Synthesis and antioxidant activity of olivil-type lignans

Article abstract of DOI:10.1271/bbb.69.113

Olivil-type lignans, an enantiomeric type of natural olivil, were synthesized for the first time to evaluate the relationship between the structure of olivil and its antioxidant activity. A comparison of the antioxidant activity with that of other synthesized tetrahydrofuran lignans indicated reduced activity with the tertiary hydroxy group. A different effect of the two phenolic groups of olivil on the antioxidant activity was also observed.

Full text of DOI:10.1271/bbb.69.113

Biosci. Biotechnol. Biochem., 69 (1), 113–122, 2005
Synthesis and Antioxidant Activity of Olivil-Type Lignans
y
2
Satoshi YAMAUCHI,1; Yoshimasa HAYASHI,1 Takuya KIRIKIHIRA,2 and Toshiya MASUDA
1Faculty of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime 790-8566, Japan
2Faculty of Integrated Arts and Sciences, University of Tokushima, Tokushima 770-8502, Japan
Received August 24, 2004; Accepted October 2, 2004
Olivil-type lignans, an enantiomeric type of natural
olivil, were synthesized for the first time to evaluate the
relationship between the structure of olivil and its
antioxidant activity. A comparison of the antioxidant
activity with that of other synthesized tetrahydrofuran
lignans indicated reduced activity with the tertiary
hydroxy group. A different effect of the two phenolic
groups of olivil on the antioxidant activity was also
observed.
having an absolute configuration opposite to that of
natural olivil and the different effect of the three
hydroxy groups of olivil on the antioxidant activity.
This is the first reported study on the relationship
between the main structure and antioxidant activity of
olivil by employing the organic synthetic technique.
Results and Discussion
Synthesis of 1–4
Key words: Eucommia ulmoides; Eucommiaceae; oliv;
antioxidant activity; olivil
The synthesis of olivil-type lignan 1 was started by
the aldol condensation of lactone 57) with 4-benzyloxy-
3-methoxybenzaldehyde to give aldol product 6 as a
mixture of erythro/threo ¼ 7=3 (Scheme 1). After con-
version to olefin 7 as a mixture of Z=E ¼ 8=2, stereo-
selective osmium oxidation was performed to give
glycol 8. The results of an NOE experiment confirmed
the preferential production of the Z form of olefin 7.
Selective dehydroxylation of the benzylic position was
accomplished by using Et3SiH and CF3CO2H,8) leading
to ꢀ-hydroxy lactone 9. This lactone 9 was subjected to
LiAlH4 reduction, and then the crude tetraol was treated
with 10-camphorsulfonic acid to give SN1 cyclization
product 10. The configuration of 10 was confirmed by a
differential NOE experiment, NOE being observed
between 7-H and 9-H2, and between 7-H and 70-H2.
Hydrogenolysis of 10 gave olivil-type lignan 1.
To synthesize olivil-type lignan 2, cis-lactone 17 was
prepared from 119) (Scheme 2). The two chiral centers
were constructed by employing Evans’s anti-aldol
condensation10) to give 12 (more than 99% d.e.). No
production of the syn-aldol product was apparent. After
protection of the hydroxy group as a triisopropylsilyl
ether, the auxiliary was reductively removed to afford
alcohol 14. After protection of the primary hydroxy
group as a pivaloyl ester, resulting olefin 15 was
converted to aldehyde 16 by oxidative cleavage.
Desilylation and subsequent oxidation of the resulting
hemiacetal gave lactone 17. Olivil-type lignan 2 was
obtained from lactone 17 by the same synthetic method
as that described for the synthesis of 1 (Scheme 3). The
enantioselective syntheses of the (þ)-olivil type lignans
were thus successful.
It is known that lignans play an important role in the
antioxidant activity of foods and plants.1) In respect of
the relationship between the antioxidant activity and
structure, the effect of the phenolic part of natural
compounds on the antioxidant activity is already
known.2) However, the effect of the main body of
natural compounds on the antioxidant activity has not
previously been reported. It has recently been found that
the antioxidant activity of furofuran lignan was affected
by the tertiary hydroxy group on the furofuran ring.3)
This discovery stimulated us to further study the effect
of the tertiary hydroxy group on the antioxidant activity
of olivil-type lignan, which is the best-known tetrahy-
drofuran lignan bearing a tertiary hydroxy group. It has
been shown that the degree of oxidation of the main
body of lignan was important for its biological activity.4)
Our project to clarify the relationship between this
oxidation degree and antioxidant activity in olivil will
contribute to biological research into lignan.
In this experiment, two olivil-type lignans, 1 and 2
which were enantiomeric types of natural olivil, and two
tetrahydrofuran lignans, 3 and 4, were synthesized
(Fig. 1); their antioxidant activity was then compared
to clarify the effect of hydroxy groups. To examine the
effect of each phenolic group of olivil, compounds 1 and
2 were valuable in having only one phenolic group at
different positions. In respect of synthetic research into
olivil, the synthesis of diastereomers of olivil-type
lignan has been reported.5,6) This article describes the
first enantioselective synthesis of olivil-type lignan
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp
Abbreviation: AAPH, 2,20-azobis(2-aminopropane)dihydrochloride

114
S. YAMAUCHI et al.
Fig. 1.
Scheme 1. Synthesis of Olivil-Type Lignan 1.
(a) KHMDS, 4-benzyloxy-3-methoxybenzaldehyde, THF, ꢀ70 ꢁC, 1 h (86%); (b) KHSO4, toluene, reflux, 30 min (100%); (c) OsO4, NMO,
aq. acetone, tert-BuOH, r.t., 16 h (52%); (d) Et3SiH, CF3CO2H, r.t., 16 h (50%); (e) LiAlH4, THF, r.t., 30 min; (f) CSA, CH2Cl2, 2 ꢁC, 16 h (56%,
2 steps); (g) H2, 5% Pd/C, EtOAc, r.t., 7 h (73%).

Olivil-Type Lignans
115
Scheme 2. Preparation of ꢁ-Butyrolactone 17.
(a) i) 4-benzyloxy-3-methoxybenzaldehyde, MgCl2, Et3N, Me3SiCl, EtOAc, r.t., 1 h; ii) CF3CO2H, MeOH, r.t., 1 h (99%, 2 steps); (b)
TIPSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 1.5 h (78%); (c) LiBH4, MeOH, THF, r.t., 16 h (61%); (d) PivCl, pyridine, CH2Cl2, r.t., 2 h (100%); (e) i)
OsO4, NMO, aq. acetone, tert-BuOH, r.t., 16 h; ii) NaIO4, MeOH, r.t., 1 h (86%); (f) i) (n-Bu)4NF, THF, 0 ꢁC, 1 h; ii) PCC, MS 4A, CH2Cl2, r.t.,
16 h (77%, 2 steps).
Scheme 3. Synthesis of Olivil-Type Lignan 2.
