First diastereoselective construction of butane-type and butyrolactone-type secocyclolignane structures

Article abstract of DOI:10.1271/bbb.90401

The first diastereoselective construction of butanetype and butyrolactone-type secocyclolignanes was achieved by the application of a high-valency heterobimetallic Ir-Sn complex to benzyl alcohols prepared from an Evans's anti-aldol product. The eliminati

Full text of DOI:10.1271/bbb.90401

Biosci. Biotechnol. Biochem., 73 (11), 2445–2451, 2009
First Diastereoselective Construction of Butane-Type
and Butyrolactone-Type Secocyclolignane Structures
y
Masao MORITA and Satoshi YAMAUCHI
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received June 8, 2009; Accepted July 17, 2009; Online Publication, November 7, 2009
[doi:10.1271/bbb.90401]
The first diastereoselective construction of butane-
type and butyrolactone-type secocyclolignanes was
achieved by the application of a high-valency hetero-
bimetallic Ir–Sn complex to benzyl alcohols prepared
from an Evans’s anti-aldol product. The elimination of
an acetoxymethyl group to give a cinnamyl structure by
using a high-valency heterobimetallic Ir–Sn complex
was also observed in this study.
was performed to furnish 16 and 18, respectively.
Diacetate 16 could be converted to tert-butyldiphenyl-
silyl ether 17 by hydrolysis followed by selective
silylation. The preparation of substrate 22 began with
LiBH4 reduction of 9, followed by protection of the
resulting primary hydroxy group as a pivaloyl ester.
Oxidative cleavage of the olefin of 19, pyridinium
chlorochromate oxidation, and ꢀ-methylation gave 21,
which was subjected to LiAlH4 reduction followed by
benzoylation, giving 22. Lactone-type substrates 23 and
24 for the synthesis of lactone-type secocyclolignanes
were prepared from 12 and 21, respectively (Scheme 3).
Desilylation of 12 gave 23. On the other hand, treatment
of 21 with an aqueous NaOH solution followed by
acidification gave desired lactones 24 (31%) and 25
(60%). Primary alcohol 25 could be transformed to 24 in
33% yield by the treatment with an aqueous NaOH
solution followed by acidification, recovering 25 in 64%
yield.
Key words: lignan; secocyclolignane; Ir–Sn complex
The lignans biosynthesized by plants display a variety
of chemical structures and biological activities.1–3) The
butanediol 1 and butyrolactone 2 type of lignans (Fig. 1)
are well known to be contained in food plants, whose
biological activities, adiponectin productive activity,4)
antimicrobial activity,5) and cytotoxic activity6) have
been reported. Secocyclolignanes 3 and 47) respectively
have rearranged structures from 1 and 2. Thus, the
phenyl group at the 7 position of 1 and 2 is moved to the
70 position, giving the corresponding diphenylmethyl
group. Since the structure-biological activity relation-
ship of secocyclolignanes has not been reported, stereo-
selective synthetic studies are important for biological
research. This report describes the diastereoselective
construction of the secocylolignane structure.
A key to the synthesis is the availability of the
recently reported high-valency heterobimetallic Ir–Sn
complex.8) Benzyl alcohol substrates 5 and 7 could
be transformed to secocyclolignane structures 6 and 8,
respectively, by this new Friedel-Crafts reaction
(Scheme 1). The Friedel-Crafts reaction using Fe(III)
to form the lignan structure has also been reported.9) In
this experiment, benzyloxybenzene was employed as
substrate using Ir–Sn complex. The stable protective
group of 5 in the presence of a Lewis acid should be
selected.
As the next stage, Friedel-Crafts reactions employing
the high-valency heterobimetallic Ir–Sn complex,
[Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2], and the prepared sub-
strates were attempted (Schemes 4 and 5).8) The reaction
of diacetate 16 did not give a Friedel-Crafts product, but
unexpected olefin 26 was obtained in 43% yield. It could
be assumed that the production of the benzylic cation of
16 was followed by elimination before the Friedel-Crafts
reaction. No other olefin derivatives were observed. This
acetoxymethyl elimination was also observed in a lower
yield when AlCl3/Cl(CH2)2Cl (80 ꢀC, 12 h, 10 mol%,
10% yield; 1 eq., 15% yield), p-TsOH/Cl(CH2)2Cl
(80 ꢀC, 12 h, 30 mol%, 13% yield) and p-TsOH/toluene
(120 ꢀC, 12 h, 10 mol%, 24% yield) were employed.
The elimination product was not obtained when TiCl4,
11)
SnCl4 or [Ir(COD)(ꢁ-Cl)]2 were used. The coupling
product was not obtained under these conditions.
Olefin 26 was obtained in the highest yield by using
[Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2] which was the best
catalyst to get a cinnamyl structure from 16.
Results and Discussion
Disilyl ether 17 gave desired secocyclolignane 27 in
low 17% yield. Starting material 17 was not recovered,
and the production of an olefin such as 26 and olefin
derivatives was not observed in this reaction. The
desired secocyclolignane structure could be obtained in
75% yield in the reaction with dibenzoate 18. The
production of olefins and olefin derivatives was not
observed. Among the protective groups for primary
hydroxy groups, a benzoate has been proven to be the
most effective to give a secocyclolignane structure.
For the stereoselective preparation of substrates for
the Friedel-Crafts reaction of 16, 17, 18, and 22, Evans’s
anti-aldol product 910) was employed (Scheme 2). After
protection of the secondary hydroxy group of 9 as a
triisopropylsilyl ether, LiBH4 reduction, oxidative cleav-
age of the olefin, pyridinium chlorochromate oxidation,
and ꢀ-methylation afforded lactone 13. The LiAlH4
reduction of 13 and subsequent acetylation or benzoy-
lation gave 14 or 15. Cleavage of silyl ethers 14 and 15
y
To whom correspondence should be addressed. Tel: +81-89–946-9846; Fax: +81-89–977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

2446
M. MORITA and S. YAMAUCHI
Ar
Ar
Ar
Ar
Ar
Ar
OH
Ar
7'
7
7'
7
7'
7
Ar
O
O
HO
OH
RO
Ar
OR
RO
Ar
OR
1
2
6
5
Ar
Ar
Ar
Ar
OH
Ar
7'
Ar
O
O
O
O
O
HO
OH
O
3
4
8
7
Fig. 1. Butane Lignan 1, Butyrolactone Lignan 2, and Secocyclo-
lignanes 3 and 4.
Scheme 1. Friedel-Crafts Type of Reaction for Benzyl Alcohols 5
and 7.
OR2
TIPSO
Ar
TIPSO
HO
Ar
Ar
R1
R
CH3
H
CH3
H
H
c
e
H
H
H
Ar
f
H
H
O
RO
OR
RO
OR
O
16: R = Ac
O
O
14: R = Ac
15: R = Bz
12: R = H
g
O
N
d
9: R1 =
R2 = H
17: R = TBDPS
18: R = Bz
a
13: R = CH3
Bn
O
O
O
N
10: R1 =
R2 = TIPS
b
Bn
11: R1 = CH2OH R2 = TIPS
OH
O
HO
Ar
O
Ar
h
i
k
CH3
H
PivO
Ar
9
H
H
R
Ar = 4-Benzyloxyphenyl
BzO
OBz
OPiv
22
19
20: R = H
j
21: R = CH3
Scheme 2. Preparation of Friedel-Crafts Substrates 16–18 and 22.
