenolic Lignans
Journal of Natural Products, 2005, Vol. 68, No. 10 1461
Scheme 3. Synthesis of 5a
a Ar1 ) 4-benzyloxy-3-methoxyphenyl. (a) (i) 4-benzyloxy-3-methoxybenzaldehyde, MgCl2, Et3N, Me3SiCl, EtOAc, rt, 1 h; (ii) CF3CO2H, MeOH, rt, 1 h
(99%, 2 steps); (b) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1.5 h (78%); (c) LiBH4, MeOH, THF, rt, 16 h, (61%); (d) PivCl, pyridine, CH2Cl2, rt, 2 h (100%); (e) (i)
OsO4, NMO, aqueous acetone, t-BuOH, rt, 16 h; (ii) NaIO4, MeOH, rt, 1 h (86%); (f) (i) (n-Bu)4NF, THF, 0 °C, 1 h; (ii) PCC, MS 4A, CH2Cl2, rt, 16 h (77%,
2 steps); (g) KHMDS, 4-benzyloxy-3-methoxybenzaldehyde, THF, -75 °C, 1 h (86%); (h) Et3SiH, BF3‚OEt2, CH2Cl2, 3 °C, 2 h (57%); (i) (i) LiAlH4, THF, rt,
30 min; (ii) N-TsIm, HaH, -20 °C, 24 h (31%, 2 steps); (j) rt, 48 h (100%); (k) H2, 5% Pd/C, rt, 16 h (100%).
group at the benzyl position and cleavage of the benzyl
protecting group by hydrogenolysis using Pd(OH)2. Ketones
6 and 9 were prepared from 38 and a mixture of 40/41,
respectively, by PCC oxidation followed by cleavage of
benzyl ether by hydrogenolysis using Pd/C. The spectro-
scopic data of 1 and 2 agreed with literature values.9-11
However, the NMR data of both 3 and 4 did not agree with
the published data for the natural compound,5 while the
published NMR data of (+)-liovil12 did not agree with that
measured for compounds 7 and 8. These observations were
used to infer that these natural products are the other
stereoisomers.
To synthesize 5, the cis-(4-hydroxy-3-methoxybenzyl))-
[(hydroxy)(4-hydroxy-3-methoxyphenyl)methyl]tetrahydro-
furan 53 was selected as a key intermediate (Scheme 3).
The anti-aldol adduct 45 was obtained by Evans’ anti-aldol
condensation.13 After protection as a TIPS ether, auxiliary
Figure 2. Antioxidant activity of compounds 1-9 in a Tween 20
micelle system [0.3 M Tween 20/0.05 M phosphate buffer (pH 7.4)].
Conditions: final concentration of a test sample and sesamol, 0.10 mM
(0.05 mM for trolox); AAPH, 10 mM; ethyl linoleate, 50 mM (AAPH:
2,2′-azobis(2-aminopropane)dihydrochloride).
material was removed by reduction with LiBH4 to yield
primary alcohol 47, which was transformed into the alde-
hyde 49 by protection as a pivaloyl ester and subsequent
oxidative cleavage of the olefin. After desilylation, the
resulting hemiacetal was subjected to PCC oxidation to give
lactone 50. The 2-benzyllactone 52 was obtained through
aldol condensation with 4-benzyloxy-3-methoxyaldehyde
and silane reduction.14 The direct benzylation to lactone
50 resulted in a poor yield. After the LiAlH4 reduction of
lactone 52 to the corresponding triol, the tetrahydrofuran
derivative 53 was obtained by etherification between two
primary hydroxy groups by treatment of the resulting triol
with N-TsIm.15 The presence of the secondary benzylic
hydroxy group was confirmed by coupling of the benzylic
proton (dd, J ) 7.3, 2.0 Hz). The tetrahydrofuran derivative
53 was unstable and gradually cyclized to 54 at room
temperature by the Friedel-Crafts-type cyclization.16 The
coupling constant between the 3-position and the 2a-
position (J ) 9.3 Hz) confirmed this steric configuration.17
Hydrogenolysis of 54 yielded 5. Two stereoisomers each of
(4-hydroxy-3-methoxybenzyl)[(hydroxy)(4-hydroxy-3-meth-
oxyphenyl)methyl]tetrahydrofuran (3 and 4) and liovil (7
and 8) were synthesized for the first time. The Friedel-
Crafts-type cyclization of cis-(4-hydroxy-3-methoxybenzyl)-
[(hydroxy)(4-hydroxy-3-methoxyphenyl)methyl]tetrahydro-
furan 53 was demonstrated.
After ethyl linoleate was treated with 2,2′-azobis(2-
aminopropane)dihydrochloride (AAPH) and 1-9, the con-
centration of the resultant ethyl linoleate hydroperoxide
was calculated in order to evaluate antioxidant activity
(Figure 2). It was shown that the antioxidant activity of
bis(4-hydroxy-3-methoxybenzyl)lactone 1 was less potent
than that of the corresponding bis(4-hydroxy-3-methoxy-
benzyl)tetrahydrofuran 2. This confirmed that the degree
of oxidation, except for the benzylic position, has an effect
on antioxidant activity for plant lignans. The activity level
of dibenzyltetrahydrofuran 2 was approximately the same
potency as that of the tetrahydronaphthalene-tetrahydro-
furan 5 and sesamol. The degree of oxidation on the ben-
zylic positions of 5 is the same as that for 1. The activities
of the (4-hydroxy-3-methoxybenzyl)[(hydroxy)(4-hydroxy-
3-methoxyphenyl)methyl]tetrahydrofurans 3 and 4 were a
little weaker than that of 2. The presence of the hydroxy
group on the benzylic position reduced the activity. This

1462 Journal of Natural Products, 2005, Vol. 68, No. 10
Yamauchi et al.
resulting reaction solution was stirred at -70 °C for 1 h before
addition of a saturated aqueous NH4Cl solution. The or-
ganic solution was separated, washed with brine, and dried
(Na2SO4). After concentration, the residue was applied to silica
gel column chromatography (EtOAc/hexane, 1:5) to give the
benzyl butyrolactone 11 (6.43 g, 0.011 mol, 41%) as a colorless
1
oil: [R]20 +5.6° (c 0.4, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
1.94-2.07 (2H, m, H-3), 2.70 (1H, dd, J ) 14.7, 10.3 Hz,
CHHAr-2), 3.07 (1H, dd, J ) 10.7, 3.9 Hz, HH-5), 3.10-3.15
(2H, m, H-2, CHHAr-2), 3.40 (1H, dd, J ) 10.7, 3.4 Hz, HH-
5), 3.82 (3H, s, OCH3), 4.44 (1H, m, H-4), 5.12 (2H, s, OCH2-
Ph), 6.63 (1H, dd, J ) 7.8, 2.0 Hz, ArH), 6.72 (1H, d, J ) 2.0
Hz, ArH), 6.80 (1H, d, J ) 7.8 Hz, ArH), 7.20-7.29 (12H, m,
ArH), 7.33-7.44 (8H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ
29.6, 36.4, 41.3, 56.0, 65.2, 71.2, 87.1, 112.6, 114.3, 120.9, 127.2,
127.3, 127.8, 127.9, 128.5, 128.6, 131.6, 137.2, 143.4, 147.0,
149.8, 179.0; anal. C 79.85%, H 6.46%, calcd for C39H36O5, C
80.11%, H 6.21%.
(2S,4S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(hydroxy)-
methyl]-5-trityloxy-4- pentanolide (12) (erythro isomer)
and (2S,4S)-2-[(R)-(4-Benzyloxy-3-methoxyphenyl)(hy-
droxy)methyl]-5-trityloxy-4-pentanolide 13 (threo iso-
mer). To a solution of LDA (33.5 mmol) in THF (200 mL) was
added a solution of the lactone 10 (10 g, 27.9 mmol) in THF
(80 mL). After the solution was stirred at -70 °C for 15 min,
a solution of 4-benzyloxy-3-methoxybenzaldehyde (3.41 g, 27.9
mmol) in THF (20 mL) was added. The resulting reaction
solution was stirred at -70 °C for 30 min, and then saturated
aqueous NH4Cl solution was added. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography (5% EtOAc/
toluene) gave the erythro aldol product 12 (7.71 g, 12.8 mmol,
46%) as a colorless oil ([R]20D +2.1° (c 1.4, CHCl3)) and the threo
aldol product 13 (7.87 g, 13.1 mmol, 47%) as colorless crystals
Figure 3. Radical scavenging activity of compounds 1-9. Condi-
tions: final concentration of a test sample, 20 µM; DPPH, 0.1 mM
(DPPH: 1,1-diphenyl-2-picrylhydrazyl).
tendency was more clearly apparent between bis(4-hy-
droxy-3-methoxybenzyl)tetrahydrofuran 2 and the less
active bis[(hydroxy)(4-hydroxy-3-methoxyphenyl)methyl]-
tetrahydrofurans 7 and 8. The presence of a carbonyl group
on the benzylic position also reduced the activity, since the
activity of (4-hydroxy-3-methoxybenzoyl)(4-hydroxy-3-meth-
oxybenzyl)tetrahydrofuran 6 was less than that of 2. The
potency level of 6 was the same as that of the bis[(hydroxy)-
(4-hydroxy-3-methoxyphenyl)methyl]tetrahydrofurans 7 and
8. It is interesting to note that bis(4-hydroxy-3-methoxy-
benzoyl)tetrahydrofuran 9, which is fully oxidized on the
benzylic position, showed the weakest activity in this assay.
The differences in activity between diastereomers 3 and 4
was not as marked as those between 7 and 8.
Radical scavenging activity of 1-9 was also examined
(Figure 3). In this assay system, a profile of activity almost
identical to that of Figure 2 was observed except for
differences between diastereomers. The activity of 3 was
weaker than that of 4. This phenomenon was more clearly
apparent between 7 and 8, with obviously higher activity
of 8 than that of 7 being shown.
This investigation confirmed that a higher degree of oxi-
dation on the benzylic position of phenolic lignans bearing
a 4-hydroxy-3-methoxyphenyl group decreased antioxidant
activity. Accordingly, the relationship between the func-
tionality at the benzylic position and the antioxidant activ-
ity of phenolic lignans bearing a 4-hydroxy-3-methoxyphen-
yl group has been clarified for the first time. This is also
the first report showing differences of radical scavenging
activity between diastereomers. The radical scavenging
activity is affected by the stereochemistry of the lignans.
(mp 159-160 °C; [R]20 +45° (c 1.2, CHCl3)). erythro isomer
D
12: 1H NMR (CDCl3, 400 MHz) δ 1.74 (1H, ddd, J ) 12.8, 9.8,
3.4 Hz, HH-3), 2.39 (1H, ddd, J ) 12.8, 8.8, 8.8 Hz, HH-3),
2.80 (1H, d, J ) 4.9 Hz, OH), 3.04 (1H, dd, J ) 10.8, 3.7 Hz,
HH-5), 3.18 (1H, m, H-2), 3.42 (1H, dd, J ) 10.8, 2.9 Hz,
HH-5), 3.82 (3H, s, OCH3), 4.59 (1H, m, H-4), 5.12 (2H, s,
OCH2Ph), 5.31 (1H, dd, J ) 4.9, 2.9 Hz, ArCHOH), 6.79 (1H,
dd, J ) 8.3, 2.0 Hz, ArH), 6.84 (1H, d, J ) 8.3 Hz, ArH), 6.88
(1H, d, J ) 2.0 Hz, ArH), 7.18-7.29 (12H, m, ArH), 7.32-
7.37 (6H, m, ArH), 7.41-7.43 (2H, m, ArH); 13C NMR (CDCl3,
100 MHz) δ 23.7, 48.2, 55.9, 65.3, 70.97, 71.0, 77.9, 87.0, 109.1,
113.9, 117.3, 127.1, 127.2, 127.8, 127.9, 128.48, 128.52, 134.9,
137.0, 143.3, 147.4, 149.7, 178.2; anal. C 77.72%, H 6.12%,
calcd for C39H36O6, C 77.98%, H 6.04%. threo isomer 13: 1H
NMR (CDCl3, 400 MHz) δ 1.73 (1H, ddd, J ) 13.2, 10.0, 2.4
Hz, HH-3), 1.90 (1H, ddd, J ) 13.2, 9.3, 9.3 Hz, HH-3), 3.02
(1H, dd, J ) 10.7, 3.4 Hz, HH-5), 3.25 (1H, m, H-2), 3.46 (1H,
dd, J ) 10.7, 2.9 Hz, HH-5), 3.79 (3H, s, OCH3), 4.32 (1H, s,
OH), 4.46 (1H, m, H-4), 4.68 (1H, d, J ) 8.8 Hz, ArCHOH),
5.14 (2H, s, OCH2Ph), 6.76 (1H, dd, J ) 8.3, 2.0 Hz, ArH),
6.83 (1H, d, J ) 8.3 Hz, ArH), 6.91 (1H, d, J ) 2.0 Hz, ArH),
7.20-7.30 (12H, m, ArH), 7.33-7.38 (6H, m, ArH),7.41-7.46
(2H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 27.6, 46.4, 55.9,
65.1, 71.0, 74.7, 77.5, 87.2, 109.8, 113.7, 119.0, 127.22, 127.24,
127.8, 127.9, 128.5, 128.6, 133.5, 137.0, 143.2, 148.1, 149.9,
179.4; anal. C 77.58%, H 6.04%, calcd for C39H36O6, C 77.98%,
H 6.04%.
Experimental Section
(2S,4S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triiso-
propylsilyloxy)methyl]-5-trityloxy-4-pentanolide (14). To
an ice-cooled solution of the erythro aldol product 12 (8.62 g,
14.3 mmol) and 2,6-lutidine (3.66 mL, 31.4 mmol) in
CH2Cl2 (80 mL) was added TIPSOTf (4.23 mL, 15.7 mmol).
The resulting reaction solution was stirred at room tem-
perature for 30 min before addition of saturated aqueous
NaHCO3 solution. The organic solution was separated, washed
with saturated aqueous CuSO4 solution, saturated aqueous
NaHCO3 solution, and brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography (EtOAc/
hexane, 1:9) gave the silyl ether 14 (9.25 g, 12.2 mmol, 85%)
as a colorless oil: [R]20D -12° (c 1.4, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 0.99-1.09 (21H, m, i-Pr), 1.74 (1H, ddd, J ) 12.2,
General Experimental Procedures. Melting points are
uncorrected. Optical rotation values were measured on a
Horiba SEPA-200 instrument. NMR data were obtained using
a JNM-EX400 spectrometer. FABMS data were measured with
a JMS-MS700V spectrometer. The silica gel used was Wakogel
C-300 (Wako, 200-300 mesh). The numbering of compounds
follows IUPAC nomenclatural rules.