(a) (i) KHMDS, 3,4-dimethoxybenzaldehyde, THF, ꢀ70 ꢁC, 1 h (81%); (ii) KHSO4, toluene, reflux, 30 min, recrystallization (62%); (iii)
OsO4, NMO, aq. acetone, tert-BuOH, r.t., 16 h (66%); (b) Et3SiH, CF3CO2H, r.t., 16 h (51%); (c) (i) LiAlH4, THF, r.t., 30 min; (ii) CSA,
CH2Cl2, 2 ꢁC, 16 h (56%, 2 steps); (d) H2, 5% Pd/C, EtOAc, r.t., 7 h (61%).
Tetrahydrofuran lignan 3 lacking the tertiary hydroxy
group of olivil-type lignan was synthesized from aldol
product 6 (Scheme 4). Dehydroxylation of the benzylic
hydroxy group was achieved by employing Et3SiH in
in the presence of 10-camphorsulfonic acid. The
presence of NOE between 7-H and 9-H2 in 22 suggested
this configuration. Hydrogenolysis of 22 gave tetrahy-
drofuran lignan 3. Tetrahydrofuran lignan 4 was also
obtained by the same method as that described for the
synthesis of 3 (Scheme 4).
11)
.
the presence of BF3 OEt2 to give 21 as a mixture of
7R=7S ¼ 1=1. Epimerization at the 4-position was
observed in this stage. Since this 4-position would be
stereoconvergently converted to the 2-position of 22,
this epimerization was no problem. After LiAlH4
reduction of 21, the resulting crude triol was stereo-
convergently cyclized to tetrahydrofuran derivative 22
Antioxidant activity
The antioxidant activity of compounds 1–4 was
examined in a Tween 20 micelle system12) (Fig. 2).
The activity of all compounds was weaker than that of

116
S. YAMAUCHI et al.
Scheme 4. Synthesis of Tetrahydrofuran Lignans 3 and 4.
ꢁ
.
(a) Et3SiH, BF3 OEt2, CH2Cl2, 2 C, 1 h (55%); (b) (i) LiAlH4, THF, r.t., 30 min; (ii) CSA, CH2Cl2, r.t., 40 h (50%, 2 steps); (c) H2, 5% Pd/C,
EtOAc, r.t., 7 h (96%); (d) (i) Et3SiH, BF3 OEt2, CH2Cl2, 2 C, 1 h (52%); (ii) LiAlH4, THF, r.t., 30 min; (iii) CSA, CH2Cl2, r.t., 40 h (53%, 2
ꢁ
.
steps); (e) H2, 5% Pd/C, EtOAc, r.t., 7 h (99%).
Fig. 2. Antioxidant Activity of Olivil-Type Lignans and Tetrahydrofuran Lignans 1–4 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.
sesamol, although an effect of the tertiary hydroxy group
of the tetrahydrofuran ring on the antioxidant activity
was found. A comparison of 1 with 3 showed that the
presence of the tertiary hydroxy group reduced the
activity. This tendency was more clearly apparent
between 2 and 4, the obviously higher activity of 4
than that of compound 2 being shown. As well as in the
furofuran lignans,3) the tertiary hydroxy group on
tetrahydrofuran ring reduced the antioxidant activity.
The different effect of the phenolic groups of olivil on
the antioxidant activity was also shown, the activity of 1
being higher than that of 2. This fact suggested that the

Olivil-Type Lignans
117
phenolic group on the 40-position of olivil played a more
important role in the antioxidant activity than the
phenolic group on 4-position. It could be assumed that
the structure of the benzylic position connected to the
phenolic group was related to the degree of antioxidant
activity. In the case of olivil, the primary benzylic
position (70-position) was more important for higher
antioxidant activity than the secondary benzylic position
(7-position).
This is the first report on the relationship between the
antioxidant activity and main structure of olivil. The
different effect of three hydroxy groups of olivil on the
antioxidant activity was demonstrated for the first time.
This discovery is important to evaluate the antioxidant
activity of other lignans and will contribute to the
effective utilization of natural resources containing
lignan.
(5 ml). After concentration, the residue was dissolved in
H2O and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (20%
EtOAc/toluene) gave glycol 8 (1.87 g, 3.14 mmol, 52%)
20
as a colorless oil, ½ꢀꢂ
¼ ꢀ7:9 (c 1.1, CHCl3). IR ꢂmax
D
(CHCl3): 3590, 3029, 2967, 1781, 1727, 1518, 1466,
1
1266, 1240, 1144, 1026 cmꢀ1. H-NMR (CDCl3) ꢃ 1.18
(9H, s, tert-Bu), 2.73 (1H, br. s, OH), 2.95 (1H, m, 3-H),
3.09 (1H, s, OH), 3.84 (3H, s, OCH3), 3.858 (3H, s,
OCH3), 3.863 (3H, s, OCH3), 3.89 (1H, dd, J ¼ 12:0,
2.1, CHHOPiv), 4.42 (1H, dd, J ¼ 12:0, 4.2, CHHO-
Piv), 4.88 (1H, s, ArCHOH), 5.12 (2H, s, OCH2Ar), 5.97
(1H, d, J ¼ 5:4, 4-H), 6.81–6.89 (4H, m, ArH), 7.00
(1H, dd, J ¼ 8:3, 2.0, ArH), 7.13 (1H, d, J ¼ 2:0, ArH),
7.28–7.31 (1H, m, ArH), 7.34–7.38 (2H, m, ArH), 7.42–
7.43 (2H, m, ArH). 13C-NMR (CDCl3) ꢃ 27.0, 38.6,
49.8, 55.9, 55.96, 56.00, 60.2, 70.9, 72.8, 79.0, 80.1,
108.6, 111.1, 112.3, 113.3, 117.6, 120.6, 127.2, 127.3,
127.9, 128.5, 130.5, 136.9, 148.4, 148.8, 149.1, 149.2,
173.6, 177.7. Anal. Calcd. for C33H38O10: C, 66.65; H,
6.44. Found: C, 66.41; H, 6.48.
Experimental
Melting point data (mp) are uncorrected. NMR data
were measured by a JNM-EX400 spectrometer, IR
spectra were determined with a Shimadzu FTIR-8100
spectrophotometer, FABMS data were measured with a
JMS-MS700V spectrometer, and optical rotation values
were evaluated with a HORIBA SEPA-200 instrument.
The silica gel used was Wakogel C-300 (Wako, 200–
300 mesh). The numbering of compounds was changed
to follow IUPAC nomenclature rules.
