Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane

Article abstract of DOI:10.1080/09168451.2014.877833

All the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans' auxiliaries to construct the stereochemistry. (+)- and (-)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco-2,7′-cyclolignane was more than 99%ee.

Full text of DOI:10.1080/09168451.2014.877833

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Syntheses of all the stereoisomers of butanol type
1,7-seco-2,7′-cyclolignane
Satoshi Yamauchiab, Chisato Tomiyamaa, Tuti Wukirsaria & Hisashi Nishiwakia
a Faculty of Agriculture, Ehime University, Matsuyama, Japan
b South Ehime Fisheries Research Center, Ainan, Japan
Published online: 14 Apr 2014.
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To cite this article: Satoshi Yamauchi, Chisato Tomiyama, Tuti Wukirsari & Hisashi Nishiwaki (2014) Syntheses of all the
stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane, Bioscience, Biotechnology, and Biochemistry, 78:1, 19-28, DOI:
10.1080/09168451.2014.877833
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Bioscience, Biotechnology, and Biochemistry, 2014
Vol. 78, No. 1, 19–28
Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane
Satoshi Yamauchi1,2,*, Chisato Tomiyama1, Tuti Wukirsari1 and Hisashi Nishiwaki1
2
1Faculty of Agriculture, Ehime University, Matsuyama, Japan; South Ehime Fisheries Research Center, Ainan,
Japan
Received September 20, 2013; accepted October 16, 2013
http://dx.doi.org/10.1080/09168451.2014.877833
All the stereoisomers of butanol type 1,7-seco-2,7′-
cyclolignane were stereoselectively synthesized by
employing (S)- and (R)-Evans’ auxiliaries to con-
struct the stereochemistry. (+)- and (−)-Kadangustin
J and their diastereomers were also prepared. The
optical purity of the synthesized butanol type 1,7-
seco-2,7′-cyclolignane was more than 99%ee.
this article. The success of this project would enable us
to estimate the biological activity of all the stereoiso-
mers of butanol type 1,7-seco-2,7′-cyclolignane con-
taining kadangustin J.
Results and discussion
As illustrated in Scheme 1, the diphenylmethyl struc-
tures of target compounds 3 and 5 can be, respectively,
obtained by the Friedel-Crafts reaction from benzyl
alcohols 9 and 10. The stereochemistry at C-3 of
benzyl alcohols 9 and 10 can be constructed by
methylations to 11 and 12, respectively, bearing S- and
R-Evans’ auxiliaries. Requisite intermediates 11 and 12
can be transformed from alcohol 1315) by reductive
elimination of the primary hydroxy group and oxidative
cleavage of the olefin to carboxylic acid, introduction
of the auxiliary. Enantiomers 4 and 6 can be obtained
from the enantiomer of 13 by the same route.
Positional isomer 7 can be converted from amide 14,
which can be obtained from protected lactone type
1,7-seco-2,7′-cyclolignane 15, which had previously
been synthesized in our laboratory.14) Compound 8 can
be obtained from the enantiomer of 15.
Key words: lignan; 1,7-seco-2,7′-cyclolignane; neo-
lignan; kadangustin J
Lignans, which are biosynthesized as secondary
metabolites in many plant families, are constructed
from two phenylpropanoid units. The biological activity
of many kinds of classical lignan that are bonded at the
8 and 8′ positions of phenyl propane has been
clarified.1) Neolignans with combinations other than the
8-8′ bond have also been reported.2,3) 1,7-Seco-2,7′-cy-
clolignane, in which the shift of the 7-aryl group to the
7′ position has been observed, are types of neolign-
ans.3) Some 1,7-seco-2,7′-cyclolignanes bearing a lac-
tone4–6) or butanol7,8) structure have been isolated and
the cytotoxic activity and anti-HIV activity have been
found. Stimulated by the unique lignan bearing diphe-
nyl methyl structure and its biological activity, we
turned our attention to synthesizing all the stereoiso-
mers of butane type 1,7-seco-2,7′-cyclolignanes 1, 2
and butanol type 1,7-seco-2,7′-cyclolignanes 3–8, 34–
37 (Fig. 1). Although many kinds of biological activity
have been discovered in the course of lignan and neo-
lignan research, we have been unable to find informa-
tion on the effect of stereochemistry on this biological
activity in many cases. Our efforts to establish the rela-
tionship between the stereochemistry and biological
activity of lignans and neolignans have been contin-
uing.9–13) We began this synthetic research to develop
a study on the effects of the stereochemistry of butane
or butanol on their biological activity. The collation of
stereoisomer libraries of natural products should con-
tribute to the process for determination of the receptor.