(2R,4S)-2-(4-Benzyloxy-3-methoxybenzyl)-5-trityloxy-
4-pentanolide (11). To a solution of LDA (0.013 mol) in THF
(150 mL) was added a solution of the butyrolactone 10 (9.50
g, 0.027 mol) in THF (50 mL). After stirring at -70 °C for 30
min, a solution of 4-benzyloxy-3-methoxybenzyl bromide (8.10
g, 0.026 mol) in THF (50 mL) was added, and then the

Antioxidant Activity of Phenolic Lignans
Journal of Natural Products, 2005, Vol. 68, No. 10 1463
9.8, 3.4 Hz, HH-3), 2.65 (1H, ddd, J ) 12.2, 8.3, 8.3 Hz,
HH-3), 2.94 (1H, dd, J ) 9.8, 8.3 Hz, H-2), 3.05 (1H, dd, J )
10.3, 3.9 Hz, HH-5), 3.40 (1H, dd, J ) 10.3, 2.9 Hz, HH-5),
3.84 (3H, s, OCH3), 4.65 (1H, m, H-4), 5.14 (2H, s, OCH2Ph),
5.47 (1H, s, ArCHOSi), 6.79 (1H, d, J ) 8.3 Hz, ArH), 6.84
(1H, d, J ) 6.8 Hz, ArH), 6.89 (1H, s, ArH), 7.17-7.26 (12H,
m, ArH), 7.29-7.37 (7H, m, ArH), 7.43-7.45 (1H, m, ArH);
13C NMR (CDCl3, 100 MHz) δ 12.6, 17.9, 18.0, 23.0, 50.0, 55.9,
65.5, 71.1, 72.7, 77.7, 86.9, 109.3, 113.8, 117.6, 127.1, 127.3,
127.8, 128.5, 128.6, 136.8, 137.1, 143.4, 147.3, 149.5, 177.8;
anal. C 76.02%, H 7.49%, calcd for C48H56O6Si, C 76.15%, H
7.46%.
3.50 (3H, m, CH2OH), 3.67-3.78 (3H, m, CH2OH, H-2), 3.86
(3H, s, OCH3), 4.85 (1H, d, J ) 4.9 Hz, ArCHOSi), 5.11 (2H, s,
OCH2Ph), 6.73 (1H, d, J ) 8.3 Hz, ArH), 6.81 (1H, d, J ) 8.3
Hz, ArH), 6.95 (1H, s, ArH), 7.27-7.37 (3H, m, ArH), 7.41-
7.43 (2H, m, ArH); 13C NMR (CDCl3, 400 MHz) δ 12.2, 17.9,
18.0, 31.7, 44.2, 55.9, 63.2, 66.9, 69.9, 71.1, 77.9, 110.7, 113.4,
119.4, 127.3, 127.8, 128.4, 135.0, 137.0, 147.36, 147.41, 149.3;
anal. C 67.45%, H 8.93%, calcd for C29H46O6Si, C 67.14%, H
8.94.
(2S,4R)-4-[(R)-(4-Benzyloxy-3-methoxyphenyl)(triiso-
propylsilyloxy)methyl]-1,2,5-pentanetriol (18): colorless
oil; 46% yield; [R]20D +36° (c 1.2, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 0.94-1.04 (21H, m, i-Pr), 1.35 (1H, ddd, J ) 14.7, 7.8,
2.9 Hz, HH-3), 1.47 (1H, ddd, J ) 14.7, 9.3, 4.9 Hz, HH-3),
2.10 (1H, m, H-4), 2.18 (1H, brs, OH), 2.87 (1H, brs, OH), 3.21
(1H, brs, OH), 3.38 (1H, dd, J ) 10.7, 7.8 Hz, CHHOH), 3.48
(1H, dd, J ) 10.7, 4.3 Hz, CHHOH), 3.61 (1H, dd, J ) 9.5, 4.9
Hz, CHHOH), 3.65 (1H, dd, J ) 9.5, 4.9 Hz, CHHOH), 3.75
(1H, m, H-2), 3.86 (3H, s, OCH3), 4.88 (1H, d, J ) 5.4 Hz,
ArCHOSi), 5.11 (2H, s, OCH2O), 6.74 (1H, dd, J ) 8.3, 2.0 Hz,
ArH), 6.81 (1H, d, J ) 8.3 Hz, ArH), 6.94 (1H, d, J ) 2.0 Hz,
ArH), 7.26-7.37 (3H, m, ArH), 7.41-7.43 (2H, m, ArH); 13C
NMR (CDCl3, 100 MHz) δ 12.3, 17.9, 18.0, 31.3, 45.3, 55.9,
63.1, 66.9, 70.2, 71.1, 77.4, 110.8, 113.4, 119.3, 127.3, 127.8,
128.4, 135.6, 137.0, 147.4, 149.3; anal. C, 66.73%, H 9.07%,
calcd for C29H46O6Si, C 67.14%, H 8.94%.
(2S,4S)-2-[(R)-(4-Benzyloxy-3-methoxyphenyl)(triiso-
propylsilyloxy)methyl]-5-trityloxy-4-pentanolide (15): col-
orless oil; 83% yield; [R]20 +26° (c 1.6, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 0.99-1.03 (18H, m, i-Pr), 1.04-1.17 (3H,
m, i-Pr), 2.05 (1H, m, HH-3), 2.20 (1H, m, HH-3), 2.91 (1H,
dd, J ) 10.5, 3.7 Hz, HH-5), 3.32 (1H, dd, J ) 10.5, 3.2 Hz,
HH-5), 3.43 (1H, m, H-2), 3.85 (3H, s, OCH3), 3.80-3.88 (1H,
m, H-4), 5.11 (2H, s, OCH2Ph), 5.44 (1H, d, J ) 4.4 Hz,
ArCHOSi), 6.83 (1H, d, J ) 8.3 Hz, ArH), 6.87 (1H, d, J ) 8.3
Hz, ArH), 6.99 (1H, s, ArH), 7.20-7.34 (12H, m, ArH), 7.38-
7.42 (8H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.1, 17.9,
18.0, 24.4, 49.6, 55.8, 65.1, 71.0, 72.8, 77.8, 86.9, 110.3, 113.6,
118.7, 127.1, 127.4, 127.8, 127.9, 128.4, 128.6, 133.4, 137.0,
143.4, 147.5, 149.2, 176.9; anal. C 76.05%, H 7.63%, calcd for
C48H56O6Si, C 76.15%, H 7.46%.
(3R)-3-(4-Benzyloxy-3-methoxybenzyl)-4-butanolide
(19). A reaction mixture of the triol 16 (1.10 g, 3.18 mmol)
and NaIO4 (0.76 g, 3.55 mmol) in MeOH (40 mL) was stirred
at room temperature for 3 h. After concentration, the residue
was dissolved in H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentra-
tion gave a crude hemiacetal. A reaction mixture of this
hemiacetal and PCC (0.75 g, 3.50 mmol) in CH2Cl2 (80 mL)
was stirred at room temperature for 16 h before filtration. The
filtrate was concentrated, and then the residue was subjected
to silica gel column chromatography (hexane/EtOAc, 1:1) to
give the butanolide 19 (0.89 g, 2.85 mmol, 90%) as colorless
crystals: mp 73 °C (EtOH); [R]20D -16° (c 0.4, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 2.27 (1H, dd, J ) 17.6, 6.8 Hz, H-2), 2.59
(1H, dd, J ) 17.6, 7.8 Hz, H-2), 2.67 (1H, dd, J ) 13.7, 8.3
Hz, CHHAr-3), 2.72 (1H, dd, J ) 13.7, 7.1 Hz, CHHAr-3),
2.80 (1H, m, H-3), 3.87 (3H, s, OCH3), 4.02 (1H, dd, J ) 9.0,
6.1 Hz, H-4), 4.32 (1H, dd, J ) 9.0, 7.1 Hz, H-4), 5.12 (2H, s,
OCH2Ph), 6.62 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 6.67 (1H, d, J
) 2.0 Hz, ArH), 6.82 (1H, d, J ) 8.3 Hz, ArH), 7.25-7.38 (3H,
m, ArH), 7.42-7.44 (2H, m, ArH); 13C NMR (CDCl3, 100 MHz)
δ 34.2, 37.2, 38.6, 56.0, 71.1, 72.6, 112.4, 114.4, 120.6, 127.2,
127.8, 128.5, 131.4, 137.1, 147.1, 149.8, 176.8; anal. C 73.20%,
H 6.56%, calcd for C19H20O4, C 73.06%, H 6.45%.
(2S,4R)-4-(4-Benzyloxy-3-methoxybenzyl)-1,2,5-pen-
tanetriol (16). To an ice-cooled suspension of LiAlH4 (0.20 g,
5.27 mmol) in THF (20 mL) was added a solution of the
benzylbutyrolactone 11 (3.10 g, 5.30 mmol) in THF (40 mL).
After the reaction mixture was stirred at room temperature
for 1 h, saturated aqueous MgSO4 solution and K2CO3 were
added. The resulting mixture was stirred at room temperature
for 30 min and then filtered. After the filtrate was concen-
trated, the residue was dissolved in EtOH (150 mL). To this
solution was added concentrated HCl (1.5 mL), and then the
reaction solution was stirred at room temperature for 1.5 h
before addition of saturated aqueous NaHCO3 solution. After
concentration, the residue was dissolved in EtOAc and H2O.
The organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration, the residue was subjected
to silica gel column chromatography (hexane/EtOAc, 1:1) to
give the triol 16 (1.41 g, 4.08 mmol, 77%) as a colorless oil:
[R]20D -17° (c 0.4, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.42-
1.57 (2H, m, H-3), 2.05 (1H, brs, OH), 2.48 (1H, dd, J ) 13.7,
7.3 Hz, ArCHH-4), 2.60 (1H, dd, J ) 13.7, 7.8 Hz, ArCHH-4),
2.70-3.45 (2H, br, OH), 3.40 (1H, dd, J ) 10.7, 7.8 Hz,
CHHOH), 3.48-3.52 (2H, m, CH2OH), 3.62 (1H, dd, J ) 10.7,
3.4 Hz, CHHOH), 3.80-3.86 (1H, m, H-2), 3.84 (3H, s, OCH3),
5.09 (2H, s, OCH2Ph), 6.62 (1H, d, J ) 8.4 Hz, ArH), 6.71 (1H,
s, ArH), 6.78 (1H, d, J ) 8.4 Hz, ArH), 7.26-7.36 (3H, m, ArH),
7.41-7.43 (2H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 35.2,
37.4, 38.9, 56.1, 65.1, 66.9, 69.3, 71.2, 113.0, 114.3, 121.1, 127.3,
127.8, 128.5, 133.4, 137.3, 146.6, 149.6; HREIMS m/z 346.1778
(calcd for C20H26O5, 346.1767).
(2S,4R)-4-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triiso-
propylsilyloxy)methyl]-1,2,5-pentanetriol (17). To an ice-
cooled suspension of LiAlH4 (0.46 g, 12.2 mmol) in THF (20
mL) was added a solution of the lactone 14 (9.25 g, 12.2 mmol).
The resulting reaction mixture was stirred at room tempera-
ture for 30 min before additions of saturated aqueous MgSO4
and K2CO3. After the mixture was filtered, the filtrate was
concentrated to give a crude diol. To a solution of this crude
diol in ether (500 mL) was added HCO2H (500 mL) at -10 °C.
After the mixture was stirred at -10 °C for 10 min, EtOAc
and H2O were added. The organic solution was separated,
washed with saturated aqueous NaHCO3 solution and brine,
and dried (Na2SO4). Concentration, followed by silica gel
column chromatography (EtOAc/hexane, 1:6 and 1:1), gave the
triol 17 (2.79 g, 5.38 mmol, 44%) as a 4:1 mixture with the
benzylic epimer 18. The production of some unknown products
was observed. 1H NMR (CDCl3, 400 MHz) δ 0.95-1.05
(21H, m, i-Pr), 1.15 (1H, m, HH-3), 1.51 (1H, m, HH-3), 2.27
(1H, m, H-4), 3.03 (1H, br s, OH), 3.09 (1H, br s, OH), 3.40-
(3R)-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triisopropyl-
silyloxy)methyl]-4- butanolide (20): colorless oil; 77% yield
1
(4:1 mixture with benzylic epimer 21); H NMR (CDCl3, 400
MHz) δ 0.94-1.02 (21H, m, i-Pr), 2.53 (1H, dd, J ) 17.6, 8.8
Hz, HH-2), 2.65 (1H, dd, J ) 17.6, 8.8 Hz, HH-2), 2.85 (1H,
m, H-3), 3.87 (3H, s, OCH3), 4.08 (1H, dd, J ) 9.3, 7.1 Hz,
HH-4), 4.14 (1H, dd, J ) 9.3, 7.3 Hz, HH-4), 4.70 (1H, d, J )
6.4 Hz, ArCHOSi), 5.13 (2H, s, OCH2Ar), 6.71 (1H, dd, J )
7.8, 2.0 Hz, ArH), 6.83 (1H, d, J ) 7.8 Hz, ArH), 6.89 (1H, d,
J ) 2.0 Hz, ArH), 7.29-7.37 (3H, m, ArH), 7.41-7.43 (2H, m,
ArH); 13C NMR (CDCl3, 100 MHz) δ 12.4, 17.86, 17.93, 30.9,
44.5, 55.9, 69.6, 71.0, 75.4, 109.8, 113.7, 118.7, 127.3, 127.8,
128.4, 135.1, 136.9, 147.9, 149.8, 176.8; anal. C 69.55%, H
8.29%, calcd for C28H40O5Si, C 69.38%, H 8.32%.
(3R)-[(R)-(4-Benzyloxy-3-methoxyphenyl)(triisopro-
pylsilyloxy)methyl]-4- butanolide (21): colorless oil; 82%
yield; [R]20D +44° (c 1.4, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
0.94-0.99 (21H, m, i-Pr), 2.31 (2H, d, J ) 8.3 Hz, H2-2), 2.84
(1H, m, H-3), 3.87 (3H, s, OCH3), 4.33 (1H, dd, J ) 9.3, 7.2
Hz, HH-4), 4.39 (1H, dd, J ) 9.3, 6.8 Hz, HH-4), 4.65 (1H, d,
J ) 7.3 Hz, ArCHOSi), 5.13 (2H, s, OCH2Ph), 6.71 (1H, dd, J
) 8.3, 2.0 Hz, ArH), 6.82 (1H, d, J ) 8.3 Hz, ArH), 6.87 (1H,
d, J ) 2.0 Hz, ArH), 7.26-7.37 (3H, m, ArH), 7.41-7.43 (2H,
m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.4, 17.9, 18.0, 31.2,
44.6, 55.9, 70.2, 71.0, 75.8, 109.8, 113.7, 118.8, 127.3, 127.8,

1464 Journal of Natural Products, 2005, Vol. 68, No. 10
Yamauchi et al.
