Stereoselective syntheses of all stereoisomers of lariciresinol and their plant growth inhibitory activities

Article abstract of DOI:10.1021/jf203222w

All stereoisomers of lariciresinol were synthesized to examine the effect of stereochemistry on plant growth. Configuration of benzylic 7-positions was constructed through S_N1 or S_N2 intramolecular etherification. 8- and 8′-position configurations were established from the starting material except for all cis stereoisomers, the 8-position configurations of which were achieved by employing stereoselective hydroboration. (-)-Lariciresinol and its 7S,8S,8′R stereoisomer inhibited the root growth of Italian ryegrass to 51-55% relative to the negative control, whereas other stereoisomers had less effect. These results demonstrate that the stereochemistry of lignans is one of the important factors influencing their inhibitory activity.

Full text of DOI:10.1021/jf203222w

ARTICLE
pubs.acs.org/JAFC
Stereoselective Syntheses of All Stereoisomers of Lariciresinol and
Their Plant Growth Inhibitory Activities
Hisashi Nishiwaki, Mitsuko Kumamoto, Yoshihiro Shuto, and Satoshi Yamauchi*
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
ABSTRACT: All stereoisomers of lariciresinol were synthesized to examine the effect of stereochemistry on plant growth.
Configuration of benzylic 7-positions was constructed through SN1 or SN2 intramolecular etherification. 8- and 80-position
configurations were established from the starting material except for all cis stereoisomers, the 8-position configurations of which
were achieved by employing stereoselective hydroboration. (ꢀ)-Lariciresinol and its 7S,8S,80R stereoisomer inhibited the root
growth of Italian ryegrass to 51ꢀ55% relative to the negative control, whereas other stereoisomers had less effect. These results
demonstrate that the stereochemistry of lignans is one of the important factors influencing their inhibitory activity.
KEYWORDS: lariciresinol, lignan, plant growth inhibitory, lettuce, Italian ryegrass
and Aldrich Chemical Co. (Milwaukee, WI). Melting points were
uncorrected. Optical rotations were measured on a Horiba SEPA-200
instrument. NMR data were obtained using a JNM-EX400 spectrom-
eter. EI and FABMS data were measured with a JMS-MS700 V
spectrometer. The silica gel used was Wakogel C-300 (Wako, 200ꢀ300 mesh).
HPLC analysis for compounds 1ꢀ8 was performed with Shimadzu LC-
6AD and SPD-6AV instruments. The column used for HPLC analyses
was a 250 mm ꢁ 4.6 mm i.d., 5 μm, CHIRALCEL AD-H (DAICEL
Chemical Industries, Ltd., Tokyo, Japan). The numbering of com-
pounds follows the nomenclature of lignans.15
’ INTRODUCTION
Among natural plant products, the lignan family is one of
the most attractive chemical groups because of not only their
original structures, including C6ꢀC3 units with asymmetric carbon
atoms, but also their activities to various biological species
including plants, insects, and microorganisms and anticancer
activity.1,2 Various types of lignans have been isolated from plants
to evaluate their bioactivity, and many reports of their syntheses
have been published. Numerous studies on lignans are still being
conducted; for example, a novel lignan with a unique epoxy
structure was recently discovered.3 We have also analyzed the
structureꢀactivity relationship (SAR) of various lignans using
enantiomerically pure compounds to demonstrate clear differences
in biological activity depending on their absolute structures.4ꢀ6
In the field of natural products chemistry, the collation of stereo-
isomer libraries is necessary to study the relationship between
stereochemistry and biological activity.
(ꢀ)- and (+)-lariciresinol, 1 and 2, respectively (Figure 1), are
trisubstituted tetrahydrofuran lignans that are biosynthesized by
plants.7 (ꢀ)-Lariciresinol reportedly shows plant growth inhib-
itory activity, and (()-lariciresinol inhibits lettuce germination.8ꢀ10
However, the effect of the compound’s stereochemistry on its
activity has not been evaluated, probably due to the difficulty in
isolating enantiomerically pure lariciresinol.11,12 To elucidate the
role of stereochemistry in the bioactivity of lariciresinol, we
developed a synthetic pathway to all stereoisomers of lariciresinol,
1ꢀ8 (Figure 1). In addition, their plant growth regulatory activity
was evaluated. This is the first report on the syntheses of all
stereoisomers of lariciresinol and the relationship between
lariciresinol stereochemistry and plant regulatory activity.
(7R,8S,80S)-3,30-Dimethoxy-7,90-epoxylignane-4,40,9-triol, (ꢀ)-
Lariciresinol (1). The title compound was synthesized according to the
described method:13 >99% ee (AD-H, iso-PrOH/hexane = 1:2 (v/v),
1 mL/min, 280 nm, tR11 min).
(7S,8R,80R)-Stereoisomer, (+)-lariciresinol (2): >99% ee (AD-H, iso-
PrOH/hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR10 min.
(70S,8R,80S)-4,40-Dibenzyloxy-3,30-dimethoxy-90-(triisopropylsilyloxy)
lignano-9,70-lactone (17). A reaction mixture of alcohol 95 (0.43 g, 0.78
mmol), imidazole (0.26 g, 3.82 mmol), and TIPSCl (0.63 mL, 2.94
mmol) in DMF (1 mL) was stirred at room temperature for 20 h before
additions of H2O and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography with EtOAc/hexane (1:4, v/v) gave
silyl ether 17 (0.47 g, 0.66 mmol, 85%) as a colorless oil: [α]20 +33
D
(c 2.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.88ꢀ1.02 (21H, m,
CH(CH3)2 ꢁ 3), 2.64 (1H, m, H-80), 2.92ꢀ2.96 (1H, overlapped, H-8),
2.95 (1H, dd, J = 13.6, 5.0 Hz, H-7a), 3.10 (1H, dd, J = 13.6, 4.4 Hz,
H-7b), 3.14 (1H, dd, J = 10.3, 6.9 Hz, H-90a), 3.25 (1H, dd, J = 10.3, 6.2
Hz, H-90b), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.11 (2H, s,
OCH2Ph), 5.12(2H, s, OCH2Ph), 5.35 (1H, d, J=7.8Hz, H-70), 6.68 (1H,
dd, J= 8.3, 2.1 Hz, H-6), 6.71 (1H, dd, J= 8.3, 2.1 Hz, H-60), 6.75 (1H, d, J=
2.1 Hz, H-2), 6.80 (1H, d, J = 2.1 Hz, H-20), 6.81 (1H, d, J = 8.3 Hz, H-5),
6.82 (1H, d, J = 8.3 Hz, H-50), 7.27ꢀ7.30 (2H, m, OCH2PhH), 7.32ꢀ7.36
(4H, m, OCH2PhH), 7.40ꢀ7.43 (4H, m, OCH2PhH); 13C NMR (100
MHz, CDCl3) δ11.7 (CH, CH(CH3)2 ꢁ 3), 17.7 (CH3, CH(CH3)2 ꢁ 3),
35.3 (CH, C-80), 44.1 (CH, C-8), 46.5 (CH2, C-7), 55.96 (CH3, OCH3),
’ MATERIALS AND METHODS
Chemicals. (ꢀ)- and (+)-lariciresinol were synthesized according
to a previously described method.13 To synthesize stereoisomers of
lariciresinol other than 1 and 2, lactone 914 or 13 was used as the starting
material (Figure 2). Reagents used for the syntheses were purchased
from Wako Pure Chemical Industries, Ltd. (Osaka, Japan), Nacalai Tesque,
Inc. (Kyoto, Japan), Tokyo Chemical Industry Co, Ltd. (Tokyo, Japan),
Received: August 11, 2011
Revised:
November 8, 2011
Accepted: November 9, 2011
Published: November 09, 2011
r
2011 American Chemical Society
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Figure 1. (ꢀ)- and (+)-lariciresinol and their stereoisomers.