(a) TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 1 h (96% yield); (b) LiBH4, MeOH, THF, r.t., 1 h (59% yield); (c) (1) OsO4, NMO, aq. acetone, tert-
BuOH, r.t., 12 h, (2) NaIO4, MeOH, r.t., 1 h, (3) PCC, MS 4A, CH2Cl2, r.t., 12 h (76% yield, 3 steps); (d) KHMDS, MeI, THF, ꢁ70 ꢀC, 1 h (57%
yield, 12 (42%) was recovered); (e) 14: (1) LiAlH4, THF, 0 ꢀC, 1 h, (2) Ac2O, Pyr, r.t., 12 h (86% yield, 2 steps), 15: (1) LiAlH4, THF, 0 ꢀC, 1 h,
(2) BzCl, Pyr, r.t., 12 h (64% yield, 2 steps); (f) 16: (n-Bu)4NF, THF, 0 ꢀC, 1 h (68% yield), 18: (n-Bu)4NF, THF, 0 ꢀC, 1 h (61% yield); (g) (1)
1 M aq. NaOH solution, EtOH, r.t., 16 h, (2) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 1 h (70% yield, 2 steps); (h) (1) LiBH4, MeOH, THF, 0 ꢀC,
1 h, (2) PivCl, Pyr, r.t., 30 min (72% yield, 2 steps); (i) (1) OsO4, NMO, aq. acetone, tert-BuOH, r.t., 12 h, (2) NaIO4, MeOH, r.t., 1 h, (3) PCC,
MS 4A, CH2Cl2, r.t., 12 h (52% yield, 3 steps); (j) KHMDS, MeI, THF, ꢁ70 ꢀC, 1 h (57% yield, 12 (43%) was recovered); (k) (1) LiAlH4, THF,
0 ꢀC, 1 h, (2) BzCl, Pyr, r.t., 12 h (67% yield, 2 steps).
Diastereomeric compound 30 was also obtained from
benzoate 22 in 67% yield. No olefin and olefin
derivatives were observed. The deprotection of 28 and
30 was performed to give 29 and 31, respectively.
Lactone-type secocyclolignanes 34 and 35 were also
respectively obtained from butyrolactones 23 and 24
bearing a benzylic hydroxy group. The Friedel-Crafts
reaction of 23 and 24 employing the high-valency
heterobimetallic Ir–Sn complex gave a (diphenyl)methyl
structure. These products were converted to secocyclo-
lignanes 34 and 35.
by using a high-valency heterobimetallic Ir–Sn complex.
The cinnamyl structure was obtained by acetoxymethyl
elimination when the high-valency heterobimetallic Ir–
Sn complex was employed.
Experimental
General experimental procedures. Melting point (mp) data are
uncorrected. NMR data were measured by a JNM-EX400 spectrom-
eter, using TMS as a standard (0 ppm), MS data were measured with a
JMS-MS700V spectrometer, and optical rotation values were evaluated
with a Horiba SEPA-200 instrument. Elemental analysis was carried
out with a Yanako MT-5 CHN coder, and the silica gel used was
Wakogel C-300 (Wako, 200–300 mesh).
In conclusion, diastereoselective syntheses of seco-
cyclolignane structures were achieved for the first time

Syntheses of Secocyclolignanes
2447
HO
OH
Ar
Ar
H
a
Ar
R
12
H
c
a
23
CH3
O
HO
O
O
O
O
23
32: R = H
O
b
34
33: R = CH3
O
O
HO
H
Ar
Ar
CH3
OH
b
+
21
H
CH3
d
O
O
OH
24
CH3
O
HO
24
25
Ar = 4-Benzyloxyphenyl
O
c
Ar = 4-Benzyloxyphenyl
35
Scheme 5. Preparation of the Butyrolactone Type of Secocyclo-
lignane Structures.
Scheme 3. Preparation of Friedel-Crafts Substrates 23 and 24.
(a) (n-Bu)4NF, AcOH, THF, r.t., 1 h (60% yield); (b) (1) aq.
NaOH, EtOH, r.t., 12 h, (2) 6 M aq. HCl solution (24, 31% yield; 25,
60% yield); (c) (1) aq. NaOH, EtOH, r.t., 12 h, (2) 6 M aq. HCl
solution (24, 33% yield; 25, 64% yield).
(a)
benzyloxybenzene,
[Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2],
Cl(CH2)2Cl, 80 ꢀC, 12 h (65%); (b) KHMDS, MeI, THF, ꢁ70 ꢀC,
1 h (75% yield); (c) H2, 5% Pd/C, THF, r.t., 6 h (60% yield); (d) (1)
benzyloxybenzene, [Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2], Cl(CH2)2Cl,
80 ꢀC, 12 h, (2) H2, 5% Pd/C, THF, r.t., 6 h (56% yield, 2 steps).
Ar
H
Ar
CH3
Ar
CH3
a
a
H
17
H
H
16
17%
43%
H
OAc
TBDPSO
OTBDPS
26
27
OH
Ar
Ar
CH3
b
a
H
H
18
HO
CH3
H
70%, 2 steps
75%
H
OBz
BzO
28
HO
OH
29
OH
Ar
Ar
CH3
H
a
b
H
BzO
22
HO
CH3
H
56%, 2 steps
67%
H
OBz
30
HO
OH
31
Ar = 4-Benzyloxyphenyl
Scheme 4. Preparation of the Butane Type of Secocyclolignane Structures.
(a) benzyloxybenzene, [Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2], Cl(CH2)2Cl, 80 ꢀC, 12 h; (b) (1) 1 M aq. NaOH, EtOH, r.t., 12 h, (2) H2, 5% Pd/C,
THF, r.t., 6 h.
(4S)-4-Benzyl-3-{(2R)-2-[(S)-(4-benzyloxyphenyl)(hydroxy)methyl]-
4-pentenoyl}-2-oxazolidinone (9). A reaction mixture of (S)-4-benzyl-
3-(4-pentenyl)-2-oxazolidinone (29.2 g, 0.11 mol), 4-benzyloxybenzal-
dehyde (22.0 g, 0.10 mol), Et3N (32.4 ml, 0.23 mol), Me3SiCl (21.0 ml,
0.17 mol), and MgCl2 (1.10 g, 0.012 mol) in EtOAc (150 ml) was
stirred at room temperature for 20 h before filtration through silica gel
with ether. The filtrate was concentrated, and then the residue
was dissolved in MeOH (250 ml). After addition of CF3CO2H (5 ml),
the resulting reaction solution was stirred at room temperature for
30 min before addition of Et3N. The mixture was concentrated, and
then the residue was applied to silica gel column chromatography
(EtOAc:hexane ¼ 1:3) to give 9 (52.1 g, 0.11 mol, 100%) as a colorless
20
oil, ½ꢀꢂD ¼ ꢁ7:4 (c 1.2, CHCl3). 1H-NMR (CDCl3) ꢂ: 2.17 (1H, m),
2.41 (1H, m), 2.60 (1H, dd, J ¼ 13:6, 9.4 Hz), 3.15 (1H, dd, J ¼ 13:6,
3.4 Hz), 3.15 (1H, d, J ¼ 7:5 Hz), 4.06–4.13 (2H, m), 4.53 (1H, m),
4.64 (1H, m), 4.82 (1H, dd, J ¼ 7:5, 7.5 Hz), 4.98 (1H, d, J ¼ 9:3 Hz),
5.03 (1H, d, J ¼ 17:0 Hz), 5.03 (2H, s), 5.72 (1H, m), 6.97 (2H, d,
J ¼ 8:7 Hz), 7.12 (2H, d, J ¼ 6:5 Hz), 7.24–7.42 (10H, m). 13C-NMR
(CDCl3) ꢂ: 34.2, 37.5, 49.0, 55.3, 65.8, 69.9, 75.5, 114.8, 117.4, 127.2,
127.4, 127.7, 127.9, 128.5, 128.8, 129.4, 134.5, 135.2, 136.8, 153.5,
158.5, 175.4. Anal. Found: C, 73.62%; H, 6.35%; N, 2.99%. Calcd. for
C29H29O5N: C, 73.87%; H, 6.20%; N, 2.97%.

2448
M. MORITA and S. YAMAUCHI
(4S)-4-Benzyl-3-{(2R)-2-[(S)-(4-benzyloxyphenyl)(triisopropylsilyl-
ꢁ70 ꢀC for 20 min, MeI (1.37 ml, 22.0 mmol) was added. The resulting
reaction solution was stirred at ꢁ70 ꢀC for 1 h before addition of sat.
aq. NH4Cl solution and EtOAc. The organic solution was separated,
washed with brine, dried (Na2SO4), and evaporated. The residue was
applied to silica gel column chromatography (5% EtOAc in hexane),
oxy)methyl]-4-pentenoyl}-2-oxazolidinone (10). To an ice-cooled solu-
tion of 9 (28.2 g, 0.060 mol) and 2,6-lutidine (11.8 ml, 0.10 mol) in
CH2Cl2 (250 ml) was added TIPSOTf (18.8 ml, 0.07 mol). After the
reaction solution was stirred at room temperature for 1 h, sat. aq.