128.4, 135.4, 136.9, 147.9, 149.8, 176.6; anal. C 69.23%, H
8.45%, calcd for C28H40O5Si, C 69.38%, H 8.32%.
(2S,3R)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(hy-
droxy)methyl]-3-[(R)-(4-benzyloxy-3-methoxyphenyl)-
(triisopropylsilyloxy)methyl]-4-butanolide (25): colorless
oil; 81% yield; [R]20D +11° (c 1.9, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 0.86-0.91 (21H, m, i-Pr), 2.65 (1H, m, H-2), 2.71 (1H,
m, H-3), 2.92 (1H, d, J ) 4.4 Hz, OH), 3.71 (3H, s, OCH3),
3.78 (3H, s, OCH3), 4.23 (1H, d, J ) 6.4 Hz, ArCHOSi), 4.28
(1H, dd, J ) 8.8, 8.3 Hz, HH-4), 4.59 (1H, dd, J ) 8.8, 4.4 Hz,
HH-4), 5.05-5.15 (5H, m, OCH2Ph, ArCHOH), 6.36 (1H, d, J
) 8.3 Hz, ArH), 6.47 (1H, s, ArH), 6.59 (1H, d, J ) 8.3 Hz,
ArH), 6.64 (1H, d, J ) 8.3 Hz, ArH), 6.70 (1H, s, ArH), 6.73
(1H, d, J ) 7.8 Hz, ArH), 7.27-7.33 (6H, m, ArH), 7.40-7.42
(4H, m, ArH). By hydrogenolysis to the corresponding diphenol
lactone, the J value of ArCHOH appeared as 3.6, 3.6 Hz. 13C
NMR (CDCl3, 100 MHz) δ 12.4, 17.8, 17.9, 43.9, 50.5, 55.5,
55.7, 69.2, 70.77, 70.81, 72.3, 75.5, 108.8, 109.5, 113.1, 113.3,
117.3, 118.6, 127.2, 127.4, 127.8, 128.41, 128.44, 133.8, 134.9,
136.9, 137.0, 147.4, 147.6, 149.3, 149.5, 178.7; anal. C 71.02%,
H 7.52%, calcd for C43H54O8Si, C 71.04%, H 7.49%.
(2S,3R)-3-(4-Benzyloxy-3-methoxybenzyl)-2-[(S)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide (26). To an ice-cooled solution of the erythro-
aldol product 22 (0.26 g, 0.47 mmol) and 2,6-lutidine (0.11 mL,
0.94 mmol) in CH2Cl2 (40 mL) was added TIPSOTf (0.19
mL, 0.71 mmol). The resulting reaction solution was stirred
at 0 °C for 1.5 h before addition of saturated aqueous
NaHCO3 solution. The organic solution was separated, washed
with saturated aqueous CuSO4 solution, saturated aqueous
NaHCO3 solution, and brine, and dried (Na2SO4). After
concentration, the residue was applied to silica gel column
chromatography (EtOAc/hexane, 1:3) to give the silyl ether 26
(0.29 g, 0.41 mmol, 87%) as a colorless oil: [R]20D -37° (c 0.8,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.98-1.09 (21H, m, i-Pr),
2.24 (1H, dd, J ) 13.7, 7.3 Hz, CHHAr-3), 2.42 (1H, dd, J )
13.7, 8.3 Hz, CHHAr-3), 2.46 (1H, d, J ) 5.4 Hz, H-2), 2.99
(1H, m, H-3), 3.76 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.97 (1H,
dd, J ) 8.6, 4.9 Hz, H-4), 4.36 (1H, dd, J ) 8.6, 8.6 Hz, H-4),
5.06 (1H, d, J ) 12.2 Hz, OCHHPh), 5.09 (1H, d, J ) 12.2 Hz,
OCHHPh), 5.10 (1H, d, J ) 12.2 Hz, OCHHPh), 5.14 (1H, d,
J ) 12.2 Hz, OCHHPh), 5.47 (1H, s, ArCHOTIPS), 6.25 (1H,
d, J ) 8.3 Hz, ArH), 6.33 (1H, s, ArH), 6.64 (1H, s, ArH), 6.74
(1H, d, J ) 8.3 Hz, ArH), 6.78 (1H, d, J ) 8.8 Hz, ArH), 6.83
(1H, s, ArH), 7.25-7.35 (6H, m, ArH), 7.39-7.42 (4H, m, ArH);
13C NMR (CDCl3, 100 MHz) δ 12.6, 18.0, 35.8, 39.6, 54.5, 55.8,
71.0, 71.1, 72.6, 73.7, 109.2, 112.4, 113.7, 114.0, 117.5, 120.5,
127.3, 127.4, 127.7, 127.8, 128.5, 131.1, 135.6, 137.0, 137.2,
146.8, 147.4, 149.5, 177.9; anal. C, 72.62%, H 7.64%, calcd for
C43H54O7Si, C 72.64%, H 7.66%.
(2S,3R)-3-(4-Benzyloxy-3-methoxybenzyl)-2-[(S)-(4-ben-
zyloxy-3-methoxyphenyl)(hydroxy)methyl]-4-butano-
lide (22). To a solution of KHMDS (3.07 mL, 0.5 M in tol-
uene, 1.54 mmol) in THF (10 mL) was added a solution of
the butanolide 19 (0.40 g, 1.28 mmol) in THF (10 mL) at -70
°C. After stirring at -70 °C for 15 min, a solution of 4-ben-
zyloxy-3-methoxybenzaldehyde (0.31 g, 1.28 mmol) in THF
(5 mL) was added. The reaction solution was stirred at
-70 °C for 2 h before addition of saturated aqueous NH4Cl
solution. The organic solution was separated, washed with
brine, and dried (Na2SO4). After concentration, the residue
was purified by silica gel column chromatography (hexane/
EtOAc, 1:1) to give the erythro-aldol product 22 (0.62 g, 1.12
1
mmol, 88%) as a colorless oil: [R]20 -34° (c 1.1, CHCl3); H
D
NMR (CDCl3, 400 MHz) δ 2.24 (1H, dd, J ) 13.7, 6.8 Hz,
ArCHH), 2.39 (1H, dd, J ) 13.7, 8.3 Hz, ArCHH), 2.63 (1H,
dd, J ) 6.6, 3.2 Hz, H-2), 2.77 (1H, m, H-3), 2.85 (1H, d, J )
4.9 Hz, OH), 3.76 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.92 (1H,
dd, J ) 8.8, 5.9 Hz, H-4), 4.28 (1H, dd, J ) 8.8, 8.8 Hz, H-4),
5.05-5.15 (4H, m, OCH2Ar), 5.25 (1H, dd, J ) 4.9, 3.4 Hz,
ArCHOH), 6.30 (1H, dd, J ) 7.8, 2.0 Hz, ArH), 6.35 (1H, d, J
) 2.0 Hz, ArH), 6.66 (1H, d, J ) 7.8 Hz, ArH), 6.71 (1H, dd, J
) 8.3, 1.5 Hz, ArH), 6.79 (1H, d, J ) 8.3 Hz, ArH), 6.81 (1H,
d, J ) 1.5 Hz, ArH), 7.24-7.35 (6H, m, ArH), 7.39-7.41 (4H,
m, ArH); 13C NMR (CDCl3, 100 MHz) δ 36.4, 39.1, 52.7, 55.8,
55.9, 70.9, 71.6, 72.6, 108.9, 112.3, 113.8, 113.9, 117.3, 120.4,
127.2, 127.8, 128.5, 130.9, 134.0, 136.9, 137.1, 146.8, 147.5,
149.5, 149.7, 178.3; anal. C 73.45%, H 6.33%, calcd for
C34H34O7, C 73.63%, H 6.18%.
(2S,3R)-3-(4-Benzyloxy-3-methoxybenzyl)-2-[(R)-(4-ben-
zyloxy-3-methoxyphenyl)(hydroxy)methyl]-4-butano-
lide (23). To a solution of LDA (13.2 mmol) in THF (60 mL)
was added a solution of the butanolide 19 (3.43 g, 11.0 mmol)
in THF (20 mL) at -70 °C. After the mixture was stirred at
-70 °C for 30 min, a solution of 4-benzyloxy-3-methoxyben-
zaldehyde (2.93 g, 12.1 mmol) in THF (40 mL) was added. The
reaction solution was stirred at -70 °C for 1 h before addition
of saturated aqueous NH4Cl solution. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentra-
tion and silica gel column chromatography (hexane/EtOAc, 2:1)
gave the erythro-aldol product 22 (2.55 g, 4.60 mmol, 42%) and
the threo-aldol product 23 (2.50 g, 4.51 mmol, 41%) as colorless
crystals: mp 128 °C (EtOH); [R]20 -47° (c 0.7, CHCl3); 1H
D
NMR (CDCl3, 400 MHz) δ 2.06 (1H, dd, J ) 13.9, 4.9 Hz,
CHHAr-3), 2.15 (1H, dd, J ) 13.9, 9.5 Hz, CHHAr-3), 2.45 (1H,
m, H-3), 2.58 (1H, dd, J ) 9.3, 8.3 Hz, H-2), 3.79 (3H, s, OCH3),
3.89 (3H, s, OCH3), 4.09 (1H, d, J ) 8.3 Hz, H-4), 4.11 (1H, d,
J ) 8.3 Hz, H-4), 4.79 (1H, d, J ) 8.3 Hz, ArCHOH), 5.10-
5.15 (4H, m, OCH2Ph), 6.32 (1H, dd, J ) 7.8, 2.0 Hz, ArH),
6.35 (1H, d, J ) 2.0 Hz, ArH), 6.70 (1H, d, J ) 7.8 Hz, ArH),
6.86 (2H, s, ArH), 6.99 (1H, s, ArH), 7.22-7.31 (6H, m, ArH),
7.33-7.42 (4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 38.0,
39.8, 51.5, 55.9, 56.1, 71.0, 72.0, 74.4, 82.1, 110.0, 112.3, 113.9,
114.2, 119.0, 120.3, 127.2, 127.8, 128.5, 130.9, 133.2, 136.8,
137.1, 146.9, 148.3, 149.6, 150.2, 179.0; HREIMS m/z 554.2300
(calcd for C34H34O7, 554.2304).
(2S,3R)-3-(4-Benzyloxy-3-methoxybenzyl)-2-[(R)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide (27): colorless oil; 65% yield; [R]20D -50° (c 0.1,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.00-1.05 [18H, m,
(CH3)2CH], 1.05-1.15 [3H, m, (CH3)2CH], 2.51 (1H, dd, J )
13.2, 10.3 Hz, ArCHH), 2.60 (1H, m, H-3), 2.88 (1H, dd, J )
7.1, 3.7 Hz, H-2), 3.12 (1H, dd, J ) 13.2, 4.4 Hz, ArCHH), 3.44
(1H, dd, J ) 9.1, 7.3 Hz, HH-4), 3.71 (1H, dd, J ) 9.1, 6.3 Hz,
HH-4), 3.836 (3H, s, OCH3), 3.845 (3H, s, OCH3), 5.11 (4H, s,
OCH2Ph), 5.45 (1H, d, J ) 3.4 Hz, ArCHOTIPS), 6.56 (1H, d,
J ) 8.3 Hz, ArH), 6.60 (1H, s, ArH), 6.77 (1H, d, J ) 8.2 Hz,
ArH), 6.84 (1H, d, J ) 8.3 Hz, ArH), 6.89 (1H, d, J ) 8.3 Hz,
ArH), 6.99 (1H, s, ArH), 7.27-7.37 (6H, m, ArH), 7.41-7.43
(4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.1, 17.98, 18.05,
38.0, 39.5, 54.8, 55.91, 55.94, 71.1, 71.2, 71.6, 73.2, 110.0, 112.4,
113.8, 114.4, 118.4, 120.5, 127.2, 127.4, 127.8, 127.9, 128.48,
128.52, 128.6, 131.8, 133.9, 137.0, 137.2, 147.0, 147.7, 149.4,
149.8, 176.6; HRFABMS m/z 733.3529 (calcd for C43H54O7SiNa,
733.3536).
(2S,3R)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(hy-
droxy)methyl]-3-[(S)-(4-benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]-4-butanolide (24): colorless
oil: 79% yield; [R]20 +19° (c 1.3, CHCl3); 1H NMR (CDCl3,
D
400 MHz) δ 0.86-0.98 (21H, m, i-Pr), 2.79 (1H, m, H-2), 2.90
(2H, m, H-3, OH), 3.76 (3H, s, OCH3), 3.82 (3H, s, OCH3),
4.31-4.33 (2H, m, H2-4), 4.59 (1H, d, J ) 4.4 Hz, ArCHOSi),
5.05-5.14 (4H, m, OCH2Ph), 5.17 (1H, dd, J ) 3.7, 3.7 Hz,
ArCHOH), 6.35 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 6.61 (1H, d, J
) 2.0 Hz, ArH), 6.65-6.67 (2H, m, ArH), 6.74-6.77 (2H, m,
ArH), 7.25-7.37 (6H, m, ArH), 7.39-7.40 (4H, m, ArH); 13C
NMR (CDCl3, 100 MHz) δ 12.4, 17.85, 17.9, 43.1, 49.0, 55.79,
55.8, 69.5, 70.9, 71.0, 72.5, 75.2, 109.2, 110.0, 113.2, 113.7,
117.6, 118.8, 127.17, 127.21, 127.3, 127.4, 127.78, 127.84,
128.4, 128.47, 128.51, 133.8, 134.2, 136.98, 137.05, 147.61,
147.65, 149.3, 149.6, 178.6; anal. C 70.75%, H 7.56%, calcd
for C43H54O8Si, C 71.04%, H 7.49%.
