Syntheses of all eight stereoisomers of conidendrin

Article abstract of DOI:10.1080/09168451.2020.1777081

All eight stereoisomers of conidendrin were synthesized from (1 R,2 S,3 S)-1-(4-benzyloxy-3-methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)-4) and its enantiomer with high optical purity. The configurations at 4-positio

Full text of DOI:10.1080/09168451.2020.1777081

Bioscience, Biotechnology, and Biochemistry
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Syntheses of all eight stereoisomers of
conidendrin
Hinako Shirakata , Hisashi Nishiwaki & Satoshi Yamauchi
To cite this article: Hinako Shirakata , Hisashi Nishiwaki & Satoshi Yamauchi (2020): Syntheses
of all eight stereoisomers of conidendrin, Bioscience, Biotechnology, and Biochemistry, DOI:
10.1080/09168451.2020.1777081
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BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY
https://doi.org/10.1080/09168451.2020.1777081
Syntheses of all eight stereoisomers of conidendrin
Hinako Shirakata, Hisashi Nishiwaki and Satoshi Yamauchi
Graduate School of Agriculture, Ehime University, Matsuyama, Japan
ABSTRACT
ARTICLE HISTORY
Received 13 May 2020
Accepted 29 May 2020
All eight stereoisomers of conidendrin were synthesized from (1 R,2 S,3 S)-1-(4-benzyloxy-3-
methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)-4) and
its enantiomer with high optical purity. The configurations at 4-positions of the conidendrin
stereoisomers were constructed by intramolecular Friedel-Crafts reaction of protected 4. After
conversion to tetrahydronaphthalene intermediate 7a, the 2- and 3-position of tetrahydro-
naphthalene structure 7a were converted to 3a- and 9a-position of (+)-α-conidendrin (3a),
respectively. By the epimerization process of 2- or 3-position of 7a, the other diastereomers
were obtained. All enantiomers were also synthesized from (−)-4.
KEYWORDS
Lignan; α-conidendrin;
β-conidendrin; 6,7ʹ-lignan;
neolignan
(−)-α-Conidendrin ((−)-3a) was isolated from Taxus
wallichiana [1] as a tricyclic neolignan and identified
as an oxidative metabolite of lignan, lariciresinol 2[2],
containing in dietary plants (Figure 1)[3]. The produc-
tion of β-conidendrin by the isomerization from α-
conidendrin was suggested at the same time.
Lariciresinol has also been determined as a product of
the antioxidation reaction of secoisolariciresinol 1,
which is an another dietary lignan, in oxidizing lipid
media[4]. These facts suggest that the vegetable intake
would accumulate α- and β-conidendrins inside the
body by the metabolism from lignans. The biological
activity of α-conidendrin has been studied. [5,6]
Because the biosyntheses of some lignans as enantio-
meric mixtures were reported[7], the effect of stereo-
chemistry on the biological activities should be noted in
the further studies on lignans. Our project on the synth-
eses of all stereoisomers of conidendrin (Figure 2) was
started considering the existence of the stereoisomers
inside the body. Comparing with the previous synthetic
research on (−)-α [8–12]- and ( )-β[13]-conidendrins,
the strategy described in this article is for assembling all
stereoisomers. The tricyclic neolignan structure formed
by 8–8ʹ and 6–7ʹ bonding of phenylpropanoid [14] in α-
conidendrin are found in well-known cytotoxic podo-
phyllotoxin[15]. However, the cytotoxicity of α-coni-
dendrin was not reported[16], suggesting the possibility
of biological assay for the human health by employing
cell line systems after the success of this synthetic
research.
tetrahydronaphthalene structure. It was expected that
the four stereoisomers of conidendrin ((+)-3a, (−)-3b,
(+)-3 c, (−)-3d) would be obtained from this tetrahydro-
naphthalene by the epimeric process (Scheme 1). The
protection of one of the primary hydroxy groups was
performed using pivaloyl chloride in pyridine, giving
desired pivaloyl ester 5 in 31% yield. The reaction at a
lower temperature (0°C) caused the recovery of the start-
ing material. The undesired pivaloyl ester 6 (21% yield)
and di-pivaloate (32% yield) were converted to starting
material (+)-4 by the hydrolysis in 95–100% yields. The
HMBC experiment revealed the position of the pivaloyl
ester in 5. The intramolecular Friedel-Crafts reaction by
employing 10-camphorsulfonic acid (CSA) was stereose-
lectively proceeded to form tetrahydronaphthalene struc-
ture 7a in 55% yield along with tri-substituted
tetrahydrofuran (22% yield), which was formed by the
migration of the pivaloyl group to the primary hydroxy
group followed by SN1 intramolecular dehydration
between the occurred primary hydroxy group and the
benzylic hydroxy group. The stereochemistry at 4-posi-
tion of 7a was determined by coupling constant (10.6 Hz)
between the diaxial 3-H/4-H. To obtain 3-epimer of 7a,
the primary hydroxy group of 7a was converted to corre-
sponding mesylate, which was reacted with (PhSe)2 and
LiBHEt3[18], to give phenylselenide 8 in 86% yield. The
transformation to methylidene 9 was performed by treat-
ment with m-chloroperoxybenzoic acid followed by
Et3 N and 1-hexene [19] in 78% yield. The mesylation
of 7a, followed by the reaction with NaI and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) resulted in a lower yield
to give 9 in 46% yield. Many high polar products were
produced. The hydroxymethyl epimer 7 c was obtained
Results and discussion
We planned to utilize triol (+)-4, which was obtained
from corresponding lactone[17], to construct the
by the hydroboration to 9 with BH3 SMe2 in 50% yield.
The production of 7a was not observed in this
_
CONTACT Satoshi Yamauchi
yamauchi.satoshi.mm@ehime-u.ac.jp
Supplemental data for this artcile can be accessed here.
© 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry

2
H. SHIRAKATA ET AL.
Figure 1. Antioxidation reaction of (−)-secoisolariciresinol [1] and oxidation metabolite of lariciresinol [2].
Figure 2. All stereoisomers of conidendrin.
hydroboration. The configuration was confirmed by the
coupling constant between equatorial 3-H and axial 4-H
(5.2 Hz). After the protections of the primary hydroxy
groups of 7a and 7 c as triisopropylsilyl ethers (10a: 91%
yield, 10 c: 77% yield) (Scheme 2), the reductive cleavages
of the pivaloyl esters were performed by using diisobuty-
laluminum hydride to give primary alcohols 11a (88%
yield) and 11 c (93% yield), whose primary hydroxy
groups were oxidized to the aldehydes 12a (62% yield)
and 12 c (79% yield) by pyridinium chlorochromate
(PCC) oxidation and swern oxidations, respectively.
The PCC oxidation produced many by-products.
Furthermore, Pinnick oxidations of the resulting
aldehydes 12a and 12 c gave carboxylic acids 13a and
13 c, respectively. The preparations of four important
substrates 12a, 12 c, 13a, and 13 c for the cyclizations to
the tricyclic neolignans were now completed. To obtain
α-conidendrin benzyl ether 14a and all cis-form benzyl
ether 14 c, carboxylic acids 13a and 13 c were applied to
the desilylations using tetra-n-butyl ammonium fluoride
(TBAF), followed by the dehydrations using p-toluene-
sulfonic acid in heating toluene, giving α-conidendrin
benzyl ether 14a (93% yield) and all cis-form 14 c (84%
yield), respectively. The epimerizations of α-positions of
carbaldehydes 12a and 12 c were attempted. The expo-
sure of carbaldehyde 12a to TBAF followed by PCC gave

SYNTHESIS OF CONIDENDRIN
3
Scheme 1. Preparations of the tetrahydronaphthalene intermediates 7a and 7c. (a) PivCl, Pyr., CH2Cl2, r.t., 24 h (5: 31%, 6: 21%). (b)
CSA, CH2Cl2, r.t., 19 h (55% yield). (c) [1] MsCl, Et3 N, CH2Cl2, r.t., 1 h [2]; (PhSe)2, LiBHEt3, THF, r.t., 16 h (86% yield). (d) [1] MCPBA,
CH2Cl2, 0°C, 1 h; Et3 N, 1-hexene, toluene, 80°C, 1 h (78%, 2 steps). (e) [1] BH3 SMe2, THF, 0°C, 19 h [2]; sat. aq. NaHCO3, 30% aq.
_
H2O2, r.t., 12 h (50% yield, 2 steps).
β-conidendrin benzyl ether 14b, which is a 9a-epimer of
14a, in 38% yield along with α-conidendrin benzyl ether
14a (28% yield). The 13C-NMR spectroscopic data of 14b
closely matched those in the literature[13]. On the other
hand, the epimerization of carbaldehyde 12 c was tried
using DBU before desilylation to give 3/1 mixture of 2 R/
2 S in 92% yield, which underwent oxidation to car-
boxylic acid and desilylation followed by treatment with
CSA gave 14d (21% yield, 3 steps) along with 14 c (7%
yield, 3 steps). The NOE studies provided the support
information on the configurations of 14 c and 14d. In the
stereoisomer 14 c, NOEs of 4-H/9-Haxial (4.1%) and 4-H/
9a-H (0.7%) were observed. These NOEs were not
observed in the stereoisomer 14d. Finally, all stereoi-
somers (+)-3a, (−)-3b, (+)-3 c, (−)-3d were obtained by
hydrogenolysis of 14a-14d in the presence of Pd/C under
H2 gas atmosphere in 76–86% yields. The enantiomers
were also synthesized from (−)-4 by the same method.