NaHCO3 solution was added. The organic solution was separated,
washed with sat. aq. CuSO4 solution and sat. aq. NaHCO3 solution,
and dried (Na2SO4). After evaporation, the residue was recrystallized
from iso-Pr2O, giving 10 (36.1 g, 0.058 mol, 96%) as colorless crystals,
20
giving 13 (4.15 g, 8.85 mmol, 57%) as a colorless oil, ½ꢀꢂD ¼ ꢁ45
(c 1.2, CHCl3). Lactone 12 (2.93 g, 6.45 mmol, 42%) was recovered.
13: 1H-NMR (CDCl3) ꢂ: 0.93–0.98 (24H, m), 2.37–2.50 (2H, m), 4.24
(1H, dd, J ¼ 9:0, 9.0 Hz), 4.30 (1H, dd, J ¼ 9:0, 7.4 Hz), 4.75 (1H, d,
J ¼ 5:4 Hz), 5.06 (2H, s), 6.95 (2H, d, J ¼ 8:5 Hz), 7.19 (2H, d,
J ¼ 8:5 Hz), 7.33–7.44 (5H, m). 13C-NMR (CDCl3) ꢂ: 12.4, 14.4, 17.9,
18.0, 36.5, 52.4, 68.4, 70.0, 75.3, 114.8, 127.5, 127.6, 128.0, 128.5,
134.6, 136.7, 158.6, 179.8. Anal. Found: C, 71.71%; H, 8.65%. Calcd.
for C28H40O4Si: C, 71.75%; H, 8.60%.
20
mp 142–143 ꢀC; ½ꢀꢂD ¼ ꢁ29 (c 1.3, CHCl3). 1H-NMR (CDCl3) ꢂ:
0.89–0.98 (21H, m), 1.91 (1H, m), 2.12 (1H, ddd, J ¼ 13:7, 9.7,
9.7 Hz), 2.63 (1H, dd, J ¼ 13:1, 11.2 Hz), 3.53 (1H, dd, J ¼ 13:1,
2.9 Hz), 4.06 (1H, dd, J ¼ 8:7, 8.7 Hz), 4.12 (1H, dd, J ¼ 8:7, 2.6 Hz),
4.55 (1H, m), 4.61 (1H, m), 4.87 (1H, d, J ¼ 10:7 Hz), 4.92 (1H, d,
J ¼ 16:3 Hz), 5.06 (2H, s), 5.08 (1H, d, J ¼ 8:4 Hz), 5.61 (1H, m),
6.94 (2H, d, J ¼ 8:6 Hz), 7.24–7.29 (4H, m), 7.32–7.40 (7H, m), 7.44
(1H, d, J ¼ 7:7 Hz). 13C-NMR (CDCl3) ꢂ: 12.5, 17.9, 18.0, 34.1, 38.3,
51.4, 55.8, 65.9, 69.9, 114.4, 116.8, 127.2, 127.5, 127.9, 128.5, 128.9,
129.3, 134.7, 134.9, 135.9, 136.9, 153.3, 158.6, 174.6. FABMS m=z
(%): 628 [ðM þ HÞþ, 0.8], 372 (50), 307 (53), 154 (100), 136 (63).
HRFABMS m=z ðM þ HÞþ: calcd. for C38H50O5NSi, 628.3458; found,
628.3461.
(2S,3S)-2-[(S)-(4-Benzyloxyphenyl)(triisopropylsilyloxy)methyl]-3-
methyltetramethylene diacetate (14). To an ice-cooled suspension of
LiAlH4 (0.35 g, 9.22 mmol) in THF (10 ml) was added a solution of 13
(2.00 g, 4.27 mmol) in THF (10 ml). After the reaction mixture was
stirred at 0 ꢀC for 1 h, sat. aq. MgSO4 solution and K2CO3 were added,
and then the resulting mixture was stirred at room temperature for
30 min before filtration. The filtrate was concentrated, and then the
residue was dissolved in pyridine (4 ml) and Ac2O (4 ml). The resulting
reaction solution was stood at room temperature for 12 h before
addition of ice. After additional 6 h at room temperature, the mixture
was dissolved in CH2Cl2 and H2O. The organic solution was separated,
washed with 6 M aq. HCl solution and sat. aq. NaHCO3 solution, dried
(Na2SO4), and evaporated. The residue was applied to silica gel
column chromatography (EtOAc:hexane ¼ 1:6), giving 14 (2.04 g,
(2S)-2-[(S)-(4-Benzyloxyphenyl)(triisopropylsilyloxy)methyl]-4-penten-
1-ol (11). To an ice-cooled solution of LiBH4 (2.15 g, 0.099mol) in THF
(20ml) were added MeOH (4.30ml, 0.11mol) and a solution of 10
(29.0g, 0.046mol) in THF (100ml). The resulting reaction solution was
stirred at room temperature for 1h before addition of sat aq. NH4Cl
solution. After the mixture was concentrated, the residue was dissolved in
EtOAc and H2O. The organic solution was separated, washed with brine,
and dried (Na2SO4). Evaporation and subsequent silica gel column
chromatography (EtOAc:hexane ¼ 1:7) gave 11 (12.3 g, 0.027mol,
20
3.66 mol, 86%, 2 steps) as a colorless oil, ½ꢀꢂD ¼ ꢁ14 (c 1.2,
CHCl3). 1H-NMR (CDCl3) ꢂ: 0.91–0.97 (24H, m), 1.87 (1H, m), 2.00
(3H, s), 2.02 (1H, m), 2.05 (3H, s), 3.66 (1H, dd, J ¼ 11:0, 7.7 Hz),
3.85 (1H, dd, J ¼ 11:0, 5.5 Hz), 4.31 (1H, dd, J ¼ 11:5, 4.7 Hz), 4.36
(1H, dd, J ¼ 11:5, 5.3 Hz), 4.94 (1H, d, J ¼ 7:6 Hz), 5.06 (2H, s), 6.93
(2H, d, J ¼ 8:7 Hz), 7.25 (2H, d, J ¼ 8:6 Hz), 7.30–7.44 (5H, m).
13C-NMR (CDCl3) ꢂ: 12.5, 17.1, 17.9, 18.0, 21.1, 31.0, 50.0, 62.1,
66.7, 70.0, 73.6, 114.5, 127.5, 127.9, 128.2, 128.5, 135.5, 136.9, 158.3,
170.8. Anal. Found: C, 68.84%; H, 8.73%. Calcd. for C32H48O6Si: C,
69.03%; H, 8.69%.
20
59%) as a colorless oil, ½ꢀꢂD ¼ ꢁ45 (c 1.4, CHCl3). 1H-NMR (CDCl3)
ꢂ: 0.86–1.05 (21H, m), 1.85–1.94 (2H, m), 2.19 (1H, m), 2.76 (1H, dd,
J ¼ 5:5, 5.5Hz), 3.56 (1H, ddd, J ¼ 11:1, 5.8, 5.8Hz), 3.77 (1H, ddd,
J ¼ 11:1, 5.5, 2.7Hz), 4.89 (1H, d, J ¼ 5:4 Hz), 4.99 (1H, d,
J ¼ 10:6 Hz), 5.00 (1H, d, J ¼ 16:9 Hz), 5.05 (2H, s), 5.73 (1H, m),
6.93 (2H, d, J ¼ 8:7 Hz), 7.25 (2H, d, J ¼ 8:7 Hz), 7.32–7.44 (5H, m).
13C-NMR (CDCl3) ꢂ: 12.5, 17.9, 18.0, 32.4, 48.3, 63.1, 70.0, 78.1, 114.3,
116.4, 127.5, 127.9, 127.99, 128.02, 128.1, 128.47, 128.51, 135.6, 136.9,
158.1. Anal. Found: C, 73.73%; H, 9.05%. Calcd. for C28H42O3Si: C,
73.96%; H, 9.31%.