In our previous research, a synthetic route to com-
pounds 1 and 2 was developed.14) The syntheses of all
the stereoisomers of butanol type 1,7-seco-2,7′-cyclo-
lignanes 3–8 and kadangustin J 34–37 are described in
Syntheses of stereoisomers 3 and 5 were started with
alcohol 1315) (Scheme 2). After the reduction of the
hydroxy methyl group to the methyl group via a tosyl-
ate, resulting compound 16 was converted to carboxylic
acid 17 by oxidative cleavage of the alkene which was,
respectively, combined with (S)- and (R)-Evans’ auxil-
iaries to give 18 and 19. Stereoselective methylation
followed by the removal of auxiliary gave primary
alcohols 22 and 23, whose hydroxy groups were,
respectively, protected as benzoyl esters 24 and 25. To
obtain the substrates for the Friedel-Crafts reaction, the
silyl ethers were cleaved, giving benzyl alcohols 26
and 27. The Friedel-Crafts reactions of 26 and 27 with
3-benzyloxy-4-methoxyphenol in the presence of
16)
FeCl3 gave diphenylmethyl compounds with diaste-
reomeric ratios of 1:1. After conversion of the resulting
phenolic hydroxy groups to triflates, removal of the
resulting aromatic triflates was performed by using
LiCl, HCO2NH4, and Pd(Ph3P)2Cl217), respectively,
giving 28 and 29. Finally, deprotection of 28 and 29,
*Corresponding author. Email: syamauch@agr.ehime-u.ac.jp
© 2014 Japan Society for Bioscience, Biotechnology, and Agrochemistry

20
S. Yamauchi et al.
Fig. 1. All the stereoisomers of butane-type 1,7-seco-2,7′-cyclolignane 1 and 2, Butanol-type 1,7-seco-2,7′-cyclolignane 3–8, and Kadangustin J
34–37.
1
respectively, gave stereoisomers 3 and 5. (+)-Kadangu-
stin J8) (34) and 36 were, respectively, obtained from 3
and 5 by selective methylation of the phenolic hydroxy
groups using dimethyl sulfate and K2CO3.
confirmed by H NMR. HPLC analysis was performed
with Shimadzu LC-6AD and SPD-6AV instruments.
The chiral column used for HPLC analysis of enantio-
meric excess was a 250 mm × 4.6 mm i.d., 5 μM,
CHIRALCEL AD-H (DAICEL Chemical Industries,
Ltd, Tokyo, Japan).
Protected lactone type 1,7-seco-2,7′-cyclolignane
1514) was selected as a starting material for the synthe-
sis of 7 (Scheme 3). Ring opening of the lactone to
amide 30 was accomplished by reaction with diethyl-
amine in the presence of AlMe3, whose hydroxy group
was protected as a silyl ether. After a two-steps reduc-
tion of the silyloxy amide 31 to the corresponding pri-
mary alcohol, mesylation followed by treatment with
Super-hydride gave 32. The reduction of the mesylate
was not successful by NaBH4 reduction in HMPA.
Wolff–Kishner reduction of the aldehyde prepared from
silyloxy amide 31 by DIBAL-H reduction gave 33 in a
very low yield. Finally, deprotection of 33 afforded 7.
Enantiomers 4 and 6 were obtained from the enantio-
mer of 13 by applying the same method. Enantiomer 8
was obtained by the same synthetic method as that
described for 7 from the enantiomer of 15 (Scheme 4).
The enantiomeric excess of all synthesized compounds
was more than 99%. (−)-Kadangustin J18) (35) and 37
were also, respectively, obtained from 4 and 6.
(4S,5R)-5-(4-Benzyloxy-3-methoxyphenyl)-4-methyl-5-
(triisopropylsilyloxy)-1-pentene (16).
To an ice-
cooled solution of alcohol 13 (16.5 g, 34.0 mmol) and
pyridine (9.52 mL, 0.12 mol) in CH2Cl2 (80 mL) was
added p-TsCl (12.5 g, 65.6 mmol). The reaction solu-
tion was stirred at room temperature for 5 h before
additions of H2O and CH2Cl2. The organic solution
was separated and washed with 1 M aq. HCl solution.
After further washing with sat. aq. NaHCO3
solution, the organic solution was dried (Na2SO4).
After concentration, the residue was applied to silica
gel column chromatography (EtOAc/hexane = 1/9) to
give unstable tosylate (20.3 g, 32.8 mmol, 96%) as a
colorless oil; ½aꢀD +24 (c 1.2, CHCl3); H NMR (400
MHz, CDCl3) δ: 0.90–0.95 (21H, m), 1.59 (1H, m),
2.08 (1H, m), 2.20 (1H, m), 2.44 (3H, s), 3.85 (3H, s),
3.93 (1H, dd, J = 9.6, 8.3 Hz), 4.13 (1H, dd, J = 9.6,
4.8 Hz), 4.79 (1H, d, J = 6.1 Hz), 4.84 (1H, d, J = 17.5
Hz), 4.91 (1H, d, J = 10.0 Hz), 5.12 (2H, s), 5.55 (1H,
m), 6.62 (1H, d, J = 8.2, 2.0 Hz), 6.75 (1H, d, J = 8.2
Hz), 6.86 (1H, d, J = 2.0 Hz), 7.26–7.38 (5H, m), 7.43
(2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz); 13C NMR
(100 MHz, CDCl3) δ: 12.4, 17.95, 18.02, 21.6, 30.1,
46.3, 55.9, 69.6, 71.1, 73.6, 110.7, 113.4, 117.1, 119.4,
127.4, 127.8, 128.0, 128.5, 129.8, 133.1, 134.9, 135.6,
137.1, 144.7, 147.5, 149.4, 158.0. A solution of
tosylate (20.3 g, 31.8 mmol) in THF (20 mL) was added
to an ice-cooled suspension of LiAlH4 (1.21 g, 31.9
20
1
Experimental setup
Optical rotations were measured on a Horiba SEPA-
200 instrument. IR data were measured with a Horiba
FT-720 instrument. NMR data were obtained using a
JNM-EX400 spectrometer. EIMS data were measured
with a JMS-MS700V spectrometer. IR data were mea-
sured with a Horiba FT-720 instrument. The silica gel
used was Wakogel C-300 (Wako, 200–300 mesh). The
purity of each compound containing enantiomers was

1,7-seco-2,7′-cyclolignane
21
Scheme 1. Proposed general strategy for synthesis of butanol-type 1,7-seco-2,7′-cyclolignane.