The optical purities were measured by employing chiral
column ((+)-3a: >99%ee, (−)-3b: >99ee, (+)-3 c: 99%ee,
(−)-3d: 97%ee, (−)-3a: 99%ee, (+)-3b: 99%ee, (−)-3 c:
99%ee, (+)-3d: 99%ee). The NMR spectra of synthesized
(+)-α-conidendrin ((+)-3a) and (−)-α-conidendrin
((−)-3a) agreed with those of the literature described for
(−)-form [1,9].
(3aR,4 R,9aS)-stereoisomer ((+)-3 c), (−)-3 c,
(3aR,4 R,9aR)-stereoisomer ((−)-3d), and (+)-3d were
synthesized for the first time. All stereoisomers obtained
in this research would contribute to the further biologi-
cal research.
Experimental
Melting points (mp) data are uncorrected. Optical rota-
tions were measured on a JASCO P-2100 instrument.
NMR data were obtained using a JNM-EX400 spectro-
meter. EI and FABMS data were measured with a JMS-
MS700 V spectrometer. The silica gel used was Silica Gel
60 N (spherical, neutral, Kanto Chemical, 40–50 μm).
The HPLC analysis was performed with Shimadzu LC-
6AD and SPD-6AV instruments. The chiral column used
for HPLC analysis of enantiomeric excess was
CHIRALCEL AD-H (250 mm x 4.6 mm, i.d., 5 μm,
DAICEL Chemical Industries, Ltd., Tokyo, Japan, 20%
iso-PrOH/hexane, 1 mL/min, detected at 283 nm). The
numbering of compounds follows IUPAC rule.
(1 R,2 S,3 S)-3-(4-Benzyloxy-3-methoxybenzyl)-1-
(4-benzyloxy-3-methoxyphenyl)-2-
hydroxymethyl-1,4-butanediol ((+)-4)
In summary, all eight stereoisomers of conidendrin
were synthesized from one common material and its
enantiomer. (+)-α-Conidendrin ((+)-3a), (−)-β-coni-
To an ice-cooled suspension of LiAlH4 (3.86 g, 0.10 mol)
in THF (20 mL) was added a solution of (2 R,3 S)-3-(4-
Benzyloxy-3-methoxybenzyl)-2-[(R)-(4-benzyloxy-3-
dendrin
((-)-3b),
(+)-β-conidendrin
((+)-3b),

4
H. SHIRAKATA ET AL.
Scheme 2. Syntheses of the conidendrin stereoisomers. (f) TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 1 h (10a: 91% yield, 10 c: 77% yield).
(g) DIBAL-H, toluene, −10°C, 1 h (11a: 88% yield, 11 c: 93% yield). (h) PCC, MS 4A, CH2Cl2, r.t., 22 h (62% yield). (i) (COCl)2, DMSO,
CH2Cl2, −70°C, 2 h, then (iso-Pr)2EtN, warmed to 0°C (79% yield). (j) 2-methyl-2-butene, NaH2PO4 2H2O, NaClO2, aq. tert-BuOH, r.t.,
_
4 h (13a: 80% yield, 13 c: 61% yield). (k) [1] n-Bu4NF, THF, r.t., 19 h [2]; p-TsOH, toluene, 60°C, 24 h (14a: 93% yield in 2 steps, 14 c:
84% yield in 2 steps). (l) [1] n-Bu4NF, THF, r.t., 22 h [2]; PCC, MS 4A, CH2Cl2, r.t., 21 h (14b: 38% yield in 2 steps, 14a: 28% yield in 2
steps). (m) [1] DBU, CH2Cl2, r.t., 23 h (92% yield, 2 R/S = 3:1) [2]; 2-methyl-2-butene, NaH2PO4 2H2O, NaClO2, aq. tert-BuOH, r.t., 4 h
_
(86%, 2 R/S = 3:1) [3]; n-Bu4NF, THF, r.t., 22 h [4]; CSA, CH2Cl2, 3 h (14d: 24% yield in 2 steps, 14 c: 8% yield in 2 steps). (n) H2, 5%
Pd/C, EtOAc, r.t., 5 h (3a: 76% yield, 3b: 83% yield, 3 c: 83% yield, 3d: 86% yield). All stereoisomers of conidendrin with 97–100%ee
were synthesized from common starting materials and its enantiomers with epimerization.
methoxyphenyl)(hydroxy)methyl]-4-butanolide
[17]
C34 H39O7 559.2697, found 559.2691. ent-4: 80% yield;
[α]20D = −3.4 (c 1.6, CHCl3).
(17.0 g, 0.03 mol) in THF (20 mL). The reaction mixture
was stirred at room temperature for 1 h before additions
o
of sat. aq. MgSO4 and K2CO3 at 0 C. After stirring at
(2 S,3 S,4 R)-2-(4-Benzyloxy-3-methoxybenzyl)-4-
(4-benzyloxy-3-methoxyphenyl)-4-hydroxy-3-
hydroxymethyl-1-butyl pivaloate (5)
room temperature for 30 min., the mixture was filtrated
through celite with EtOAc. The filtrate was concentrated,
and then the residue was applied to silica gel column
chromatography (EtOAc/hexane = 3/1) to give triol 4
(14.4 g, 0.025 mol, 84%) as a colorless oil: [α]20D = +2.5 (c
1.6, CHCl3); 1 H NMR (400 MHz, CDCl3) δ = 1.87 (1 H,
m), 2.11 (1 H, m), 2.25–2.40 (1 H, br), 2.35 (1 H, dd,
J = 13.3, 8.6 Hz), 2.55 (1 H, dd, J = 13.3, 7.0 Hz), 3.45
(1 H, dd, J = 9.2, 8.6 Hz), 3.58–3.66 (2 H, m), 3.71 (3 H,
s), 3.73 (3 H, s), 3.81–3.85 (2 H, m), 4.71 (1 H, br s), 4.93
(1 H, d, J = 4.8 Hz), 5.06 (2 H, s), 5.07 (2 H, s), 6.37 (1 H,
d, J = 8.1 Hz), 6.43 (1 H, s), 6.59 (1 H, d, J = 8.1 Hz), 6.65
To an ice-cooled solution of triol 4 (14.4 g, 25.8 mmol)
and pyridine (5.40 mL, 66.9 mmol) in CH2Cl2 (10 mL)
was added PivCl (4.10 mL, 33.3 mmol). The reaction
mixture was stirred at room temperature for 24 h
before additions of H2O and CH2Cl2. The organic
solution was separated, washed with sat. aq. CuSO4
and sat. aq. NaHCO3, and dried (Na2 SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 1/1) gave pivaloyl ester 5
(5.18 g, 8.06 mmol, 31%) as a colorless oil, 6 (3.48 g,
5.42 mmol, 21%) as a colorless oil, and dipivaloyl ester
(1 H, d, J = 7.9 Hz), 6.70 (1 H, s), 6.73 (1 H, d, J = 7.9 Hz),
13
7.24–7.34 (6 H, m), 7.39–7.41 (4 H, m);
C NMR
(6.00 g, 8.26 mmol, 32%). 5: [α]20 = +16 (c 0.3,
(100 MHz, CDCl3) δ = 36.3, 39.1, 48.1, 55.7, 55.8, 60.1,
61.8, 70.86, 70.93, 72.9, 109.5, 112.5, 113.4, 113.7, 117.9,
120.9, 127.2, 127.7, 127.8, 128.42, 128.44, 133.0, 136.3,
137.1, 137.2, 146.3, 146.8, 149.2, 149.3; FABMS m/z
(M + H)+ 559; HRFABMS m/z (M + H)+ calcd for
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ = 1.21 (9 H,
s), 1.66 (1 H, br s), 1.88 (1 H, m), 2.29 (1 H, m), 2.53
(1 H, dd, J = 13.8, 8.6 Hz), 2.75 (1 H, dd, J = 13.8,
6.6 Hz), 2.92 (1 H, d, J = 3.9 Hz), 3.70 (1 H, m), 3.75–

SYNTHESIS OF CONIDENDRIN
5
3.77 (1 H, overlapped), 3.77 (3 H, s), 3.82 (3 H, s), 4.05
(1 H, dd, J = 11.3, 6.7 Hz), 4.47 (1 H, dd, J = 11.3,
4.3 Hz), 4.94 (1 H, dd, J = 5.3, 3.9 Hz), 5.11 (2 H, s),
5.13 (2 H, s), 6.43 (1 H, dd, J = 8.2, 1.8 Hz), 6.48 (1 H,
d, J = 1.8 Hz), 6.62 (1 H, dd, J = 8.2, 1.8 Hz), 6.70 (1 H,
d, J = 8.2 Hz), 6.75 (1 H, d, J = 8.2 Hz), 6.81 (1 H, d,
(M + H)+ calcd for C39 H45O7 625.3166, found:
625.3171. ent-7a: 48% yield; [α]20D = −13 (c 1.3, CHCl3).