(2S,3S)-2-[(S)-(4-Benzyloxyphenyl)(triisopropylsilyloxy)methyl]-3-
methyltetramethylene dibenzoate (15). To an ice-cooled suspension of
LiAlH4 (0.18 g, 4.74 mmol) in THF (10 ml) was added a solution of 13
(1.00 g, 2.13 mmol) in THF (10 ml). After the reaction mixture was
stirred at 0 ꢀC for 1 h, sat. aq. MgSO4 solution and K2CO3 were added,
and then the resulting mixture was stirred at room temperature for
30 min before filtration. The filtrate was concentrated, and then the
residue was dissolved in pyridine (10 ml). To this ice-cooled solution
was added BzCl (0.55 ml, 4.74 mmol), and then the reaction mixture
was stirred at room temperature for 12 h before additions of H2O and
CH2Cl2. The organic solution was separated, washed with 6 M aq. HCl
solution and sat. aq. NaHCO3 solution, and dried (Na2SO4). Concen-
tration and subsequent silica gel column chromatography (5% EtOAc
in hexane) gave 15 (0.93 g, 1.37 mmol, 64%, 2 steps) as a colorless oil,
(3S)-3-[(S)-(4-Benzyloxyphenyl)(triisopropylsilyloxy)methyl]-4-bu-
tanolide (12). A reaction solution of 11 (9.57 g, 0.021 mol) and NMO
(3.20 g, 0.027 mol), and OsO4 (aq. 2% solution, 3 ml) in acetone
(240 ml), tert-BuOH (60 ml), and H2O (60 ml) was stirred at room
temperature for 12 h before addition of sat. aq. Na2S2O3 solution. After
concentration of the mixture, the residue was dissolved in EtOAc and
H2O. The organic solution was separated, washed with brine, and dried
(Na2SO4). After evaporation, the residue was dissolved in MeOH
(200 ml). To this solution was added NaIO4 (5.60 g, 0.026 mol), 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, dried (Na2SO4),
and concentrated. A reaction mixture of the residue, PCC (5.70 g,
0.026 mol), and MS 4A (0.10 g) in CH2Cl2 (150 ml) was stirred at
room temperature for 12 h before addition of ether and filtration. The
filtrate was concentrated, and then the residue was applied to silica gel
column chromatography (EtOAc:hexane ¼ 1:4) to give 12 (7.21 g,
20
½ꢀꢂD ¼ þ1:5 (c 1.3, CHCl3). 1H-NMR (CDCl3) ꢂ: 0.90–0.96 (21H,
m), 1.14 (3H, d, J ¼ 7:1 Hz), 2.17 (1H, m), 2.32 (1H, m), 4.01 (1H, dd,
J ¼ 11:0, 7.5 Hz), 4.18 (1H, dd, J ¼ 11:0, 7.2 Hz), 4.63 (1H, dd,
J ¼ 11:6, 5.3 Hz), 4.68 (1H, dd, J ¼ 11:6, 5.9 Hz), 5.03 (2H, s), 5.10
(1H, d, J ¼ 7:3 Hz), 6.93 (2H, d, J ¼ 8:7 Hz), 7.31–7.43 (12H, m),
7.51–7.55 (2H, m), 7.97–7.99 (2H, m), 8.03 (1H, m). 13C-NMR
(CDCl3) ꢂ: 12.5, 17.3, 17.9, 18.1, 31.4, 50.0, 63.1, 67.3, 70.0, 73.8,
114.6, 127.5, 127.9, 128.1, 128.29, 128.33, 128.5, 129.47, 129.52,
130.2, 130.3, 132.8, 132.9, 135.4, 136.9, 158.4, 166.4, 166.5. Anal.
Found: C, 74.16%; H, 7.89%. Calcd. for C42H52O6Si: C, 74.08%;
H, 7.70%.
20
0.016 mol, 76%, 3 steps) as a colorless oil, ½ꢀꢂD ¼ ꢁ39 (c 1.2,
CHCl3). 1H-NMR (CDCl3) ꢂ: 0.93–0.98 (21H, m), 2.31 (2H, d,
J ¼ 8:4 Hz), 2.85 (1H, m), 4.33 (1H, dd, J ¼ 9:2, 7.4 Hz), 4.40 (1H,
dd, J ¼ 9:2, 6.9 Hz), 4.68 (1H, d, J ¼ 7:3 Hz), 5.05 (2H, s), 6.94 (2H,
d, J ¼ 8:7 Hz), 7.20 (2H, d, J ¼ 8:7 Hz), 7.33–7.44 (5H, m). 13C-NMR
(CDCl3) ꢂ: 12.4, 17.9, 18.0, 31.1, 44.7, 70.0, 70.3, 75.5, 114.8, 127.5,
127.6, 128.0, 128.5, 134.6, 136.7, 158.6, 176.7. Anal. Found: C,
71.34%; H, 8.56%. Calcd. for C27H38O4Si: C, 71.32%; H, 8.42%.
(2S,3S)-2-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-3-methyltetra-
methylene diacetate (16). To an ice-cooled solution of 14 (2.04 g,
3.66 mmol) in THF (10 ml) was added (n-Bu)4NF (4.33 ml, 1 M in
THF, 4.33 mol). The reaction solution was stirred at 0 ꢀC for 1 h before
additions of sat. aq. NH4Cl solution and EtOAc. The organic solution
was separated, washed with sat. aq. CuSO4 solution, sat. aq. NaHCO3
solution, and brine, and dried (Na2SO4). Concentration and subsequent
(2S,3S)-3-[(S)-(4-Benzyloxyphenyl)(triisopropylsilyloxy)methyl]-2-
methyl-4-butanolide (13). To a solution of KHMDS (21.9 ml, 0.5 M in
toluene, 10.9 mmol) in THF (20 ml) was added a solution of 12 (7.00 g,
15.4 mmol) in THF (10 ml) at ꢁ70 ꢀC. After the mixture was stirred at

Syntheses of Secocyclolignanes
2449
silica gel column chromatography (EtOAc:hexane ¼ 1:2) gave 16
(3S,4S)-4-(4-Benzyloxyphenyl)-3-pivaloyloxymethyl-4-butanolide
(20). Compound 19 was converted to compound 20 as colorless
crystals, mp 83–84 ꢀC (iso-Pr2O), in 52% yield by the same method as
20
(1.00 g, 2.50 mmol, 68%) as a colorless oil, ½ꢀꢂD ¼ ꢁ7:2 (c 1.3,
CHCl3). 1H-NMR (CDCl3) ꢂ: 1.04 (3H, d, J ¼ 6:8 Hz), 1.96–2.03 (2H,
m), 1.98 (3H, s), 2.03 (3H, s), 2.51 (1H, br. s), 3.88 (1H, dd, J ¼ 11:1,
6.9 Hz), 4.06 (1H, dd, J ¼ 11:1, 5.7 Hz), 4.29 (1H, dd, J ¼ 11:4,
4.3 Hz), 4.33 (1H, dd, J ¼ 11:4, 5.2 Hz), 4.81 (1H, d, J ¼ 5:2 Hz), 5.05
(2H, s), 6.96 (2H, d, J ¼ 8:6 Hz), 7.25 (2H, d, J ¼ 8:6 Hz), 7.30–7.43
(5H, m). 13C-NMR (CDCl3) ꢂ: 15.9, 20.85, 20.93, 32.2, 47.4, 61.9,
66.9, 70.0, 72.5, 114.8, 127.2, 127.3, 127.35, 127.39, 127.9, 128.5,
135.5, 136.8, 158.2, 170.9, 171.0. Anal. Found: C, 68.97%; H, 7.20%.
Calcd. for C23H28O6: C, 68.98%; H, 7.05%.
20
that described for the synthesis of compound 12, ½ꢀꢂD ¼ ꢁ0:8 (c 1.2,
CHCl3). 1H-NMR (acetone-d6) ꢂ: 1.13 (9H, s), 2.56 (1H, dd, J ¼ 17:2,
4.0 Hz), 2.94 (1H, dd, J ¼ 17:2, 8.8 Hz), 3.20 (1H, m), 3.63 (1H, dd,
J ¼ 11:4, 5.1 Hz), 3.81 (1H, dd, J ¼ 11:4, 5.2 Hz), 5.12 (2H, s), 5.77
(1H, d, J ¼ 6:8 Hz), 7.06 (2H, d, J ¼ 8:7 Hz), 7.31 (2H, d, J ¼ 8:7 Hz),
7.34–7.43 (3H, m), 7.47–7.69 (2H, m). 13C-NMR (acetone-d6) ꢂ: 27.1,
32.7, 38.9, 39.8, 63.7, 70.3, 82.5, 115.4, 116.4, 127.6, 128.2, 128.4,
129.02, 129.04, 137.94, 159.4, 176.0, 177.7. Anal. Found: C, 71.97%;
H, 6.86%. Calcd. for C23H26O5: C, 72.23%; H, 6.85%.