(2R,3S,4S)-2-(4-Benzyloxy-3-methoxybenzyl)-4-(3,4-
dimethoxyphenyl)-2-hydroxy-3-pivaloyloxymethyl-4-bu-
tanolide (9). To an ice-cooled solution of glycol 8
(1.19 g, 2.00 mmol) and Et3SiH (7.14 ml, 44.7 mmol) in
CH2Cl2 (20 ml) was added CF3CO2H (0.97 ml, 12.6
mmol). The reaction solution was stirred at room
temperature for 16 h before addition of sat. aq. NaHCO3
solution. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (10% EtOAc/
(2S,3S,4S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)-
(hydroxy)methyl]-4-(3,4-dimethoxyphenyl)-2-hydroxy-3-
pivaloyloxymethyl-4-butanolide (8). To a solution of
KHMDS (30.8 ml, 0.5 M in toluene, 15.4 mmol) in THF
(150 ml) was added a solution of lactone 5 (4.71 g,
14.0 mmol) in THF (50 ml) at ꢀ70 ꢁC. After stirring at
ꢀ70 ꢁC for 15 min, a solution of 4-benzyloxy-3-me-
thoxybenzaldehyde (3.73 g, 15.4 mmol) in THF (20 ml)
was added, and then the reaction mixture was stirred at
ꢀ70 ꢁC for 1 h before addition of sat. aq. NH4Cl
solution. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (10% EtOAc/
toluene) gave aldol product 6 (6.95 g, 12.0 mmol, 86%)
as an erythro/threo mixture of 7/3. A reaction mixture
of aldol product 6 (3.49 g, 6.03 mmol) and KHSO4
(1.55 g, 11.4 mmol) in toluene (80 ml) was heated under
refluxing for 30 min. After cooling to room temperature,
H2O was added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography
(EtOAc/hexane ¼ 2=3) gave benzylidene 7 (3.38 g,
6.03 mmol, 100%) as a Z=E mixture of 8/2. A reaction
solution of benzylidene (3.38 g, 6.03 mmol), 4-methyl-
morpholine N-oxide (0.85 g, 7.26 mmol), and OsO4
(2.5 ml, 2% aq. solution) in acetone (30 ml), tert-BuOH
(10 ml), and H2O (10 ml) was stirred at room temper-
ature for 16 h before addition of Na2S2O3 (5 g) in H2O
toluene) gave ꢀ-hydroxy lactone 9 (0.58 g, 1.00 mmol,
20
50%) as a colorless oil, ½ꢀꢂ
¼ þ17 (c 0.88, CHCl3).
D
IR ꢂmax (CHCl3): 3550, 3029, 2967, 1781, 1728, 1518,
1466, 1260, 1237, 1179, 1144, 1028, 909 cmꢀ1 1H-
.
NMR (CDCl3) ꢃ 1.21 (9H, s, tert-Bu), 2.78 (1H, m, 3-
H), 2.83 (1H, s, OH), 2.85 (1H, d, J ¼ 5:1, ArCHH),
3.23 (1H, d, J ¼ 5:1, ArCHH), 3.72 (1H, dd, J ¼ 12:2,
0.5, CHHOPiv), 3.85 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.17 (1H, dd, J ¼ 12:2, 3.9,
CHHOPiv), 5.13 (2H, s, OCH2Ar), 5.99 (1H, d, J ¼ 5:9,
4-H), 6.81–6.86 (5H, m, ArH), 6.99 (1H, s, ArH), 7.30–
7.31 (1H, m, ArH), 7.34–7.38 (2H, m, ArH), 7.42–7.44
(2H, m, ArH). 13C-NMR (CDCl3) ꢃ 27.0, 37.9, 38.6,
49.5, 55.9, 56.0, 59.7, 70.9, 76.6, 80.2, 108.4, 111.2,
113.9, 114.5, 117.5, 122.7, 126.8, 127.2, 127.3, 127.8,
128.5, 137.0, 147.6, 148.9, 149.2, 149.5, 175.8, 177.7.
Anal. Calcd. for C33H38O9: C, 68.50; H, 6.62. Found: C,
68.25; H, 6.64.
(2R,3S,4R)-4-(4-Benzyloxy-3-methoxybenzyl)-2-(3,4-
dimethoxyphenyl)-4-hydroxy-3-hydroxymethyltetrahydro-
furan (10). To an ice-cooled suspension of LiAlH4
(0.27 g, 7.11 mmol) in THF (10 ml) was added a solution
of lactone 9 (0.26 g, 0.45 mmol) in THF (10 ml). The
reaction mixture was stirred at room temperature for 1 h

118
S. YAMAUCHI et al.
before additions of sat. aq. MgSO4 and K2CO3. After
stirring at room temperature for 30 min, the mixture was
filtered. The filtrate was concentrated to give crude
tetraol. The crude tetraol was dissolved in CH2Cl2
(8 ml). To this solution was added 10-camphorsulfonic
acid (5 mg). The reaction solution was stood at 2 ꢁC for
16 h before addition of a few drops of Et3N and
concentration. The residue was applied to silica gel
column chromatography (EtOAc/hexane ¼ 6=1) to give
(12). A reaction mixture of acylated oxazolidinone 11
(7.62 g, 29.4 mmol), 4-benzyloxy-3-methoxybenzalde-
hyde (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 ether. After the filtrate was concentrated, the
residue was dissolved in MeOH (100 ml), and then a few
drops of CF3CO2H was 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 anti-aldol
tetrahydrofuran derivative 10 (0.12 g, 0.25 mmol, 56%)
20
as colorless crystals, mp 144–145 ꢁC, ½ꢀꢂ
¼ þ32 (c
D
1.1, CHCl3). IR ꢂmax (CHCl3): 3631, 3011, 2900, 1514,
1466, 1264, 1237, 1161, 1142, 1028 cmꢀ1 1H-NMR
.
product 12 (14.7 g, 29.3 mmol, 99%, more than 99%
20
(CDCl3) ꢃ 2.20 (1H, s, OH), 2.51 (1H, m, 3-H), 2.96
(1H, d, J ¼ 13:7, ArCHH), 3.07 (1H, d, J ¼ 13:7,
ArCHH), 3.68 (1H, d, J ¼ 9:3, 5-HH), 3.82–3.90 (1H,
m, OCHHOH), 3.87 (3H, s, OCH3), 3.89 (6H, s, OCH3),
3.93 (1H, d, J ¼ 9:3, 5-HH), 3.94–4.00 (1H, m,
CHHOH), 4.73 (1H, d, J ¼ 7:8, 2-H), 5.15 (2H, s,
OCH2Ar), 6.76 (1H, dd, J ¼ 8:3, 2.0, ArH), 6.82–6.91
(3H, m, ArH), 6.93 (1H, d, J ¼ 8:3, ArH), 7.03 (1H, d,
J ¼ 2:0, ArH), 7.30–7.32 (1H, m, ArH), 7.35–7.39 (2H,
m, ArH), 7.43–7.45 (2H, m, ArH). 13C-NMR (sp3-C,
C5D5N) ꢃ 40.7, 55.7, 55.9, 56.0, 60.5, 62.2, 71.4, 78.1,
81.9, 84.7. 13C-NMR (sp2-C, CDCl3) ꢃ 109.4, 110.9,
114.0, 114.2, 118.7, 122.2, 127.3, 127.8, 128.5, 129.5,
134.5, 137.2, 147.3, 148.8, 149.3, 149.7. EIHRMS
(Mþ þ 1, m=z): 481.2223. Calcd. for C28H33O7:
481.2224.
d.e.) as colorless crystals, mp 124 ꢁC, ½ꢀꢂ
¼ ꢀ5:9 (c
D
1.0, CHCl3). IR ꢂmax (CHCl3): 3526, 3013, 1779, 1698,
1514, 1385, 1254, 1235, 1196, 1140, 1019, 909 cmꢀ1
.