(2 S,3 S,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
phenylselenylmethyl-2-naphthyl]methyl pivaloate
(8)
J = 1.8 Hz), 7.26–7.30 (2 H, m), 7.32–7.36 (4 H, m),
13
7.41–7.43 (4 H, m);
C NMR (100 MHz, CDCl3)
δ = 27.2, 36.5, 37.8, 38.8, 47.5, 55.7, 55.8, 61.2, 65.8,
70.9, 71.0, 74.6, 109.3, 112.4, 113.4, 113.8, 117.9, 120.8,
127.2, 127.7, 127.8, 128.4, 128.5, 132.9, 136.0, 137.0,
137.2, 146.3, 147.2, 149.4, 149.5, 178.7; FABMS m/z
(M + H)+ 643; HRFABMS m/z (M + H)+ calcd for
To an ice-cooled solution of hydroxymethyl 7a (3.51 g,
5.62 mmol) and Et3 N (1.57 mL, 11.3 mmol) in
CH2Cl2 (20 mL) was added MsCl (0.87 mL,
11.2 mmol). The reaction mixture was stirred at
room temperature for 1 h before the addition of
H2O. The organic solution was separated and dried
(Na2 SO4). Concentration gave crude mesylate. To a
solution of crude mesylate in THF (20 mL) was added
a reaction mixture of LiBHEt3 (14.0 mL, 1.0 M in THF,
14.0 mmol) with (PhSe)2 (1.75 g, 5.61 mmol) in THF
(20 mL) at 0°C. The resulting reaction mixture was
stirred at room temperature for 16 h before additions
of sat. aq. NH4Cl and EtOAc. The organic solution was
separated and dried (Na2 SO4). Concentration fol-
lowed by silica gel column chromatography (EtOAc/
C
39 H47O8 643.3272, found 643.3279. ent-5: 31% yield;
[α]20 = −16 (c 0.3, CHCl3).
D
Hydrolysis of undesired pivaloyl ester
A reaction mixture of undesired mono-pivaloyl ester 6
(2.16 g, 3.36 mmol) in 6 M aq. NaOH (17 mL) and
EtOH (17 mL) was stirred at room temperature for
16 h before additions of CHCl3 and brine. The organic
solution was separated and dried (Na2 SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 3/1) gave triol 4 (1.78 g,
3.19 mmol, 95%). Dipivaloyl ester (6.00 g, 8.26 mmol)
was converted to triol 4 (4.61 g, 8.26 mmol, 100%) by
the same method.
hexane = 6/1) gave selenide 8 (3.69 g, 4.83 mmol, 86%)
1
as a colorless oil: [α]20 = −11 (c 0.9, CHCl3);
H
D
NMR (400 MHz, CDCl3) δ = 1.19 (9 H, s), 2.11 (1 H,
m), 2.26 (1 H, m), 2.82 (2 H, d, J = 6.4 Hz), 2.83 (1 H,
dd, J = 11.8, 3.8 Hz), 3.10 (1 H, dd, J = 11.8, 3.6 Hz),
3.64 (3 H, s), 3.85 (3 H, s), 3.97 (1 H, d, J = 10.2 Hz),
4.05 (1 H, dd, J = 11.1, 6.2 Hz), 4.17 (1 H, dd, J = 11.1,
3.5 Hz), 4.83 (1 H, d, J = 12.6 Hz), 4.88 (1 H, d,
J = 12.6 Hz), 5.16 (2 H, s), 6.18 (1 H, s), 6.47 (1 H,
dd, J = 8.6, 1.9 Hz), 6.48 (1 H, br s), 6.59 (1 H, s), 6.72
(2 S,3 S,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-3-
hydroxymethyl-7-methoxy-2-naphthyl]methyl
pivaloate (7a)
(1 H, d, J = 8.6 Hz), 7.13–7.23 (8 H, m), 7.30 (1 H, m),
13
7.34–7.39 (4 H, m), 7.46–7.48 (2 H, m);
C NMR
A reaction mixture of pivaloate 5 (0.81 g, 1.26 mmol)
and CSA (20 mg, 0.086 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature for 19 h before addition of a
few drops of Et3 N. Concentration followed by silica gel
column chromatography (EtOAc/hexane = 1/2) gave
tetrahydronaphthalene derivative 7a (0.43 g,
0.69 mmol, 55%) as a colorless oil: [α]20 = +12 (c 0.5,
CHCl3); 1 H NMR (400 MHz, CDCl3) δ D= 1.21 (9 H, s),
1.72–1.77 (2 H, m), 2.28 (1 H, m), 2.78 (1 H, dd, J = 15.9,
10.9 Hz), 2.85 (1 H, dd, J = 15.9, 5.3 Hz), 3.41 (1 H, br d,
J = 10.6 Hz), 3.66 (1 H, dd, J = 10.6, 2.2 Hz), 3.72 (3 H, s),
3.85 (3 H, s), 3.92 (1 H, d, J = 10.6 Hz), 4.10 (1 H, dd,
J = 11.2, 6.1 Hz), 4.28 (1 H, dd, J = 11.2, 4.2 Hz), 4.83
(1 H, d, J = 12.6 Hz), 4.88 (1 H, d, J = 12.6 Hz), 5.16 (2 H,
s), 6.21 (1 H, s), 6.50 (1 H, d, J = 1.7 Hz), 6.60 (1 H, dd,
J = 8.1, 1.7 Hz), 6.60 (1 H, s), 6.79 (1 H, d, J = 8.1 Hz),
(100 MHz, CDCl3) δ = 27.2, 31.4, 32.4, 37.1, 38.9, 43.6,
49.2, 55.7, 55.9, 66.2, 70.7, 70.9, 111.1, 112.1, 113.5,
115.3, 121.4, 126.8, 127.2, 127.5, 127.8, 127.9, 128.3,
128.5, 129.0, 130.3, 131.1, 132.6, 137.0, 137.1, 137.2,
146.0, 146.6, 147.8, 149.4, 178.3; FABMS m/z (M + H)+
764; HRFABMS m/z (M
+
H)+ calcd for
C45 H48O680Se 764.2616, found 764.2610. ent-8: 82%
yield; [α]20 = +7.6 (c 1.3, CHCl3).
D
(2 S,4 R)-[6-Benzyloxy-1-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro- 3-
methylidene-7-methoxy-2-naphthyl]methyl
pivaloate (9)
To an ice-cooled solution of selenide 8 (3.69 g,
4.83 mmol) in CH2Cl2 (20 mL) was added MCPBA
(1.55 g, 70%, 6.29 mmol) in CH2Cl2 (20 mL). The reac-
tion solution was stirred at 0°C for 1 h before addition of
sat. aq. Na2 S2O3. The organic solution was separated,
washed with sat. aq. NaHCO3, and dried (Na2 SO4).
Concentration gave crude selenoxide. To a solution of
crude selenoxide in toluene (20 mL) was added 1-hexene
7.14–7.16 (2 H, m), 7.20–7.21 (3 H, m), 7.28 (1 H, m),
13
7.34–7.38 (2 H, m), 7.46–7.48 (2 H, m);
C NMR
(100 MHz, CDCl3) δ = 27.1, 33.0, 35.0, 38.8, 46.1, 46.7,
55.8, 55.9, 60.9, 66.9, 70.7, 70.9, 111.1, 112.2, 113.6, 115.5,
121.5, 127.2, 127.3, 127.5, 127.7, 128.0, 128.2, 128.4,
131.8, 137.0, 137.2, 137.7, 145.9, 146.6, 147.6, 149.6,
178.5; FABMS m/z (M + H)+ 625; HRFABMS m/z

6
H. SHIRAKATA ET AL.
(6.84 mL, 54.5 mmol) and Et3 N (1.80 mL, 13.0 mmol).
The reaction solution was stirred at 80°C for 1 h.
Concentration followed by silica gel column chromato-
graphy (EtOAc/hexane = 1/6) gave methylidene 9 (2.28 g,
3.76 mmol, 78%) as a colorless oil: [α]20 = +23 (c 0.7,
CHCl3); 1 H NMR (400 MHz, CDCl3) δ D= 1.19 (9 H, s),
2.59 (1 H, dd, J = 16.4, 11.1 Hz), 2.86–2.92 (2 H, m), 3.71
(3 H, s), 3.88 (3 H, s), 3.97 (1 H, dd, J = 10.8, 7.9 Hz), 4.23
(1 H, dd, J = 10.8, 5.5 Hz), 4.53 (1 H, s), 4.68 (1 H, s), 4.93
(1 H, d, J = 12.3 Hz), 4.94 (1 H, br s), 4.98 (1 H, d,
J = 12.3 Hz), 5.15 (2 H, s), 6.43 (1 H, s), 6.48 (1 H, dd,
J = 7.9, 1.9 Hz), 6.49 (1 H, br s), 6.65 (1 H, s), 6.76 (1 H, d,
J = 7.9 Hz), 7.20–7.26 (5 H, m), 7.29 (1 H, m), 7.34–7.38
(2 S,3 S,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethyl-2-naphthyl]methyl
pivaloate (10a)
To an ice-cooled solution of alcohol 7a (0.43 g,
0.69 mmol) and 2,6-lutidine (0.20 mL, 1.70 mmol) in
CH2Cl2 (10 mL) was added TIPSOTf (0.23 mL,
0.85 mmol). The reaction solution was stirred at
room temperature for 1 h before additions of sat. aq.