(1S,2S,3S)-1-(4-Benzyloxyphenyl)-4-(tert-butyldiphenylsilyloxy)-2-
(tert-butyldiphenylsilyloxymethyl)-3-methyl-1-butanol (17). A reaction
solution of 16 (0.22 g, 0.55 mmol) in EtOH (10 ml) and 1 M aq. NaOH
solution was stirred at room temperature for 16 h. After additions of
H2O and CHCl3, the organic solution was separated, dried (Na2SO4),
and concentrated. A reaction solution of the residue, TBDPSCl
(0.29 ml, 1.10 mmol), Et3N (0.17 ml, 1.22 mmol), and DMAP (3 mg,
0.025 mmol) in CH2Cl2 (5 ml) was stirred at room temperature for 1 h
before additions of H2O and CH2Cl2. The organic solution was
separated, dried (Na2SO4), and evaporated. The residue was applied to
silica gel column chromatography (EtOAc:hexane ¼ 1:6) to give 17
(2R,3S,4S)-4-(4-Benzyloxyphenyl)-2-methyl-3-pivaloyloxymethyl-
4-butanolide (21). Compound 20 was converted to compound 21 as a
colorless oil in 57% yield by the same method as that described for the
synthesis of compound 13. Compound 20 was recovered in 43%. 21:
20
½ꢀꢂD ¼ þ36 (c 1.5, CHCl3). 1H-NMR (CDCl3) ꢂ: 1.17 (9H, s), 1.37
(3H, d, J ¼ 7:0 Hz), 2.61 (1H, m), 2.74 (1H, m), 3.70 (1H, dd,
J ¼ 11:4, 7.1 Hz), 3.80 (1H, dd, J ¼ 11:4, 5.7 Hz), 5.04 (2H, s), 5.62
(1H, d, J ¼ 7:8 Hz), 6.95 (2H, d, J ¼ 8:6 Hz), 7.13 (2H, d, J ¼ 8:6 Hz),
7.31–7.43 (5H, m). 13C-NMR (CDCl3) ꢂ: 14.7, 27.1, 36.6, 38.6, 46.6,
62.9, 70.0, 80.2, 114.8, 114.9, 126.4, 127.0, 127.40, 127.43, 128.0,
128.5, 136.5, 158.9, 177.9, 178.7. FABMS m=z (%): 397 [ðM þ HÞþ,
19], 91 (100). HRFABMS m=z ðM þ HÞþ: calcd. for C24H29O5,
397.2015; found, 397.2017.
20
(0.30 g, 0.38 mmol, 70%) as a colorless oil, ½ꢀꢂD ¼ þ11 (c 0.8,
CHCl3). 1H-NMR (CDCl3) ꢂ: 1.00 (3H, d, J ¼ 6:8 Hz), 1.06 (18H, s),
1.92 (1H, m), 1.96 (1H, m), 3.36 (1H, dd, J ¼ 10:2, 4.8 Hz), 3.44 (1H,
dd, J ¼ 10:2, 4.5 Hz), 3.75 (1H, dd, J ¼ 10:7, 5.0 Hz), 3.79 (1H, dd,
J ¼ 10:7, 3.4 Hz), 4.53 (1H, d, J ¼ 5:1 Hz), 4.97 (1H, dd, J ¼ 5:1,
5.1 Hz), 5.05 (2H, s), 6.90 (2H, d, J ¼ 8:7 Hz), 7.22–7.46 (19H, m),
7.50–7.57 (4H, m), 7.69–7.72 (4H, m). 13C-NMR (CDCl3) ꢂ: 19.0,
26.5, 34.1, 48.4, 63.5, 65.9, 70.0, 75.7, 114.5, 127.3, 127.5, 127.56,
127.58, 127.7, 127.8, 127.9, 128.6, 129.55, 129.61, 129.8, 129.9,
132.4, 132.5, 133.5, 133.6, 134.8, 135.2, 135.5, 135.59, 135.64, 136.6,
137.2, 157.8. FABMS m=z (%): 793 [ðM þ HÞþ, 2], 135 (79), 91 (100).
HRFABMS m=z ðM þ HÞþ: calcd. for C51H61O4Si2, 793.41090; found,
793.41090.
(2S,3R)-2-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-3-methyltetra-
methylene dibenzoate (22). Compound 21 was converted to compound
22 as a colorless oil in 67% yield by the same method as that described
20
for the synthesis of compound 15, ½ꢀꢂD ¼ ꢁ32 (c 0.8, CHCl3). 1H-
NMR (CDCl3) ꢂ: 1.08 (3H, d, J ¼ 7:0 Hz), 2.11 (1H, m), 2.42 (1H, m),
2.57 (1H, br. s), 4.31 (1H, dd, J ¼ 11:1, 6.3 Hz), 4.37 (1H, dd,
J ¼ 11:1, 7.2 Hz), 4.62–4.69 (2H, m), 4.85 (1H, d, J ¼ 7:4 Hz), 5.01
(2H, s), 6.93 (2H, d, J ¼ 8:7 Hz), 7.29 (2H, d, J ¼ 8:7 Hz), 7.31–7.40
(9H, m), 7.42–7.57 (2H, m), 7.96–8.00 (4H, m). 13C-NMR (CDCl3) ꢂ:
13.4, 32.2, 45.9, 62.6, 68.2, 70.0, 73.2, 114.9, 127.4, 128.0, 128.4,
128.54, 129.45, 129.49, 129.6, 130.0, 130.2, 132.9, 135.1, 136.9,
158.4, 166.4, 166.7; FABMS m=z (%): 525 [ðM þ HÞþ, 0.7], 154 (78),
91 (100). HRFABMS m=z ðM þ HÞþ: calcd. for C33H33O6, 525.2277;
found, 525.2275.
(2S,3S)-2-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-3-methyltetra-
methylene dibenzoate (18). Title compound 18 was obtained from 15
by the same method as that described for the synthesis of compound 16
20
in 61% yield as a colorless oil, ½ꢀꢂD ¼ þ8 (c 1.7, CHCl3). 1H-NMR
(CDCl3) ꢂ: 1.20 (3H, d, J ¼ 6:8 Hz), 2.20–2.30 (2H, m), 2.55 (1H, d,
J ¼ 3:8 Hz), 4.24 (1H, dd, J ¼ 11:1, 6.8 Hz), 4.38 (1H, dd, J ¼ 11:1,
5.6 Hz), 4.59 (1H, dd, J ¼ 11:7, 3.6 Hz), 4.68 (1H, dd, J ¼ 11:7,
5.4 Hz), 4.96 (1H, dd, J ¼ 3:8, 3.8 Hz), 4.99 (2H, s), 6.93 (2H, d,
J ¼ 8:7 Hz), 7.28–7.40 (11H, m), 7.42–7.55 (2H, m), 7.93–8.00 (4H,
m). 13C-NMR (CDCl3) ꢂ: 16.0, 32.7, 47.8, 62.5, 67.5, 70.0, 72.6,
114.9, 127.3, 127.4, 127.9, 128.3, 128.5, 129.4, 129.5, 129.9, 130.1,
132.9, 133.0, 135.5, 136.9, 158.3, 166.4, 166.6. Anal. Found: C,
75.31%; H, 6.34%. Calcd. for C33H32O6: C, 75.55%; H, 6.15%.
(S)-3-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-4-butanolide (23).
To an ice-cooled solution of 12 (1.84 g, 4.05 mmol) in THF (10 ml)
were added AcOH (0.25 ml, 4.37 mmol) and (n-Bu)4NF (6.05 ml, 1 M in
THF, 6.05 mmol). After the resulting reaction solution was stirred at
room temperature for 1 h before additions of sat. aq. NaHCO3 solution
and EtOAc. The organic solution was separated, washed with sat. aq.
CuSO4 solution, sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration and subsequent silica gel column chromatog-
raphy (EtOAc:hexane ¼ 1:2) gave 23 (0.72 g, 2.41 mmol, 60%) as
20
colorless crystals, mp 95–96 ꢀC (EtOAc), ½ꢀꢂD ¼ ꢁ38 (c 0.8, CHCl3).