Figure 2. Synthesis scheme of lariciresinol stereoisomers.
56.10 (CH3, OCH3), 62.1 (CH2, C-90), 71.1 (CH2, OCH2Ph ꢁ 2), 81.1
(CH, C-70), 109.7, 112.7, 113.9, 114.1, 118.2, 121.2, 127.21, 127.23, 127.8,
127.9, 128.5, 128.9, 130.9, 136.9, 137.2, 147.2, 147.9, 149.6, 149.8, 178.6;
MS (EI) m/z 710 (M+, 41), 91 (100); HRMS (EI) m/z calcd for
C43H54O7Si (M+) 710.3639, found 710.3633.
(70R,8S,80R)-(17): [α]20D ꢀ30 (c 2.0, CHCl3).
(7S,8S,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-9-(triisopropylsilyloxy)-7,
90-epoxylignane (18). To a solution of lactone 17 (2.38 g, 3.34 mmol) in
CH2Cl2 (15 mL) was added DIBAL-H (6.68 mL, 1 M in toluene, 6.68
mol) at ꢀ70 °C. After 2 h of stirring at ꢀ70 °C, 1 M aqueous HCl
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solution was added. The organic solution was separated, washed with
saturated aqueous NaHCO3 solution, dried (Na2SO4), and concen-
trated to give crude hemiacetal. To an ice-cooled solution of crude
hemiacetal in EtOH (15 mL) was added NaBH4 (0.38 g, 10.1 mmol).
After the reaction mixture was stirred at room temperature for 1 h,
saturated aqueous NH4Cl solution was added. The mixture was con-
centrated, and then the mixture was dissolved in EtOAc and H2O. The
organic solution was separated, washed with brine, and dried (Na2SO4).
Concentration gave crude diol. To an ice-cooled solution of crude diol
and pyridine (1.15 mL, 14.2 mmol) in CH2Cl2 (15 mL) was added
p-TsCl (0.59 g, 3.10 mmol). After the reaction solution was stirred at room
temperature for 44 h, H2O was added. The organic solution was
separated, washed with 1 M aqueous HCl solution and saturated
aqueous NaHCO3 solution, and dried (Na2SO4). Concentration fol-
lowed by silica gel column chromatography with EtOAc/hexane (1:6, v/v)
gave epoxylignane 18 (1.66 g, 2.38 mmol, 71%, three steps) as a
colorless oil: [α]20D ꢀ29 (c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.93ꢀ0.97 (21H, m, CH(CH3)2 ꢁ 3), 2.33 (1H, m, H-8), 2.58ꢀ2.63
(2H, m, H-70a, H-80), 2.96 (1H, dd, J = 18.1, 9.5 Hz, H-70b), 3.19 (1H,
dd, J = 10.2, 6.0 Hz, H-9a), 3.26 (1H, dd, J = 10.2, 8.9 Hz, H-9b), 3.63
(1H, dd, J = 8.8, 6.3 Hz, H-90a), 3.86 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 4.15 (1H, dd, J = 8.8, 6.5 Hz, H-90b), 5.07 (1H, d, J = 7.1 Hz,
H-7), 5.12 (4H, s, OCH2Ph ꢁ 2), 6.67 (1H, dd, J = 8.1, 1.8 Hz, H-6),
6.73 (1H, dd, J = 8.1, 1.8 Hz, H-60), 6.74 (1H, d, J = 1.8 Hz, H-2), 6.80
(1H, d, J = 8.1 Hz, H-5), 6.82 (1H, d, J = 8.1 Hz, H-50), 6.83 (1H, d, J =
1.8 Hz, H-20), 7.27ꢀ7.31 (2H, m, OCH2PhH), 7.33ꢀ7.37 (4H, m,
OCH2PhH), 7.41ꢀ7.45 (4H, m, OCH2PhH); 13C NMR (100 MHz,
CDCl3) δ 11.8 (CH, CH(CH3)2 ꢁ 3), 18.0 (CH3, CH(CH3)2), 39.4
(CH, C-8), 43.7 (CH, C-80), 51.4 (CH2, C-70), 55.9 (CH3, OCH3), 56.0
(CH3, OCH3), 63.3 (CH2, C-9), 71.2 (CH2, OCH2Ph ꢁ 2), 73.1 (C-90),
81.8 (CH, C-7), 110.1, 112.5, 114.0, 114.2, 118.4, 120.6, 127.27, 127.29,
127.7, 127.8, 128.47, 128.51, 132.9, 133.8, 137.3, 137.4, 146.7, 147.1,
149.4, 149.6; MS (EI) m/z 696 (M+, 26), 91 (100); HRMS (EI) m/z
calcd for C43H56O6Si 696.3846, found 696.3857.
in EtOAc (10 mL) was stirred under H2 gas at ambient temperature for
12 h before filtration. The filtrate was concentrated, and then the residue
was applied to silica gel column chromatography with EtOAc/hexane
(2:1, v/v) to give the 7S,8S,80R isomer, 3 (44 mg, 0.12 mmol, 86%), as
colorless crystals: mp 65ꢀ66 °C; [α]20D ꢀ44 (c 0.8, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.24 (1H, t, J = 2.1 Hz, OH), 2.29 (1H, m, H-8),
2.48 (1H, m, H-80), 2.66 (1H, dd, J = 13.8, 8.6 Hz, H-70a), 2.84 (1H, dd,
J = 13.8, 6.7 Hz, H-70b), 3.26ꢀ3.29 (2H, m, H-9), 3.58 (1H, dd, J = 8.7,
7.7 Hz, H-90a), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.19 (1H, dd,
J = 8.7, 7.4 Hz, H-90b), 5.04 (1H, d, J = 7.2 Hz, H-7), 5.70 (1H, br s,
PhOH), 5.80 (1H, br s, PhOH), 6.69 (1H, dd, J = 8.1, 1.8 Hz, H-6), 6.70
(1H, d, J = 1.8 Hz, H-2), 6.79 (1H, dd, J = 8.1, 1.8 Hz, H-60), 6.82 (1H, d,
J = 8.1 Hz, H-5), 6.85 (1H, d, J = 1.8 Hz, H-20), 6.87 (1H, d, J = 8.1 Hz,
H-50); 13C NMR (100 MHz, CDCl3) δ 39.0 (CH, C-8), 43.5 (CH,
C-80), 51.1 (CH2, C-70), 55.9 (CH3, OCH3), 56.0 (CH3, OCH3), 62.6
(CH2, C-9), 73.0 (CH2, C-90), 81.8 (CH, C-7), 108.6 (C-2), 111.3 (C-20),
114.46 (C-5), 114.50 (C-50), 118.9 (C-6), 121.3 (C-60), 131.0
(C-1), 131.9 (C-10), 144.1 (C-40), 145.0 (C-4), 146.6 (C-30), 146.7 (C-3);
MS (EI) m/z 360 (M+, 62), 137 (100); HRMS (EI) m/z calcd for
C20H24O6 360.1573, found 360.1548; >99% ee (AD-H, iso-PrOH/
hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR11 min).