CuSO4 and CH2Cl2. The organic solution was sepa-
rated, washed with sat. aq. NaHCO3 and dried
(Na2 SO4). Concentration followed by silica gel col-
umn chromatography (EtOAc/hexane = 1/6) gave silyl
13
(2 H, m), 7.45–7.47 (2 H, m); C NMR (100 MHz,
ether 10a (0.49 g, 0.63 mmol, 91%) as a colorless oil:
CDCl3) δ = 27.2, 33.5, 38.8, 40.0, 52.2, 55.8, 56.0, 66.9,
70.89, 70.91, 111.3, 111.5, 112.7, 113.3, 115.0, 121.5, 127.2,
127.3, 127.6, 127.8, 128.3, 128.5, 128.6, 131.0, 135.7, 137.0,
137.2, 146.3, 146.6, 148.0, 148.9, 149.3, 178.4; FABMS m/z
(M + H)+ 607; HRFABMS m/z (M + H)+ calcd for
C39 H43O8 607.3060, found 607.3069. ent-9: 68% yield;
[α]20D = −24 (c 1.4, CHCl3).
1
[α]20 = +1.6 (c 0.8, CHCl3); H NMR (400 MHz,
D
CDCl3) δ = 0.97–1.06 (21 H, m), 1.19 (9 H, s), 1.81
(1 H, m), 2.34 (1 H, m), 2.76 (1 H, dd, J = 15.8, 9.9 Hz),
2.85 (1 H, dd, J = 15.8, 5.3 Hz), 3.50 (1 H, dd, J = 10.1,
3.2 Hz), 3.70 (1 H, dd, J = 10.1 3.2 Hz), 3.74 (3 H, s),
3.85 (3 H, s), 3.92 (1 H, d, J = 10.2 Hz), 4.08 (1 H, dd,
J = 10.9, 7.1 Hz), 4.27 (1 H, dd, J = 10.9, 3.6 Hz), 4.84
(1 H, d, J = 12.4), 4.89 (1 H, d, J = 12.4 Hz), 5.16 (2 H,
s), 6.23 (1 H, s), 6.53 (1 H, d, J = 1.9 Hz), 6.55 (1 H, dd,
J = 8.1, 1.9 Hz), 6.61 (1 H, s), 6.78 (1 H, d, J = 8.1 Hz),
(2 S,3 R,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-3-
hydroxymethyl-7-methoxy-2-naphthyl]methyl
pivaloate (7 c)
7.15–7.18 (2 H, m), 7.20–7.23 (3 H, m), 7.29 (1 H, m),
13
7.33–7.38 (2 H, m), 7.46–7.48 (2 H, m);
C NMR
(100 MHz, CDCl3) δ = 12.0, 18.0, 18.1, 27.2, 32.7, 35.4,
38.9, 45.8, 46.3, 55.7, 55.9, 62.3, 66.7, 70.8, 71.0, 111.3,
112.4, 113.7, 115.5, 121.5, 127.2, 127.3, 127.5, 127.7,
128.2, 128.4, 128.5, 132.1, 137.1, 137.3, 137.9, 146.0,
146.5, 147.6, 149.5, 178.4; FABMS m/z (M + H)+ 781;
HRFABMS m/z (M + H)+ calcd for C48H65O7Si
781.4499, found 781.4498. ent-10a: 89% yield;
To a solution of methylidene 9 (1.23 g, 2.04 mmol) in
THF (10 mL) was added BH3 SMe2 (0.60 mL,
_
6.32 mmol) at 0°C. The reaction mixture was stirred
at 0°C for 19 h before additions of sat. aq. NaHCO3
(20 mL) and 30% aq. H2O2 (20 mL). After stirring at
room temperature for 12 h, EtOAc was added. The
organic solution was separated, washed with brine,
and dried (Na2 SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/3)
[α]20 = −1.7 (c 0.6, CHCl3).
D
(2 S,3 R,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethyl-2-naphthyl]methyl
pivaloate (10 c)
gave hydroxymethyl 7 c (0.64 g, 1.02 mmol, 50%) as
1
a colorless oil: [α]20 = +35 (c 0.1, CHCl3); H NMR
D
(400 MHz, CDCl3) δ = 1.14 (9 H, s), 2.18 (1 H, m), 2.34
(1 H, m), 2.64 (1 H, dd, J = 16.7, 11.6 Hz), 2.71 (1 H,
dd, J = 16.7, 6.0 Hz), 3.44–3.54 (2 H, m), 3.66 (3 H, s),
3.80 (3 H, s), 4.11 (1 H, dd, J = 11.0, 8.0 Hz), 4.17 (1 H,
d, J = 5.2 Hz), 4.23 (1 H, dd, J = 11.0, 5.9 Hz), 4.78
(1 H, d, J = 12.5 Hz), 4.88 (1 H, d, J = 12.5 Hz), 5.08
(2 H, s), 6.44 (1 H, s), 6.47 (1 H, dd, J = 8.2, 1.4 Hz),
6.56 (1 H, s), 6.57 (1 H, d, J = 1.4 Hz), 6.68 (1 H, d,
Alcohol 10 c was obtained by silylation of 7 c in 77%
yield as a colorless oil: [α]20D = +68 (c 0.5, CHCl3); 1 H
NMR (400 MHz, CDCl3) δ = 0.85–0.92 (21 H, m), 1.22
(9 H, s), 2.28 (1 H, m), 2.43 (1 H, m), 2.82–2.93 (2 H,
m), 3.39 (1 H, dd, J = 10.5, 3.8 Hz), 3.60 (1 H, dd,
J = 10.5, 10.4 Hz), 3.73 (3 H, s), 3.89 (3 H, s), 4.26 (1 H,
d, J = 5.3 Hz), 4.30–4.37 (2 H, m), 4.86 (1 H, d,
J = 12.4 Hz), 4.96 (1 H, d, J = 12.4 Hz), 5.17 (2 H, s),
6.48 (1 H, br d, J = 8.2 Hz), 6.54 (1 H, s), 6.56 (1 H, br
s), 6.66 (1 H, s), 6.72 (1 H, d, J = 8.2 Hz), 7.22–7.26
(5 H, m), 7.29 (1 H, m), 7.35–7.39 (2 H, m), 7.45–7.47
(2 H, m); 13 C NMR (100 MHz, CDCl3) δ = 11.6, 17.87,
17.94, 27.3, 29.7, 38.8, 39.1, 44.2, 49.4, 55.86, 55.90,
60.3, 68.9, 70.8, 71.0, 111.9, 113.3, 113.6, 114.9, 121.8,
127.1, 127.2, 127.6, 127.7, 128.4, 128.5, 128.8, 129.1,
135.7, 137.1, 137.3, 145.9, 146.5, 147.9, 149.1, 178.5;
J = 8.2 Hz), 7.15–7.16 (5 H, m), 7.22 (1 H, m), 7.27–
13
7.31 (2 H, m), 7.37–7.39 (2 H, m);
C NMR
(100 MHz, CDCl3) δ = 27.3, 29.6, 38.3, 38.9, 44.3,
49.3, 55.9, 59.9, 67.3, 70.9, 71.0, 111.8, 113.1, 113.9,
115.4, 121.3, 127.2, 127.3, 127.6, 127.9, 128.4, 128.6,
128.8, 128.9, 135.9, 137.07, 137.13, 146.0, 146.8, 148.1,
149.5, 178.5; FABMS m/z (M + H)+ 625; HRFABMS
m/z (M + H)+ calcd for C39H45O7 625.3166, found
625.3158. ent-7 c: 49% yield; [α]20 = −23 (c 1.3,
D
CHCl3).

SYNTHESIS OF CONIDENDRIN
7
FABMS m/z (M + H)+ 781; HRFABMS m/z (M + H)+
calcd for C48H65O7Si 781.4499, found 781.4493. ent-
113.7, 114.6, 121.9, 127.1, 127.2, 127.6, 127.8, 128.3,
128.4, 128.5, 129.4, 135.5, 137.1, 137.3, 145.7, 146.6,
148.0, 149.3; FABMS m/z (M + H)+ 697; HRFABMS
m/z (M + H)+ calcd for C43 H57O6Si 697.3924, found
10 c: 84% yield; [α]20 = −69 (c 1.6, CHCl3).
D
697.3918. ent-11 c: 90% yield; [α]20 = −90 (c 0.9,
D
(2 S,3 S,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethyl-2-naphthyl]methanol
(11a)
CHCl3).
(2S,3 S,4 R)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethylnaphthalene-2-
carbaldehyde (12a)
To a solution of pivaloyl ester 10a (0.41 g, 0.52 mmol)
in toluene (20 mL) was added DIBAL-H (1.57 mL, 1 M
o
in toluene, 1.57 mmol) at −10 C. The reaction solu-
o
tion was stirred at −10 C for 1 h before additions of
A reaction mixture of alcohol 11a (0.37 g, 0.53 mmol),
PCC (0.27 g, 1.25 mmol), and MS 4A (0.5 g) in CH2Cl2
(20 mL) was stirred at room temperature for 22 h before
addition of ether and filtration through celite.