(2S,3R)-2,3-Bis[(S)-(4-benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]-4-butanolide (28): colorless
oil: 84% yield; [R]20 +11° (c 1.5, CHCl3); 1H NMR (CDCl3,
D
400 MHz) δ 0.84-1.06 (42H, m, i-Pr), 2.57 (1H, dd, J ) 4.9,
2.0 Hz, H-2), 3.18 (1H, m, H-3), 3.72 (3H, s, OCH3), 3.82 (3H,
s, OCH3), 4.40 (1H, dd, J ) 8.8, 4.9 Hz, HH-4), 4.46 (1H, dd,

Antioxidant Activity of Phenolic Lignans
Journal of Natural Products, 2005, Vol. 68, No. 10 1465
J ) 8.8, 8.8 Hz, HH-4), 4.56 (1H, d, J ) 4.4 Hz, ArCHOSi-3),
5.04 (1H, d, J ) 11.7 Hz, PhCHHO), 5.08 (1H, d, J ) 11.7 Hz,
PhCHHO), 5.09 (1H, d, J ) 12.2 Hz, PhCHHO), 5.13 (1H, d,
J ) 12.2 Hz, PhCHHO), 5.44 (1H, d, J ) 2.0 Hz, ArCHOSi),
6.12 (1H, d, J ) 8.3 Hz, ArH), 6.47 (1H, s, ArH), 6.58 (1H, d,
J ) 8.3 Hz, ArH), 6.63-6.77 (3H, m, ArH), 7.26-7.35 (6H, m,
ArH), 7.39-7.40 (4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ
12.4, 12.6, 17.88, 17.90, 18.0, 42.0, 50.8, 55.71, 55.75, 69.4, 70.9,
71.0, 73.8, 75.3, 109.2, 110.1, 113.1, 113.6, 117.6, 118.9, 127.26,
127.34, 127.7, 127.8, 128.41, 128.44, 133.6, 135.7, 137.1, 147.4,
147.5, 149.2, 149.4, 178.2; anal. C 70.91%, H 8.48%, calcd for
C52H74O8Si2, C 70.71%, H 8.44%.
149.5, 149.6; HRFABMS m/z 737.3868 (calcd for C43H58O7SiNa,
737.3849).
(2R,3R)-2,3-Bis[(S)-(4-Benzyloxy-3-methoxyphenyl)-
(triisopropylsilyloxy)methyl]-1,4-butanediol (32). To a
solution of the lactone 28 (1.50 g, 1.70 mmol) in CH2Cl2 (30
mL) was added DIBAL-H (2.04 mL, 1 M in toluene, 2.04 mmol)
at -70 °C. The reaction solution was stirred at -70 °C for 30
min before addition of 6 M aqueous HCl solution. The organic
solution was separated, washed with saturated aqueous
NaHCO3 solution and brine, and dried (Na2SO4). Concentra-
tion gave a crude hemiacetal. To a solution of LiBH4 (0.17 g,
7.80 mmol) in THF (10 mL) was added a solution of this
hemiacetal in THF (10 mL) at 0 °C. After the reaction solution
was stirred at room temperature for 20 h, saturated aqueous
NH4Cl solution was added. The mixture was concentrated, and
then the residue was dissolved in EtOAc and H2O. The or-
ganic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chro-
matography (EtOAc/hexane, 1:6 and 1:4) gave the diol 32 (0.87
g, 0.98 mmol, 58%) as a colorless oil: [R]20D -49° (c 0.7, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.88-0.97 (42H, m, i-Pr), 2.35
(2H, m, H-2, H-3), 3.44 (2H, br s, OH), 3.47 (2H, dd, J ) 11.0,
6.8 Hz, CHHOH), 3.72 (2H, dd, J ) 11.0, 4.2 Hz, CHHOH),
3.79 (6H, s, OCH3), 4.92 (2H, d, J ) 5.4 Hz, ArCHOSi), 5.09
(2H, d, J ) 12.2 Hz, OCHHPh), 5.14 (2H, d, J ) 12.2 Hz,
OCHHPh), 6.56 (2H, d, J ) 8.3 Hz, ArH), 6.69 (2H, d, J ) 8.3
Hz, ArH), 6.74 (2H, s, ArH), 7.26-7.37 (6H, m, ArH), 7.43-
7.45 (4H, m, ArH); 13CNMR (CDCl3, 100 MHz) δ 12.5, 18.0,
46.2, 55.6, 60.4, 70.9, 76.3, 109.9, 113.1, 118.8, 127.4, 127.8,
128.4, 135.9, 137.2, 147.1, 149.2; anal. C, 70.54%; H, 8.92%,
calcd for C52H78O8Si2, C 70.39%, H 8.86%.
(2S,3R)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]-3-[(R)-(4-benzyloxy-3-meth-
oxyphenyl)(triisopropylsilyloxy)methyl]-4-butanolide
1
(29): colorless oil; 100% yield; [R]20 -2.7° (c 1.5, CHCl3); H
D
NMR (CDCl3, 400 MHz) δ 0.81-0.89 (21H, m, i-Pr), 0.96-1.06
(21H, m, i-Pr), 2.51 (1H, dd, J ) 3.4, 1.4 Hz, H-2), 2.83
(1H, m, H-3), 3.73 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.17
(1H, d, J ) 6.4 Hz, ArCHOSi), 4.28 (1H, dd, J ) 8.8, 8.3 Hz,
HH-4), 4.64 (1H, dd, J ) 8.8, 3.4 Hz, HH-4), 5.05-5.17 (4H,
m, OCH2Ph), 5.43 (1H, d, J ) 1.4 Hz, ArCHOSi), 6.33 (1H, d,
J ) 8.3 Hz, ArH), 6.47 (1H, s, ArH), 6.61-6.66 (2H, m, ArH),
6.73 (1H, s, ArH), 6.78 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 7.26-
7.35 (6H, m, ArH), 7.41-7.44 (4H, m, ArH); 13C NMR (CDCl3,
100 MHz) δ 12.5, 12.6, 17.87, 17.93, 18.0, 43.5, 52.5, 55.6, 55.7,
68.8, 70.8, 70.9, 74.0, 75.5, 109.1, 109.5, 113.1, 113.3, 117.5,
118.5, 127.4, 127.8, 128.42, 128.44, 135.07, 135.10, 137.0,
137.1, 147.4, 147.5, 149.3, 178.1; anal. C 70.80%, H 8.49%,
calcd for C52H74O8Si2, C 70.71%, H 8.44%.
(2R,3R)-2-(4-Benzyloxy-3-methoxybenzyl)-3-[(S)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
1,4-butanediol (30). To an ice-cooled suspension of LiAlH4
(15 mg, 0.40 mmol) in THF (5 mL) was added a solution of
the lactone 26 (0.28 g, 0.39 mmol) in THF (10 mL). After
stirring at room temperature for 30 min, saturated aqueous
MgSO4 solution and K2CO3 were added. The mixture was
stirred at room temperature for 30 min and then filtered. The
filtrate was concentrated. The residue was purified by silica
gel column chromatography (EtOAc/hexane, 2:3) to give the
diol 30 (0.20 g, 0.28 mmol, 72%) as a colorless oil: [R]20D -42°
(2R,3R)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]-3-[(R)-(4-benzyloxy-3-meth-
oxyphenyl)(triisopropylsilyloxy)methyl]-1,4-butane-
diol (33). To a solution of LiBH4 (1.11 g, 51.0 mmol) in THF
(15 mL) was added a solution of the lactone 29 (3.00 g, 3.40
mmol) in THF (15 mL) at 0 °C. After the reaction solution was
stirred at room temperature for 2 days, saturated aqueous
NH4Cl solution was added. The mixture was concentrated, and
then the residue was dissolved in EtOAc and H2O. The or-
ganic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chro-
matography (EtOAc/hexane, 1:6 and 1:4) gave the diol 33 (1.95
1
(c 0.7, CHCl3); H NMR (CDCl3, 400 MHz) δ 0.95-0.96 (21H,
m, i-Pr), 1.63 (1H, s, OH), 1.91 (1H, m), 2.25 (1H, m), 2.53
(1H, dd, J ) 13.7, 7.8 Hz, CHHAr-2), 2.77 (1H, dd, J ) 13.7,
8.3 Hz, CHHAr-2), 2.85-3.09 (1H, br, OH), 3.39 (1H, dd, J )
11.2, 5.4 Hz, CHHOH), 3.48 (1H, dd, J ) 11.0, 4.6 Hz,
CHHOH), 3.61 (1H dd, J ) 11.2, 2.9 Hz, CHHOH), 3.80 (3H,
s, OCH3), 3.82 (3H, s, OCH3), 3.85 (1H, dd, J ) 11.0, 5.4 Hz,
CHHOH), 5.01 (1H, d, J ) 6.4 Hz, ArCHOTIPS), 5.11 (2H, s,
OCH2Ph), 5.12 (2H, s, OCH2Ph), 6.55 (1H, dd, J ) 8.3, 2.0
Hz, ArH), 6.63 (1H, d, J ) 2.0 Hz, ArH), 6.71-6.79 (3H, m,
ArH), 6.86 (1H, s, ArH), 7.27-7.37 (6H, m, ArH), 7.42-7.44
(4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.5, 18.0, 36.6,
40.2, 50.3, 55.85, 55.93, 59.7, 61.2, 71.1, 71.2, 75.3, 110.7, 112.7,
113.5, 114.2, 119.3, 121.0, 127.3, 127.4, 127.7, 127.8, 128.5,
133.7, 136.2, 137.1, 137.4, 146.5, 147.4, 149.4, 149.6; anal. C,
72.13%; H, 8.19%, calcd for C43H58O7Si, C 72.23%, H 8.18%.
(2R,3R)-2-(4-Benzyloxy-3-methoxybenzyl)-3-[(R)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
g, 2.21 mmol, 65%) as a colorless oil: [R]20 +7.3° (c 0.8,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.87-0.90 (42H, m, i-Pr),
1.86 (1H, m, CHCH2OH), 2.19 (1H, m, CHCH2OH), 2.88 (1H,
s, OH), 2.95 (1H, s, OH), 3.41 (1H, dd, J ) 10.7, 4.4 Hz,
CHHOH), 3.46 (1H, dd, J ) 11.2, 5.4 Hz, CHHOH), 3.62 (1H,
dd, J ) 10.7, 5.9 Hz, CHHOH), 3.78 (1H, dd, J ) 11.2, 7.8 Hz,
CHHOH), 3.81 (6H, s, OCH3), 4.78 (1H, d, J ) 9.3 Hz,
ArCHOSi), 4.81 (1H, d, J ) 4.9 Hz, ArCHOSi), 5.07-5.15 (4H,
m, OCH2Ph), 6.62-6.67 (2H, m, ArH), 6.73-6.79 (4H, m, ArH),
7.29-7.37 (6H, m, ArH), 7.42-7.44 (4H, m, ArH); 13C NMR
(CDCl3, 100 MHz) δ 12.3, 12.6, 17.8, 17.9, 18.1, 46.8, 47.4, 55.8,
55.9, 60.3, 60.6, 70.96, 71.01, 77.1, 78.1, 110.6, 113.2, 119.1,
120.0, 127.3, 127.5, 127.8, 128.45, 128.47, 135.2, 136.6, 137.1,
147.4, 147.7, 149.2; anal. C 70.33%, H 8.95%, calcd for
C52H78O8Si2, C 70.39%, H 8.86%.
(3R,4R)-3-(4-Benzyloxy-3-methoxybenzyl)-4-[(S)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
tetrahydrofuran (34). To an ice-cooled solution of the diol
30 (0.37 g, 0.52 mmol) and pyridine (0.08 mL, 0.99 mmol) in
CH2Cl2 (20 mL) was added p-TsCl (0.10 g, 0.52 mmol). The
reaction solution was stirred at room temperature for 21 h
before addition of H2O. The organic solution was separated,
washed with 1 M aqueous HCl solution, saturated aqueous
NaHCO3 solution, and brine, and dried (Na2SO4). After
concentration, the residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:4) to give the tetrahydro-
furan derivative 34 (0.28 g, 0.40 mmol, 77%) as a colorless oil:
[R]20D -53° (c 0.6, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.90-
0.99 (21H, m, i-Pr), 2.32 (1H, m, H-4), 2.48 (1H, dd, J ) 12.7,
10.3 Hz, CHHAr-3), 2.55 (1H, m, H-3), 2.82 (1H, dd, J ) 12.7,
4.4 Hz, CHHAr-3), 3.48-3.54 (2H, m, HH-2, HH-5), 3.65 (1H,
dd, J ) 8.6, 6.8 Hz, HH-2), 3.71 (1H, dd, J ) 8.6, 7.8 Hz,
1,4-butanediol (31): colorless oil; 84% yield; [R]20 +39° (c
D
0.6, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.91-0.98 (21H, m,
i-Pr), 1.71 (1H, m, H-2 or H-3), 1.80 (1H, m, H-2 or H-3), 2.52
(1H, dd, J ) 14.1, 8.3 Hz, ArCHH), 2.65 (1H, dd, J ) 14.1, 7.1
Hz, ArCHH), 2.80 (1H, br s), 3.20 (1H, br s), 3.48 (1H, dd, J )
11.2, 5.4 Hz, HOCHH), 3.63 (1H, dd, J ) 11.2, 3.4 Hz,
HOCHH), 3.746 (3H, s, OCH3), 3.751 (3H, s, OCH3), 3.89 (1H,
dd, J ) 11.2, 4.4 Hz, HOCHH), 4.05 (1H, dd, J ) 11.2, 2.9 Hz,
HOCHH), 4.99 (1H, d, J ) 8.3 Hz, ArCHOTIPS), 5.10 (2H, s,
OCH2Ar), 5.12 (2H, s, OCH2Ar), 6.40 (1H, dd, J ) 8.1, 1.5 Hz,
ArH), 6.47 (1H, d, J ) 1.5 Hz, ArH), 6.63 (1H, dd, J ) 8.1, 1.5
Hz, ArH), 6.70-6.75 (3H, m, ArH), 7.28-7.37 (6H, m, ArH),
7.41-7.43 (4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.7,
17.9, 18.1, 36.5, 41.1, 49.7, 55.79, 55.81, 60.0, 62.4, 71.0, 71.1,
77.2, 110.5, 112.7, 113.4, 114.0, 119.8, 120.9, 127.2, 127.3,
127.7, 127.8, 128.5, 133.3, 136.7, 137.1, 137.4, 146.4, 147.5,

1466 Journal of Natural Products, 2005, Vol. 68, No. 10
Yamauchi et al.