1H-NMR (CDCl3) ꢃ 2.33 (1H, m, CH2=CH–CHH), 2.45
(1H, m, CH2=CH–CHH), 2.56 (1H, dd, J ¼ 13:7, 9.3,
ArCHH), 3.11 (1H, dd, J ¼ 13:7, 3.4, ArCHH), 3.19
(1H, d, J ¼ 7:8, OH), 3.90 (3H, s, OCH3), 4.06–4.14
(2H, m, 5-H2), 4.56 (1H, m, O=CCH), 4.63 (1H, m, 4-
H), 4.81 (1H, dd, J ¼ 7:8, 7.3, ArCHOH), 4.98–5.07
(2H, m, CH2=CH), 5.12 (2H, s, ArCH2O), 5.74 (1H, m,
CH2=CH), 6.85 (1H, d, J ¼ 8:3, ArH), 6.90 (1H, d,
J ¼ 8:3, 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) ꢃ 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. Calcd. for C30H31O6N:
C, 71.84; H, 6.23. Found: C, 71.97; H, 6.20.
(2R,3S,4R)-2-(3,4-Dimethoxyphenyl)-4-hydroxy-4-(4-
hydroxy-3-methoxybenzyl)-3-hydroxymethyltetrahydro-
furan (1). A reaction mixture of benzyl ether 10 (55 mg,
0.12 mmol) and 5% Pd/C (30 mg) in EtOAc (10 ml) was
stirred at ambient temperature for 7 h before filtration.
After the filtrate was concentrated, the residue was
applied to silica gel TLC (3% MeOH/CHCl3) to give
(4S)-4-Benzyl-3-{(R)-2-[(S)-(4-benzyloxy-3-methoxy-
phenyl)(triisopropylsilyloxy)methyl]-4-pentenoyl}-2-ox-
azolidinone (13). To an ice-cooled solution of alcohol 12
(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 in an
ice-bath for 1.5 h before addition of sat. aq. NaHCO3
solution. The organic solution was separated, washed
with sat. aq. CuSO4 solution, and brine, and dried
(Na2SO4). After concentration, the residue was recrys-
tallized from MeOH to give silyl ether 13 (5.57 g,
olivil-type lignan 1 (34 mg, 0.087 mmol, 73%) as
20
colorless crystals, mp 137–138 ꢁC, ½ꢀꢂ
¼ þ29 (c
D
0.31, CHCl3). IR ꢂmax (CHCl3): 3548, 3011, 2938, 1514,
1466, 1269, 1240, 1161, 1140, 1038, 909 cmꢀ1 1H-
.
NMR (CDCl3) ꢃ 1.77 (1H, br. s, OH), 2.26 (1H, s, OH),
2.50 (1H, m, 3-H), 2.94 (1H, d, J ¼ 13:9, ArCHH), 3.05
(1H, d, J ¼ 13:9, ArCHH), 3.68 (1H, d, J ¼ 8:8, 5-HH),
3.82 (1H, dd, J ¼ 10:3, 5.4, CHHOH), 3.866 (3H, s,
OCH3), 3.877 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.93
(1H, d, J ¼ 8:8, 5-HH), 3.96 (1H, dd, J ¼ 10:3, 6.9,
CHHOH), 4.73 (1H, d, J ¼ 7:8, 2-H), 5.62 (1H, s,
ArOH), 6.77 (1H, dd, J ¼ 7:8, 2.0, ArH), 6.81–6.92 (4H,
m, ArH), 7.02 (1H, d, J ¼ 1:5, ArH). 13C-NMR (sp3-C,
C5D5N) ꢃ 40.7, 55.7, 55.8, 56.0, 60.5, 62.1, 78.2, 82.0,
84.8. 13C-NMR (sp2-C, CDCl3) ꢃ 109.4, 110.9, 112.8,
114.4, 118.6, 122.9, 128.2, 134.4, 144.7, 146.5, 148.8,
149.2. EIHRMS (Mþ, m=z): 390.1680. Calcd. for
C21H26O7: 390.1678.
8.47 mmol, 78%) as colorless crystals, mp 115 ꢁC,
20
½ꢀꢂ
¼ ꢀ27:1 (c 1.33, CHCl3). IR ꢂmax (CHCl3):
D
2946, 2869, 1781, 1698, 1510, 1466, 1455, 1385, 1350,
1254, 1235, 1196, 1098, 1065, 1017, 909 cmꢀ1 1H-
.
NMR (CDCl3) ꢃ 0.91–0.99 (21H, m, iso-pr), 1.90 (1H,
m, CH2=CH–CHH), 2.13 (1H, m, CH2=CH–CHH),
2.61 (1H, dd, J ¼ 11:2, 3.2, ArCHH), 3.53 (1H, dd,
J ¼ 13:2, 2.9, ArCHH), 3.92 (3H, s, OCH3), 4.06 (1H,
dd, J ¼ 8:8, 8.8, 5-HH), 4.11 (1H, dd, J ¼ 8:8, 2.4, 5-
HH), 4.54 (1H, m, O=CCH), 4.60 (1H, m, 4-H), 4.87–
4.94 (2H, m, CH2=CH), 5.04 (1H, d, J 8.8, ArCHOH),
5.14 (2H, s, ArCH2O), 5.57 (1H, m, CH2=CH), 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) ꢃ 12.6, 17.9, 18.1, 34.3, 38.4, 51.4,
(4S)-4-Benzyl-3-{(R)-2-[(S)-(4-benzyloxy-3-methoxy-
phenyl)(hydroxy)methyl]-4-pentenoyl}-2-oxazolidinone

Olivil-Type Lignans
119
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. Calcd. for
C39H31O6NSi: C, 71.20; H, 7.81; N, 2.13. Found: C,
71.32; H, 8.10; N, 2.10.
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. Calcd. for
C34H32O5: C, 71.79; H, 9.21. Found: C, 71.89; H, 9.37.
(3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-3-pivaloyl-
oxymethyl-4-(triisopropylsilyloxy)butanal (16). A reac-
tion mixture of olefin 15 (14.5 g, 25.5 mmol), NMO
(3.69 g, 31.5 mmol), and OsO4 (2 ml, 2% aq. solution) in
acetone (150 ml), tert-BuOH (40 ml), and H2O (40 ml)
was stirred at room temperature for 16 h under N2 gas in
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 dis-
solved 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
(2S)-2-[(S)-(4-Benzyloxy-3-methoxyphenyl)(triisopro-
pylsilyloxy)methyl]-4-penten-1-ol (14). 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
acyl oxazolidinone 13 (36.3 g, 55.2 mmol) in THF (200
ml). The reaction solution was stirred at room temper-
ature for 16 h before addition of sat. aq. 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 silica
gel column chromatography (EtOAc=hexane ¼ 1=9)
gave alcohol 14 (16.2 g, 33.4 mmol, 61%) as a colorless
20
oil, ½ꢀꢂ
¼ ꢀ45 (c 1.4, CHCl3). IR ꢂmax (CHCl3):
D
3500, 2946, 2869, 1512, 1466, 1260, 1140, 1084, 1036,
1
1015, 884 cmꢀ1. H-NMR (CDCl3) ꢃ 0.96–1.02 (21H,
m, iso-Pr), 1.83–1.96 (2H, m, 2-H, OH), 2.18 (1H, m,
CH2=CH–CHH), 2.65 (1H, m, CH2=CH–CHH), 3.58
(1H, m, 1-HH), 3.79 (1H, m, 1-HH), 3.88 (3H, s, OCH3),
4.85 (1H, d, J ¼ 5:4, ArCHOTIPS), 4.98–5.14 (2H, m,
CH2=CH), 5.14 (2H, s, ArCH2O), 5.73 (1H, m,
CH2=CH), 6.57 (1H, dd, J ¼ 8:3, 1.5, ArH), 6.82
(1H, d, J ¼ 8:3, ArH), 6.95 (1H, d, J ¼ 1:5, 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) ꢃ 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. Calcd. for C29H44O4Si: C, 71.85; H, 9.15.