Concentration of the filtrate, followed by silica gel col-
umn chromatography (EtOAc/hexane = 1/4) gave car-
2 M aq. HCl and EtOAc. The organic solution was
separated, washed with sat. aq. NaHCO3 and brine,
and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/2)
gave methyl alcohol 11a (0.32 g, 0.46 mmol, 88%) as
a colorless oil: [α]20D = −5.3 (c 0.5, CHCl3); 1 H NMR
(400 MHz, CDCl3) δ = 0.88–0.93 (21 H, m), 1.82–1.96
(2 H, m), 2.67 (1 H, dd, J = 16.0, 4.1 Hz), 2.91 (1 H, dd,
J = 16.0, 11.3 Hz), 3.44 (1 H, d, J = 10.6 Hz), 3.55–3.65
(3 H, m), 3.69–3.73 (1 H, overlapped), 3.72 (3 H, s),
3.84 (3 H, s), 3.90 (1 H, m), 4.82 (1 H, dd, J = 12.5 Hz),
4.86 (1 H, d, J = 12.5 Hz), 5.17 (2 H, s), 6.16 (1 H, s),
6.46 (1 H, d, J = 1.8 Hz), 6.54 (1 H, dd, J = 8.0, 1.8 Hz),
6.59 (1 H, s), 6.77 (1 H, d, J = 8.0 Hz), 7.13–7.15 (2 H,
m), 7.20–7.21 (3 H, m), 7.28 (1 H, m), 7.34–7.38 (2 H,
m), 7.45–7.47 (2 H, m); 13 C NMR (100 MHz, CDCl3)
δ = 11.7, 17.7, 17.8, 33.2, 42.0, 47.3, 48.2, 55.8, 55.9,
65.5, 65.8, 70.8, 71.0, 111.2, 112.1, 113.7, 115.7, 121.8,
127.1, 127.2, 127.5, 127.7, 128.2, 128.5, 129.1, 131.2,
137.1, 137.3, 138.2, 145.8, 146.7, 147.7, 149.8; FABMS
m/z (M + H)+ 697; HRFABMS m/z (M + H)+ calcd for
C43 H57O6Si 697.3924, found 697.3920. ent-11a: 78%
baldehyde 12a (0.23 g, 0.33 mmol, 62%) as a colorless
1
oil: [α]20 = −9.6 (c 0.5, CHCl3); H NMR (400 MHz,
D
CDCl3) δ = 0.90–1.01 (21 H, m), 2.35 (1 H, m), 2.75–
2.84 (2 H, m), 3.08 (1 H, m), 3.53 (1 H, dd, J = 10.0,
6.6 Hz), 3.69–3.72 (2 H, m), 3.73 (3 H, s), 3.85 (3 H, s),
4.83 (1 H, d, J = 12.4 Hz), 4.88 (1 H, d, J = 12.4 Hz), 5.17
(2 H, s), 6.21 (1 H, s), 6.47 (1 H, d, J = 1.6 Hz), 6.52 (1 H,
dd, J = 8.1, 1.6 Hz), 6.63 (1 H, s), 6.77 (1 H, d,
J = 8.1 Hz), 7.15–7.17 (2 H, m), 7.20–7.23 (3 H, m),
7.28 (1 H, m), 7.34–7.38 (2 H, m), 7.45–7.47 (2 H, m),
9.68 (1 H, d, J = 2.3 Hz); 13 C NMR (100 MHz, CDCl3)
δ = 11.9, 17.9, 18.0, 28.1, 45.8, 46.0, 50.1, 55.8, 56.0, 64.3,
70.8, 71.0, 111.3, 112.1, 113.8, 115.4, 121.6, 126.6, 127.2,
127.3, 127.6, 127.8, 128.3, 128.5, 130.7, 137.0, 137.1,
137.2, 146.3, 146.8, 148.0, 149.7, 203.2; FABMS m/z
(M + H)+ 695; HRFABMS m/z (M + H)+ calcd for
C43 H55O6Si 695.3768, found 695.377. ent-12a: 76%
yield; [α]20D = +8.9 (c 0.6, CHCl3).
yield; [α]20 = +5.3 (c 1.0, CHCl3).
D
(2S,3 R,4 R)-[6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethyl-2-naphthyl]methanol
(11 c)
(2S,3 R,4 R)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethylnaphthalene-2-
carbaldehyde (12 c)
Methyl alcohol 11 c was obtained by DIBAL-H reduc-
tion of 10 c in 93% yield as a colorless oil; [α]20D = +90
(c 0.5, CHCl3); 1 H NMR (400 MHz, CDCl3) δ = 0.80–
0.90 (21 H, m), 2.26 (1 H, m), 2.35 (1 H, m), 2.66 (1 H,
dd, J = 17.1, 4.7 Hz), 3.08 (1 H, dd, J = 17.1, 13.1 Hz),
3.46 (1 H, dd, J = 10.5, 2.2 Hz), 3.59 (1 H, dd, J = 10.5,
10.5 Hz), 3.71 (1 H, m), 3.74 (3 H, s), 3.82 (1 H, m),
3.88 (3 H, s), 3.93 (1 H, dd, J = 8.5, 5.4 Hz), 4.28 (1 H,
d, J = 5.3 Hz), 4.85 (1 H, d, J = 12.5 Hz), 4.96 (1 H, d,
J = 12.5 Hz), 5.18 (2 H, s), 6.48 (1 H, br d, J = 8.3 Hz),
6.55 (1 H, s), 6.60 (1 H, s), 6.66 (1 H, s), 6.74 (1 H, d,
To a solution of (COCl)2 (0.42 mL, 4.90 mmol) in
CH2Cl2 (30 mL) was added DMSO (0.52 mL,
7.32 mmol) at −70°C, and then a solution of hydroxy-
methyl compound 11 c (0.57 g, 0.82 mmol) in CH2Cl2
(5 mL) was added. After the resulting reaction solution
was stirred at −70°C for 2 h, N,N-diisopropylethylamine
(2.56 mL, 15.0 mmol) was added. The reaction solution
was warmed to 0°C, and then sat. aq. NH4Cl and
CH2Cl2 were added. The organic solution was separated
and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/6)
J = 8.3 Hz), 7.24–7.25 (5 H, m), 7.31 (1 H, m), 7.36–
gave carbaldehyde 12 c (0.45 g, 0.65 mmol, 79%) as a
13
1
7.40 (2 H, m), 7.46–7.48 (2 H, m);
C NMR
colorless oil: [α]20 = +107 (c 0.34, CHCl3); H NMR
D
(100 MHz, CDCl3) δ = 11.6, 17.7, 17.8, 27.7, 40.7,
45.4, 50.1, 55.9, 59.4, 65.8, 70.8, 71.1, 111.9, 113.5,
(400 MHz, CDCl3) δ = 0.88–0.90 (21 H, m), 2.72 (1 H,
ddd, J = 11.4, 5.3, 2.5 Hz), 2.89 (1 H, m), 3.02 (1 H, dd,

8
H. SHIRAKATA ET AL.
1
J = 17.0, 5.3 Hz), 3.11 (1 H, dd, J = 17.0, 11.4 Hz), 3.29
(1 H, dd, J = 10.1, 5.0 Hz), 3.53 (1 H, dd, J = 10.1,
10.1 Hz), 3.71 (3 H, s), 3.89 (3 H, s), 4.33 (1 H, d,
J = 5.3 Hz), 4.85 (1 H, d, J = 12.4), 4.96 (1 H, d,
J = 12.4 Hz), 5.17 (2 H, s), 6.48–6.50 (2 H, m), 6.51
(1 H, s), 6.71 (1 H, s), 6.75 (1 H, d, J = 8.3 Hz), 7.23–7.25
(5 H, m), 7.30 (1 H, m), 7.35–7.39 (2 H, m), 7.45–7.47
[α]20 = +63 (c 0.3, CHCl3); H NMR (400 MHz,
D
CDCl3) δ = 0.87–0.89 (21 H, m), 2.88–2.99 (3 H, m),
3.25 (1 H, dd, J = 15.4, 3.9 Hz), 3.30 (1 H, dd, J = 10.7,
4.9 Hz), 3.58 (1 H, dd, J = 10.7, 10.7 Hz), 3.72 (3 H, s), 3.89
(3 H, s), 4.32 (1 H, d, J = 5.0 Hz), 4.85 (1 H, d, J = 12.4 Hz),
4.96 (1 H, d, J = 12.4 Hz) 5.16 (2 H, s), 6.45–6.56 (2 H, m),
6.52 (1 H, s), 6.71 (1 H, s), 6.72 (1 H, d, J = 9.1 Hz), 7.24–
7.25 (6 H, m), 7.29 (1 H, m), 7.34–7.38 (2 H, m), 7.44–
13
(2 H, m), 9.75 (1 H, s); C NMR (100 MHz, CDCl3)
13
δ = 11.7, 17.78, 17.81, 24.7, 43.3, 48.6, 49.8, 55.8, 55.9,
60.7, 70.8, 71.0, 112.0, 112.8, 113.7, 114.9, 121.5, 127.2,
127.6, 127.8, 128.0, 128.3, 128.5, 135.1, 137.0, 137.1,
146.0, 146.6, 148.1, 149.2, 202.1; FABMS m/z
(M + H)+ 695; HRFABMS m/z (M + H)+ calcd for
C43 H55O6Si 695.3768, found 695.3776. ent-12 c: 92%
yield; [α]20D = −109 (c 1.06, CHCl3).