(2S)-2-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-4-pentenyl piva-
loate (19). To a solution of 9 (23.3 g, 49.4 mmol) and MeOH (4.3 ml)
in THF (260 ml) was added a solution of LiBH4 (2.15 g, 98.7 mmol) in
THF (115 ml) at below 0 ꢀC, and then the resulting reaction solution
was stirred at 0 ꢀC for 1 h. After additions of 1 M aq. NaOH solution
and EtOAc, the organic solution was separated, washed with brine,
dried (Na2SO4), and concentrated. The residue was dissolved in
pyridine (20 ml). To the ice-cooled solution was added PivCl (6.10 ml,
49.5 mmol), and then the resulting reaction mixture was stirred at room
temperature for 30 min before additions of CH2Cl2 and H2O. The
organic solution was separated, washed with 6 M aq. HCl solution and
sat. aq. NaHCO3, and dried (Na2SO4). Concentration and subsequent
silica gel column chromatography (EtOAc:hexane ¼ 1:5) gave 19
1H-NMR (CDCl3) ꢂ: 2.22 (1H, dd, J ¼ 17:9, 7.3 Hz), 2.35 (1H, dd,
J ¼ 17:9, 9.0 Hz), 2.42 (1H, s), 2.84 (1H, m), 4.36 (1H, dd, J ¼ 9:5,
6.2 Hz), 4.40 (1H, dd, J ¼ 9:5, 6.5 Hz), 4.53 (1H, d, J ¼ 7:9 Hz), 5.05
(2H, s), 6.95–6.97 (2H, m), 7.21–7.25 (2H, m), 7.31–7.43 (5H, m).
13C-NMR (CDCl3) ꢂ: 31.3, 42.4, 70.0, 70.5, 74.9, 115.1, 127.3, 127.4,
128.0, 128.6, 134.1, 136.7, 158.8, 176.9. Anal. Found: C, 72.08%; H,
5.98%. Calcd. for C18H18O4: C, 72.47%; H, 6.08%.
(2R,3S)-3-[(S)-(4-Benzyloxyphenyl)(hydroxy)methyl]-2-methyl-4-
butanolide (24) and (2R,3S,4S)-4-(4-benyzloxyphenyl)-3-hydroxymeth-
yl-2-methyl-4-butanolide (25). A reaction solution of 21 (1.81 g,
4.57 mmol) in EtOH (20 ml) and 1 M aq. NaOH solution (20 ml) was
stirred at room temperature for 12 h before additions of 6 M aq. HCl
solution and CHCl3. The organic solution was separated, washed with
sat. aq. NaHCO3 solution, and dried (Na2SO4). Concentration and
subsequent silica gel column chromatography (EtOAc:hexane ¼ 1:1)
gave 24 (0.44 g, 1.41 mmol, 31%) and 25 (0.86 g, 2.75 mmol, 60%). 24:
20
(13.6 g, 35.6 mmol, 72%) as a colorless oil, ½ꢀꢂD ¼ ꢁ0:8 (c 1.2,
CHCl3). 1H-NMR (CDCl3) ꢂ: 1.22 (9H, s), 1.92 (1H, m), 2.02–2.08
(2H, m), 2.56 (1H, br. s), 4.09 (1H, dd, J ¼ 11:2, 4.3 Hz), 4.36 (1H, dd,
J ¼ 11:2, 4.3 Hz), 4.54 (1H, d, J ¼ 7:1 Hz), 4.98 (1H, d, J ¼ 13:7 Hz),
5.03 (1H, d, J ¼ 12:3 Hz), 5.05 (2H, s), 5.70 (1H, m), 6.95 (2H, d,
J ¼ 8:7 Hz), 7.23 (2H, d, J ¼ 8:7 Hz), 7.30–7.44 (5H, m). 13C-NMR
(CDCl3) ꢂ: 27.2, 32.2, 38.9, 44.9, 63.1, 70.0, 70.1, 114.8, 117.0, 127.4,
127.7, 127.9, 128.5, 134.9, 135.7, 136.9, 158.3, 178.7. Anal. Found: C,
75.30%; H, 7.99%. Calcd. for C24H30O4: C 75.36%; H, 7.91%.
20
Mp 138–139 ꢀC (iso-Pr2O), ½ꢀꢂD ¼ ꢁ58 (c 0.2, CHCl3). 1H-NMR
(CDCl3) ꢂ: 1.32 (3H, d, J ¼ 7:3 Hz), 1.81 (1H, d, J ¼ 3:4 Hz), 2.68
(1H, m), 2.80 (1H, m), 4.22 (1H, dd, J ¼ 9:6, 6.9 Hz), 4.37 (1H, dd,
J ¼ 9:6, 4.1 Hz), 4.90 (1H, dd, J ¼ 4:5, 3.4 Hz), 5.08 (2H, s), 6.98–

2450
M. MORITA and S. YAMAUCHI
7.01 (2H, m), 7.24–7.30 (2H, m), 7.32–7.45 (5H, m). 13C-NMR
(CDCl3) ꢂ: 10.3, 36.6, 45.1, 67.4, 70.1, 71.5, 115.2, 127.1, 127.5,
128.1, 128.6, 134.2, 136.7, 141.6, 158.7, 179.7. EIMS m=z (%) 312
before additions of H2O and CHCl3. The organic solution was
separated, dried (Na2SO4), and concentrated. A reaction mixture of the
residue and 5% Pd/C (0.30 g) in THF (25 ml) was stirred under H2 gas
at the ambient temperature for 6 h before filtration. The filtrate was
concentrated, and then the residue was recrystallized from MeOH to
give 29 (0.093 g, 0.31 mmol, 72%) as colorless crystals, mp 207–
(Mþ, 65), 213 (100), 91 (99). HREIMS m=z Mþ: calcd. for C19H20O4,
20
312.1362; found, 312.1362. 25: Mp 81–82 ꢀC (iso-Pr2O), ½ꢀꢂD
¼
þ9:5 (c 0.4, CHCl3). 1H-NMR (CDCl3) ꢂ: 1.35 (3H, d, J ¼ 6:7 Hz),
1.58 (1H, br. s), 2.61–2.67 (2H, m), 3.32 (1H, br. m), 3.51 (1H, br. d,
J ¼ 11:0 Hz), 5.06 (2H, s), 5.63 (1H, d, J ¼ 7:0 Hz), 6.98–7.00 (2H,
m), 7.19 (2H, d, J ¼ 8:7 Hz), 7.31–7.43 (5H, m). 13C-NMR (CDCl3) ꢂ:
14.6, 35.7, 49.7, 61.0, 70.1, 80.6, 115.1, 127.1, 127.5, 128.1, 128.7,
158.9, 179.4. EIMS m=z (%): 312 (Mþ, 99), 213 (38), 91 (100).
HREIMS m=z Mþ: calcd. for C19H20O4, 312.1362; found, 312.1362. A
reaction solution of 25 (0.86 g, 2.75 mmol) in EtOH (15 ml) and 1 M aq.
NaOH solution (15 ml) was stirred at room temperature for 12 h before
additions of 6 M aq. HCl solution and CHCl3. The organic solution was
separated, washed with sat. aq. NaHCO3 solution, and dried (Na2SO4).
Concentration and subsequent silica gel column chromatography
(EtOAc:hexane ¼ 1:1) gave 24 (0.28 g, 0.90 mmol, 33%) and 25
(0.55 g, 1.76 mmol, 64%).
20
208 ꢀC, ½ꢀꢂD ¼ ꢁ15 (c 0.1, MeOH). 1H-NMR (C5D5N) ꢂ: 1.34 (3H,
d, J ¼ 7:1 Hz), 2.39 (1H, m), 2.67 (1H, m), 3.80 (1H, dd, J ¼ 11:2,
4.3 Hz), 3.88 (1H, dd, J ¼ 11:2, 4.4 Hz), 4.10 (1H, dd, J ¼ 8:2,
0.9 Hz), 4.20 (1H, dd, J ¼ 8:2, 3.9 Hz), 4.63 (1H, d, J ¼ 12:0 Hz),
5.60–6.60 (2H, br.), 7.14–7.21 (4H, m), 7.51–7.58 (4H, m), 11.0–11.6
(2H, br.). 13C-NMR (C5D5N) ꢂ: 17.2, 35.5, 48.4, 50.5, 58.5, 62.8,
116.2, 116.4, 129.8, 136.3, 136.7, 156.98, 157.03. EIMS m=z (%) 302
(Mþ, 2), 199 (100). HREIMS m=z Mþ: calcd. for C18H22O4, 302.1519;
found, 302.1519.