Found: C, 72.03; H, 9.12.
(EtOAc/hexane ¼ 1=8) to give aldehyde 16 (13.6 g,
20
21.9 mmol, 86%) as a colorless oil, ½ꢀꢂ
¼ ꢀ9:5 (c
D
1.1, CHCl3). IR ꢂmax (CHCl3): 2946, 2869, 1725, 1512,
1464, 1283, 1262, 1233, 1161, 1142, 1088, 909 cmꢀ1
.
1H-NMR (CDCl3) ꢃ 0.95–1.01 (21H, m, iso-Pr), 1.22
(9H, s, tert-Bu), 2.05 (1H, ddd, J ¼ 16:6, 6.1, 1.0, 2-
HH), 2.50 (1H, ddd, J ¼ 16:6, 6.6, 2.7, 2-HH), 2.89 (1H,
m, 3-H), 3.88 (3H, s, OCH3), 3.88 (1H, dd, J ¼ 11:2,
8.3, PivOCHH), 3.98 (1H, dd, J ¼ 11:2, 5.9, Piv-
OCHH), 4.97 (1H, d, J ¼ 5:4, ArCHOTIPS), 5.13 (2H,
s, ArCH2O), 6.66 (1H, dd, J ¼ 8:3, 1.5, ArH), 6.82 (1H,
d, J ¼ 8:3, ArH), 6.87 (1H, d, J ¼ 1:5, 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) ꢃ 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. Calcd. for C37H30O6Si: C,
69.43; H, 8.83. Found: C, 69.51; H, 8.65.
(4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-4-pivaloyl-
oxymethyl-5-(triisopropylsilyloxy)-1-pentene (15). To an
ice-cooled solution of alcohol 14 (16.2 g, 33.4 mmol)
and pyridine (5.41 mmol, 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 aq. HCl solution and
brine, and dried (Na2SO4). Concentration and silica gel
column chromatography (5% EtOAc in hexane) gave
(3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-3-pivaloyl-
oxymethyl-4-butanolide (17). To an ice-cooled solution
of silyl ether 16 (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, sat. aq. NH4Cl solution was added. The organic
solution was separated, washed with brine, and dried
(Na2SO4). After concentration, the residue was applied
to silica gel column chromatography (EtOAc/hexane ¼
1=2) to give 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 the addition of dry ether.
After the mixture was filtered, the filtrate was concen-
trated. The residue was applied to silica gel column
chromatography (EtOAc/hexane ¼ 1=4) to give lactone
pivaloyl ester 15 (19.1 g, 33.5 mmol, 100%) as a
20
colorless oil, ½ꢀꢂ
¼ ꢀ8:9 (c 1.5, CHCl3). IR ꢂmax
D
(CHCl3): 2946, 2869, 1721, 1510, 1464, 1285, 1262,
1
1163, 1140, 1092 cmꢀ1. H-NMR (CDCl3) ꢃ 0.96–1.01
(21H, m, iso-Pr), 1.23 (9H, s, tert-Bu), 1.54 (1H, m, 4-
H), 2.21 (1H, m, 3-HH), 2.36 (1H, m, 3-HH), 3.81 (1H,
dd, J ¼ 11:2, 8.3, PivOCHH), 3.86 (3H, s, OCH3), 4.16
(1H, dd, J ¼ 11:2, 4.4, PivOCHH), 4.91–4.98 (3H, m, 1-
H2, 5-H), 5.13 (2H, s, ArCH2O), 5.72 (1H, m, 2-H), 6.69
(1H, dd, J ¼ 8:3, 2.0, ArH), 6.81 (1H, d, J ¼ 8:3, ArH),
6.89 (1H, d, J ¼ 2:0, ArH), 7.26–7.38 (3H, m, ArH),
7.43–7.45 (2H, m, ArH). 13C-NMR (CDCl3) ꢃ 12.4,
18.0, 18.1, 27.3, 30.2, 38.8, 45.8, 55.9, 63.9, 71.1, 73.9,

120
S. YAMAUCHI et al.
17 (6.78 g, 16.4 mmol, 82%) as colorless crystals, mp
20
148.7, 149.3, 149.9, 173.6, 177.7. Anal. Calcd. for
C33H38O10: C, 66.65; H, 6.44. Found: C, 66.35; H, 6.55.
94 ꢁC (iso-Pr2O), ½ꢀꢂ
¼ ꢀ34 (c 1.1, CHCl3). IR ꢂmax
D
(CHCl3): 3031, 2973, 1782, 1727, 1516, 1279, 1260,
1
1233, 1167, 1144, 1034, 1022 cmꢀ1. H-NMR (CDCl3)
(2R,3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-2-(3,4-
dimethoxybenzyl)-2-hydroxy-3-pivaloyloxymethyl-4-bu-
tanolide (19). ꢀ-Hydroxy lactone 19 was obtained from
ꢃ 1.14 (9H, s, tert-Bu), 2.57 (1H, dd, J ¼ 17:3, 4.2, 2-
HH), 2.82 (1H, dd, J ¼ 17:3, 8.5, 2-HH), 3.04 (1H, m,
3-H), 3.64 (1H, dd, J ¼ 11:5, 6.6, PivOCHH), 3.86 (1H,
dd, J ¼ 11:5, 5.4, PivOCHH), 3.87 (3H, s, OCH3), 5.13
(2H, s, ArCH2O), 5.62 (1H, d, J ¼ 6:8, 4-H), 6.75 (1H,
dd, J ¼ 7:8, 2.0, ArH), 6.81 (1H, d, J ¼ 2:0, ArH), 6.88
(1H, d, J ¼ 7:8, ArH), 7.27–7.38 (3H, m, ArH), 7.42–
7.44 (2H, m, ArH). 13C-NMR (CDCl3) ꢃ 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. Calcd. for C24H28O6: C, 69.88; H, 6.84.
Found: C, 69.94; H, 6.95.