HH-5), 3.86 (6H, s, OCH3), 4.62 (1H, d, J ) 7.3 Hz,
ArCHOTIPS), 5.12 (2H, s, OCH2Ph), 5.13 (2H, s, OCH2Ar),
6.62 (1H, d, J ) 7.3 Hz, ArH), 6.70-6.72 (2H, m, ArH), 6.78-
6.80 (2H, m, ArH), 6.97 (1H, s, ArH), 7.27-7.37 (6H, m, ArH),
7.41-7.44 (4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.6,
18.0, 18.1, 40.1, 43.3, 54.2, 55.9, 56.0, 69.7, 71.2, 73.0, 76.5,
110.8, 112.7, 113.6, 114.2, 119.4, 120.7, 127.3, 127.4, 127.7,
127.8, 128.5, 134.0, 136.8, 137.1, 137.4, 146.6, 147.6, 149.5,
149.6; HRFABMS m/z 719.3736 (calcd for C43H56O6SiNa,
719.3744).
s, OCH3), 4.52 (1H, d, J ) 7.8 Hz, ArCHOH), 5.11 (2H, s, OCH2-
Ph), 5.13 (2H, s, OCH2Ar), 6.59 (1H, d, J ) 8.3 Hz, ArH), 6.67
(1H, d, J ) 1.5 Hz, ArH), 6.71-6.87 (4H, m, ArH), 7.25-7.36
(6H, m, ArH), 7.41-7.45 (4H, m, ArH); 13C NMR (CDCl3, 100
MHz) δ 39.9, 43.5, 52.0, 55.9, 70.5, 71.0, 71.1, 73.5, 76.3, 109.9,
112.7, 113.8, 114.2, 118.5, 120.7, 127.2, 127.7, 127.8, 128.4,
128.5, 133.8, 136.3, 137.0, 137.3, 146.5, 147.7, 149.5, 149.7;
HRFABMS m/z 563.2413 (calcd for C34H36O6Na, 563.2409).
(3R,4R)-3-(4-Benzyloxy-3-methoxybenzyl)-4-[(R)-(4-
benzyloxy-3-methoxyphenyl)(hydroxy)methyl]tet-
rahydrofuran (39): colorless crystals; mp 128 °C (EtOH); 87%
yield; [R]20D -14° (c 0.7, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
2.03-2.12 (2H, m, H-4, OH), 2.18-2.23 (1H, m, H-3), 2.20 (1H,
dd, J ) 13.7, 6.3 Hz, ArCHH), 2.35 (1H, dd, J ) 13.7, 8.8 Hz,
ArCHH), 3.44 (1H, dd, J ) 8.8, 5.9 Hz, HH-2), 3.76 (3H, s,
OCH3), 3.80-3.84 (1H, m, HH-5), 3.82 (3H, s, OCH3), 3.92-
3.99 (2H, m, HH-2, HH-5), 4.35 (1H, dd, J ) 8.3, 2.5 Hz,
ArCHOH), 5.08 (2H, s, OCH2Ar), 5.11 (1H, d, J ) 12.3,
OCHHAr), 5.14 (1H, d, J ) 12.3 Hz, OCHHAr), 6.33 (1H, d, J
) 8.3 Hz, ArH), 6.37 (1H, s, ArH), 6.67-6.69 (2H, m, ArH),
6.79-6.80 (2H, m, ArH), 7.25-7.35 (6H, m, ArH), 7.40-7.41
(4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 39.3, 43.8, 52.0,
55.8, 55.9, 70.8, 71.0, 71.1, 73.5, 76.4, 110.0, 112.5, 113.8, 114.1,
118.7, 120.4, 127.21, 127.23, 127.4, 127.7, 127.8, 128.4, 128.5,
133.5, 136.4, 137.0, 137.3, 146.5, 147.8, 149.5, 149.9; HR-
FABMS m/z 541.2592 (calcd for C34H37O6, 541.2591).
(3R,4R)-3-(4-Benzyloxy-3-methoxybenzyl)-4-[(R)-(4-ben-
zyloxy-3-methoxyphenyl)(triisopropylsilyloxy)methyl]-
tetrahydrofuran (35): colorless oil; 62% yield; [R]20 -6.9°
D
1
(c 1.6, CHCl3); H NMR (CDCl3, 400 MHz) δ 0.90-0.98 (21H,
m, i-Pr), 2.05 (1H, m, H-4), 2.15-2.24 (1H, m, H-3), 2.18 (1H,
dd, J ) 13.4, 5.6 Hz, ArCHH), 2.27 (1H, dd, J ) 13.4, 9.5 Hz,
ArCHH), 3.46 (1H, dd, J ) 8.8, 5.4 Hz, HH-5), 3.68-3.83 (2H,
m, H2-2), 3.77 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.98 (1H, dd,
J ) 6.8, 3.4 Hz, HH-5), 4.49 (1H, d, J ) 7.8 Hz, ArCHOTIPS),
5.09 (2H, s, OCH2Ar), 5.11 (1H, d, J ) 12.2, OCHHAr), 5.15
(1H, d, J ) 12.2 Hz, OCHHAr), 6.30 (1H, dd, J ) 7.8, 2.0 Hz,
ArH), 6.36 (1H, d, J ) 2.0 Hz, ArH), 6.67 (1H, d, J ) 7.8 Hz,
ArH), 6.68 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 6.78 (1H, d, J ) 8.3
Hz, ArH), 6.84 (1H, d, J ) 2.0 Hz, ArH), 7.25-7.35 (6H, m,
ArH), 7.40-7.42 (4H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ
12.5, 17.9, 39.5, 43.6, 54.2, 55.77, 55.84, 71.06, 71.08, 71.13,
73.5, 77.2, 110.5, 112.4, 113.4, 114.0, 119.2, 120.4, 127.2,
127.29, 127.34, 127.7, 127.8, 128.4, 133.8, 137.0, 137.2, 137.4,
146.4, 147.5, 149.4, 149.6; anal. C 74.10%, H 8.10%, calcd for
C43H56O6Si, C 73.82%, H 8.10%.
(3R,4R)-Bis[(S)-(4-benzyloxy-3-methoxyphenyl)(hy-
droxy)methyl]tetrahydrofuran (40): colorless crystals; mp
1
148-150 °C; 100% yield; [R]20 -11° (c 0.6, CHCl3); H NMR
D
(CDCl3, 400 MHz) δ 2.55 (2H, m, H-3, H-4), 3.31 (2H, dd, J )
8.2, 6.8 Hz, OCHH), 3.48 (2H, dd, J ) 8.2, 7.8 Hz, OCHH),
3.88 (6H, s, OCH3), 4.35 (2H, d, J ) 9.3 Hz, ArCHOH), 4.40
(2H, s, OH), 5.13 (4H, s, OCH2Ph), 6.74 (2H, d, J ) 8.3 Hz,
ArH), 6.81 (2H, d, J ) 8.3 Hz, ArH), 6.90 (2H, s, ArH), 7.25-
7.37 (6H, m, ArH), 7.42-7.44 (4H, m, ArH); 13C NMR (CDCl3,
100 MHz) δ 52.6, 56.0, 71.0, 71.7, 76.8, 110.0, 113.7, 119.0,
127.2, 127.8, 128.5, 136.0, 137.0, 148.0, 149.9; HRFABMS m/z
557.2537 (calcd for C34H37O7, 557.2539).
(3R,4R)-3,4-Bis[(S)-(4-benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]tetrahydrofuran (36): colorless
oil; 50% yield; [R]20 -6.1° (c 1.1, CHCl3); 1H NMR (CDCl3,
D
400 MHz) δ 0.94-1.01 (42H, m, i-Pr), 2.85 (2H, m, H-3, H-4),
3.50 (2H, dd, J ) 9.3, 3.4 Hz, OCHH), 3.58 (2H, dd, J ) 9.3,
6.8 Hz, OCHH), 3.86 (6H, s, OCH3), 4.51 (2H, d, J ) 8.3 Hz,
ArCHOSi), 5.13 (4H, s, OCH2Ph), 6.71 (2H, dd, J ) 8.3, 1.5
Hz, ArH), 6.78 (2H, d, J ) 8.3 Hz, ArH), 6.95 (2H, d, J ) 1.5
Hz, ArH), 7.25-7.37 (6H, m, ArH), 7.42-7.44 (4H, m, ArH);
13C NMR (CDCl3, 100 MHz) δ 12.5, 18.0, 18.2, 50.2, 55.7, 69.3,
71.0, 76.0, 110.6, 113.2, 119.9, 127.3, 127.8, 128.4, 137.09,
137.14, 147.5, 149.5; anal. C 72.00%, H 8.92%, calcd for
C52H76O7Si2, C 71.84%, H 8.81%.
(3R,4R)-3-[(S)-(4-Benzyloxy-3-methoxyphenyl)(hy-
droxy)methyl]-4-[(R)-(4-benzyloxy-3-methoxyphenyl)-
(hydroxy)methyl]tetrahydrofuran (41): colorless oil; 70%
yield; [R]20D -12° (c 1.6, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
2.38 (1H, m, H-3), 2.62 (1H, m, H-4), 3.21 (1H, brs, OH), 3.37-
3.48 (1H, br, OH), 3.39 (1H, dd, J ) 9.3, 5.9 Hz, HH-2), 3.46
(1H, dd, J ) 9.3, 8.3 Hz, HH-2), 3.72 (1H, dd, J ) 8.0, 6.8 Hz,
HH-5), 3.79 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.86 (1H, dd, J
) 8.0, 7.8 Hz, HH-5), 4.36 (1H, d, J ) 7.8 Hz, ArCHOH-4),
4.55 (1H, br s, ArCHOH-3), 5.06-5.13 (4H, m, OCH2Ph), 6.62
(1H, d, J ) 6.8 Hz, ArH), 6.64 (1H, d, J ) 9.8 Hz, ArH), 6.67-
6.79 (3H, m, ArH), 6.85 (1H, d, J ) 1.5 Hz, ArH), 7.25-7.35
(6H, m, ArH), 7.39-7.42 (4H, m, ArH); 13C NMR (CDCl3, 100
MHz) δ 48.1, 49.5, 55.8, 55.9, 70.4, 70.87, 70.91, 70.95, 74.0,
76.1, 109.8, 110.3, 113.4, 113.6, 118.4, 118.9, 127.19, 127.22,
127.8, 128.4, 135.4, 135.8, 136.97, 136.99, 147.5, 147.6, 149.4,
149.5; anal. C 73.17%, H 6.65%, calcd for C34H36O7, C 73.36%,
H 6.52%.
(3R,4R)-3-[(S)-(4-Benzyloxy-3-methoxyphenyl)(tri-
isopropylsilyloxy)methyl]-4-[(R)-(4-benzyloxy-3-meth-
oxyphenyl)(triisopropylsilyloxy)methyl]tetrahydro-
furan (37): colorless oil; 52% yield; [R]20D +13° (c 1.0, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.87-0.97 (42H, m, i-Pr), 2.39-
2.47 (2H, m, H-3, H-4), 3.50 (1H, dd, J ) 8.8, 6.8, HH-2), 3.72-
3.74 (2H, m, HH-2, HH-5), 3.83 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 3.95 (1H, dd, J ) 9.0, 5.1 Hz, HH-5), 4.35 (1H, d, J )
6.5 Hz, ArCHOSi-3), 4.67 (1H, d, J ) 6.3 Hz, ArCHOSi-4), 5.13
(4H, s, OCH2Ph), 6.63 (1H, dd, J ) 10.3, 1.5 Hz, ArH), 6.67-
6.82 (4H, m, ArH), 6.86 (1H, dd, J ) 10.3, 1.5 Hz, ArH), 7.28-
7.45 (6H, m, ArH), 7.42-7.75 (4H, m, ArH); 13C NMR (CDCl3,
100 MHz) δ 12.4, 12.6, 17.9, 18.0, 18.06, 18.10, 50.3, 50.5, 55.8,
69.7, 70.1, 71.0, 71.1, 76.2, 76.8, 110.4, 111.0, 113.1, 113.4,
119.0, 119.7, 127.34, 127.37, 127.75, 127.80, 128.4, 128.5,
136.3, 137.1, 137.5, 147.4, 147.5, 149.2, 149.4; anal. C 71.85%,
H 8.93%, calcd for C52H76O7Si2, C 71.84%, H 8.81%.
(3R,4R)-3-(4-Benzyloxy-3-methoxybenzoyl)-4-(4-ben-
zyloxy-3-methoxybenzyl)tetrahydrofuran (42). A reaction
mixture of the benzyl alcohol 38 (0.10 g, 0.18 mmol), PCC (47
mg, 0.22 mmol), and MS 4A (10 mg) in CH2Cl2 (10 mL) was
stirred at room temperature for 16 h before addition of dry
diethyl ether (20 mL). After filtration, the filtrate was con-
centrated. The residue was subjected to silica gel column
chromatography (EtOAc/hexane, 1:2) to give the ketone 42 (90
(3R,4R)-3-(4-Benzyloxy-3-methoxybenzyl)-4-[(S)-(4-
benzyloxy-3-methoxyphenyl)(hydroxy)methyl]tet-
rahydrofuran (38). A reaction solution of the silyl ether 34
(0.84 g, 1.21 mmol) and (n-Bu)4NF (1.05 mL, 1 M in THF, 1.05
mmol) in THF (30 mL) was stirred at room temperature for 1
h before addition of saturated aqueous NH4Cl solution. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration and silica gel column chromatography
(EtOAc/benzene, 3:7) gave the benzyl alcohol 38 (0.50 g, 0.92
mg, 0.17 mmol, 94%) as a colorless oil: [R]20 -17° (c 0.4,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.71 (2H, d, J ) 7.8 Hz,
ArCH2CH), 3.01 (1H, m, H-4), 3.65 (1H, dd, J ) 8.8, 5.9 Hz,
HH-2), 3.72 (1H, m, H-3), 3.78 (3H, s, OCH3), 3.88 (1H, dd, J
) 8.3, 6.3 Hz, HH-5), 3.90 (3H, s, OCH3), 3.94 (1H, dd, J )
8.8, 6.8 Hz, HH-2), 4.19 (1H, dd, J ) 8.3, 8.3 Hz, HH-5), 5.07
(2H, s, OCH2Ph), 5.20 (2H, s, OCH2Ph), 6.60 (1H, dd, J ) 8.3,
2.0 Hz, ArH), 6.66 (1H, d, J ) 2.0 Hz, ArH), 6.73 (1H, d, J )
8.3 Hz, ArH), 6.80 (1H, d, J ) 8.3 Hz, ArH), 7.20 (1H, dd, J )
8.3, 2.0 Hz, ArH), 7.25-7.45 (11H, m, ArH); 13C NMR (CDCl3,
100 MHz) δ 38.7, 45.0, 51.5, 55.8, 56.0, 70.7, 71.0, 71.1, 73.2,
mmol, 76%) as colorless crystals: mp 124 °C; [R]20 -47° (c
D
0.6, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.05 (1H, br s, OH),
2.29 (1H, m, H-4), 2.52 (1H, dd, J ) 13.2, 9.5 Hz, CHHAr-3),
2.59 (1H, m, H-3), 2.78 (1H, dd, J ) 13.2, 5.4 Hz, CHHAr-3),
3.49-3.52 (2H, m, HH-2, HH-5), 3.69 (1H, dd, J ) 9.3, 7.3 Hz,
HH-2), 3.83-3.86 (1H, m, HH-5), 3.84 (3H, s, OCH3), 3.86 (3H,

Antioxidant Activity of Phenolic Lignans
Journal of Natural Products, 2005, Vol. 68, No. 10 1467
110.8, 111.9, 112.5, 114.1, 120.9, 122.6, 127.1, 127.2, 127.4,
127.7, 128.1, 128.4, 128.5, 128.6, 130.0, 132.9, 136.1, 137.2,
146.7, 149.58, 149.62, 152.6, 198.0; HRFABMS m/z 539.2441
(calcd for C34H35O6, 539.2433).