(2S,3R)-2-[Bis(4-benzyloxyphenyl)]methyl-3-methyltetramethylene
dibenzoate (30). Compound 22 was converted to compound 30 as a
colorless oil in 67% yield by the same method as that described for the
20
synthesis of compound 26, ½ꢀꢂD ¼ ꢁ27 (c 1.1, CHCl3). 1H-NMR
(CDCl3) ꢂ: 1.05 (3H, d, J ¼ 6:9 Hz), 2.27 (1H, m), 3.05 (1H, m), 3.95
(1H, d, J ¼ 12:0 Hz), 4.25 (1H, dd, J ¼ 10:7, 6.5 Hz), 4.30 (1H, dd,
J ¼ 10:7, 6.4 Hz), 4.36 (1H, dd, J ¼ 12:0, 3.1 Hz), 4.40 (1H, dd,
J ¼ 12:0, 12.0 Hz), 4.91 (2H, s), 4.97 (2H, s), 6.83 (2H, d, J ¼ 8:9 Hz),
6.85 (2H, d, J ¼ 8:7 Hz), 7.24–7.47 (18H, m), 7.51–7.56 (2H, m),
7.96–8.05 (4H, m). 13C-NMR (CDCl3) ꢂ: 11.3, 32.6, 41.2, 51.0, 63.8,
68.8, 69.88, 69.94, 115.1, 127.4, 127.9, 128.4, 128.5, 128.7, 129.4,
129.5, 130.0, 130.3, 132.9, 135.67, 135.73, 136.96, 136.98, 157.4,
166.2, 166.3. FABMS m=z (%): 691 [ðM þ HÞþ, 2.2], 154 (100), 136
(67). HRFABMS m=z ðM þ HÞþ: calcd. for C46H43O6, 691.3059;
found, 691.3057.
(E)-(S)-4-(4-Benzyloxyphenyl)-2-methyl-3-buten-1-yl acetate (26).
A reaction mixture of 16 (112 mg, 0.28 mmol), benzyloxybenzene
(63 mg, 0.34 mmol), and [Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2] (3 mg,
0.0025 mmol) in Cl(CH2)2Cl (1 ml) was stirred at 80 ꢀC for 12 h
before addition of a few drops of Et3N and concentration. The residue
was applied to silica gel column chromatography (5% EtOAc in
hexane) to give 26 (36 mg, 0.12 mmol, 43%) as a colorless oil,
20
½ꢀꢂD ¼ ꢁ39 (c 0.1, CHCl3). 1H-NMR (CDCl3) ꢂ: 1.12 (3H, d,
J ¼ 6:8 Hz), 2.05 (3H, s), 2.66 (1H, m), 3.98 (1H, dd, J ¼ 10:7,
6.6 Hz), 4.06 (1H, dd, J ¼ 10:7, 7.0 Hz), 5.07 (2H, s), 5.96 (1H, dd,
J ¼ 16:3, 7.4 Hz), 6.37 (1H, d, J ¼ 16:3 Hz), 6.92 (2H, d, J ¼ 8:7 Hz),
7.28 (2H, d, J ¼ 8:7 Hz), 7.32–7.44 (5H, m). 13C-NMR (CDCl3) ꢂ:
17.0, 21.0, 36.5, 68.6, 70.0, 114.9, 127.3, 127.4, 128.0, 128.6, 129.6,
129.7, 130.4, 137.0, 158.1, 171.2. EIMS m=z (%): 310 (Mþ, 12), 250
(94), 91 (100). HREIMS m=z Mþ: Calcd. for C20H22O3, 310.1569;
found, 310.1570.
(2S,3R)-2-[Bis(4-hydroxyphenyl)]methyl-3-methyl-1,4-butanediol
(31). Compound 30 was converted to compound 31 as a colorless oil in
56% yield through 2 steps by the same method as that described for the
20
synthesis of 29, ½ꢀꢂD ¼ ꢁ9 (c 0.2, MeOH). 1H-NMR (CD3OD) ꢂ:
0.88 (3H, d, J ¼ 7:1 Hz), 1.81 (1H, m), 2.56 (1H, m), 3.42 (2H, d,
J ¼ 5:4 Hz), 3.56 (2H, d, J ¼ 5:6 Hz), 3.60 (1H, d, J ¼ 12:1 Hz), 6.66–
6.68 (4H, m), 7.12–7.16 (4H, m). 13C-NMR (CD3OD) ꢂ: 11.6, 37.5,
48.1, 53.1, 62.3, 69.3, 117.06, 117.08, 130.5, 130.7, 137.7, 138.2,
157.3. FABMS m=z (%): 303 [ðM þ 1Þþ, 12], 154 (100), 136 (68).
HRFABMS m=z ðM þ HÞþ: calcd. for C18H23O4, 303.1597; found,
303.1595.
(2S,3S)-1,1-Bis(4-benzyloxyphenyl)-4-(tert-butyldiphenylsilyloxy)-
2-(tert-butyldiphenylsilyloxy)methyl-3-methylbutane (27). Compound
27 was obtained from 17 by the same method as that described for the
20
synthesis of 26 in 17% yield as a colorless oil, ½ꢀꢂD ¼ þ8 (c 0.5,
CHCl3). 1H-NMR (CDCl3) ꢂ: 0.89 (9H, s), 0.99 (9H, s), 1.02 (3H, d,
J ¼ 7:0 Hz), 2.09 (1H, m), 2.44 (1H, m), 3.44 (1H, dd, J ¼ 9:9,
9.9 Hz), 3.57 (2H, d, J ¼ 4:1 Hz), 3.74 (1H, dd, J ¼ 9:9, 5.4 Hz), 3.94
(1H, d, J ¼ 11:9 Hz), 4.96 (2H, s), 4.97 (2H, s), 6.73 (2H, d,
J ¼ 8:7 Hz), 6.80 (2H, d, J ¼ 8:7 Hz), 7.03 (2H, d, J ¼ 8:7 Hz), 7.08
(2H, d, J ¼ 8:7 Hz), 7.17–7.21 (2H, m), 7.26–7.48 (24H, m), 7.56–7.60
(4H, m). 13C-NMR (CDCl3) ꢂ: 19.0, 19.2, 26.9, 36.3, 46.9, 50.0, 62.5,
66.8, 69.9, 70.0, 114.7, 114.8, 127.35, 127.42, 127.46, 127.51, 127.88,
128.55, 128.65, 128.82, 129.3, 129.4, 133.3, 133.4, 134.1, 134.2,
135.5, 135.59, 135.64, 135.7, 137.0, 137.3, 156.97, 157.04. FABMS
m=z (%): 959 [ðM þ HÞþ, 0.6], 91 (100). HRFABMS m=z ðM þ HÞþ:
calcd. for C64H71O4Si2, 959.4891; found, 959.4893.
(R)-3-[Bis(4-benzyloxyphenyl)]methyl-4-butanolide (32). Compound
23 was converted to compound 32 as colorless crystals, mp 154–
155 ꢀC (EtOAc), in 65% yield by the same method as that described for
20
the synthesis of compound 26, ½ꢀꢂD ¼ ꢁ3 (c 1.3, CHCl3). 1H-NMR
(CDCl3) ꢂ: 2.22 (1H, dd, J ¼ 17:8, 8.0 Hz), 2.52 (1H, dd, J ¼ 17:8,
8.3 Hz), 3.30 (1H, m), 3.69 (1H, d, J ¼ 11:5 Hz), 3.93 (1H, dd,
J ¼ 9:4, 7.0 Hz), 4.22 (1H, dd, J ¼ 9:4, 7.4 Hz), 4.99 (4H, s), 6.87–
6.91 (4H, m), 7.11–7.14 (4H, m), 7.29–7.41 (10H, m). 13C-NMR
(CDCl3) ꢂ: 34.0, 40.1, 53.7, 70.0, 72.2, 115.1, 115.2, 127.4, 127.9,
128.39, 128.41, 128.5, 134.5, 135.0, 136.80, 136.83, 157.6, 157.7,
176.6. Anal. Found: C, 79.95%; H, 6.10%. Calcd. for C31H28O4: C,
80.15%; H, 6.08%.