(7R,8R,80S)-Stereoisomer (4): [α]20 +45 (c 1.0, CHCl3); >99% ee
D
(AD-H, iso-PrOH/hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR 14 min).
(7R,8S,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-9-(triisopropylsilyloxy)-7,
90-epoxylignane (20). A reaction solution of crude diol prepared from
lactone 17 (0.13 g, 0.18 mmol) and 10-camphorsulfonic acid (6.0 mg,
0.026 mmol) was stirred at room temperature for 37 h before the
addition of a few drops of Et3N, and then the mixture was concentrated.
The residue was applied to silica gel column chromatography with
EtOAc/hexane (1:4, v/v) to give epoxylignane 20 (62 mg, 0.089 mmol,
49% from lactone) as a colorless oil: [α]20D +4 (c 0.4, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 1.00ꢀ1.10 (21H, m, CH(CH3)2), 1.94 (1H, m,
H-8), 2.56ꢀ2.64 (2H, m, H-80 and H-70a), 2.83 (1H, dd, J = 17.6, 10.0
Hz, H-70b), 3.66 (1H, dd, J = 10.1, 4.1 Hz, H-9a), 3.72 (1H, dd, J = 10.1,
5.0 Hz, H-9b), 3.81 (1H, dd, J = 8.7, 5.5 Hz, H-90a), 3.85 (3H, s, OCH3),
3.89 (3H, s, OCH3), 3.91 (1H, dd, J = 8.7, 5.5 Hz, H-90b), 4.73 (1H, d,
J = 8.2 Hz, H-7), 5.12 (2H, s, OCH2Ph), 5.15 (2H, s, OCH2Ph), 6.62
(1H, dd, J = 8.1, 1.9 Hz, H-6), 6.69 (1H, d, J = 1.9 Hz, H-2), 6.78 (1H, d,
J = 8.1 Hz, H-5), 6.85 (2H, s, H-20 and H-50), 6.95 (1H, s, H-60),
7.27ꢀ7.29 (2H, m, OCH2PhH), 7.31ꢀ7.38 (4H, m, OCH2PhH),
7.43ꢀ7.44 (4H, m, OCH2PhH); 13C NMR (100 MHz, CDCl3) δ 11.9
(CH, CH(CH3)2), 18.1 (CH3, CH(CH3)2), 39.4 (CH, C-8), 43.7 (CH,
C-80), 55.88 (CH2, C-70 and CH3, OCH3), 55.98 (CH3, OCH3), 62.3
(CH2, C-9), 71.1 (CH2, OCH2Ph), 71.2 (CH2, OCH2Ph), 73.1 (CH2,
C-90), 83.0 (CH, C-7), 110.0, 112.4, 114.0, 114.1, 118.5, 120.6, 127.3,
127.8, 128.5, 133.8, 135.6, 137.3, 137.4, 147.5, 149.6, 149.7; MS (EI) m/z
696 (M+, 58), 431 (50), 121 (49), 91 (100); HRMS (EI) m/z calcd for
C43H56O6Si 696.3847, found 696.3839.
(7R,8R,80S)-(18): [α]20D +30 (c 2.4, CHCl3).
(7S,8S,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-7,90-epoxylignan-9-ol
(19). To a solution of silyl ether 18 (0.11 g, 0.16 mmol) in THF (10 mL)
was added (n-Bu)4NF (0.16 mL, 1 M THF solution, 0.16 mmol). The
resulting reaction solution was stirred at room temperature for 1 h before
additions of EtOAc and saturated aqueous CuSO4 solution. The organic
solution was separated, washed with saturated aqueous NaHCO3
solution, and dried (Na2SO4). Concentration followed by silica gel
column chromatography with EtOAc/hexane (1:1, v/v) gave alcohol 19
(76 mg, 0.14 mmol, 88%) as colorless crystals: mp 113ꢀ114 °C; [α]20
D
ꢀ40 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.65ꢀ1.85 (1H, br,
OH), 2.28 (1H, m, H-8), 2.48 (1H, m, H-80), 2.65 (1H, dd, J = 13.8, 8.6
Hz, H-70a), 2.84 (1H, dd, J = 13.8, 6.6 Hz, H-70b), 3.26 (2H, d, J = 6.3 Hz,
H-9), 3.57 (1H, dd, J = 8.7, 7.7 Hz, H-90a), 3.86 (3H, s, OCH3), 3.87
(3H, s, OCH3), 4.18 (1H, dd, J = 8.7, 7.4 Hz, H-90b), 5.03 (1H, d, J = 7.1
Hz, H-7), 5.11 (4H, s, OCH2Ph), 6.67 (1H, dd, J = 8.1, 1.8 Hz, H-6),
6.74 (1H, d, J = 1.8 Hz, H-2), 6.77 (1H, dd, J = 8.3, 1.8 Hz, H-60), 6.81
(1H, d, J = 8.1 Hz, H-5), 6.85 (1H, d, J = 8.3 Hz, H-50), 6.88 (1H, d, J =
1.8 Hz, H-20), 7.27ꢀ7.30 (2H, m, OCH2PhH), 7.33ꢀ7.36 (4H, m,
OCH2PhH), 7.41ꢀ7.43 (4H, m, OCH2PhH); 13C NMR (100 MHz,
CDCl3) δ 38.9 (CH, C-8), 43.3 (CH, C-80), 51.1 (CH2, C-70), 56.03
(CH3, OCH3), 56.05 (CH3, OCH3), 62.5 (CH2, C-9), 71.1 (CH2,
OCH2Ph), 71.2 (CH2, OCH2Ph), 73.1 (CH, C-90), 81.7 (CH, C-7),
109.8, 112.6, 114.1, 114.3, 118.1, 120.6, 127.30, 127.32, 127.79, 127.83,
128.50, 128.51, 132.3, 133.3, 137.1, 137.3, 146.7, 147.4, 149.7, 149.8; MS
(EI) m/z 540 (M+, 44), 149 (52), 121 (66), 91 (100); HRMS (EI) m/z
calcd for C34H36O6 540.2512, found 540.2497.