3.78 (2H, dd, J ) 8.8, 7.3 Hz, OCHH), 3.88 (2H, dd, J ) 8.8,
7.3 Hz, OCHH), 4.90 (2H, d, J ) 8.8 Hz, ArCHOH), 5.01 (2H,
br s, OH), 7.20 (2H, dd, J ) 7.8, 2.0 Hz, ArH), 7.26 (2H, d, J
) 7.8 Hz, ArH), 7.41 (2H, d, J ) 2.0 Hz, ArH), 7.87 (2H, br s,
OH); 13C NMR (C5D5N, 100 MHz) δ 53.7, 55.9, 72.2, 77.0, 111.3,
116.2, 120.5, 136.4, 147.8, 148.7; EIMS m/z 376 [M+] (7), 358
(M+ - H2O, 15), 340 (M+ - 2H2O, 32), 279 (M+ - 2OCH3 -
2OH, 8), 259 (M+ - 3H2O - 2OCH3 - H, 29), 206 [M+ - H2O
- (4-HO-3-CH3OC6H3)C(H)OH, 48], 153 [(4-HO-3-CH3OC6H3)C-
(H)OH, 100]; HREIMS m/z 376.1524 (calcd for C20H24O7,
376.1522).
(3R,4R)-3,4-Bis(4-benzyloxy-3-methoxybenzoyl)tetrahy-
drofuran (43): colorless crystals; mp 134-136 °C (EtOAc);
78% yield; [R]20 +12° (c 0.9, CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 3.92 (6H, s, OCH3), 3.92-3.97 (2H, m, H-3, H-4), 4.27
(2H, dd, J ) 8.3, 7.8 Hz, OCHH), 4.59 (2H, dd, J ) 5.4, 5.4
Hz, OCHH), 5.21 (4H, s, OCH2Ph), 6.89 (2H, d, J ) 8.3 Hz,
ArH), 7.26-7.42 (10H, m, ArH), 7.49-7.54 (4H, m, ArH); 13C
NMR (CDCl3, 100 MHz) δ 49.2, 56.0, 70.8, 72.0, 111.0, 112.2,
123.2, 127.2, 128.1, 128.7, 129.4, 136.1, 149.6, 152.9, 197.1;
anal. C 73.50%, H 5.56%, calcd for C32H32O7, C 73.89%, H
5.84%.
(3R,4R)-3-[(S)-(Hydroxy)(4-hydroxy-3-methoxyphen-
yl)methyl]-4-[(R)-(hydroxy)(4-hydroxy-3-methoxyphenyl)-
methyl]tetrahydrofuran (8): colorless crystals; mp 150-152
°C; 80% yield; [R]20 -11° (c 0.5, C5H5N); 1H NMR (C5D5N,
D
(2R,3R)-2,3-Bis(4-hydroxy-3-methoxybenzyl)-4-butano-
lide (Matairesinol) (1). A reaction mixture of the benzyl
alcohols 22 and 23 (1.40 g, 2.52 mmol) and Pd(OH)2 (1.2 g) in
EtOAc (10 mL) was stirred at ambient temperature for 22 h
under H2 gas. After filtration, the filtrate was concentrated.
The residue was subjected to silica gel column chromatography
(EtOAc/hexane, 1:1) to give matairesinol (1) (0.57 g, 1.59 mmol,
63%) as a colorless oil: [R]20 -61° (c 0.3, CHCl3) {lit.9 [R]20
400 MHz) δ 3.23 (1H, m, H-3), 3.35 (1H, m, H-4), 3.68 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 4.02 (1H, dd, J ) 8.5, 5.6 Hz, HH-
5), 4.09 (1H, dd, J ) 15.4, 7.6 Hz, HH-2), 4.23 (1H, dd, J )
15.4, 8.1 Hz, HH-2), 4.54 (1H, dd, J ) 8.5, 6.1 Hz, HH-5), 4.95
(1H, d, J ) 7.8 Hz, ArCHOH-4), 5.01 (2H, br s, OH), 5.38 (1H,
d, J ) 5.4 Hz, ArCHOH-3), 7.05 (1H, br s, OH), 7.16-7.30 (6H,
m, ArH, OH), 7.47 (1H, d, J ) 1.5 Hz, ArH); 13C NMR (C5D5N,
100 MHz) δ 50.1, 51.1, 55.7, 55.8, 70.3, 71.4, 74.1, 76.0, 111.1,
111.2, 116.0, 120.0, 120.2, 136.8, 137.1, 147.0, 147.3, 148.47,
148.49; EIMS m/z 376 [M+] (19), 358 (M+ - H2O, 49), 340 (M+
- 2H2O, 62), 279 (M+ - 2OCH3 - 2OH, 16), 259 (M+ - 3H2O
- 2OCH3 - H, 85), 206 [M+ - H2O - (4-HO-3-CH3OC6H3)C-
(H)OH, 99], 153 [(4-HO-3-CH3OC6H3)C(H)OH, 100], 137 [(4-
HO-3-CH3OC6H3)CH2, 58]; HREIMS m/z 376.1524 (calcd for
C20H24O7, 376.1522).
D
D
-42.2° (c 1, acetone)}. NMR data were in agreement with
reported data.10 Benzyl alcohol (0.64 g, 1.78 mmol, 37%) was
recovered.
(3R,4R)-3,4-Bis(4-hydroxy-3-methoxybenzyl)tetrahy-
drofuran (2): 78% yield; colorless crystals; mp 107-109 °C;
[R]20 -43° (c 1.0, THF) {lit.11 mp 105-107 °C; [R]20 -43° (c
D
D
0.9, THF)}. NMR data were in agreement with reported data.
(3R,4R)-4-[(S)-(Hydroxy)(4-hydroxy-3-methoxyphen-
yl)methyl]-3-(4-hydoxy-3-methoxybenzyl)tetrahydrofu-
ran (3). A reaction mixture of the benzyl ether 38 (95 mg,
0.18 mmol) and 5% Pd/C (20 mg) in EtOAc (10 mL) was stirred
under H2 gas at ambient temperature for 2 h before filtration.
The filtrate was concentrated, and then the residue was
subjected to silica gel column chromatography (EtOAc/hexane,
3:2) to give the trans isomer, 3 (43 mg, 0.12 mmol, 67%), as a
colorless oil: [R]20D -49° (c 0.3, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 1.97 (1H, br s, OH), 2.30 (1H, m, H-4), 2.54 (1H, dd, J
) 12.2, 8.8 Hz, CHHAr-3), 2.52-2.44 (1H, m, H-3), 2.78 (1H,
dd, J ) 12.2, 5.4 Hz, CHHAr-3), 3.51-3.56 (2H, m, HH-2, HH-
5), 3,72 (1H, dd, J ) 9.3, 7.3 Hz, HH-2), 3.85 (3H, s, OCH3),
3.87 (3H, s, OCH3), 3.88 (1H, dd, J ) 9.3, 8.8 Hz, HH-5), 4.54
(1H, d, J ) 7.8 Hz, ArCHOH), 5.49 (1H, s, ArOH), 5.59 (1H, s,
ArOH), 6.59 (1H, d, J ) 1.5 Hz, ArH), 6.62 (1H, d, J ) 8.3 Hz,
ArH), 6.77-6.81 (3H, m, ArH), 6.85 (1H, d, J ) 8.3 Hz, ArH);
13C NMR (CDCl3, 100 MHz) δ 40.0, 43.6, 51.9, 55.8, 55.9, 70.6,
73.6, 76.5, 108.6, 111.2, 114.1, 119.1, 121.4, 128.3, 132.4, 135.1,
143.9, 145.3, 146.4, 146.6; EIMS m/z 360 [M+] (21), 342 (M+
- H2O, 8), 208 [M+ - (4-HO-3-CH3OC6H3)C(OH)H, 5], 153 [(4-
HO-3-CH3OC6H3)C(OH)H, 100], 137 [(4-HO-3-MeOC6H3)CH2,
32]; HREIMS m/z 360.1562 (calcd for C20H24O6, 360.1570).
(3R,4R)-4-[(R)-(Hydroxy)(4-hydroxy-3-methoxyphen-
yl)methyl]-3-(4-hydoxy-3-methoxybenzyl)tetrahydrofu-
ran (4): colorless oil; 92% yield; [R]20D -41° (c 0.5, CHCl3); 1H
NMR (CDCl3, 400 MHz) δ 1.96 (1H, s, OH), 2.06 (1H, m, H-4),
2.19-2.25 (1H, m, H-3), 2.23 (1H, dd, J ) 13.4, 7.6 Hz,
ArCHH), 2.40 (1H, dd, J ) 13.4, 8.1 Hz, ArCHH), 3.48 (1H,
dd, J ) 8.5, 5.1 Hz, HH-2), 3.74 (3H, s, OCH3), 3.80 (3H, s,
OCH3), 3.87 (1H, dd, J ) 7.8, 7.8 Hz, HH-5), 3.95-4.03 (2H,
m, HH-2, HH-5), 4.36 (1H, d, J ) 8.8 Hz, ArCHOH), 5.47 (1H,
s, ArOH), 5.63 (1H, s, ArOH), 6.23 (1H, s, ArH), 6.41 (1H, d,
J ) 7.3 Hz, ArH), 6.67 (1H, s, ArH), 6.68-6.73 (2H, m, ArH),
6.84 (1H, d, J ) 8.3 Hz, ArH); 13C NMR (CDCl3, 100 MHz) δ
39.6, 43.9, 51.8, 55.6, 55.7, 70.8, 73.5, 76.6, 108.4, 110.9, 113.7,
113.9, 119.8, 121.3, 132.1, 135.2, 143.8, 145.4, 146.3, 146.8;
EIMS m/z 361 [M+ + 1] (100), 360 [M+] (95), 343 (M+ - OH,
5), 208 [M+ - (4-HO-3-MeOC6H3)C(OH)H, 23], 153 [(4-HO-3-
MeOC6H3)C(OH)H, 82], 137 [(4-HO-3-MeOC6H3)CH2, 93];
HREIMS m/z 360.1566 (calcd for C20H24O6, 360.1572).
(3R,4R)-3-(4-Hydroxy-3-methoxybenzoyl)-4-(4-hydroxy-
3-methoxybenzyl)tetrahydrofuran (6): colorless oil; 66%
yield; [R]20D +5.0° (c 0.4, CHCl3); 1H NMR (CDCl3) δ 2.72 (2H,
d, J ) 8.3 Hz, ArCH2-4), 3.00 (1H, m, H-4), 3.67 (1H, dd, J )
8.3, 5.4 Hz, HH-2), 3.72-3.80 (1H, m, H-3), 3.79 (3H, s, OCH3),
3.89-3.93 (1H, m, HH-5), 3.92 (3H, s, OCH3), 3 95 (1H, dd, J
) 8.3, 6.8 Hz, HH-2), 4.22 (1H, dd, J ) 8.3, 8.3 Hz, HH-5),
5.53 (1H, s, OH), 6.18 (1H, s, OH), 6.62 (1H, s, ArH), 6.64 (1H,
d, J ) 8.3 Hz, ArH), 6.78 (1H, d, J ) 8.3 Hz, ArH), 6.87 (1H,
d, J ) 8.3 Hz, ArH), 7.23 (1H, dd, J ) 8.3, 2.0 Hz, ArH), 7.42
(1H, d, J ) 2.0 Hz, ArH); 13C NMR (CDCl3) δ 38.8, 45.3, 51.4,
55.8, 56.0, 71.1, 73.2, 110.1, 111.3, 113.7, 114.3, 121.6, 123.5,
129.6, 131.6, 144.1, 146.5, 146.8, 150.6, 198.1; EIMS m/z 358
[M+] (67), 222 [M+ - (4-HO-3-CH3OC6H3)CH2, 5], 163 [(4-HO-
3-CH3OC6H3)C(dO)C, 69], 151 [(4-HO-3-CH3OC6H3)CdO, 100];
HREIMS m/z 358.1417 (calcd for C20H22O6, 358.1416).
(3R,4R)-3,4-Bis(4-hydroxy-3-methoxybenzoyl)tetrahy-
drofuran (9): colorless crystals; mp 168-169 °C; 100% yield;
[R]20D +69° (c 0.4, C5H5N); 1H NMR (C5D5N, 400 MHz) δ 3.74
(6H, s, OCH3), 4.28 (2H, dd, J ) 8.3, 5.9 Hz, H-3, H-4), 4.54
(2H, dd, J ) 8.3, 7.8 Hz, OCHH), 5.01-5.05 (4H, m, OCHH,
OH), 7.20 (2H, d, J ) 8.3 Hz, ArH), 7.84 (2H, dd, J ) 8.3, 2.4
Hz, ArH), 7.88 (2H, d, J ) 2.4 Hz, ArH); 13C NMR (C5D5N,
100 MHz) δ 49.9, 55.7, 72.3, 112.1, 116.2, 124.6, 128.6, 148.7,
154.0, 197.2; EIMS m/z 372 [M+] (5), 220 [M+ - (4-HO-3-CH3-
OC6H3)CdO, 10], 194 [(4-HO-3-CH3OC6H3)(CdO)CHCH2O,
27], 151 [(4-HO-3-CH3OC6H3)CdO, 100], 123 [(4-HO-3-CH3-
OC6H3), 11]; MREIMS m/z 372.1208 (calcd for C20H20O7,
372.1209).
(4S)-4-Benzyl-3-{(R)-2-[(S)-(4-benzyloxy-3-methoxy-
phenyl)(hydroxy)methyl]-4-pentenoyl}-2-oxazolidino-
ne (45). A reaction mixture of the acylated oxazolidinone 44
(7.62 g, 29.4 mmol), 4-benzyloxy-3-methoxybenzaldehyde (8.54
g, 35.2 mmol), MgCl2 (2.80 g, 29.4 mmol), Et3N (8.20 mL, 58.8
mmol), and Me3SiCl (5.60 mL, 44.1 mmol) in EtOAc (100 mL)
was stirred at room temperature for 16 h before filtration
through silica gel with diethyl ether. After the filtrate was
concentrated, the residue was dissolved in MeOH (100 mL),
and then a few drops of CF3CO2H were added. The reaction
mixture was stirred at room temperature for 1 h. After
addition of a few drops of Et3N, the mixture was concentrated.