7.46 (2 H, m); C NMR (100 MHz, CDCl3) δ = 11.8,
17.8, 17.9, 26.6, 42.6, 43.1, 49.0, 55.87, 55.91, 60.8, 70.8,
71.0, 111.9, 113.0, 113.7, 115.0, 121.6, 127.17, 127.21,
127.6, 127.8, 128.3, 128.4, 128.5, 128.6, 135.1, 137.0,
137.2, 146.1, 146.6, 148.0, 149.2, 180.1; FABMS m/z
(M + H)+ 711; HRFABMS m/z (M + H)+ calcd for
C43 H55O7Si 711.37164, found 711.37174. ent-13 c: 61%
yield; [α]20D = −86 (c 0.3, CHCl3).
(2S,3 S,4 R)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethylnaphthalene-2-
carboxylic acid (13a)
(3aS,4 R,9aS)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-3a,4,9,9a-tetrahydro-7-
methoxynaphtho[2,3-c]furan-1(3 H)-one (14a)
To an ice-cooled mixture of carbaldehyde 12a (0.21 g,
0.30 mmol), 2-methyl-2-butene (0.14 mL, 1.32 mmol),
To a solution of carboxylic acid 13a (0.11 g, 0.15 mmol) in
THF (10 mL) was added n-Bu4NF (0.20 mL, 1.0 M in
THF, 0.20 mmol). The reaction solution was stirred at
room temperature for 19 h before additions of sat. aq.
CuSO4 and EtOAc. The organic solution was separated,
washed with sat. aq. NaHCO3, and dried (Na2SO4).
Concentration gave crude hydroxycarboxylic acid. A
reaction solution of crude hydroxycarboxylic acid and
p-TsOH (3 mg) in toluene (10 mL) was stirred at 60 oC
for 24 h before addition of a few drops of Et3 N.
Concentration followed by silica gel column chromato-
graphy (10% EtOAc in toluene) gave α-conidendrin ben-
zyl ether 14a (74 mg, 0.14 mmol, 93%) as a colorless oil:
[α]20D = +98 (c 0.6, CHCl3); 1 H NMR (400 MHz, CDCl3)
δ = 2.43–2.59 (2 H, m), 2.95 (1 H, dd, J = 15.8, 11.4 Hz),
3.19 (1 H, dd, J = 15.8, 4.7 Hz), 3.71 (3 H, s), 3.80 (1 H, d,
J = 10.3 Hz), 3.87 (3 H, s), 3.97 (1 H, dd, J = 10.3, 9.6 Hz),
4.17 (1 H, dd, J = 10.3, 6.2 Hz), 4.83 (1 H, d, J = 12.5 Hz),
4.91 (1 H, d, J = 12.5 Hz), 5.17 (2 H, s), 6.28 (1 H, s), 6.42
(1 H, br s), 6.56 (1 H, dd, J = 8.1, 1.8 Hz), 6.67 (1 H, s), 6.81
(1 H, d, J = 8.1 Hz), 7.13–7.15 (2 H, m), 7.20–7.21 (3 H,
m), 7.30 (1 H, m), 7.35–7.39 (2 H, m), 7.46–7.48 (2 H, m);
13 C NMR (100 MHz, CDCl3) δ = 29.1, 41.8, 47.3, 49.9,
55.9, 56.0, 70.7, 71.0, 71.8, 110.9, 112.2, 113.8, 114.9,
120.7, 127.2, 127.3, 127.4, 127.7, 127.9, 128.3, 128.6,
130.6, 135.0, 136.8, 137.1, 146.4, 147.3, 148.4, 150.0,
176.9; FABMS m/z (M + H)+ 537; HRFABMS m/z
(M + H)+ calcd for C34H33O6 537.2278, found 537.2273.
ent-14a: 80% yield; [α]20D = −80 (c 1.5, CHCl3).
and NaH2PO4 2 H2O (48 mg, 0.31 mmol) in tert-BuOH
_
(4.5 mL) and H2O (1.2 mL) was added NaClO2 (93 mg,
80%, 0.82 mmol). The reaction mixture was stirred at
room temperature for 4 h before additions of 1 M aq.
HCl and CHCl3 at 0 oC. The organic solution was
separated, washed with H2O, and dried (Na2SO4).
Concentration followed by silica gel column chromato-
graphy (EtOAc/hexane = 1/3) gave carboxylic acid 13a
(0.17 g, 0.24 mmol, 80%) as a colorless oil: [α]20D = −20
(c 0.3, CHCl3); 1 H NMR (400 MHz, CDCl3) δ = 0.98–
1.06 (21 H, m), 2.24 (1 H, m), 2.95–3.05 (2 H, m), 3.14
(1 H, m), 3.52 (1 H, dd, J = 10.1, 3.9 Hz), 3.74 (3 H, s),
3.74–3.78 (1 H, overlapped), 3.85 (3 H, s), 3.85–3.87
(1 H, overlapped), 4.83 (1 H, d, J = 12.5 Hz), 4.88 (1 H,
d, J = 12.5 Hz), 5.17 (2 H, s), 6.21 (1 H, s), 6.52 (1 H, d,
J = 1.6 Hz), 6.59 (1 H, dd, J = 8.1, 1.6 Hz), 6.61 (1 H, s),
6.78 (1 H, d, J = 8.1 Hz), 7.14–7.16 (2 H, m), 7.21–7.22
(4 H, m), 7.28 (1 H, m), 7.34–7.37 (2 H, m), 7.45–7.47
(2 H, m); 13 C NMR (100 MHz, CDCl3) δ = 12.0, 18.00,
18.03, 32.4, 42.5, 45.6, 45.7, 55.8, 56.0, 63.1, 70.8, 71.0,
111.0, 112.2, 113.8, 115.3, 121.7, 127.0, 127.28, 127.30,
127.5, 127.8, 128.3, 128.5, 131.6, 137.0, 137.1, 137.3,
146.3, 146.7, 147.8, 149.6, 180.2; FABMS m/z
(M + H)+ 711; HRFABMS m/z (M + H)+ calcd for
C43 H55O7Si 711.37164, found 711.37173. ent-13a:
67% yield; [α]20D = +15 (c 1.1, CHCl3).
(2S,3 R,4 R)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-1,2,3,4-tetrahydro-7-methoxy-3-
(triisopropylsilyl)oxymethylnaphthalene-2-
carboxylic acid (13 c)
(3aS,4 R,9aR)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-3a,4,9,9a-tetrahydro-7-
methoxynaphtho[2,3-c]furan-1(3 H)-one (14b)
Carboxylic acid 13 c was obtained by the oxidation of
carbaldehyde 12 c in 61% yield as a colorless oil:
To a solution of (2S,3 S,4 R)-carbaldehyde 12a (0.18 g,
0.26 mmol) in THF (10 mL) was added n-Bu4NF

SYNTHESIS OF CONIDENDRIN
9
(0.28 mL, 1.0 M in THF, 0.28 mmol). The reaction
solution was stirred at room temperature for 22 h
before the additions of sat. aq. CuSO4 and EtOAc.
The organic solution was separated, washed with sat.
aq. NaHCO3, and dried (Na2SO4). Concentration gave
crude hemiacetal. A reaction mixture of crude hemi-
acetal, PCC (68 mg, 0.32 mmol), and MS 4A (0.2 g) in
CH2Cl2 (20 mL) was stirred at room temperature for
21 h before addition of ether. After filtration of the
mixture through celite, the filtrate was concentrated.
The residue was applied to silica gel column chroma-
tography (EtOAc/hexane = 1/2) to give β-conidendrin
benzyl ether 14b (53 mg, 0.099 mmol, 38%, 2 steps) as
a colorless oil and α-conidendrin benzyl ether 14a
537.2271. ent-14 c: 88% yield; [α]20 = −96 (c 0.6,
D
CHCl3).