mmol) in THF (10 mL). The reaction mixture was stir-
red at room temperature for 1 h before additions of sat.
aq. MgSO4 solution (5 mL) and K2CO3. The mixture
was filtered, and then the filtrate was concentrated. The
residue was applied to silica gel column chromatogra-
phy (EtOAc/hexane = 1/9) to give 16 (11.3 g, 24.1
mmol, 76%) as a colorless oil; ½aꢀ2D0 +40 (c 0.3,
(3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-3-methyl-4-
(triisopropylsilyloxy)butanoic acid (17). A reaction
solution of 16 (9.94 g, 21.2 mmol), 4-methylmorpholine
N-oxide (2.95 g, 25.2 mmol), and OsO4 (2% aq. solu-
tion, 1.60 mL) in acetone (90 mL), tert-BuOH (20 mL),
and H2O (20 mL) was stirred at room temperature for
20 h before the addition of sat. aq. Na2S2O3 solution.
After concentration of the mixture, the residue was dis-
solved in EtOAc and H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration gave crude glycol. A reaction mixture of
crude glycol and NaIO4 (5.40 g, 25.2 mmol) in MeOH
(200 mL) was stirred at room temperature for 1 h before
concentration to give crude aldehyde. To an ice-cooled
solution of crude aldehyde, 2-methyl-2-butene (8.90
mL, 84.0 mmol), and NaH2PO4·2H2O (32.8 g, 0.21
mol) in tert-BuOH/H2O (3/1, 100 mL) was added a
solution of NaClO2 (11.4 g, 0.13 mol) in tert-BuOH/
H2O (3/1, 50 mL). The reaction mixture was stirred at
room temperature for 1 h before additions of sat. aq.
NH4Cl solution and CHCl3. The organic solution was
separated, washed with H2O, and dried (Na2SO4). Con-
centration followed by silica gel column chromatogra-
phy (EtOAc/hexane = 1/5) gave carboxylic acid 17
1
CHCl3); H NMR (400 MHz, CDCl3) δ: 0.87 (3H, d, J
= 6.8 Hz, CH3), 0.89–1.00 (21H, m), 1.57 (1H, m,
4-H), 1.83 (1H, m, 3-H), 2.32 (1H, m, 3-H), 3.87 (3H,
s, CH3), 4.59 (1H, d, J = 5.2 Hz, 5-H), 4.94 (1H d, J =
16.7 Hz, 1-H), 4.95 (1H, d, J = 16.5 Hz, 1-H), 5.12
(2H, s, OCH2Bn), 5.72 (1H, m, 2-H), 6.69 (1H, dd, J
= 8.7, 1.8 Hz, ArH), 6.79 (1H, d, J = 8.7 Hz, ArH),
6.91 (1H, d, J = 1.8 Hz, ArH), 7.25–7.37 (3H, m, ArH),
7.43–7.45 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
δ: 12.5, 15.4, 18.05, 18.12, 36.2, 41.8, 55.9, 71.2, 78.8,
111.0, 113.20, 113.23, 115.5, 119.2, 119.4, 127.4,
127.8, 128.5, 136.8, 137.4, 138.0, 147.1, 149.1; IR
(CHCl3) cm−1: 2945, 2868, 1510, 1463, 1261, 1090.
MS (EI) m/z: 468 (M+, 3), 399 (100). Anal. Calcd for
C29H44O3Si: C, 74.31; H, 9.48%. Found: C, 74.34; H,
20
9.50%. (4R,5S)-(16). 81% yield, ½aꢀD −40 (c 1.1,
CHCl3).

22
S. Yamauchi et al.
Scheme 2. Synthesis of butanol-type 1,7-seco-2,7′-cyclolignane (I).
Scheme 3. Synthesis of butanol type 1,7-seco-2,7′-cyclolignane (II).
Scheme 4. Syntheses of the enantiomers.