The residue was recrystallized from EtOH to give the anti-
aldol product 45 (14.7 g, 29.3 mmol, 99%) as colorless crys-
tals: mp 124 °C; [R]20D -5.9° (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 2.33 (1H, m, CH2dCH-CHH), 2.45 (1H, m,
(3R,4R)-3,4-Bis[(S)-(Hydroxy)(4-hydroxy-3-methoxy-
phenyl)methyl]tetrahydrofuran (7): colorless crystals; mp
1
184-186 °C; 84% yield; [R]20 -18° (c 0.7, C5H5N); H NMR
D
(C5D5N, 400 MHz) δ 3.11 (2H, m, H-3, H-4), 3.77 (6H, s, OCH3),

1468 Journal of Natural Products, 2005, Vol. 68, No. 10
Yamauchi et al.
CH2dCH-CHH), 2.56 (1H, dd, J ) 13.7, 9.3 Hz, ArCHH), 3.11
(1H, dd, J ) 13.7, 3.4 Hz, ArCHH), 3.19 (1H, d, J ) 7.8 Hz,
OH), 3.90 (3H, s, OCH3), 4.06-4.14 (2H, m, H2-5), 4.56 (1H,
m, OdCCH), 4.63 (1H, m, H-4), 4.81 (1H, dd, J ) 7.8, 7.3 Hz,
ArCHOH), 4.98-5.07 (2H, m, CH2dCH), 5.12 (2H, s, ArCH2O),
5.74 (1H, m, CH2dCH), 6.85 (1H, d, J ) 8.3 Hz, ArH), 6.90
(1H, d, J ) 8.3 Hz, ArH), 7.02 (1H, s, ArH), 7.09-7.11 (2H, m,
ArH), 7.25-7.34 (6H, m, ArH), 7.40-7.42 (2H, m, ArH); 13C
NMR (CDCl3) δ 34.3, 37.5, 48.7, 55.3, 56.0, 65.8, 71.0, 75.5,
109.8, 113.7, 117.4, 118.6, 127.2, 127.3, 127.8, 128.5, 128.9,
129.4, 134.5, 135.1, 135.3, 137.0, 147.8, 149.8, 153.5, 175.5;
anal. C, 71.97%, H 6.20%, N 2.64%, calcd for C30H31O6N, C
71.84%, H 6.23%, N 2.79%.
(1H, m, H-4), 2.21 (1H, m, HH-3), 2.36 (1H, m, HH-3), 3.81
(1H, dd, J ) 11.2, 8.3 Hz, pivOCHH), 3.86 (3H, s, OCH3), 4.16
(1H, dd, J ) 11.2, 4.4 Hz, pivOCHH), 4.91-4.98 (3H, m, H2-1,
H-5), 5.13 (2H, s, ArCH2O), 5.72 (1H, m, H-2), 6.69 (1H, dd, J
) 8.3, 2.0 Hz, ArH), 6.81 (1H, d, J ) 8.3 Hz, ArH), 6.89 (1H,
d, J ) 2.0 Hz, ArH), 7.26-7.38 (3H, m, ArH), 7.43-7.45 (2H,
m, ArH); 13C NMR (CDCl3, 100 MHz) δ 12.4, 18.0, 18.1, 27.3,
30.2, 38.8, 45.8, 55.9, 63.9, 71.1, 73.9, 110.8, 113.4, 116.4, 119.3,
127.4, 127.8, 128.5, 135.0, 136.6, 137.2, 147.4, 149.3, 178.2;
anal. C 71.89%, H 9.37%, calcd for C34H52O5Si, C 71.79%, H
9.21%.
(2S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triisopro-
pylsilyloxy)methyl]-3-formylpropyl pivaloate (49). A re-
action mixture of the olefin 48 (14.5 g, 25.5 mmol), NMO (3.69
g, 31.5 mmol), and OsO4 (2 mL, 2% aqueous solution) in
acetone (150 mL), t-BuOH (40 mL), and H2O (40 mL) was
stirred at room temperature for 16 h under N2 gas in the dark.
After addition of Na2S2O3, the mixture was filtered. The filtrate
was concentrated, and then the residue was dissolved in H2O
and EtOAc. The organic solution was separated, washed with
brine, and dried (Na2SO4). After concentration, the residue was
dissolved in MeOH (100 mL). To this solution was added NaIO4
(6.25 g, 29.2 mmol), and then the reaction mixture was stirred
at room temperature for 1 h before concentration. The residue
was dissolved in H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4). After
concentration, the residue was applied to silica gel column
chromatography (EtOAc/hexane, 1:8) to give the aldehyde 49
(13.6 g, 21.9 mmol, 86%) as a colorless oil: [R]20D -9.5° (c 1.1,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.95-1.01 (21H, m, i-Pr),
1.22 (9H, s, t-Bu), 2.05 (1H, ddd, J ) 16.6, 6.1, 1.0 Hz, HH-2),
2.50 (1H, ddd, J ) 16.6, 6.6, 2.7 Hz, HH-2), 2.89 (1H, m, H-3),
3.88 (3H, s, OCH3), 3.88 (1H, dd, J ) 11.2, 8.3 Hz, pivOCHH),
3.98 (1H, dd, J ) 11.2, 5.9 Hz, pivOCHH), 4.97 (1H, d, J )
5.4 Hz, ArCHOTIPS), 5.13 (2H, s, ArCH2O), 6.66 (1H, dd, J )
8.3, 1.5 Hz, ArH), 6.82 (1H, d, J ) 8.3 Hz, ArH), 6.87 (1H, d,
J ) 1.5 Hz, ArH), 7.26-7.38 (3H, m, ArH), 7.42-7.44 (2H, m,
ArH), 9.73 (1H, dd, J ) 2.7, 1.0 Hz, CHO); 13C NMR (CDCl3,
100 MHz) δ 12.3, 17.9, 18.0, 27.2, 38.8, 41.1, 41.3, 55.9, 64.4,
71.1, 73.9, 110.7, 113.4, 119.2, 127.3, 127.8, 128.5, 133.6, 137.0,
147.7, 149.5, 178.0, 200.9; anal. C 69.51%, H 8.65%, calcd for
C37H50O6Si, C 69.43%, H 8.83%.
(3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-3-pival-
oyloxymethyl-4-butanolide (50). To an ice-cooled solu-
tion of the silyl ether 49 (12.3 g, 19.9 mmol) in THF (80
mL) was added (n-Bu)4NF (22.2 mL, 1 M in THF, 22.2
mmol). After the reaction solution was stirred in an ice-bath
for 1 h, saturated aqueous NH4Cl solution was added. The
organic solution was separated, washed with brine, and dried
(Na2SO4). After concentration, the residue was subjected to
silica gel column chromatography (EtOAc/hexane, 1:2) to give
a hemiacetal (7.76 g, 18.8 mmol, 94%) as a colorless oil. A
reaction mixture of this hemiacetal (7.76 g, 18.8 mmol), PCC
(4.62 g, 21.4 mmol), and MS 4A (0.3 g) in CH2Cl2 (40 mL) was
stirred at room temperature for 16 h before addition of dry
diethyl ether. After the mixture was filtered, the filtrate was
concentrated. The residue was subjected to silica gel column
chromatography (EtOAc/hexane, 1:4) to give the lactone 50
(6.78 g, 16.4 mmol, 82%) as colorless crystals: mp 94 °C
(i-Pr2O); [R]20D -34° (c 1.1, CHCl); 1H NMR (CDCl3, 400 MHz)
δ 1.14 (9H, s, t-Bu), 2.57 (1H, dd, J ) 17.3, 4.2 Hz, HH-2),
2.82 (1H, dd, J ) 17.3, 8.5 Hz, HH-2), 3.04 (1H, m, H-3), 3.64
(1H, dd, J ) 11.5, 6.6 Hz, pivOCHH), 3.86 (1H, dd, J ) 11.5,
5.4 Hz, pivOCHH), 3.87 (3H, s, OCH3), 5.13 (2H, s, ArCH2O),
5.62 (1H, d, J ) 6.8 Hz, H-4), 6.75 (1H, dd, J ) 7.8, 2.0 Hz,
ArH), 6.81 (1H, d, J ) 2.0 Hz, ArH), 6.88 (1H, d, J ) 7.8 Hz,
ArH), 7.27-7.38 (3H, m, ArH), 7.42-7.44 (2H, m, ArH); 13C
NMR (CDCl3, 100 MHz) δ 27.0, 32.5, 38.6, 39.3, 56.1, 62.7,
71.0, 82.0, 109.0, 114.0, 117.6, 127.2, 127.86, 127.89, 128.5,
136.8, 148.3, 149.9, 175.6, 177.9; anal. C 69.94%, H 6.95%,
calcd for C24H28O6, C 69.88%, H 6.84%.
(4S)-4-Benzyl-3-{(R)-2-[(S)-(4-benzyloxy-3-methoxy-
phenyl)(triisopropylsilyloxy)methyl]-4-pentenoyl}-2-ox-
azolidinone (46). To an ice-cooled solution of the alcohol 45
(5.47 g, 10.9 mmol) and 2,6-lutidine (2.54 mL, 21.8 mmol) in
CH2Cl2 (60 mL) was added TIPSOTf (5.00 mL, 14.9 mmol).
The resulting solution was stirred on an ice-bath for 1.5 h
before addition of saturated aqueous NaHCO3 solution. The
organic solution was separated, washed with saturated aque-
ous CuSO4 solution and brine, and dried (Na2SO4). After
concentration, the residue was recrystallized from MeOH to
give the silyl ether 46 (5.57 g, 8.47 mmol, 78%) as colorless
crystals: mp 115 °C; [R]20 -27° (c 1.3, CHCl3); 1H NMR
D
(CDCl3) δ 0.91-0.99 (21H, m, i-Pr), 1.90 (1H, m, CH2dCH-
CHH), 2.13 (1H, m, CH2dCH-CHH), 2.61 (1H, dd, J ) 11.2,
3.2 Hz, ArCHH), 3.53 (1H, dd, J ) 13.2, 2.9 Hz, ArCHH), 3.92
(3H, s, OCH3), 4.06 (1H, dd, J ) 8.8, 8.8 Hz, HH-5), 4.11 (1H,
dd, J ) 8.8, 2.4 Hz, HH-5), 4.54 (1H, m, OdCCH), 4.60 (1H,
m, H-4), 4.87-4.94 (2H, m, CH2dCH), 5.04 (1H, d, J ) 8.8
Hz, ArCHOH), 5.14 (2H, s, ArCH2O), 5.57 (1H, m, CH2dCH),
6.82 (2H, s, ArH), 7.08 (1H, s, ArH), 7.25-7.30 (5H, m, ArH),
7.33-7.37 (3H, m, ArH), 7.42-7.44 (2H, m, ArH); 13C NMR
(CDCl3) δ 12.6, 17.9, 18.1, 34.3, 38.4, 51.4, 56.0, 65.9, 71.0,
111.0, 113.3, 116.8, 120.1, 127.2, 127.3, 127.8, 128.4, 128.9,
129.3, 134.9, 135.5, 135.9, 137.0, 147.9, 149.7, 153.4, 174.6;
anal. C 71.32%, H 8.10%, N 2.10%, calcd for C39H51O6NSi, C
71.20%, H 7.81%, N 2.13%.
(2S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triisopro-
pylsilyloxy)methyl]-4-penten-1-ol (47). To an ice-cooled
solution of LiBH4 (2.79 g, 0.13 mol) and MeOH (5.36 mL, 0.13
mol) in THF (150 mL) was added a solution of the acyl
oxazolidinone 46 (36.3 g, 55.2 mmol) in THF (200 mL). The
reaction solution was stirred at room temperature for 16 h
before addition of saturated aqueous NH4Cl solution. After
concentration, the residue was dissolved in EtOAc and H2O.
The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration and subsequent silica gel
column chromatography (EtOAc/hexane, 1:9) gave the alcohol
47 (16.2 g, 33.4 mmol, 61%) as a colorless oil: [R]20 -45° (c
D
1.4, CHCl3); 1H NMR (CDCl3) δ 0.96-1.02 (21H, m, i-Pr), 1.83-
1.96 (2H, m, H-2, OH), 2.18 (1H, m, CH2dCH-CHH), 2.65 (1H,
m, CH2dCH-CHH), 3.58 (1H, m, HH-1), 3.79 (1H, m, HH-1),
3.88 (3H, s, OCH3), 4.85 (1H, d, J ) 5.4 Hz, ArCHOTIPS),
4.98-5.14 (2H, m, CH2dCH), 5.14 (2H, s, ArCH2O), 5.73 (1H,
m, CH2dCH), 6.57 (1H, dd, J ) 8.3, 1.5 Hz, ArH), 6.82 (1H, d,
J ) 8.3 Hz, ArH), 6.95 (1H, d, J ) 1.5 Hz, ArH), 7.28-7.31
(1H, m, ArH), 7.34-7.37 (2H, m, ArH), 7.42-7.44 (2H, m,
ArH); 13C NMR (CDCl3) δ 12.5, 17.9, 18.0, 32.4, 48.4, 55.9, 63.1,
71.1, 78.3, 110.5, 113.4, 116.4, 119.2, 127.3, 127.8, 128.5, 136.5,
136.8, 137.1, 147.5, 149.5; anal. C 72.03%, H 9.12%, calcd for
C29H44O4Si, C 71.85%, H 9.15%.