18 by the same method as that described above in 51%
20
yield as colorless crystals, mp 152 ꢁC (MeOH), ½ꢀꢂ
¼
D
þ35 (c 1.2, CHCl3). IR ꢂmax (CHCl3): 3548, 3029, 2965,
1781, 1728, 1516, 1466, 1264, 1238, 1181, 1146, 1028
1
cmꢀ1. H-NMR (CDCl3) ꢃ 1.21 (9H, s, tert-Bu), 2.53
(1H, s, OH), 2.80 (1H, m, 3-H), 2.88 (1H, d, J ¼ 5:1,
ArCHH), 3.22 (1H, d, J ¼ 5:1, ArCHH), 3.74 (1H, dd,
J ¼ 12:2, 2.9, CHHOPiv), 3.86 (3H, s, OCH3), 3.88
(3H, s, OCH3), 3.89 (3H, s, OCH3), 4.17 (1H, dd, J ¼
12:2, 4.1, OCHHOPiv), 5.14 (2H, s, OCH2Ar), 5.98 (1H,
d, J ¼ 5:9, 4-H), 6.79–6.90 (5H, m, ArH), 6.97 (1H, s,
ArH), 7.30–7.32 (1H, m, ArH), 7.35–7.38 (2H, m, ArH),
7.42–7.44 (2H, m, ArH). 13C-NMR (CDCl3) ꢃ 27.0,
37.8, 38.6, 49.4, 55.79, 55.82, 56.1, 59.6, 71.0, 76.6,
80.2, 109.0, 111.2, 113.8, 114.0, 117.5, 122.7, 126.3,
127.2, 127.3, 127.85, 127.94, 128.4, 128.5, 136.7, 148.0,
148.4, 148.8, 149.8, 175.8, 177.6. Anal. Calcd. for
C33H38O9: C, 68.50; H, 6.62. Found: C, 68.22; H, 6.67.
(2S,3S,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-2-[(S)-
(3,4-dimethoxyphenyl)(hydroxy)methyl]-2-hydroxy-3-
pivaloyloxymethyl-4-butanolide (18). Aldol condensa-
tion of lactone 17 with 3,4-dimethoxybenzaldehyde by
the same method as that described above gave aldol
product in 81% yield as an erythro/threo mixture of 1/1
as a colorless oil. Z-Benzylidene was obtained from the
resulting aldol product by the same method as that
described for dehydration of 6 and recrystallization from
20
(2R,3S,4R)-2-(4-Benzyloxy-3-methoxyphenyl)-4-(3,4-
dimethoxybenzyl)-4-hydroxy-3-hydroxymethyltetrahydro-
furan (20). Tetrahydrofuran derivative 20 was obtained
from 19 by the same method as that described above in
EtOH, mp 110 ꢁC, in 62% yield, ½ꢀꢂ
¼ þ11 (c 0.35,
D
CHCl3). IR ꢂmax (CHCl3): 3013, 1744, 1728, 1516,
1
1275, 1146 cmꢀ1. H-NMR (CDCl3) ꢃ 1.11 (9H, s, tert-
Bu), 3.59 (1H, m, 3-H), 3.83–3.94 (2H, m, CH2OPiv),
3.88 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.96 (3H, s,
OCH3), 5.15 (2H, s, OCH2Ar), 5.67 (1H, d, J ¼ 6:8, 4-
H), 6.81 (1H, d, J ¼ 8:3, ArH), 6.86–6.90 (3H, m, ArH),
6.93 (1H, s, ArH), 7.26–7.32 (2H, m, ArH), 7.35–7.38
(2H, m, ArH), 7.42–7.44 (2H, m, ArH), 8.21 (1H, d,
J ¼ 1:5, C=CHAr). 13C-NMR (CDCl3) ꢃ 27.0, 38.7,
47.2, 55.8, 55.9, 56.1, 63.6, 71.1, 79.4, 109.3, 110.3,
113.7, 114.0, 118.1, 123.0, 126.1, 126.7, 127.2, 127.9,
128.1, 128.5, 136.9, 142.0, 148.2, 148.5, 149.9, 150.9,
168.6, 178.0. Anal. Calcd. for C33H36O8: C, 70.70; H,
6.47. Found: C, 70.63; H, 6.59. Glycol 18 was obtained
56% yield as colorless crystals, mp 153–154 ꢁC,
20
½ꢀꢂ
¼ þ19 (c 2.0, CHCl3). IR ꢂmax (CHCl3): 3679,
D
3011, 2945, 1732, 1516, 1466, 1264, 1242, 1142,
1028 cmꢀ1 1H-NMR (CDCl3) ꢃ 1.63 (1H, s, OH),
.
2.21 (1H, s, OH), 2.51 (1H, m, 3-H), 2.96 (1H, d,
J ¼ 3:7, ArCHH), 3.08 (1H, d, J ¼ 3:7, ArCHH), 3.68
(1H, d, J ¼ 9:3, 5-HH), 3.81–3.99 (2H, m, CH2OH),
3.879 (3H, s, OCH3), 3.882 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 3.93 (1H, d, J ¼ 9:3, 5-HH), 4.72 (1H, d,
J ¼ 8:3, 2-H), 5.15 (2H, s, OCH2Ar), 6.83–6.84 (5H, m,
ArH), 7.04 (1H, s, ArH), 7.29–7.31 (1H, m, ArH), 7.34–
7.37 (2H, m, ArH), 7.42–7.44 (2H, m, ArH); 13C-NMR
(CDCl3) ꢃ 39.1, 55.90, 55.92, 56.0, 58.9, 60.7, 71.1,
77.2, 81.3, 83.0, 109.9, 111.3, 113.5, 113.8, 118.6,
122.2, 127.2, 127.8, 128.5, 128.9, 135.0, 137.1, 147.9,
148.1, 148.9, 149.9. EIHRMS (Mþ þ 1, m=z): 481.2226.
Calcd. for C28H33O7: 481.2224.
from Z-benzylidene by the same method as that
20
described above in 66% yield as a colorless oil, ½ꢀꢂ
¼
D
ꢀ6:4 (c 0.78, CHCl3). IR ꢂmax (CHCl3): 3598, 3027,
2967, 1781, 1727, 1516, 1262, 1233, 1179, 1144,
1
1026 cmꢀ1. H-NMR (CDCl3) ꢃ 1.18 (9H, s, tert-Bu),
2.63 (1H, d, J ¼ 4:2, ArCHOH), 2.95–2.97 (1H, m, 3-
H), 2.96 (1H, s, OH), 3.85 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 3.87 (3H, s, OCH3), 3.88 (1H, dd, J ¼ 12:0, 2.6,
CHHOPiv), 4.44 (1H, dd, J ¼ 12:0, 4.2, CHHOPiv),
4.90 (1H, d, J ¼ 4:2, ArCHOH), 5.13 (2H, s, OCH2Ar),
5.97 (1H, d, J ¼ 5:4, 4-H), 6.79 (1H, d, J ¼ 8:3, ArH),
6.85–6.88 (2H, m, ArH), 7.07 (1H, d, J ¼ 8:3, ArH),
7.10 (1H, s, ArH), 7.26–7.32 (2H, m, ArH), 7.34–7.38
(2H, m, ArH), 7.42–7.43 (2H, m, ArH); 13C-NMR
(CDCl3) ꢃ 27.1, 38.6, 49.8, 55.8, 55.9, 56.2, 60.2, 71.1,
72.9, 79.0, 80.0, 109.2, 110.8, 111.7, 114.0, 117.6,
120.6, 127.3, 127.9, 128.0, 128.5, 129.9, 136.8, 148.0,
(2R,3S,4R)-4-(3,4-Dimethoxybenzyl)-4-hydroxy-2-(4-
hydroxy-3-methoxyphenyl)-3-hydroxymethyltetrahydro-
furan (2). Olivil-type lignan 2 was obtained from 20 by
the same method as that described above in 61% yield as
20
colorless crystals, mp 211–212 ꢁC, ½ꢀꢂ
¼ þ19 (c
D
1
0.26, C5H5N); H-NMR (DMSO-d6) ꢃ 2.14 (1H, m, 3-
H), 2.80 (1H, d, J ¼ 13:7, ArCHH), 2.88 (1H, d,
J ¼ 13:7, ArCHH), 3.43 (1H, d, J ¼ 8:8, 5-HH), 3.56
(1H, dd, J ¼ 11:0, 6.1, CHHOH), 3.62 (1H, d, J ¼ 8:8,
5-HH), 3.67 (1H, dd, J ¼ 11:0, 4.9, CHHOH), 3.72 (3H,
s, OCH3), 3.73 (3H, s, OCH3), 3.74 (3H, s, OCH3), 4.60

Olivil-Type Lignans
121
1
(1H, d, J ¼ 7:3 Hz, 2-H), 6.69 (1H, d, J ¼ 8:3, ArH),
6.77–6.90 (4H, m, ArH), 7.03 (1H, d, J ¼ 1:5, ArH),
8.79 (1H, br. s, ArOH); 13C-NMR (sp3-C, C5H5N) ꢃ
40.6, 55.7, 55.8, 55.9, 60.4, 62.2, 78.0, 81.9, 84.8; 13C-
NMR (sp2-C, DMSO-d6) ꢃ 110.9, 111.3, 114.3, 114.7,
119.2, 122.1, 130.9, 134.4, 145.6, 147.1, 147.2, 148.0.