(10.0 g, 20.5 mmol, 97%) as a colorless oil; ½aꢀ2D0 +34
(c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 0.92
(3H, d, J = 6.9 Hz, CH3), 0.95–1.01 (21H, m, TIPSi),
1.90 (1H, dd, J = 15.3, 9.1 Hz, 2-H), 2.41 (1H, m,
3-H), 2.61 (1H, dd, J = 15.3, 4.8 Hz, 2-H), 3.88 (3H, s,
OCH3), 4.68 (1H d, J = 4.8 Hz, 4-H), 5.14 (2H, s,

1,7-seco-2,7′-cyclolignane
23
1
OCH2Bn), 6.69 (1H, d, J = 7.2 Hz, ArH), 6.80 (1H, d,
J = 7.2 Hz, ArH), 6.93 (1H, s, ArH), 7.26–7.38 (3H, m,
ArH), 7.43–7.45 (2H, m, ArH), 7.26–7.45 (1H,
overlapped, CO2H); 13C NMR (100 MHz, CDCl3) δ:
12.4, 16.3, 18.0, 18.1, 36.3, 38.4, 55.9, 71.1, 78.0,
110.9, 113.2, 119.4, 127.4, 127.8, 128.5, 135.2, 137.2,
147.3, 149.1, 179.8; IR (CHCl3) cm−1: 3500, 2945,
1707, 1508, 1464, 1261, 1093. MS (EI) m/z: 486 (M+,
6), 399 (100). Anal. Calcd. for C28H42O5Si: C, 69.10;
H, 8.70%. Found: C, 69.22; H, 8.78%. (2R,3S)-(17).
(c 1.5, CHCl3); H NMR (400 MHz, CDCl3) δ: 0.91–
1.05 (21H, m, TIPSi), 1.08 (3H, d, J = 6.9 Hz, CH3),
1.09 (3H, d, J = 6.8 Hz, CH3), 2.51 (1H, m, C =
OCHCHCH3), 2.63 (1H, dd, J = 13.3, 9.5 Hz, CH2Bn),
3.08 (1H, dd, J = 13.3, 2.0 Hz, CH2Bn), 3.63 (1H, m, C
= OCHCH3), 3.87 (1H, d, J = 8.7 Hz, 5-H), 3.90 (3H, s,
OCH3), 3.98 (1H, d, J = 8.7 Hz, OCH3), 4.20 (1H, m,
4-H), 4.47 (1H, d, J = 6.7 Hz, ArCHOTIPS), 5.09 (2H,
s, OCH2Bn), 6.76 (2H, s, ArH), 6.95 (1H, s, ArH),
7.13–7.17 (2H, m, ArH), 7.26–7.31 (6H, m, ArH),
7.37–7.38 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
δ: 12.7, 13.3, 15.5, 18.0, 18.1, 37.8, 38.5, 42.4, 55.3,
55.8, 65.7, 71.1, 79.7, 111.6, 113.0, 120.3, 127.2,
127.4, 127.9, 128.5, 128.9, 129.4, 135.4, 136.5, 137.1,
147.1, 148.9, 152.6, 177.0; IR (CHCl3) cm−1: 2945,
1781, 1700, 1508, 1466, 1382, 1093. MS (EI) m/z: 659
(M+, 7), 617 (100); HRMS (EI) m/z calcd for
C39H53O6NSi: 659.3642, found: 659.3632. (4R)-3-
20
87% yield, ½aꢀD −34 (c 2.1, CHCl3).
(S)-4-Benzyl-3-[(3S,4R)-4-(4-benzyloxy-3-methox-
yphenyl)-3-methyl-4-(triisopropylsilyloxy)butanoyl]-
2-oxazolidinone (18).
To a solution of carboxylic
acid 17 (4.66 g, 9.57 mmol) in THF (100 mL) were
added Et3 N (1.34 mL, 9.61 mmol) and PivCl (1.18 mL,
9.58 mmol) added at −75 °C. After the mixture was
stirred at 0 °C for 1 h, lithium salt of (S)-4-benzyl-2-ox-
azolidinone, which was prepared from (S)-4-benzyl-2-
oxazolizinone (1.70 g, 9.59 mmol) and n-BuLi (3.70
mL, 2.70 M in hexane, 9.99 mmol) in THF (80 mL) at
−75 °C, was added at −75 °C. The reaction mixture
was stirred at 0 °C for 1 h before the addition of sat.
aq. NH4Cl solution. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography
(EtOAc/hexane = 1/5) gave alkanoly oxazolidinone 18
(6.18 g, 9.57 mmol, 100%) as a colorless oil; ½aꢀ2D0 +33
20
[(2R,3R,4S)]-(20). 33% yield, ½aꢀD −46 (c 1.1, CHCl3).
(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dim-
ethyl-4-(triisopropylsilyloxy)-1-butanol (22). To an ice-
cooled solution of LiBH4 (0.32 g, 14.7 mmol) and
MeOH (0.65 mL, 16.0 mmol) in THF (50 mL) was
added a solution of alkanoyl oxazolidinone 20 (2.20 g,
3.33 mmol) in THF (20 mL). The reaction solution was
stirred at room temperature for 1 h, and then sat. aq.