(7S,8R,80S)-(20): [α]20D ꢀ4 (c 2, CHCl3).
(7R,8S,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-7,90-epoxylignan-9-ol
(21). To a solution of silyl ether 20 (0.22 g, 0.32 mmol) in THF (20 mL)
was added (n-Bu)4NF (0.33 mL, 1 M in THF, 0.33 mmol). After the
reaction solution had been stirred at room temperature for 1 h, EtOAc
and saturated aqueous CuSO4 solution 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 with EtOAc/hexane (1:2, v/v) gave
alcohol 21 (0.17 g, 0.31 mmol, 97%) as a colorless oil: [α]20D +8 (c 0.04,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.67 (1H, br s, OH), 1.98 (1H,
m, H-8), 2.47 (1H, m, H-80), 2.66 (1H, dd, J = 13.8, 8.6 Hz, H-70a), 2.77
(1H, dd, J = 13.8, 6.8 Hz, H-70b), 3.59 (2H, d, J = 5.4 Hz, H-9), 3.83 (1H,
dd, J = 8.9, 5.9 Hz, H-90a), 3.84 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.94
(1H, dd, J = 8.9, 7.3 Hz, H-90b), 4.60 (1H, d, J = 7.9 Hz, H-7), 5.10 (2H, s,
OCH2Ph), 5.13 (2H, s, OCH2Ph), 6.62 (1H, dd, J = 8.1, 2.0 Hz, H-6),
(7R,8R,80S)-(19): [α]20D +40 (c 1.8, CHCl3).
(7S,8S,80R)-3,30-Dimethoxy-7,90-epoxylignane-4,40,9-triol (3). A reac-
tion mixture of benzyl ether 19 (76 mg, 0.14 mmol) and 5% Pd/C (0.10 g)
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6.69 (1H, d, J = 2.0 Hz, H-2), 6.79 (1H, d, J = 8.1 Hz, H-5), 6.84 (2H, s,
H-20 and H-50), 6.96 (1H, s, H-60), 7.27ꢀ7.30 (2H, m, OCH2PhH),
(5 mL) was added BH3 SMe2 (0.021 mL, 0.22 mmol). After the
3
reaction solution had been stirred at room temperature for 1 h, saturated
aqueous NaHCO3 solution (1 mL) and 30% aqueous H2O2 solution
(1 mL) were added. The resulting mixture was stirred at room
temperature for 1 h, and then CHCl3 and H2O were added. The organic
solution was separated and dried (Na2SO4). Concentration followed by
silica gel column chromatography with EtOAc/hexane (1:2, v/v) gave
7.33ꢀ7.36 (4H, m, OCH2PhH), 7.41ꢀ7.43 (4H, m, OCH2PhH); 13
C
NMR (100 MHz, CDCl3) δ 39.3 (CH, C-8), 44.1 (CH, C-80), 55.4
(CH2, C-70), 56.0 (CH3, OCH3), 56.1 (CH3, OCH3), 62.8 (CH2, C-9),
71.1 (CH2, OCH2Ph), 71.2 (CH2, OCH2Ph), 73.0 (CH2, C-90), 83.9
(CH, C-7), 110.0, 112.6, 114.0, 114.3, 118.5, 120.7, 127.27, 127.32,
127.8, 128.50, 128.52, 133.4, 135.3, 137.2, 137.3, 146.7, 147.7, 149.7,
149.8; MS (EI) m/z 540 (M+, 93), 91 (100); HRMS (EI) m/z calcd for
C34H36O6 540.2512, found 540.2523.
alcohol 23 (0.10 g, 0.18 mmol, 95%) as a colorless oil: [α]20 +33
D
(c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.75 (1H, br s, OH), 2.40
(1H, m, H-8), 2.70 (1H, dd, J = 15.3, 11.7 Hz, H-70a), 2.88ꢀ2.93 (2H, m,
H-80 and H-70b), 3.49 (1H, dd, J = 11.4, 3.7 Hz, H-9a), 3.55 (1H, dd,
J = 11.4, 5.1 Hz, H-9b), 3.83 (1H, dd, J = 8.3, 6.6 Hz, H-90a), 3.86 (6H, s,
OCH3 ꢁ 2), 3.98 (1H, dd, J = 8.3, 7.8 Hz, H-90b), 5.09 (1H, d, J = 5.4 Hz,
H-7), 5.12 (2H, s, OCH2Ph), 5.13 (2H, s, OCH2Ph), 6.70 (1H, dd, J = 8.2,
1.8 Hz, H-6), 6.76 (1H, d, J = 1.8 Hz, H-2), 6.81 (1H, d, J = 8.2 Hz, H-5),
6.84ꢀ6.89 (2H, m, H-50 and H-60), 6.91 (1H, d, J = 1.4 Hz, H-20),
7.27ꢀ7.31 (2H, m, OCH2PhH), 7.33ꢀ7.37 (4H, m, OCH2PhH),
7.42ꢀ7.44 (4H, m, OCH2PhH); 13C NMR (100 MHz, CDCl3)
δ 34.0 (CH, C-8), 44.1 (CH, C-80), 47.9 (CH2, C-70), 55.9 (CH3, OCH3),
59.4 (CH2, C-9), 71.0 (CH2, OCH2Ph), 71.1 (CH2, OCH2Ph), 72.4
(CH2, C-90), 83.0 (CH, C-7), 109.1, 112.2, 114.1, 114.2, 117.5, 120.2,
127.2, 127.3, 127.7, 127.8, 128.5, 132.3, 133.7, 137.0, 137.2, 146.5, 147.3,
149.6, 149.8; MS (EI) m/z 540 (M+, 82), 91 (100); HRMS (EI) m/z calcd
for C34H36O6 540.2512, found 540.2515.
(7S,8R,80S)-(21): [α]20D ꢀ8 (c 0.5, CHCl3).