(3aR,4 R,9aR)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-3a,4,9,9a-tetrahydro-7-
methoxynaphtho[2,3-c]furan-1(3 H)-one (14d)
A reaction solution of (2S,3 R,4 R)-carbaldehyde 12 c
(0.37 g, 0.53 mmol) and DBU (0.16 mL, 1.07 mmol) in
CH2Cl2 (10 mL) was stirred at room temperature for
23 h before addition of H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 1/4) gave (2 R/S,3 R,4 R)-
silyloxy carbaldehyde (0.34 g, 0.49 mmol, 92%, 2 R/
S = 3/1). (2 R/S,3 R,4 R)-Silyloxy carbaldehyde (0.34 g,
0.49 mmol) was oxidized to (2 R/S,3 R,4 R)-carboxylic
acid (0.30 g, 0.42 mmol, 86%, 2 R/S = 3/1) by the same
method described for the synthesis of 14a. (2 R/
S,3 R,4 R)-Silyloxy carboxylic acid (0.30 g,
0.42 mmol) was treated with n-Bu4NF (0.46 mL, 1 M
in THF, 0.46 mmol) in THF (5 mL) and CSA (5 mg) in
CH2Cl2 (5 mL) at room temperature for 3 h, followed
by silica gel column chromatography (EtOAc/hex-
ane = 1/2) to give tricyclic lactone 14d (54 mg,
0.10 mmol, 24% in 3 steps) as a colorless oil and 14 c
(18 mg, 0.034 mmol, 8% in 3 steps). 14d: [α]20D = −10
(39 mg, 0.073 mmol, 28%, 2 steps). β-Conidendrin
1
benzyl ether 14b: [α]20 = −5.9 (c 1.1, CHCl3);
H
D
NMR (400 MHz, CDCl3) δ = 2.90 (1 H, dd, J = 14.5,
5.6 Hz), 2.88–2.96 (1 H, overlapped), 3.04–3.14 (1 H,
overlapped), 3.14 (1 H, dd, J = 14.5, 8.7 Hz), 3.53 (1 H,
d, J = 9.8 Hz), 3.76 (3 H, s), 3.87 (3 H, s), 3.98 (1 H, dd,
J = 9.5, 3.2 Hz), 4.30 (1 H, dd, J = 9.5, 7.3 Hz), 4.89
(1 H, d, J = 12.8 Hz), 4.92 (1 H, d, J = 12.8 Hz), 5.20
(2 H, s), 6.23 (1 H, s), 6.56 (1 H, dd, J = 7.8, 1.8 Hz),
6.57 (1 H, br s), 6.75 (1 H, s), 6.86 (1 H, d, J = 7.8 Hz),
7.15–7.18 (2 H, m), 7.21–7.25 (3 H, m), 7.30 (1 H, m),
13
7.38 (2 H, m), 7.48 (2 H, m); C NMR (100 MHz,
CDCl3) δ = 28.0, 38.7, 40.9, 46.6, 55.9, 56.1, 70.9, 71.0,
71.3, 111.5, 112.2, 114.0, 114.1, 120.8, 127.1, 127.2,
127.6, 127.7, 127.9, 128.3, 128.5, 131.4, 132.8, 136.9,
137.0, 146.4, 147.1, 148.3, 149.8, 179.5. The 13 C-NMR
spectroscopic data matched those in the literature for
the synthesis of ( )-β-conidendrin.13) ent-14b: 36%
1
(c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ = 2.60
(1 H, ddd, J = 14.0, 11.9, 5.4 Hz), 2.74 (1 H, dddd,
J = 14.0, 11.0, 6.8, 5.6 Hz), 2.83 (1 H, dd, J = 16.1,
11.9 Hz), 3.21 (1 H, dd, J = 16.1, 5.4 Hz), 3.56 (1 H, dd,
J = 11.0, 8.6 Hz), 3.76 (3 H, s), 3.89 (3 H, s), 4.29 (1 H,
d, J = 5.6 Hz), 4.40 (1 H, dd, J = 8.6, 6.8 Hz), 4.97 (2 H,
s), 5.13 (2 H, s), 6.26 (1 H, dd, J = 8.2, 1.5 Hz), 6.34
(1 H, d, J = 1.5 Hz), 6.50 (1 H, s), 6.71 (1 H, s), 6.76
(1 H, d, J = 8.2 Hz), 7.24–7.26 (2 H, m), 7.28 (1 H, m),
yield (2 steps); [α]20 = +5.1 (c 0.2, CHCl3).
D
(3aR,4 R,9aS)-6-Benzyloxy-4-(4-benzyloxy-3-
methoxyphenyl)-3a,4,9,9a-tetrahydro-7-
methoxynaphtho[2,3-c]furan-1(3 H)-one (14 c)
7.30–7.32 (3 H, m), 7.35–7.38 (2 H, m), 7.42–7.44
13
(2 H, m);
C NMR (100 MHz, CDCl3) δ = 28.7,
35.4, 43.8, 45.1, 55.9, 56.1, 70.1, 70.8, 71.0, 111.9,
113.3, 113.6, 115.9, 120.0, 127.2, 127.4, 127.8, 127.9,
128.4, 128.6, 129.0, 133.5, 136.7, 137.0, 146.9, 147.2,
148.8, 149.4, 177.1; FABMS m/z (M + H)+ 537;
HRFABMS m/z (M + H)+ calcd for C34H33O6
Tricyclic lactone 14 c was obtained by desilylation and
lactonization of (2S,3 R,4 R)-carboxylic acid 13 c in
84% yield as a colorless oil: [α]20 = +96 (c 0.068,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ = 2.96 (1 H,
dd, J = 15.3, 8.6 Hz), 3.11 (1 H, dd, J = 15.3, 2.3 Hz),
3.18 (1 H, ddd, J = 10.5, 8.6, 2.3 Hz), 3.33 (1 H, dddd,
J = 10.5, 8.8, 8.8, 4.3 Hz), 3.76 (1 H, dd, J = 8.8, 8.8 Hz),
3.79 (3 H, s), 3.88 (3 H, s), 3.99 (1 H, d, J = 4.3 Hz),
4.27 (1 H, dd, J = 8.8, 8.8 Hz), 4.94 (2 H, s), 5.21 (2 H,
s), 6.40 (1 H, dd, J = 8.2, 1.7 Hz), 6.41 (1 H, s), 6.58
(1 H, d, J = 1.7 Hz), 6.77 (1 H, s), 6.82 (1 H, d,
J = 8.2 Hz), 7.17–7.20 (2 H, m), 7.22–7.24 (3 H, m),
7.32 (1 H, m), 7.37–7.41 (2 H, m), 7.47–7.49 (2 H, m);
13 C NMR (100 MHz, CDCl3) δ = 29.0, 39.1, 39.5, 45.3,
55.9, 56.1, 69.9, 70.97, 71.04, 111.9, 113.0, 114.0, 114.2,
120.4, 127.2, 127.3, 127.6, 127.7, 127.9, 128.4, 128.6,
130.0, 132.0, 136.9, 137.0, 146.5, 147.2, 148.4, 149.7,
180.0; FABMS m/z (M + H)+ 537; HRFABMS m/z
(M + H)+ calcd for C34H33O6 537.2278, found
537.2278, found 537.2274. ent-14d: [α]20 = +10 (c
D
0.6, CHCl3).
(3aS,4 R,9aS)-3a,4,9,9a-Tetrahydro-6-hydroxy-4-
(4-hydroxy-3-methoxyphenyl)-7-methoxynaphtho
[2,3-c]furan-1(3 H)-one, (+)-α-conidendrin ((+)-3a)
A reaction mixture of α-conidendrin benzyl ether
14a (34 mg, 0.063 mmol) and 5% Pd/C (0.10 g) in
EtOAc (10 mL) was stirred under H2 gas at room
temperature for 5 h before filtration through celite
with EtOAc. Concentration of the filtrate, followed
by silica gel column chromatography (EtOAc/hex-
ane = 1/1) gave (+)-α-conidendrin ((+)-3a) (17 mg,

10
H. SHIRAKATA ET AL.
0.048 mmol, 76%) as colorless crystals, mp 255–256°
C; [α]20D = +53 (c 0.3, acetone); 1 H NMR (400 MHz,
CDCl3) δ = 2.49–2.62 (2 H, m), 2.98 (1 H, dd,
J = 15.8, 10.4 Hz), 3.21 (1 H, dd, J = 15.8, 4.4 Hz),
3.82 (3 H, s), 3.86 (1 H, d, J = 9.7 Hz), 3.89 (3 H, s),
4.01 (1 H, dd, J = 10.3, 9.0 Hz), 4.23 (1 H, dd, J = 9.0,
6.1 Hz), 5.42 (1 H, s), 5.58 (1 H, s), 6.40 (1 H, s), 6.54
CDCl3) δ = 29.2, 39.0, 39.6, 45.5, 55.9, 56.1, 70.0,
110.8, 111.8, 113.9, 114.7, 121.4, 126.4, 130.8, 131.3,
144.4, 144.8, 145.2, 146.7, 180.1; EIMS m/z 356 (M+,
100), 241 (51); HREIMS m/z M+ calcd for C20H20O6
356.1260, found 356.1252; 99%ee, tR30 min.
(3aS,4 S,9aR)-((-)-3 c): 100% yield; colorless crystals,
mp 99–104°C; [α]20 = −62 (c 0.4, acetone); 99%ee,
D
(1 H, d, J = 1.6 Hz), 6.65 (1 H, dd, J = 8.0, 1.6 Hz),
tR17 min.