NH4Cl solution was added. After concentration, the
residue was dissolved in EtOAc and H2O. The organic
solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/hexane = 1/3) gave alcohol 22
1
(c 1.9, CHCl3); H NMR (400 MHz, CDCl3) δ: 0.95–
1.01 (24H, m, TIPSi, CH3), 2.53 (1H, m, CHCH3),
2.61–2.72 (2H, m, C = OCH2), 3.21–3.26 (2H, m,
CH2Bn), 3.91 (3H, s, OCH3), 4.08 (2H, d, J = 5.1 Hz,
5-CH2), 4.54 (1H, m, 4-H), 4.67 (1H, d, J = 5.4 Hz,
TIPSOCHAr), 5.12 (2H, s, OCH2Bn), 6.72 (1H, d, J =
8.2 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.98 (1H,
s, ArH), 7.16–7.18 (2H, m, ArH), 7.28–7.36 (6H, m,
ArH), 7.42–7.43 (2H, m, ArH); 13C NMR (100 MHz,
CDCl3) δ: 12.5, 16.5, 18.0, 18.1, 37.77, 37.83, 38.0,
55.1, 55.8, 66.0, 71.1, 78.4, 110.8, 113.0, 119.6, 127.3,
127.4, 127.8, 128.5, 128.9, 129.4, 135.4, 136.1, 137.2,
147.2, 149.2, 153.3, 172.8; IR (CHCl3) cm−1: 2945,
1783, 1699, 1508, 1456, 1384, 1261,1090. MS (EI) m/
z: 645 (M+, 7), 602 (100); HRMS (M+) m/z calcd for
C38H51O6NSi: 645.3485, found: 645.3480. (4R)-3-
20
(1.50 g, 3.08 mmol, 92%) as a colorless oil; ½aꢀD +41
(c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 0.68
(3H, d, J = 6.8 Hz, CH3), 0.93–0.99 (21H, m, TIPSi),
0.97 (3H, d, J = 6.1 Hz, CH3), 1.47 (1H, m, 3-H), 1.57
(1H, br. s, OH), 1.96 (1H, m, 2-H), 3.40 (2H, d, J =
6.7 Hz, 1-H), 3.86 (3H, s, OCH3), 4.53 (1H, d, J = 7.4
Hz, 4-H), 5.12 (2H, s, OCH2Bn), 6.72 (1H, d, J = 8.1
Hz, ArH), 6.78 (1H, d, J = 8.1 Hz, ArH), 6.95 (1H, s,
ArH), 7.27–7.37 (3H, m, ArH), 7.42–7.44 (2H, m,
ArH); 13C NMR (100 MHz, CDCl3) δ: 11.60, 11.63,
12.5, 18.0, 18.1, 35.3, 42.3, 56.0, 67.5, 71.1, 78.8,
110.7, 113.3, 119.6, 127.4, 127.8, 128.5, 137.2, 137.3,
147.3, 149.5; IR (CHCl3) cm−1: 3566, 2945, 1505,
1452, 1259, 1139, 1059, 1025. MS (EI) m/z: 486 (M+,
6), 400 (100); HRMS (EI) m/z calcd for C29H46O4Si:
486.3166, found: 486.3167. (2R,3R,4S)-(22). 95%
20
[(3R,4S)]-(18). 97% yield, ½aꢀD −34 (c 1.6, CHCl3).
20
(4S)-4-Benzyl-3-[(2S,3S,4R)-4-(4-benzyloxy-3-methox-
yphenyl)-2,3-dimethyl-4-(triisopropylsilyloxy)butanoyl]-
yield, ½aꢀD −41 (c 1.2, CHCl3).
2-oxazolidinone (20).
To a solution of KHMDS
(14.4 mL, 0.50 M in toluene, 7.20 mmol) in THF
(20 mL) was added a solution of 18 (3.10 g, 4.80 mmol)
in THF (10 mL) at −75 °C. After the mixture was stirred
at −75 °C for 20 min, MeI (12.0 mL, 0.19 mmol) was
added. The reaction solution was stirred at −70 °C for
1 h, and then warmed to −15 °C. After 1.5 h at −15 °C,
sat. aq. NH4Cl solution and EtOAc were added. The
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc/hexane = 1/8) gave 20
(1.00 g, 1.52 mmol, 32%) as a colorless oil along
with recovered 18 (1.92 g, 2.97 mmol, 62%); ½aꢀ2D0 +46
(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dim-
ethyl-4-(triisopropylsilyloxy)butyl benzoate (24). To an
ice-cooled solution of alcohol 22 (1.50 g, 3.08 mmol)
and pyridine (0.49 mL, 6.06 mmol) in CH2Cl2 (5 mL)
was added BzCl (0.54 mL, 4.65 mmol). The reaction
mixture was stirred at room temperature for 20 h before
additions of H2O and CH2Cl2. The organic solution
was separated and washed with 1 M aq. HCl solution.