(7R,8S,80R)-3,30-Dimethoxy-7,90-epoxylignane-4,40,9-triol (5). A reac-
tion mixture of benzyl ether 21 (47 mg, 0.087 mmol) and 5% Pd/C
(0.10 g) in EtOAc (20 mL) was stirred under H2 gas at the ambient
temperature for 12 h before filtration. The filtrate was concentrated, and
then the residue was applied to silica gel column chromatography with
EtOAc/hexane (1:3, v/v) to give the 7R,8S,80R stereoisomer, 5 (24 mg,
0.067 mmol, 77%), as a colorless oil: [α]20D +8 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ1.72 (1H, br s, OH), 1.99 (1H, m, H-8), 2.49 (1H, m,
H-80), 2.67 (1H, dd, J = 13.8, 8.6 Hz, H-70a), 2.79 (1H, dd, J = 13.8, 6.8 Hz,
H-70b), 3.63 (2H, d, J = 5.5 Hz, H-9), 3.84 (1H, dd, J = 8.8, 5.9 Hz, H-90a),
3.85 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.95 (1H, dd, J = 8.8, 7.3 Hz,
H-90b), 4.60 (1H, d, J= 7.9 Hz, H-7), 5.60 (1H, br s, PhOH), 5.70 (1H, br s,
PhOH), 6.65 (1H, d, J = 2.0 Hz, H-2), 6.66 (1H, dd, J = 8.2, 2.0 Hz, H-6),
6.82 (1H, d, J = 8.2 Hz, H-5), 6.85 (1H, dd, J = 7.8, 1.9 Hz, H-60), 6.88 (1H,
d, J = 7.8 Hz, H-50), 6.91 (1H, d, J = 1.9 Hz, H-20); 13C NMR (100 MHz,
CDCl3) δ 39.4 (CH, C-8), 44.2 (CH, C-80), 55.5 (CH2, C-70), 55.9 (CH3,
OCH3), 56.0 (CH3, OCH3), 62.8 (CH2, C-9), 73.0 (CH2, C-90), 84.1
(CH, C-7), 108.8 (C-2), 111.3 (C-20), 114.3 (C-5), 114.4 (C-50),119.2(C-6),
121.4 (C-60), 132.1 (C-1), 134.0 (C-10), 144.1 (C-40), 145.2 (C-4), 146.5
(C-30), 146.7 (C-3); MS (EI) m/z360 (M+,85),137(100);HRMS(EI) m/z
calcd for C20H24O6 360.1573, found 360.1570; >99% ee (AD-H, iso-PrOH/
hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR8 min).
(7S,8S,80S)-(23): [α]20D ꢀ31 (c 0.40, CHCl3).
(7R,8R,80R)-3,30-Dimethoxy-7,90-epoxylignane-4,40,9-triol (7). A reac-
tion mixture of benzyl ether 23 (26 mg, 0.048 mmol) and 5% Pd/C
(0.10 g) in EtOAc (10 mL) was stirred under H2 gas at ambient
temperature for 12 h before filtration. The filtrate was concentrated, and
then the residue was applied to silica gel column chromatography with
EtOAc/hexane (1:3, v/v) to give the 7R,8R,80R) stereoisomer, 7 (17 mg,
0.048 mmol, 100%) as a colorless oil: [α]20D +35 (c 0.39, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 1.62 (1H, br. s, 9-OH), 2.43 (1H, m, H-8),
2.73 (1H, m, H-80), 2.90ꢀ2.98 (2H, m, H-70), 3.54 (1H, dd, J = 11.7, 3.3
Hz, H-9a), 3.61 (1H, dd, J = 11.7, 5.5 Hz, H-9b), 3.85 (1H, dd, J = 8.3, 8.3
Hz, H-90a), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.01 (1H, dd, J =
8.3, 8.3 Hz, H-90b), 5.11 (1H, d, J = 5.5 Hz, H-7), 5.53 (1H, s, PhOH),
5.63 (1H, s, PhOH), 6.72ꢀ6.74 (2H, m, H-2 and H-6), 6.84ꢀ6.86 (2H, m,
H-5 and H-60), 6.91ꢀ6.93 (2H, m, H-20 and H-50); 13C NMR (100
MHz, CDCl3) δ 34.1 (CH, C-8), 44.3 (CH, C-80), 48.0 (CH2, C-70),
55.88 (CH3, OCH3), 55.93 (CH3, OCH3), 59.5 (CH2, C-9), 72.4 (CH2,
C-90), 83.1 (CH, C-7), 107.9 (C-2), 111.0 (C-20), 114.4 (C-5), 114.6
(C-50), 118.4 (C-6), 120.9 (C-60), 131.1 (C-1), 132.4 (C-10), 143.9 (C-40),
144.8 (C-4), 146.5 (C-30), 146.7 (C-3); MS (EI) m/z 360 (M+, 83),
137 (100); HRMS (EI) m/z calcd for C20H24O6 360.1573, found
360.1561; >99% ee (AD-H, iso-PrOH/hexane = 1:2 (v/v), 1 mL/min,
280 nm, tR 24 min).
(7S,8R,80S)-(6): [α]20 ꢀ8 (c 2, CHCl3); >99% ee (AD-H, iso-
D
PrOH/hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR7 min).
(7R,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-7,90-epoxylign-8-ene (22).
To an ice-cooled solution of alcohol 21 (0.17 g, 0.31 mmol) and Et3N
(0.060 mL, 0.43 mmol) in CH2Cl2 (5 mL) was added MsCl (0.033 mL,
0.43 mmol). After 1 h of stirring at room temperature, H2O and CH2Cl2
were added. The organic solution was separated and dried (Na2SO4).
Concentration gave crude mesylate. A reaction mixture of crude
mesylate, NaI (0.13 g, 0.87 mmol), and DBU (0.084 mL, 0.56 mmol)
in DMF (5 mL) was stirred at 80 °C for 2 h before additions of H2O and
CHCl3. The organic solution was separated and dried (Na2SO4).
Concentration followed by silica gel column chromatography with
EtOAc/hexane (1:1, v/v) gave alkene 22 (0.10 g, 0.19 mmol, 61%) as
a colorless oil; [α]20D ꢀ2 (c 3, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 2.70 (1H, dd, J = 13.8, 10.1 Hz, H-70a), 2.86 (1H, dd, J = 13.8, 6.0 Hz,
H-70b), 3.05 (1H, m, H-80), 3.85 (3H, s, OCH3), 3.85ꢀ3.90 (2H,
overlapped, H-90), 3.90 (3H, s, OCH3), 4.75 (1H, d, J = 1.9 Hz, H-9a),
4.97 (1H, d, J = 1.9 Hz, H-9b), 5.12 (2H, s, OCH2Ph), 5.15 (2H, s,
OCH2Ph), 5.20 (1H, s, H-7), 6.66 (1H, dd, J = 8.3, 1.8 Hz, H-6), 6.72
(1H, d, J = 1.8 Hz, H-2), 6.81 (1H, d, J = 8.3 Hz, H-5), 6.86 (2H, s, H-20
and H-50), 6.93 (1H, s, H-60), 7.29ꢀ7.31 (2H, m, OCH2PhH),
(7S,8S,80S)-(8): [α]20D ꢀ35 (c 0.62, CHCl3); >99% ee (AD-H, iso-
PrOH/hexane = 1:2 (v/v), 1 mL/min, 280 nm, tR15 min).
Evaluation of Plant Growth Regulatory Activity. The plant
growth regulatory activity of all stereoisomers of lariciresinol was
evaluated using lettuce (Lactuca sativa L. Green-wave (Takii Seed Co.
Ltd., Kyoto, Japan)) and Italian ryegrass (Lolium multiflorum Lam.