13
6.66 (1 H, s), 6.87 (1 H, d, J = 8.0 Hz);
C NMR
(100 MHz, CDCl3) δ = 29.3, 41.9, 47.5, 49.9, 55.9,
71.9, 110.1, 111.2, 114.6, 115.1, 121.5, 126.3, 131.7,
134.0, 144.1, 144.9, 145.4, 146.9, 177.0. These NMR
data agreed with those of the literature for the synth-
esis of (−)-α-conidendrin.9) >99%ee, tR32 min. (−)-α-
conidendrin ((−)-3a): 70% yield; colorless crystals,
(3aR,4 R,9aR)-3a,4,9,9a-Tetrahydro-6-hydroxy-4-
(4-hydroxy-3-methoxyphenyl)-7-methoxynaphtho
[2,3-c]furan-1(3H)-one ((−)-3d)
The stereoisomer (−)-3d was obtained by the hydroge-
nolysis of benzyl ether 14d in 86% yield as a colorless
oil: [α]20D = −127 (c 0.34, acetone); 1 H NMR (400 MHz,
CDCl3) δ = 2.64 (1 H, ddd, J = 13.8, 11.7, 5.3 Hz), 2.72
(1 H, dddd, J = 13.8, 10.7, 6.6, 5.4 Hz), 2.82 (1 H, dd,
J = 16.1, 11.7 Hz), 3.22 (1 H, dd, J = 16.1, 5.3 Hz), 3.57
(1 H, dd, J = 10.7, 8.5 Hz), 3.78 (3 H, s), 3.90 (3 H, s),
4.31 (1 H, d, J = 5.4 Hz), 4.40 (1 H, dd, J = 8.5, 6.6 Hz),
5.51 (1 H, s), 5.60 (1 H, s), 6.33 (1 H, dd, J = 8.3, 1.9 Hz),
6.34 (1 H, br s), 6.55 (1 H, s), 6.68 (1 H, s), 6.81 (1 H, d,
J = 8.3 Hz); 13 C NMR (100 MHz, CDCl3) δ = 28.8, 35.4,
43.8, 45.1, 55.89, 55.93, 70.2, 110.9, 112.0, 114.3, 116.1,
122.6, 126.5, 130.0, 132.5, 144.4, 144.6, 145.8, 146.4,
177.3; EIMS m/z 356 (M+, 100), 101 (52); HREIMS m/
z M+ calcd for C20H20O6 356.1260, found 136.1253; 97%
ee, tR38 min. (3aS,4 S,9aS)-((+)-3d): 81% yield; colorless
crystals, mp 124–127°C; [α]20D = +111 (c 0.56, acetone);
99%ee, tR33 min.
mp 228–230°C; mp 255°C in lit.;9) [α]20 = −53 (c
D
0.3, acetone); [α]20 = −50.4 (c 0.90, acetone) in lit;9)
D
99%ee, tR26 min.
(3aS,4 R,9aR)-3a,4,9,9a-Tetrahydro-6-hydroxy-4-
(4-hydroxy-3-methoxyphenyl)-7-methoxynaphtho
[2,3-c]furan-1(3 H)-one, (−)-β-conidendrin ((−)-3b)
(−)-β-Conidendrin ((−)-3b) was obtained by the hydro-
genolysis of 14b in 83% yield as colorless crystals, mp
1
93–97°C: [α]20 = −21 (c 0.7, acetone); H NMR
D
(400 MHz, CDCl3) δ = 2.90 (1 H, m), 3.03 (1 H, m),
3.10 (1 H, dd, J = 15.2, 8.3 Hz), 3.14 (1 H, dd, J = 15.2,
8.3 Hz), 3.60 (1 H, d, J = 9.0 Hz), 3.84 (3 H, s), 3.88 (3 H,
s), 4.02 (1 H, dd, J = 9.4, 3.4 Hz), 4.36 (1 H, dd, J = 9.4,
7.5 Hz), 5.49 (1 H, s), 5.63 (1 H, s), 6.38 (1 H, s), 6.66
(1 H, br s), 6.67 (1 H, dd, J = 7.7, 1.9 Hz), 6.73 (1 H, s),
6.90 (1 H, d, J = 7.7 Hz); 13 C NMR (100 MHz, CDCl3)
δ = 28.4, 38.9, 40.9, 46.8, 55.9, 56.1, 71.6, 110.5, 111.3,
114.2, 114.7, 121.5, 126.8, 131.6, 132.5, 144.1, 144.8,
145.2, 146.8, 179.7; EIMS m/z 356 (M+, 100), 149 (36),
121 (47); HREIMS m/z M+ calcd for C20H20O6 356.1260,
found 356.1254; >99%ee, tR44 min. (+)-β-conidendrin
Author contribution
S. Y. designed this study. H. S. carried out experiments. H. N.
contributed to analytical works. H. S. and S. Y. wrote the
manuscript.
o
((+)-4): 71% yield; colorless crystals, mp 110–115 C;
[α]20D = +27 (c 0.3, acetone); 99%ee, tR26 min.
Acknowledgments
Part of this work was performed at ADRES (Johoku station)
of Ehime University. We are grateful to Marutomo Co. for
financial support.
(3aR,4 R,9aS)-3a,4,9,9a-Tetrahydro-6-hydroxy-4-
(4-hydroxy-3-methoxyphenyl)-7-methoxynaphtho
[2,3-c]furan-1(3H)-one ((+)-3 c)
Disclosure statement
The stereoisomer (+)-3 c was obtained by the hydro-
genolysis of benzyl ether 14 c in 83% yield as color-
No potential conflict of interest was reported by the authors.
less crystals, mp 115–120°C: [α]20 = +62 (c 1.3,
D
1
acetone); H NMR (400 MHz, CDCl3) δ = 2.98
References
(1 H, dd, J = 15.3, 8.5 Hz), 3.12 (1 H, dd, J = 15.3,
2.4 Hz), 3.20 (1 H, ddd, J = 10.5, 8.5, 2.4 Hz), 3.38
(1 H, dddd, J = 10.5, 8.8, 7.3, 4.2 Hz), 3.85 (3 H, s),
3.87 (3 H, s), 3.92 (1 H, dd, J = 9.1, 7.3 Hz), 4.04 (1 H,
d, J = 4.2 Hz), 4.37 (1 H, dd, J = 9.1, 8.8 Hz), 5.52
(1 H, s), 5.65 (1 H, s), 6.55 (1 H, s), 6.62 (1 H, dd,
J = 8.0, 2.1 Hz), 6.64 (1 H, d, J = 2.1 Hz), 6.75 (1 H,
[1] Miller RW, McLaughlin JL, Powell RG, et al. Lignans
from Taxus wallichiana. J Nat Prod. 1982;45:78–82.
[2] Smeds AI, Saarinen NM, Eklund PC, et al. New lignan
metabolites in rat urine.
2005;816:87–97.
[3] Peñalvo JL, Adlercreutz H, Uehara M, et al. Lignan
content of selected foods from Japan. J Agric Food
Chem. 2008;56:401–409.
J
Chromatogr B.
13
s), 6.91 (1 H, d, J = 8.0 Hz); C NMR (100 MHz,

SYNTHESIS OF CONIDENDRIN
11
[4] Masuda T, Akiyama J, Fujimoto A, et al. Antioxidation
reaction mechanism studies of phenolic lignans, identi-
fication of antioxidation products of secoisolariciresinol
from lipid oxidation. Food Chem. 2010;123:442–450.
[5] Tezuka Y, Morikawa K, Li R, et al. Cytochrome P450
3A4 inhibitory constituents of the wood of Taxus
yunnanensis. J Nat Prod. 2011;74:102–105.
[6] Dang PH, Nguyen HXHX, Nguyen HHT, et al. Lignans
from the roots of Taxus wallichiana and their α-glucosidase
inhibitory activities. J Nat Prod. 2017;80:1876–1882.
[7] Suzuki S, Umezawa T, Shimada M. Stereochemical
diversity in lignan biosynthesis of Arctium lappa L.
Biosci Biotechnol Biochem. 2002;66:1262–1269.
[8] Boissin P, Dhal R, Brown E. Lignans 15. Première
synthèse totale de la (−)-α-conidendrine naturelle.
Tetrahedron. 1992;48:687–694.
[9] Davies HML, Jin Q. Intermolecular C-H activation
at benzylic positions: synthesis of (+)-imperanene
and (−)-α-conidendrin. Tetrahedron: Asymmetry.
2003;14:941–949.
[10] Fischer J, Reynolds AJ, Sharp LA, et al. Radical car-
boxyarylation approach to lignans. Total synthesis of
(−)-arctigenin, (−)-matairesinol, and related natural
products. Org Lett. 2004;6:1345–1348.
[12] Hartmann P, Lazzarotto M, Steiner L, et al. TRIP-
catalysed asymmetric synthesis of (+)-yatein, (-)-α-
conidendrin,(+)-isostegane, and (+)-neoisostegane. J
Org Chem. 2019;84:5831–5837.
[13] Dhal R, Nabi Y, Brown B. Etudes de lignanes 7.
Syntheses totales des ( )-α et -β-conidendrines et
des methyl ( )-α et -β-conidendrals. Tetrahedron.
1986;42:2005–2016.
[14] Moss GP. Nomenclature of lignans and neolignans.
Pure Appl Chem. 2000;72:1493–1523.
[15] Ayres DC, Loike JD. Lignans: chemical and pharma-
cology of natural products. Cambridge University
Press.Biological and clinical properties of
Podophyllotoxin and other lignans. 85–112. 1990.
[16] Dantzig A, LaLonde RT, Ramdayal FR, et al. Cytotoxic
responses to aromatic ring and configurational varia-
tions in α-conidendrin, podophyllotoxin, and sikkimo-
toxin derivatives. J Med Chem. 2001;44:180–185.
[17] Yamauchi S, Hayashi Y, Nakashima Y, et al. Effect of
benzylic oxygen on the antioxidant activity of pheno-
lic lignans. J Nat Prod. 2005;68:1459–1470.
[18] Matoba H, Watanabe T, Nagatomo M, et al.
Convergent synthesis of taxol skeleton via decarbo-
nylative radical coupling reaction. Org Lett.
2018;20:7554–7557.
[19] Birman VB, Danishefsky SJ. The total synthesis of
( )-merrilactone A. J Am Chem Soc. 2002;124:2080–
2081.
[11] Markus H, Plomp AJ, Sandberg T, et al.
Dehydrogenation of hydroxymatairesinol to oxoma-
tairesinol over carbon nanofiber-supported palladium
catalysts. J Mol Catal A Chem. 2007;274:42–49.