(2S,3S)-2-[Bis(4-benzyloxyphenyl)]methyl-3-methyltetramethylene
dibenzoate (28). Compound 28 was obtained from 18 by the same
method as that described for the synthesis of 26 in 75% yield as a
20
colorless oil, ½ꢀꢂD ¼ ꢁ32 (c 1.9, CHCl3). 1H-NMR (CDCl3) ꢂ: 1.21
(2S,3S)-3-[Bis(4-benzyloxyphenyl)]methyl-2-methyl-4-butanolide
(33). Compound 32 was converted to compound 33 as colorless
crystals, mp 125–126 ꢀC (MeOH), in 75% yield by the same method as
(3H, d, J ¼ 7:0 Hz), 2.34 (1H, m), 2.80 (1H, m), 4.15 (1H, d, J ¼ 12:0
Hz), 4.20 (1H, dd, J ¼ 11:5, 6.5 Hz), 4.24 (1H, dd, J ¼ 11:5, 5.8 Hz),
4.40 (1H, dd, J ¼ 10:8, 5.9 Hz), 4.42 (1H, dd, J ¼ 10:8, 3.1 Hz), 4.91
(2H, s), 4.98 (2H, s), 6.81 (2H, d, J ¼ 8:7 Hz), 6.90 (2H, d, J ¼ 8:7
Hz), 7.18–7.21 (2H, m), 7.27–7.42 (16H, m), 7.51–7.55 (2H, m), 7.96–
8.00 (4H, m). 13C-NMR (CDCl3) ꢂ: 16.8, 32.7, 44.9, 50.9, 63.8, 66.9,
69.9, 70.0, 115.0, 115.1, 127.4, 127.5, 127.8, 127.9, 128.30, 128.34,
128.47, 128.49, 128.53, 128.7, 129.5, 130.0, 130.3, 132.8, 132.9,
135.8, 136.97, 136.99, 157.36, 157.39, 166.21, 166.43. EIMS m=z (%):
690 (Mþ, 23), 477 (99), 469 (82), 380 (100), 289 (83), 263 (99).
HREIMS m=z Mþ: calcd. for C46H42O6, 690.2982; found, 690.2982.
20
that described for the synthesis of compound 13, ½ꢀꢂD ¼ þ14 (c 1.4,
CHCl3). 1H-NMR (CDCl3) ꢂ: 0.84 (3H, d, J ¼ 7:3 Hz), 2.32 (1H, m),
2.93 (1H, m), 3.69 (1H, d, J ¼ 11:2 Hz), 3.76 (1H, dd, J ¼ 9:5, 8.4 Hz),
4.25 (1H, dd, J ¼ 9:5, 7.8 Hz), 5.00 (4H, s), 6.85–6.91 (4H, m), 7.13–
7.18 (4H, m), 7.25–7.41 (10H, m). 13C-NMR (CDCl3) ꢂ: 15.5, 40.3,
47.4, 54.7, 69.95, 70.00, 115.19, 115.21, 127.4, 128.0, 128.4, 128.52,
128.54, 128.6, 134.3, 135.0, 136.82, 136.84, 157.7, 179.8. FABMS m=z
(%): 479 [ðM þ HÞþ, 5], 154 (100), 136 (66). HRFABMS m=z
ðM þ HÞþ: calcd. for C32H31O4, 479.2222; found, 479.2224.
(2S,3S)-2-[Bis(4-hydroxyphenyl)]methyl-3-methyl-1,4-butanediol
(29). A reaction solution of 28 (0.30 g, 0.43 mmol) in EtOH (20 ml) and
1 M aq. NaOH solution (20 ml) was stirred at room temperature for 12 h
(2S,3S)-3-[Bis(4-hydroxyphenyl)]methyl-2-methyl-4-butanolide (34).
A reaction mixture of 33 (0.38 g, 0.79 mmol) and 5% Pd/C (0.57 g) in
THF (10 ml) was stirred under H2 gas at the ambient temperature for

Syntheses of Secocyclolignanes
6 h before filtration. After the filtrate was concentrated, the residue was
2451
Acknowledgments
applied to silica gel column chromatography (EtOAc:hexane ¼ 1:1) to
give 34 (0.14 g, 0.47 mmol, 59%) as colorless crystals, mp 105–106 ꢀC
We measured the 400 MHz NMR, MS and elemental
analysis data at INCS of Ehime University. We are
grateful to Marutomo Co. for financial support.
20
(EtOAc), ½ꢀꢂD ¼ þ21 (c 0.6, MeOH). 1H-NMR (C5D5N) ꢂ: 0.96
(3H, d, J ¼ 7:2 Hz), 2.55 (1H, m), 3.13 (1H, m), 3.85 (1H, dd, J ¼ 8:9,
8.1 Hz), 3.88 (1H, d, J ¼ 11:2 Hz), 4.34 (1H, dd, J ¼ 8:9, 8.1 Hz),
7.13–7.25 (4H, m), 7.33–7.41 (4H, m). 13C-NMR (C5D5N) ꢂ: 22.8,
40.5, 47.4, 55.0, 70.8, 116.2, 116.3, 116.39, 116.43, 129.1, 129.3,
133.8, 134.5, 157.5, 179.9. FABMS m=z (%): 299 [ðM þ 1Þþ, 13], 154
(100), 136 (70). HRFABMS m=z ðM þ HÞþ: calcd. for C18H19O4,
299.1284; found, 299.1284.
References
1) MacRae WD and Towers GHN, Phytochemistry, 23, 1207–1220
(1984).
2) Ayres DC and Loike JD, ‘‘Lignans,’’ Cambridge University
Press, New York (1990).
(2R,3S)-3-[Bis(4-hydroxyphenyl)]methyl-2-methyl-4-butanolide (35).
A reaction mixture of 24 (0.44 g, 1.41 mmol), benzyloxybenzene
(1.30 g, 7.06 mmol), and [Ir2(COD)2(SnCl3)2(Cl)2(ꢁ-Cl)2] (12 mg,
0.01 mmol) in Cl(CH2)2Cl (4 ml) was stirred at 80 ꢀC for 12 h before
addition of a few drops of Et3N and concentration. The residue was
applied to silica gel column chromatography (EtOAc:hexane ¼ 1:1) to
give Friedel-Crafts product (0.40 g) as a mixture with impurity. A
reaction mixture of the Friedel-Crafts product (0.40 g) with impurity
and 5% Pd/C (0.62 g) in THF (10 ml) was stirred under H2 gas at the
ambient temperature for 6 h before filtration. After concentration of the
filtrate, the residue was applied to silica gel column chromatography
(EtOAc:hexane ¼ 1:1) to give 35 (0.24 mmol, 0.80 mmol, 57%) as
3) Ward S, Nat. Prod. Rep., 16, 75–96 (1999).
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3132 (2007).
20
colorless crystals, mp 89–90 ꢀC, ½ꢀꢂD ¼ ꢁ35 (c 0.3, MeOH). 1H-
NMR (C5D5N) ꢂ: 1.17 (3H, d, J ¼ 7:7 Hz), 2.83 (1H, m), 3.62 (1H, m),
4.00 (1H, d, J ¼ 12:0 Hz), 4.11 (2H, d, J ¼ 10:3 Hz), 5.03 (2H, br. s),
7.14–7.21 (4H, m), 7.33–7.43 (4H, m). 13C-NMR (C5D5N) ꢂ: 10.5,
37.6, 43.2, 49.0, 71.0, 116.6, 128.9, 129.0, 134.2, 134.3, 157.6, 157.7,
180.5. EIMS m=z (%): 298 (Mþ, 5), 199 (100). HREIMS m=z Mþ:
calcd. for C18H18O4, 298.1205; found, 298.1207.
9) Stadler D and Bach E, Angew. Chem. Int. Ed., 47, 7557–7559
(2008).
10) Evans DA, Tedrow JS, Shaw JT, and Dopwney CW, J. Am.
Chem. Soc., 124, 392–393 (2002).
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Osborn JA, J. Am. Chem. Soc., 95, 597–598 (1973).