After further washing with sat. aq. NaHCO3 solution,
the organic solution was dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/
hexane = 1/8) gave benzoate 24 (1.43 g, 2.42 mmol,

24
S. Yamauchi et al.
20
1
79%) as a colorless oil; ½aꢀD +69 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ: 0.80 (3H, d, J = 7.0 Hz,
CH3), 0.92–0.99 (21H, m, TIPSi), 1.05 (3H, d, J = 6.9
Hz, CH3), 1.82 (1H, m, 3-H), 2.01 (1H, m, 2-H), 3.80
(3H, s, OCH3), 4.08 (1H, dd, J = 10.7, 6.3 Hz, 1-H),
4.17 (1H, dd, J = 10.7, 7.5 Hz, 1-H), 4.55 (1H, d, J =
7.8 Hz, 4-H), 5.13 (2H, s, OCH2Bn), 6.72 (1H, dd, J =
8.2, 2.0 Hz, ArH), 6.78 (1H, d, J = 8.2 Hz, ArH), 6.92
(1H, d, J = 2.0 Hz, ArH), 7.25–7.56 (7H, m, ArH), 7.54
(1H, m, ArH), 7.96–7.97 (2H, m, ArH); 13C NMR
(100 MHz, CDCl3) δ: 11.1, 11.5, 12.6, 18.0, 18.2, 32.1,
42.5, 55.8, 68.7, 71.1, 78.3, 110.4, 113.3, 119.5, 127.4,
127.8, 128.3, 128.5, 129.5, 130.4, 132.8, 137.2, 137.6,
147.4, 149.6, 166.5; IR (CHCl3) cm−1: 2945, 1711,
1504, 1460, 1279, 1137, 1116, 1063. MS (EI) m/z: 590
(M+, 13), 547 (100); HRMS (EI) m/z calcd for
C36H50O5Si: 590.3428, found: 590.3412. (2R,3R,4S)-
Tf2O (0.27 mL, 1.60 mmol) was added at 0 °C. After
stirring at 0 °C for 40 min, H2O and CH2Cl2 were
added. The organic solution was separated and washed
with sat. aq. CuCO4 solution. After further washing
with sat. aq. NaHCO3 solution, the organic solution
was dried (Na2SO4). Concentration followed by silica
gel column chromatography (5% EtOH in EtOAc/hex-
ane = 1/3) gave triflate (0.97 g, 1.25 mmol, 77%) as a
diastereomeric mixture of 1/1. The diastereomeric iso-
20
mers could be partially separated; Rf = 0.24, ½aꢀD +31
(c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 0.77
(3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.8 Hz), 1.26 (1H,
m), 2.12 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 4.10 (1H,
d, J = 11.4 Hz), 4.13 (1H, dd, J = 10.7, 6.6 Hz), 4.24
(1H, dd, J = 10.7, 7.9 Hz), 5.04 (1H, d, J = 12.3 Hz),
5.09 (2H, s), 5.10 (1H, d, J = 12.3 Hz), 6.72 (1H, s),
6.78 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 8.4 Hz), 6.86
(1H, s), 6.87 (1H, s), 7.20–7.46 (11H, m), 7.58 (1H,
m), 7.65 (1H, m), 8.03–8.05 (2H, m); 13C NMR (100
MHz, CDCl3) δ: 9.70, 11.3, 24.4, 32.8, 55.9, 56.3,
58.3, 68.7, 71.1, 71.5, 107.3, 112.4, 114.2, 119.4,
119.8 (q, J = 278.7 Hz), 122.9, 124.1, 127.3, 127.4,
127.8, 128.3, 128.4, 128.46, 128.52, 128.7, 129.5,
129.8, 130.4, 133.0, 134.9, 136.0, 137.2, 137.3, 140.0,
144.2, 147.0, 147.1, 149.6, 149.7, 166.5; MS (EI) m/z:
778 (M+, 18), 587 (100); HRMS (EI) m/z calcd for
C42H41O9F3S: 778.2423, found: 778.2431. Rf = 0.29,
20
(24). 80% yield, ½aꢀD −69 (c 1.4, CHCl3).
(2S,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-4-hydro-
xy-2,3-dimethylbutyl benzoate (26). A reaction solu-
tion of silyl ether 24 (1.43 g, 2.42 mmol) and (n-
Bu)4NF (3.60 mmol, 1 M in THF, 3.60 mmol) in THF
(10 mL) was stirred at room temperature for 1 h before
the addition of sat. aq. NH4Cl solution and EtOAc.