Wase-fudo (Takii Seed Co. Ltd.)). A sheet of filter paper (diameter =
90 mm) was placed in a 90 mm Petri dish and wetted with 500 μL of test
sample solution dissolved in acetone at concentrations from 6.0 ꢁ 10ꢀ3
to 6.0 ꢁ 10ꢀ8 M. After the filter paper had dried, 3 mL of water was
poured into the dish to adjust the final concentration from 1.0 ꢁ 10ꢀ3 to
1.0 ꢁ 10ꢀ8 M. Thirty seeds of each plant were placed on the filter paper,
and the Petri dishes were sealed with Parafilm. The Petri dishes were
then incubated in the dark at 20 °C. The lengths of roots and shoots were
measured after 3 days for lettuce and after 5 days for ryegrass by using an
ordinary ruler. The root and shoot lengths of the control were ca. 3 and
1 cm for lettuce and 4 and 3 cm for ryegrass, respectively. We compared
7.34ꢀ7.37 (4H, m, OCH2PhH), 7.42ꢀ7.44 (4H, m, OCH2PhH); 13
C
NMR (100 MHz, CDCl3) δ 39.5 (CH, C-80), 45.8 (CH2, C-70), 55.9
(CH3, OCH3), 56.0 (CH3, OCH3), 71.0 (CH2, OCH2Ph), 71.1 (CH2,
OCH2Ph), 71.7 (CH2, H-90), 84.0 (CH, C-7), 107.6, 111.0, 112.7,
113.6, 114.1, 119.8, 120.8, 127.19, 127.22, 127.7, 128.5, 133.1, 134.0,
137.2, 146.6, 147.9, 149.5, 149.6, 154.4; MS (EI) m/z 522 (M+, 9), 91
(100); HRMS (EI) m/z calcd for C34H34O5 522.2406, found 522.2424.
(7S,80S)-(22): [α]20D +2 (c 5, CHCl3).
(7R,8R,80R)-4,40-Dibenzyloxy-3,30-dimethoxy-7,90-epoxylignan-9-ol
(23). To an ice-cooled solution of alkene 22 (0.10 g, 0.19 mmol) in THF
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the root and shoot lengths of the plants induced by each compound at
different concentrations (lettuce, 1 ꢁ 10ꢀ3 M; ryegrass, 1 ꢁ 10ꢀ3ꢀ1 ꢁ
10ꢀ8 M). Data are presented as percentage differences from the control;
positive and negative values present stimulation and inhibition of plant
growth, respectively. Experiments were performed in triplicate or more
for each sample (n = 3ꢀ7). Statistical analyses were conducted by one-
way ANOVA followed by Tukey’s multiple-comparison test using
PRISM software (Graphpad Software, San Diego, CA), and the values
of p < 0.05 were considered to be statistically significant.
The germination rates of ryegrass seeds when treated with natural
compounds 1 and 2 at a concentration of 1 ꢁ 10ꢀ3 M were recorded 3
days after seeding. The germination rate of ryegrass seeds treated with 3
(1 ꢁ 10ꢀ3 M) was also recorded because this compound has the highest
potency against ryegrass growth.
’ RESULTS AND DISCUSSION
The synthetic scheme is described in Figure 2. For the
syntheses of lariciresinol stereoisomers 3, 5, and 7, lactone 913
was employed as the starting material. After protection of the
primary hydroxy group as triisopropylsilyl ether, the resulting
lactone 17 was reduced to diol by successive diisobutylaluminum
hydride and NaBH4 reductions. The resulting diol was converted
to the 7S tetrahydrofuran intermediate 18 as a single isomer
with the retention of benzylic stereochemistry by treatment with
p-toluenesulfonyl chloride and pyridine. On the other hand,
exposure of the diol to a catalytic amount of 10-camphorsulfonic
acid gave the 7R tetrahydrofuran intermediate 20 via the benzyl
cation at the 7-position. The peak of 8-H of 20 (1.94 ppm) was
observed in a higher field than that of compound 18 (2.33 ppm)
because of the shielding effect, suggesting the presence of 7,8-cis-
18 and 7,8-trans-20. This SN1-type reaction gave the stable 7R,8S
isomer as a single isomer rather than the sterically hindered 7S,8S
isomer. Deprotection of 18 and 20 by treatment with (n-Bu)4NF
followed by hydrogenolysis in the presence of Pd/C gave
stereoisomers 3 and 5, respectively. To obtain the all-cis stereo-
isomer 7, stereoselective hydroboration of olefin 22 was em-
ployed. Olefin 22 was prepared from (7R,80R)-hydroxymethyl-
tetrahydrofuran intermediate 21 by reaction with methanesulfonyl
chloride and triethylamine followed by treatment with 1,8-diazabi-
cyclo[3.3.0]undec-7-ene and NaI. Because of the effect of the
configurations of the 7- and 80-positions, hydroboration using
Figure 3. Differential NOE of lariciresinol 1 and its stereoisomers 3, 5,
and 7. Only the important correlations for determining the configuration
are illustrated. Ar = 4-hydroxy-3-methoxyphenyl.
natural compound of lariciresinol, also had no significant effect
on the growth of lettuce roots and shoots (ꢀ14.4 and ꢀ22.0%,
respectively). When ryegrass was treated with 1 and 2 at the
concentration of 1 ꢁ 10ꢀ3 M, 1 suppressed root growth to
ꢀ44.3%, although it showed lower inhibitory activity toward
shoots (ꢀ17.1%), and 2 suppressed root growth to ꢀ29.3%,
indicating that 2 was relatively less potent than 1 (Figure 4B,C).
These results suggest that the sensitivity of ryegrass to lariciresinol
is higher than that of lettuce and that the plant regulatory activity
of lignans for ryegrass roots depends on their stereochemistry.
We examined whether the activity of 1 and 2 for ryegrass would
change relative to concentration. Dilution of the sample solution
to concentrations from 10ꢀ4 to 10ꢀ6 M slightly stimulated ryegrass
root growth (up to 20%).
The growth regulatory activity of 3ꢀ8, stereoisomers of
lariciresinol other than natural compounds, was evaluated to
investigate the effect of the stereochemistry of lariciresinol
isomers on their activity. The growth rates of lettuce roots and
shoots treated with 1ꢀ3 and 5ꢀ8 were between ꢀ20.7 and ꢀ1.6%,
respectively, indicating that most of the diastereomers were ineffec-
tive for lettuce growth (Figure 4A). For the 7R,8R,80S isomer, 4, the
growth rate of lettuce shoots was ꢀ32.3%, which was slightly
higher but not entirely effective. For ryegrass (Figure 4B,C), the
7S,8S,80R isomer, 3, was found to be equipotent to natural
compound 1 (7R,8S,80S isomer). When 3 was applied at 1 ꢁ
10ꢀ3 M, the growth rate of ryegrass roots was ꢀ48.2%, and at
concentrations from 10ꢀ4 to 10ꢀ7 M, root growth was stimulated
up to 20%. On the other hand, enantiomer 4 (7R,8R,80S isomer)
was less potent than 3. Compounds 5 and 6 showed no adverse
effect on ryegrass growth at each concentration examined.