EIHRMS (Mþ, m=z): 390.1687. Calcd. for C21H26O7:
390.1678.
1516, 1466, 1267, 1238, 1159, 1140, 1028 cmꢀ1. H-
NMR (CDCl3) ꢃ 1.30 (1H, br. s, CH2OH), 2.01 (1H, m,
4-H), 2.50 (1H, m, 3-H), 2.69 (1H, dd, J ¼ 13:7, 8.3,
ArCHH), 2.79 (1H, dd, J ¼ 13:7, 6.8, ArCHH), 3.64
(2H, d, J ¼ 5:4, CH2OH), 3.84–3.88 (1H, m, 5-HH),
3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 3.96 (1H, dd, J ¼ 8:8, 7.3, 5-HH), 4.63 (1H, d,
J ¼ 7:8, 2-H), 5.52 (1H, s, ArOH), 6.66–6.67 (2H, m,
ArH), 6.82–6.85 (2H, m, ArH), 6.91–6.95 (2H, m, ArH).
13C-NMR (CDCl3) ꢃ 39.4, 44.2, 55.4, 55.89, 55.91, 62.9,
73.0, 84.0, 109.3, 111.0, 111.2, 114.4, 118.5, 121.3,
132.0, 134.6, 144.0, 146.5, 148.5, 149.1. EIHRMS
(Mþ þ 1, m=z): 375.1807. Calcd. for C21H27O6:
375.1807.
(2R,3S,4R)-4-(4-Benzyloxy-3-methoxybenzyl)-2-(3,4-
dimethoxyphenyl)-3-hydroxymethyltetrahydrofuran (22).
To a solution of aldol product 6 (2.02 g, 3.49 mmol) and
Et3SiH (0.84 ml, 5.26 mmol) in CH2Cl2 (20 ml) was
ꢁ
.
added BF3 OEt2 (0.49 ml, 3.87 mmol) at 2 C. After the
reaction solution was stirred at 2 ꢁC for 1 h, sat. aq.
NaHCO3 solution was added. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane ¼ 1=2) gave lactone 21 (1.08
g, 1.92 mmol, 55%) as a mixture of benzylic epimers
(1/1) as a colorless oil. To a suspension of LiAlH4
(55 mg, 1.45 mmol) in THF (10 ml) was added a solution
of lactone 22 (0.69 g, 1.23 mmol) in THF (10 ml). The
reaction mixture was stirred at room temperature for 1 h,
and then sat. aq. MgSO4 and K2CO3 were added. After
stirring for 30 min, the mixture was filtered. The filtrate
was concentrated to give crude triol. A solution of this
crude triol and 10-camphorsulfonic acid (5 mg) in
CH2Cl2 (8 ml) was stirred at room temperature for
40 h before addition of a few drops of Et3N. After
concentration, the residue was applied to silica gel
column chromatography (EtOAc/hexane ¼ 1=1) to give
(2R,3S,4R)-2-(4-Benzyloxy-3-methoxyphenyl)-4-(3,4-
dimethoxybenzyl)-3-hydroxymethyltetrahydrofuran (23).
Tetrahydrofuran derivative 23 was obtained from aldol
product by the same method as that described above in
20
28% yield through 3 steps as a colorless oil, ½ꢀꢂ
¼
D
þ4:0 (c 0.50, CHCl3). IR ꢂmax (CHCl3): 3500, 3013,
2938, 1516, 1466, 1262, 1238, 1140, 1028 cmꢀ1. H-
1
NMR (CDCl3) ꢃ 1.50 (1H, br. s, OH), 1.99 (1H, m, 4-H),
2.49 (1H, m, 3-H), 2.68 (1H, dd, J ¼ 13:7, 8.8, ArCHH),
2.79 (1H, dd, J ¼ 13:7, 6.8, ArCHH), 3.61 (2H, d,
J ¼ 5:9, CH2OH), 3.82–3.85 (1H, m, 5-HH), 3.84 (6H,
s, OCH3), 3.90 (3H, s, OCH3), 3.94 (1H, dd, J ¼ 8:8,
7.3, 5-HH), 4.61 (1H, d, J ¼ 7:8, 2-H), 5.13 (2H, s,
OCH2Ph), 6.67–6.70 (2H, d, J ¼ 2:0, ArH), 6.77 (1H, d,
J ¼ 8:3, ArH), 6.84 (2H, s, ArH), 6.97 (1H, s, ArH),
7.27–7.30 (1H, m, ArH), 7.33–7.37 (2H, m, ArH), 7.42–
7.43 (2H, m, ArH). 13C-NMR (CDCl3) ꢃ 39.2, 44.0,
47.1, 55.3, 55.8, 56.0, 62.7, 71.0, 72.9, 83.8, 109.9,
111.2, 111.9, 113.9, 118.4, 120.6, 127.2, 127.7, 128.4,
132.7, 135.2, 137.1, 147.4, 147.6, 148.8, 149.7.