The organic solution was separated and washed with
sat. aq. CuSO4 solution. After further washing with sat.
aq. NaHCO3 solution followed by brine, the organic
solution was dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane =
1/2) gave alcohol 26 (0.98 g, 2.26 mmol, 93%) as a
colorless oil; ½aꢀD +60 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ: 0.92 (3H, d, J = 7.0 Hz, CH3), 1.02
(3H, d, J = 6.8 Hz, CH3), 1.85 (1H, m, 3-H), 1.92–2.12
(1H, br., OH), 2.04 (1H, m, 2-H), 3.79 (3H, s, OCH3),
4.17–4.23 (2H, m, 1-H2), 4.55 (1H, d, J = 7.4 Hz, 5-H),
5.13 (2H, s, OCH2Bn), 6.76 (1H, d, J = 8.1 Hz, ArH),
6.81 (1H, d, J = 8.1 Hz, ArH), 6.88 (1H, s, ArH), 7.25–
7.44 (7H, m, ArH), 7.55 (1H, m, ArH), 7.99–8.00 (2H,
m, ArH); 13C NMR (100 MHz, CDCl3) δ: 10.0, 12.1,
33.5, 40.9, 55.9, 68.1, 71.1, 76.7, 109.6, 113.6, 118.8,
127.3, 127.8, 128.4, 128.5, 129.5, 130.3, 132.9, 137.0,
137.2, 147.6, 149.8, 166.5; IR (CHCl3) cm−1: 3619,
1976, 1716, 1520, 1452, 1277, 1138, 1026. MS (EI) m/
z: 434 (M+, 25), 243 (100); HRMS (EI) m/z calcd for
C27H30O5: 434.2093, found: 434.2094. (2R,3R,4S)-
20
1
½aꢀD +21 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3)
δ: 0.81 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.8 Hz),
2.07 (1H, m), 2.59 (1H, m), 3.72 (3H, s), 3.87 (3H, s),
4.01 (1H, d, J = 11.9 Hz), 4.18 (1H, dd, J = 10.8, 6.5
Hz), 4.26 (1H, dd, J = 10.8, 6.3 Hz), 5.06 (1H, d, J =
12.2. Hz), 5.10 (1H, d, J = 12.2 Hz), 5.11 (2H, s), 6.73
(1H, s), 6.80 (1H, d, J = 8.4 Hz), 6.82 (1H, d, J = 8.4
Hz), 6.88 (1H, s), 6.98 (1H, s), 7.29–7.50 (12H, m),
7.60 (1H, m), 8.04–8.06 (2H, m); 13C NMR (100 MHz,
CDCl3) δ: 10.0, 11.9, 33.1, 36.7, 47.4, 55.9, 56.2, 68.5,
71.1, 71.5, 107.4, 110.6, 112.9, 114.1, 119.3, 119.7 (q,
J = 74.4 Hz), 127.3, 127.4, 127.8, 128.2, 128.46,
128.50, 128.7, 129.48, 129.51, 133.1, 135.4, 136.0,
137.3, 140.4, 146.8, 149.4, 149.5, 149.6, 166.4; MS
(EI) m/z: 778 (M+, 43), 587 (100); HRMS (EI) m/z
calcd for C42H41O9F3S: 778.2424, found: 778.2410. A
reaction mixture of triflate (0.26 g, 0.33 mmol), LiCl
(0.29 g, 6.84 mmol), HCO2NH4 (1.71 g, 27.1 mmol),
and Pd(Ph3P)2Cl2 (0.13 g, 0.19 mmol) in DMF (2.3
mL) was stirred at 140 °C under N2 gas for 20 h. After
additions of H2O and EtOAc, the organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 1/5) gave bisphenyl com-
pound 28 (0.17 g, 0.27 mmol, 82%) as a colorless oil;
20
1
20
(26). 93% yield, ½aꢀD −60 (c 1.0, CHCl3).
(2S,3R)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2,3-di-
methylbutyl benzoate (28). A reaction mixture of 3-
benzyloxy-4-methoxyphenol (0.42 g, 1.82 mmol), ben-
zyl alcohol 26 (0.71 g, 1.63 mmol), and FeCl3 (13 mg,
0.080 mmol) in CH2Cl2 (30 mL) was stirred at room
temperature for 1.5 h before the addition of sat. aq.
NaHCO3 solution. The organic solution was separated
and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/5) gave
bisphenol compound (0.95 g, 1.47 mmol, 90%) as a
diastereomeric mixture of 1/1; HRMS (EI) m/z calcd
for C41H42O7: 646.2931, found: 646.2911. To a solu-
tion of bisphenol compound (0.78 g, 1.21 mmol) and
2,6-lutidine (0.48 mL, 4.11 mmol) in CH2Cl2 (5 mL),
20
1
½aꢀD +38 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3)
δ: 0.75 (3H, d, J = 6.6 Hz, CH3), 0.87 (3H, d, J = 6.9
Hz, CH3), 2.08 (1H, m, 3-H), 2.55 (1H, m, 2-H), 3.53
(1H, d, J = 11.7 Hz, 4-H), 3.79 (3H, s, OCH3), 3.85
(3H, s, OCH3), 4.15 (1H, dd, J = 10.7, 6.6 Hz, 1-H),
4.22 (1H, dd, J = 10.7, 8.0 Hz, 1-H), 5.07 (2H, s,
OCH2Bn), 5.08 (2H, s, OCH2Bn), 6.75–6.81 (6H, m,
ArH), 7.26–7.47 (12H, m, ArH), 7.57 (1H, m, ArH),
8.03–8.05 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
δ: 9.9, 12.1, 32.9, 37.0, 55.8, 56.0, 56.1, 68.8, 71.1,
111.8, 112.1, 114.2, 119.7, 127.3, 127.8, 128.4, 128.5,
128.6, 129.48, 129.52, 130.5, 132.9, 137.4, 137.9,

1,7-seco-2,7′-cyclolignane
25
146.7, 146.8, 149.5, 149.7, 166.5; IR (CHCl3) cm−1:
3012, 2960, 1714, 1510, 1277. MS (EI) m/z: 630 (M+,
5), 204 (100); HRMS (EI) m/z calcd for C41H42O6:
630.2981, found: 630.3001. (2R,3S)-(28). 61% yield,
(4R)-4-Benzyl-3-[(2R,3S,4R)-4-(4-benzyloxy-3-methox
yphenyl)-4-(triisopropylsilyloxy)-2,3-dimethylbutanoyl]-
2-oxazolidinone (21).