Compounds 7 and 8, the 7R,8R,80R and 7S,8S,80S isomers,
respectively, suppressed the growth rate of ryegrass roots to
around ꢀ30% at 1 ꢁ 10ꢀ3 M, but the absolute values of the rate
BH3 SMe2 stereoselectively proceeded to give the all-cis tetra-
3
hydrofuran intermediate 23 as a single isomer. Finally, hydro-
genolysis in the presence of Pd/C gave the all-cis stereoisomer 7.
Stereoisomers 4, 6, and 8 were synthesized from lactone 13
according to the same process. The differential NOE experiment
was performed to confirm their stereochemistry (Figure 3). After
irradiation of 7-H (5.04 ppm) of 3, NOE effects were observed at
two 70 benzylic protons (2.66 and 2.84 ppm). Furthermore, on
irradiation of 7-H (4.60 ppm) of 5, NOE effects were observed at
9-H2 (3.63 ppm) and 80-H (2.49 ppm). In the case of stereoiso-
mer 7, correlation between 7-H (5.11 ppm) and 80-H (2.73 ppm)
was observed by irradiation of 7-H. NOE effects were observed
between neither 7-H and 9-H2 nor 7-H and 70-H2.
The plant growth regulatory activity of all prepared stereo-
isomers of lariciresinol 1ꢀ8 for lettuce and Italian ryegrass was
evaluated, as shown in Figure 4. When (ꢀ)-1, one of the natural
compounds, was applied at the concentration of 1 mM, the
growth rates of lettuce roots and shoots relative to the negative
control were ꢀ8.2 and ꢀ13.3%, respectively (Figure 4A), suggest-
ing that the compound was ineffective for lettuce growth. When
applied at the same concentration, enantiomer (+)-2, another
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Figure 4. Effects of all stereoisomers of lariciresinol on growth of test plants: (A) root (black bars) and shoot (white bars) lengths of L. sativa when
treated with each compound at the concentration of 1 ꢁ 10ꢀ3 M (the numbers of experiments are shown in parentheses); (B) root and (C) shoot
lengths of L. multiflorum when treated with each compound at the concentration from 1 ꢁ 10ꢀ3 to 1 ꢁ 10ꢀ8 M (from left to right) (the number in
parentheses is the number of experiments at 1 ꢁ 10ꢀ3 M; for all other concentrations, the number of experiments is three). Data are presented as the
mean ( standard error of the mean. Asterisks indicate that the difference in data between sample treatment and the control is statistically significant
(one-way ANOVA, Tukey post-test, p < 0.05).
decreased to below 20% by a series of dilution. When 7 and 8
were applied, the growth rates of ryegrass shoots were below
23%. Among 1ꢀ8, 1 and 3 significantly inhibited the root growth
of ryegrass relative to the control (p < 0.05, one-way ANOVA,
Tukey post test), suggesting the importance of both 8S absolute and
7,80-trans relative configurations for higher inhibitory activity.
Some lignans as well as (ꢀ)-1 reportedly inhibit the germina-
tion of lettuce and peanut seeds.9,16 This prompted us to measure
the germination rate of ryegrass seeds treated with natural
compounds 1 and 2 as well as 3, which had the highest potency.
The seed germination rates achieved with 1ꢀ3 were 80.0 (
7.91% (n = 3), 72.5 ( 6.49% (n = 3), and 72.5 ( 2.20% (n = 3),
respectively. On the other hand, the germination rate was 90.3 (
1.40% (n = 3) when the sample was not treated with these
compounds, suggesting that these compounds suppress germi-
nation to some extent. In addition, relative to the negative
control, the growth rates of germinated grass roots were ꢀ57.2 (
4.00% (n = 3), ꢀ40.7 ( 1.81% (n = 3), and ꢀ35.4 ( 6.49%
(n = 3) for compounds 1ꢀ3, respectively. These results sug-
gested that potent lignans 1 and 3 not only delayed the germination
of grass seeds but also suppressed root growth, thus inducing the
apparent root growth inhibitory activity. (+)-Lariciresinol 2, the
potency of which for seed germination and root elongation was
comparable with that of the highest potency compound, 3, did
not exhibit significant inhibitory activity; however, the reason for
this remains unknown.
Oliva et al.17 reported that the inhibition of root growth should
be related to the influence of either cell division or cell elongation
and that some aryltetralin lignans affected mitotic microtubular
formation. Furthermore, lariciresinol was recently reported to
change the membrane permeability of fungi, exhibiting antifungal
activity.18 On the other hand, the biosynthetic pathway of lignans
from coniferyl alcohol to matairesinol via lariciresinol has been
elucidated in some plants, and some enzymes in the pathway
have also been identified and crystallized.19ꢀ22 It has also been
reported that each pinoresinol/lariciresinol reductase Lu-1 and
Lu-2 of Linum usitatissimum enantiospecifically recognizes 1 and 2,
respectively.23 In addition, it has been reported that lariciresinol
affected carbon and nitrogen metabolism, reducing glutamate
synthase activity to inhibit the germination of lettuce seed
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Journal of Agricultural and Food Chemistry
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by lariciresinol.24 In this study, the activities of stereoisomers of
lariciresinol differed from each other, suggesting the involvement
of receptors or enzymes. For 1 and 3, not only the apparent
inhibition activity at 1 ꢁ 10ꢀ3 M but also low stimulation activity
at lower concentrations was observed, which might suggest
hormonal action. Although there are many possibilities for the
mode of action of the plant regulatory activity of lariciresinol, it
needs to be clarified. Recently, new stereoisomers of tetrahy-
drofuranoid lignans were isolated,25 leading us to expect the
discovery of novel stereoisomers of lariciresinol from the nature.
In addition to natural compounds 1 and 2, 3ꢀ8, which have not
been identified as natural compounds to the best of our knowl-
edge, are expected be effective in elucidating the mode of action
of lariciresinol.
In summary, we have established the synthetic pathways of all
stereoisomers of lariciresinol for the first time. This synthetic
study has enabled us to compare the biological activities of all
lariciresinol stereoisomers; the results suggest the importance of
both the 8S absolute configuration and the 7,80-trans relative
configuration for high inhibitory activity.
(11) Suzuki, S.; Umezawa, T.; Shimada, M. Stereochemical diversity
in lignan biosynthesis of Arctium lappa L. Biosci., Biotechnol., Biochem.
2002, 66, 1262–1269.
(12) Sicilia, T.; Niemeyer, H. B.; Honig, D. M.; Metzler, M.
Identification and stereochemical characterization of lignans in flaxseed
and pumpkin seeds. J. Agric. Food Chem. 2003, 51, 1181–1188.
(13) Yamauchi, S.; Sugahara, T.; Matsugi, J.; Someya, T.; Masuda,
T.; Kishida, T.; Akiyama, K.; Maruyama, M. Effect of the benzylic
structure of lignan on antioxidant activity. Biosci., Biotechnol., Biochem.