EIHRMS (Mþ, m=z): 464.2199. Calcd. for C28H32O6:
464.2199.
tetrahydrofuran derivative 22 (0.29 g, 0.62 mmol, 50%)
20
as a colorless oil, ½ꢀꢂ
¼ ꢀ9:9 (c 0.50, CHCl3). IR
D
ꢂmax (CHCl3): 3283, 3017, 1516, 1466, 1456, 1264,
1
1237, 1192, 1140, 1028 cmꢀ1. H-NMR (CDCl3) ꢃ 1.64
(1H, br. s, OH), 1.99 (1H, m, 4-H), 2.50 (1H, m, 3-H),
2.69 (1H, dd, J ¼ 13:7, 8.8, ArCHH), 2.79 (1H, dd,
J ¼ 13:7, 6.8, ArCHH), 3.62 (2H, d, J ¼ 5:4, CH2OH),
3.84 (1H, dd, J ¼ 8:8, 5.4, 5-HH), 3.86 (3H, s, OCH3),
3.87 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.91 (1H, dd,
J ¼ 8:8, 7.2, 5-HH), 4.63 (1H, d, J ¼ 7:8, 2-H), 5.11
(2H, s, OCH2Ar), 6.64 (1H, dd, J ¼ 7:8, 2.0, ArH), 6.70
(1H, d, J ¼ 2:0, ArH), 6.79–6.84 (2H, m, ArH), 6.90–
6.95 (2H, m, ArH), 7.27–7.31 (1H, m, ArH), 7.34–7.37
(2H, m, ArH), 7.42–7.44 (2H, m, ArH); 13C-NMR
(CDCl3) ꢃ 39.3, 44.0, 55.4, 55.87, 55.90, 56.0, 62.8,
71.1, 73.0, 83.9, 109.3, 111.0, 112.5, 114.3, 118.5,
120.6, 127.3, 127.8, 128.5, 133.4, 134.6, 137.2, 146.7,
148.5, 149.1, 149.6. Anal. Calcd. for C28H32O6: C,
72.39; H, 6.94. Found: C, 71.91; H, 6.93.
(2R,3S,4R)-4-(3,4-Dimethoxybenzyl)-2-(4-hydroxy-3-
methoxyphenyl)-3-hydroxymethyltetrahydrofuran (4).
Hydrogenolysis of 23 was performed by the same
method as that described above to give tetrahydrofuran
20
lignan 4 in 99% yield as a colorless oil, ½ꢀꢂ
¼ ꢀ4:2
D
(c 0.71, CHCl3). IR ꢂmax (CHCl3): 3545, 3011, 2940,
1
1516, 1460, 1264, 1240, 1157, 1142, 1030 cmꢀ1. H-
NMR (CDCl3) ꢃ 1.70 (1H, br. s. OH), 1.99 (1H, m, 4-H),
2.51 (1H, m, 3-H), 2.69 (1H, dd, J ¼ 13:7, 8.3, ArCHH),
2.81 (1H, dd, J ¼ 13:7, 6.8, ArCHH), 3.63 (2H, d,
J ¼ 5:4, CH2OH), 3.83–3.87 (1H, m, 5-HH), 3.851 (3H,
s, OCH3), 3.855 (3H, s, OCH3), 3.89 (3H, s, OCH3),
3.96 (1H, dd, J ¼ 8:8, 7.3, 5-HH), 4.60 (1H, d, J ¼ 7:8,
2-H), 5.69 (1H, s, ArOH), 6.68–6.72 (2H, m, ArH), 6.78
(1H, d, J ¼ 8:3, ArH), 6.85–6.89 (2H, m, ArH), 6.92
(1H, s, ArH). 13C-NMR (CDCl3) ꢃ 39.2, 44.0, 55.5, 55.8,
55.9, 62.7, 72.9, 84.0, 108.7, 111.2, 111.9, 114.2, 119.2,
120.6, 132.7, 133.9, 145.1, 146.6, 147.5, 148.9.
EIHRMS (Mþ, m=z): 374.1728. Calcd. for C21H26O6:
374.1729.
(2R,3S,4R)-2-(3,4-Dimethoxyphenyl)-4-(4-hydroxy-3-
methoxybenzyl)-3-hydroxymethyltetrahydrofuran (3).
Hydrogenolysis of 22 was performed by the same
method as that described above to give tetrahydrofuran
20
lignan 3 in 96% yield as a colorless oil, ½ꢀꢂ
¼ þ8:3
D
(c 0.60, CHCl3). IR ꢂmax (CHCl3): 3528, 3011, 2938,

122
S. YAMAUCHI et al.
Their Effects on Health II’’, eds. Huang, M.-T., Ho,
C.-T., and Lee, C. Y., American Chemical Society,
Washington, DC, pp. 135–149 (1992).
Examination of the antioxidant activity of olivil
derivatives 1 and 2 and related compounds 3 and 4.
The method of Masuda et al.10) was slightly modified.
To 160 ml of the DMSO solution of a test sample
(5.0 mM) were added freshly purified ethyl linoleate
(139 ml) and 0.3 M Tween 20–0.05 M phosphate buffer
(pH 7.4, 8 ml). The mixture was vigorously stirred by 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 dia.; 75 mm height),
and 100 ml 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, 20-ml aliquot was
taken from the solution and poured into 380 ml 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 ꢃ 150 mm); solvent, CH3CN–H2O=9:1;
flow rate, 1.0 ml/min; detection, 234 nm. The concen-
tration of the hydroperoxide was calculated from the
peak area obtained by the following equation: Y ¼
2:29X ꢃ 10ꢀ6 ꢀ 4:38 ꢃ 10ꢀ4, where Y is the concen-
tration of ethyl linoleate hydroperoxide (mM) and X is
the peak area of hydroperoxide.
2) Shahid, F., Janitha, P. K., and Wanasundara, P. D.,
Phenolic antioxidants. Crit. Rev. Food Sci. Nutri., 32,
67–103 (1992).
3) Yamauchi, S., Ina, T., Kirikihira, T., and Masuda, T.,
Synthesis and antioxidant activity of oxygenated furo-
furan lignans. Biosci. Biotechnol. Biochem., 68, 183–192
(2004).
4) Ayres, D. C., and Loike, J. D., ‘‘Lignans’’, Cambridge
University Press, Cambridge (1990).
5) Yamauchi, S., and Kinoshita, Y., Stereoselective model
synthesis of the optically active olivil type of lignan
from D-xylose. Biosci. Biotechnol. Biochem., 64, 1563–
1571 (2000).
6) Yamauchi, S., and Kinoshita, Y., Synthesis of optically
active olivil type of lignan from L-arabinose using threo-
selective aldol condensation as a key reaction. Biosci.
Biotechnol. Biochem., 64, 2320–2327 (2000).
7) Yamauchi, S., and Uno, H., Synthesis of the stereo-
isomers of neolignans morinol C and D. Org. Biomol.
Chem., 1, 1323–1329 (2003).
8) Carey, F. A., and Tremper, H. S., Carbonium ion-silane
hydride transfer reaction II. The 2-phenyl-2-norbornyl
cation. J. Org. Chem., 34, 4–6 (1969).
9) Maioli, A. T., Civiello, R. L., Foxman, B. M., and
Gordon, D. M., Asymmetric synthesis of sesaminone:
confirmation of its structure and determination of its
absolute configuration. J. Org. Chem., 62, 7413–7417
(1997).
10) Evans, D. A., Tedrow, J. S., Shaw, J. T., and Downey, C.
W., Diastereoselective magnesium halide-catalyzed anti-
aldol reactions of chiral N-acyloxazolidinones. J. Am.
Chem. Soc., 124, 392–393 (2002).
11) Kraus, G. A., Frazier, K. A., Roth, B. D., Taschner, M.
J., and Neuenschwander, K., Conversion of lactones into
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Takeda, Y., Nakamoto, K., Kuninaga, H., Nishizato, S.,
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Acknowledgments
We measured the 400 MHz NMR data at INCS,
Ehime University. We thank the staff of this center for
the FAB measurements. We are grateful to Marutomo
Co. for financial support.
References
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