(2S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triisopro-
pylsilyloxy)methyl]-4-pentenyl pivaloate (48). To an ice-
cooled solution of the alcohol 47 (16.2 g, 33.4 mmol) and
pyridine (5.41 mL, 66.9 mmol) in CH2Cl2 (20 mL) was added
PivCl (5.41 mL, 43.9 mmol). After the reaction mixture was
stirred at room temperature for 2 h, EtOAc and H2O were
added. The organic solution was separated, washed with 6 M
aqueous HCl solution and brine, and dried (Na2SO4). Concen-
tration and silica gel column chromatography (5% EtOAc in
hexane) gave the pivaloyl ester 48 (19.1 g, 33.5 mmol, 100%)
as a colorless oil: [R]20D -8.9° (c 1.5, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 0.96-1.01 (21H, m, i-Pr), 1.23 (9H, s, t-Bu), 1.54
(2S,3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-2-[(S)-
(4-benzyloxy-3-methoxyphenyl)(hydroxy)methyl]-3-piv-
aloyloxymethyl-4-butanolide (51). To a solution of KHMDS
(64.7 mL, 0.5 M in toluene, 32.4 mmol) in THF (150 mL) was

Antioxidant Activity of Phenolic Lignans
Journal of Natural Products, 2005, Vol. 68, No. 10 1469
added a solution of the lactone 50 (8.90 g, 21.6 mmol) in THF
(80 mL) at -75 °C. After stirring at -75 °C for 15 min, a
solution of 4-benzyloxy-3-methoxybenzaldehyde (6.27 g, 25.9
mmol) in THF (40 mL) was added. The reaction solution was
stirred at -75 °C for 1 h before addition of saturated aqueous
NH4Cl solution. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration and silica gel
column chromatography (10% EtOAc in hexane) gave the
8.3 Hz, ArH), 6.87 (1H, d, J ) 8.3 Hz, ArH), 6.95 (1H, s,
ArH), 7.25-7.44 (10H, m, ArH); 13C NMR (CDCl3, 100 MHz)
δ 32.9, 43.0, 48.8, 55.9, 56.0, 70.0, 71.0, 71.1, 72.5, 73.5, 109.9,
112.5, 113.8, 114.2, 118.5, 120.5, 127.2, 127.69, 127.72, 127.8,
128.45, 128.52, 133.8, 135.5, 136.6, 137.0, 137.2, 146.4, 147.8,
149.5, 149.9; HRFABMS m/z 540.2506 (calcd for C34H36O6,
540.2512).
(2aS,3R,8aR)-5-Benzyloxy-3-(4-benzyloxy-3-meth-
oxyphenyl)-6-methoxy-2,2a,8,8a-tetrahydronaphthalene-
[2,3-c]tetrahydrofuran (54). The tetrahydrofuran derivative
53 (0.30 g, 0.55 mmol) was stood at room temperature for 48
h before application to a silica gel column (10% EtOAc in
hexane). The compound 54 (0.29 g, 0.55 mmol, 100%) was
obtained as colorless crystals: mp 133-134 °C; [R]20D +14° (c
erythro aldol product 51 (12.1 g, 18.5 mmol, 86%) as a colorless
1
oil: [R]20 -48° (c 0.3, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
0.97 (9H, s, t-Bu), 2.72-2.89 (1H, br, OH), 2.91 (1H, dd, J )
3.9, 3.4 Hz, H-2), 3.08 (1H, m, H-3), 3.46-3.50 (2H, m,
pivOCH2), 3.86 (3H, s, OCH3), 3.89 (3H, s, OCH3), 5.11 (2H, s,
ArCH2O), 5.13 (2H, s, ArCH2O), 5.40 (1H, d, J ) 2.9 Hz,
ArCHOH), 5.70 (1H, d, J ) 7.3 Hz, H-4), 6.72 (1H, d, J ) 8.3
Hz, ArH), 6.76 (1H, s, ArH), 6.84 (1H, d, J ) 8.3 Hz, ArH),
6.88-6.91 (2H, m, ArH), 6.96 (1H, s, ArH), 7.16-7.18 (1H, m,
ArH), 7.23-7.42 (9H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ
21.4, 26.9, 38.5, 39.3, 51.7, 56.1, 56.2, 62.8, 71.1, 72.8, 82.1,
109.2, 114.0, 114.1, 117.5, 117.9, 125.3, 127.2, 127.3, 127.9,
128,2, 128.4, 128.5, 129.0, 134.1, 136.8, 136.9, 148.0, 148.2,
149.8, 150.0, 177.3, 177.8; anal. C 71.63%, H 6.50%, calcd for
C39H42O9, C 71.54%, H 6.47%.
1
0.4, CHCl3); H NMR (CDCl3, 400 MHz) δ 2.52 (1H, dd, J )
13.4, 9.8 Hz, HH-8), 2.55-2.70 (2H, m, H-2a, H-8a), 2.85 (1H,
dd, J ) 13.4, 5.1 Hz, HH-8), 3.49-3.53 (1H, dd, HH-9), 3.52
(1H, d, J ) 9.3 Hz, H-3), 3.63 (1H, dd, J ) 8.8, 4.9 Hz, HH-2),
3.75-3.79 (1H, dd, HH-2), 3.77 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 4.00 (1H, dd, J ) 8.3, 6.8 Hz, HH-9), 4.89 (2H, s,
PhCH2O), 5.20 (2H, s, PhCH2O), 6.22 (1H, s, ArH), 6.62 (1H,
d, J ) 8.3 Hz, ArH), 6.65 (1H, s, ArH), 6.73 (1H, s, ArH), 6.87
(1H, d, J ) 8.3 Hz, ArH), 7.18-7.25 (5H, m, ArH), 7.29-7.32
(1H, m, ArH), 7.36-7.40 (2H, m, ArH), 7.49-7.51 (2H, m,
ArH); 13C NMR (CDCl3, 100 MHz) δ 32.2, 39.2, 46.0, 47.2, 55.9,
56.2, 71.1 × 2, 73.6, 74.7, 111.5, 112.6, 113.7, 114.0, 121.0,
127.28, 127.30, 127.6, 127.9, 128.3, 128.6, 130.5, 133.6, 134.7,
137.2, 137.3, 146.2, 146.9, 147.8, 149.7; HRFABMS m/z
523.2482 (calcd for C34H34O5, 523.2484).
(2R,3S,4S)-2-(4-Benzyloxy-3-methoxybenzyl)-4-(4-ben-
zyloxy-3-methoxyphenyl)-3-pivaloyloxymethyl-4-butan-
olide (52). To a solution of the aldol product 51 (12.1 g, 18.5
mmol) and Et3SiH (11.8 mL, 73.9 mmol) in CH2Cl2 (550 mL)
was added BF3‚OEt2 (1.17 mL, 9.23 mmol) at 3 °C. After the
reaction solution was stirred at 3 °C for 2 h, saturated aqueous
NaHCO3 solution was added. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). The solvent was
concentrated, and then the residue was applied to silica gel
column chromatography (6% EtOAc in toluene) to give the
benzyl lactone 52 (6.68 g, 10.5 mmol, 57%) as colorless
(2aS,3S,8aR)-5-Hydroxy-3-(4-hydroxy-3-methoxy-
phenyl)-6-methoxy-2,2a,8,8a-tetrahydronaphthalene[2,3-
c]tetrahydrofuran (5): colorless crystals; mp 175-176 °C;
100% yield, [R]20D -9.7° (c 0.6, CHCl3); 1H NMR (CDCl3) δ 2.54
(1H, dd, J ) 13.4, 9.8 Hz, HH-8), 2.61 (1H, m, H-2a), 2.71 (1H,
m, H-8a), 2.85 (1H, dd, J ) 13.4, 5.1 Hz, HH-8), 3.55 (1H, dd,
J ) 9.0, 4.4 Hz, HH-9), 3.56 (1H, d, J ) 9.3 Hz, H-3), 3.64
(1H, dd, J ) 8.8, 4.9 Hz, HH-2), 3.80 (1H, dd, J ) 9.0, 7.1 Hz,
HH-9), 3.85 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.02 (1H, dd, J
) 8.8, 6.8 Hz, HH-2), 5.44 (1H, s, ArOH), 5.60 (1H, s, ArOH),
6.31 (1H, s, ArH), 6.71 (1H, s, ArH), 6.72-6.73 (2H, m, ArH),
6.90 (1H, d, J ) 8.8 Hz, ArH); 13C NMR (CDCl3) δ 32.4, 39.3,
46.0, 47.3, 55.9, 56.1, 73.6, 74.7, 110.2, 111.5, 113.6, 114.5,
121.8, 129.4, 133.4, 134.6, 143.7, 144.4, 144.7, 146.7; FABMS
m/z 342 [M+] (25), 136 [(4-HO-3-MeOC6H3)CH2, 100];
HRFABMS m/z 342.1472 (calcd for C26H22O5, 342.1468).
Antioxidant Activity of Compounds 1-9 in a Tween
20 Micelle System. The method of Masuda et al.18 was
slightly modified. To 160 µL of the DMSO solution of a test
sample (5.0 mM) were added freshly purified ethyl linoleate
(139 µL) and 0.3 M Tween 20-0.05 M phosphate buffer (pH
7.4, 8 mL). The mixture was stirred vigorously using a vortex
mixer for 2 min and then sonicated in a bath sonicator
(Branson model 2210) for 3 min to give a clear micelle solution.
Two milliliters of this micelle solution was put into a straight
vial (35 mm diameter; 75 mm height), and 100 µL of 0.2 M
AAPH aqueous solution was added to the solution. After
stirring again with the vortex mixer, the vial was incubated
at 37 °C in the dark while continuously shaking (82 shakes/
min; Taitec P-11 water bath shaker). After 3 h of incubation,
a 20 µL aliquot was taken from the solution and poured into
380 µL of a methanolic solution of trolox (0.2 mM). Ten
microliters of the diluted solution was injected into the HPLC
instrument to analyze ethyl linoleate hydroperoxide under the
following conditions: column, YMC-Pack ODS-A (4.6 × 150
mm); solvent, CH3CN/H2O ) 9:1; flow rate, 1.0 mL/min;
detection, 234 nm. The concentration of the hydroperoxide was
calculated from the peak area obtained by the following
equation: Y ) 2.29X × 10-6 - 4.38 × 10-4, where Y is the
concentration of ethyl linoleate hydroperoxide (mM) and X is
the peak area of hydroperoxide.
crystals: mp 108 °C (i-Pr2O), [R]20 +30 (c 0.6, CHCl3); 1H
D
NMR (CDCl3, 400 MHz) δ 1.09 (9H, s, t-Bu), 2.79 (1H, m, H-3),
2.87 (1H, m, H-2), 3.02 (1H, dd, J ) 14.2, 4.9 Hz, ArCHH),
3.08 (1H, dd, J ) 14.2, 6.8 Hz, ArCHH), 3.62 (1H, dd, J )
11.5, 6.4 Hz, pivOCHH), 3.77 (1H, dd, J ) 11.5, 5.9 Hz,
pivOCHH), 3.86 (3H, s, OCH3), 3.89 (3H, s, OCH3), 5.13 (4H,
s, PhCH2O), 5.32 (1H, d, J ) 6.8 Hz, 4-H), 6.66 (1H, d, J ) 8.3
Hz, ArH), 6.72-6.75 (2H, m, ArH), 6.82-6.85 (3H, m, ArH),
7.26-7.41 (10H, m, ArH); 13C NMR (CDCl3, 100 MHz) δ 27.1,
29.7, 34.8, 38.7, 42.9, 44.4, 56.1, 56.2, 62.5, 71.1, 80.5, 109.3,
113.0, 114.0, 114.3, 117.9, 121.4, 127.2, 127.3, 127.8, 127.9,
128.1, 128.5, 128.6, 130.2, 136.8, 137.1, 147.4, 148.3, 149.9,
177.7, 177.8; anal. C 73.56%, H 6.69%, calcd for C39H42O8, C
73.33%, H 6.63%.
(3R,4S)-3-(4-Benzyloxy-3-methoxybenzyl)-4-[(S)-(4-
benzyloxy-3-methoxyphenyl)(hydroxy)methyl]tet-
rahydrofuran (53). To an ice-cooled suspension of LiAlH4
(0.18 g, 4.74 mmol) in THF (10 mL) was added a solution of
the lactone 52 (1.53 g, 2.40 mmol) in THF (10 mL). After
stirring at room temperature for 30 min, saturated aqueous
MgSO4 solution and K2CO3 were added. On stirring further
at room temperature for 30 min, the mixture was filtered, and
then the filtrate was concentrated. To an ice-cooled suspension
of NaH (0.12 g, 60% oil suspension, 3.00 mmol) in THF (10
mL) was added the residue in THF (10 mL). After stirring at
-20 °C for 30 min, N-TsIm (0.62 g, 2.79 mmol) in THF (20
mL) was added. On stirring at -20 °C for 24 h, saturated
aqueous NH4Cl solution and EtOAc were added. The or-
ganic solution was separated, washed with brine, and dried
(Na2SO4). After concentration, the residue was applied to silica
gel column chromatography (EtOAc/hexane, 1:3) to give the
tetrahydrofuran derivative 53 (0.79 g, 1.47 mmol, 31%) as a
colorless oil: [R]20D -2.7° (c 1.5, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 2.04 (1H, d, J ) 2.0 Hz, OH), 2.30 (1H, m, H-4), 2.55
(1H, dd, J ) 13.7, 11.2 Hz, ArCHH), 2.71 (1H, m, H-3), 2.80
(1H, dd, J ) 13.7, 4.4 Hz, ArCHH), 3.66-3.70 (2H, m, HH-2,
HH-5), 3.80 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.98 (1H, dd, J
) 8.8, 7.3 Hz, HH-2), 4.01 (1H, dd, J ) 8.8, 7.3 Hz, HH-5),
4.81 (1H, dd, J ) 7.3, 2.0 Hz, ArCHOH), 5.09 (2H, s, PhCH2O),
5.14 (2H, s, PhCH2O), 6.49 (1H, d, J ) 8.3 Hz, ArH), 6.54
(1H, s, ArH), 6.74 (1H, d, J ) 8.3 Hz, ArH), 6.83 (1H, d, J )
Measurement for Antiradical Activity Using DPPH
(1,1-Diphenyl-2-picrylhydrazyl).19 To the appropriate amount
of sample in methanol solution (4.9 mL) was added 100 µL of
5 mM DPPH in methanol solution. After the solution stood at
25 °C for 0.5 h, the absorbance at 517 nm was measured. The

1470 Journal of Natural Products, 2005, Vol. 68, No. 10
Yamauchi et al.
(5) Hanuman, J. B.; Mishra, A. K.; Sabata, B. J. Chem. Soc., Perkin
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antiradical activity was evaluated from the decreased value
of 517 nm absorption, which was calculated by the following
equation: decrease of absorbance ) (absorbance of DPPH
solution) - (absorbance of DPPH solution + sample solution)
+ (absorbance of sample solution).
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Acknowledgment. The 400 MHz NMR data were mea-
sured at INCS, Ehime University. We thank the staff at this
Center for the EIMS and FABMS measurements. We are also
grateful to Marutomo Co., Iyo, Ehime, Japan, for financial
support.
Supporting Information Available: 1H NMR spectra of com-
pounds 1-9 are available free of charge via the Internet at
http://pubs.acs.org.
References and Notes
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Commun. 2004, 581-582.
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