2007, 71, 2283–2290.
(14) Akiyama, K.; Maruyama, M.; Yamauchi, S.; Nakashima, Y.;
Nakato, T.; Tago, R.; Sugahara, T.; Kishida, T.; Koba, Y. Antimicrobio-
logical activity of lignan: effect of benzylic oxygen and stereochemistry of
2,3-dibenzyl-4-butanolide and 3,4-dibenzyltetrahydrofuran lignans on
activity. Biosci., Biotechnol., Biochem. 2007, 71, 1745–1751.
(15) Moss, G. P. Nomenclature of lignans and neolignans (IUPAC
recommendations 2000). Pure Appl. Chem. 2000, 72, 1493–1523.
(16) Bhiravamurty, P. V.; Kanakala, R. D.; Rao, E. V.; Sastry, K. V.
Effect of some furofuranoid lignans on three species of seeds. Curr. Sci.
1978, 48, 949–950.
(17) Oliva, A.; Moraes, R. M.; Watson, S. B.; Duke, S. O.; Dayan,
F. E. Aryltetralin lignans inhibit plant growth by affecting the formation
of mitotic microtubular organizing centers. Pest. Biochem. Physiol. 2002,
72, 45–54.
’ AUTHOR INFORMATION
(18) Hwang, B.; Cho, J.; Hwang, I-s.; Jin, H.-G.; Woo, E.-R.; Lee
D. G. Antifungal activity of lariciresinol derived from Sambucus williamsii
and their membrane-active mechanisms in Candida albicans. Biochem.
Biophys. Res. Commun. 2011, DOI: 10.1016/j.bbrc.2011.06.004.
(19) Dinkova-Kostova, A. T.; Gang, D. R.; Davin, L. B.; Bedgar,
D. L.; Chu, A.; Lewis, N. G. (+)-Pinoresinol/(+)-lariciresinol reductase
from Forsythia intermedia. J. Biol. Chem. 1996, 271, 29473–29482.
(20) Okunishi, T.; Umezawa, T.; Shimada, M. Isolation and enzy-
matic formation of lignans of Daphne genkwa and Daphne odora. J. Wood
Sci. 2001, 47, 383–388.
Corresponding Author
*Phone: +81-89-946-9846. Fax: +81-89-977-4364. E-mail:
syamauch@agr.ehime-u.ac.jp.
Funding Sources
We are grateful to Marutomo Co. for financial support.
’ ACKNOWLEDGMENT
(21) Youn, B.; Moinuddin, S. G. A.; Davin, L. B.; Lewis, N. G.; Kang,
C.-H. Crystal structures of apo-form and binary/ternary complexes of
Podophyllum secoisolariciresinol dehydrogenase, an enzyme involved in
formation of health protecting and plant defense lignans. J. Biol. Chem.
2005, 280, 12917–12926.
(22) Ayella, A. K.; Trick, H. N.; Wang, W. Enhancing lignan
biosynthesis by over-expressing pinoresinol lariciresinol reductase in
transgenic wheat. Mol. Nutr. Food Res. 2007, 51, 1518–1526.
(23) Hemmati, S.; von Heimrndahl, C. B. I.; Klaes, M.; Alfermann,
A. W.; Schmidt, T. J.; Fuss, E. Pinoresinol-lariciresinol reductases with
opposite enentiospecificity determine the enantiomeric composition of
lignans in the different organs of Linum usitatissimum L. Planta Med.
2010, 76, 928–934.
(24) Carillo, P.; Cozzolino, C.; D’Abrosca, B.; Nacca, F.; DellaGreca,
M.; Fiorentio, A.; Fuggi, A. Effects of the allelochemicals dihydrodico-
niferyl alcohol and lariciresinol on metabolism of Lactuca sativa. Open
Bioact. Compd. J. 2010, 3, 18–24.
(25) Lee, J.; Lee, D.; Jang, D. S.; Nam, J.-W.; Kim, J.-P.; Park, K. H.;
Yang, M. S.; Seo, E.-K. Two new stereoisomers of tetrahydrofuranoid
lignans from the flower buds of Magnolia fargesii. Chem. Pharm. Bull.
2007, 55, 137–139.
Part of this study was performed at the INCS (Johoku station)
of Ehime University.
’ REFERENCES
(1) Whiting, D. A. Lignans and neolignans. Nat. Prod. Rep. 1985,
2, 191–211.
(2) Pinto, M. M.; Sousa, E. P. Natural and synthetic xanthonolignoids:
chemistry and biological activities. Curr. Med. Chem. 2003, 10, 1–12.
(3) DellaGreca, M.; Mancino, A.; Previtera, L.; Zarrelli, A.; Zuppolini, S.
Lignans from Phillyrea angustifolia L. Phytochem. Lett. 2011, 4, 118–121.
(4) Sugahara, T.; Yamauchi, S.; Kondo, A.; Ohno, F.; Tominaga, S.;
Nakashima, Y.; Kishida, T.; Akiyama, K.; Maruyama, M. Lignans from
Phillyrea angustifolia L. Biosci., Biotechnol., Biochem. 2007, 71, 2962–2968.
(5) Kawaguchi, Y.; Yamauchi, S.; Masuda, T.; Nishiwaki, H.; Akiyama,
K.; Maruyama, M.; Sugahara, T.; Kishida, T.; Koba, Y. Lignans from
Phillyrea angustifolia L. Biosci., Biotechnol., Biochem. 2009, 73, 1806–1810.
(6) Nishiwaki, H.; Hasebe, A.; Kawaguchi, Y.; Akamatsu, M.; Shuto,
Y.; Yamauchi, S. Larvicidal activity of (ꢀ)-dihydroguaiaretic acid
derivatives against Culex pipiens. Biosci., Biotechnol., Biochem. 2011, 75,
1735–1739.
(7) Ayres, D. C.; Loike, J. D. A registry of natural lignans. In Lignans;
Cambridge University Press: Cambridge, U.K., 1990; pp 12ꢀ84.
(8) Nakano, H.; Fujii, Y.; Yamada, K.; Kosemura, S.; Yamamura, S.;
Hasegawa, K.; Suzuki, T. Isolation and identification of plant growth
inhibitors as candidate(s) for allelopathic substance (s), from aqueous
leachate from mesquite (Prosopis juliflora (Sw.) DC.) leaves. Plant
Growth Regul. 2002, 37, 113–117.
(9) Cutillo, F.; Abrosca, B. D.; Greca, M. D.; Fiorentino, A.; Zarrelli, A.
Lignans and neolignans from Brassica fruticulosa: effects on seed germina-
tion and plant growth. J. Agric. Food Chem. 2003, 51, 6165–6172.
(10) D’Abrosca, B.; DellaGreca, M.; Fiorentino, A.; Monaco, P.;
Previtera, L.; Simoner, A. M.; Zarrelli, A. Potential allelochemicals from
Sambucus nigra. Phytochemistry 2001, 58, 1073–10081.
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