The title compound was
obtained from 19 by the same synthetic method as that
of compound 20 in 32% yield as a colorless oil along
20
two steps, ½aꢀD −37 (c 0.6, CHCl3).
20
1
with 61% recovery of 19; ½aꢀD −10 (c 1.3, CHCl3); H
NMR (400 MHz, CDCl3) δ: 0.98–1.01 (21H, m,
TIPSi), 1.08 (3H, d, J = 6.9 Hz, CH3), 1.31 (3H, d, J =
7.0 Hz, CH3), 2.08 (1H, m, C = OCHCHCH3), 2.67
(1H, dd, J = 13.3, 9.6 Hz, CH2Bn), 3.14 (1H, dd, J =
13.3, 2.8 Hz, CH2Bn), 3.82 (1H, dd, J = 8.7, 7.9 Hz, 5-
H), 3.87 (3H, s, OCH3), 3.95 (1H, dd, J = 8.7, 7.9 Hz,
5-H), 4.02 (1H, m, C = OCH), 4.32 (1H, m, 4-H), 4.86
(1H, d, J = 4.3 Hz, ArCHOTIPS), 5.10 (2H, s,
OCH2Bn), 6.71 (1H, dd, J = 8.2, 1.4 Hz, ArH), 6.77
(1H, d, J = 8.2 Hz, ArH), 6.93 (1H d, J = 1.4 Hz, ArH),
7.15–7.17 (2H, m, ArH), 7.25–7.32 (6H, m, ArH),
7.38–7.40 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
δ: 12.7, 13.2, 16.3, 18.1, 37.8, 38.8, 45.5, 55.3, 56.0,
65.8, 71.2, 75.9, 111.0, 113.4, 119.2, 127.3, 127.8,
128.5, 128.9, 129.4, 135.4, 137.3, 147.2, 149.2, 152.7,
176.5; IR (CHCl3) cm−1: 2944, 1780, 1701, 1508,
1466, 1382, 1090. MS (EI) m/z: 659 (M+, 4), 400
(100), 290 (57); HRMS (EI) m/z calcd for
C39H53O6NSi: 659.3642, found: 659.3638. (4S)-3-
(2S,3R)-4,4-Bis(4-hydroxy-3-methoxyphenyl)-2,3-dim-
ethyl-1-butanol (3). A reaction solution of benzoate
28 (0.23 g, 0.36 mmol) in EtOH (15 mL) and 1 M aq.
NaOH solution (15 mL) was stirred at room tempera-
ture for 12 h before additions of H2O and CHCl3. The
organic solution was separated and dried (Na2SO4).
Concentration gave crude alcohol. A reaction mixture
of crude alcohol and 5% Pd/C (0.20 g) in EtOAc (5
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 (EtOAc/hexane = 1/1) to give
3
20
(90 mg, 0.26 mmol, 72%) as a colorless oil; ½aꢀD +10
(c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 0.68
(3H, d, J = 6.8 Hz, CH3), 0.74 (3H, d, J = 6.9 Hz, CH3),
1.24 (1H, br. s, 1-OH), 1.75 (1H, m, 3-H), 2.58 (1H,
m, 2-H), 3.45 (1H, dd, J = 10.7, 6.6 Hz, 1-H), 3.49
(1H, d, J = 11.8 Hz, 4-H), 3.49 (1H, dd, J = 10.7, 8.3
Hz, 1-H), 3.83 (3H, s, OCH3), 3.84 (3H, s, OCH3),
5.56 (1H, s, OH), 5.57 (1H, s, OH), 6.76 (1H, s, ArH),
6.78 (1H, d, J = 1.3 Hz, ArH), 6.80–6.82 (4H, m, ArH);
13C NMR (100 MHz, CDCl3) δ: 9.6, 11.9, 35.98,
36.04, 55.9, 56.1, 67.0, 110.5, 114.3, 114.5, 120.3,
120.4, 136.7, 137.2, 143.8, 146.5, 146.6; IR (CHCl3)
cm−1 3630, 3017, 2974, 1512, 1269, 1219, 1036. MS
(EI) m/z: 346 (M+, 59), 260 (100), 229 (70); HRMS
(EI) m/z calcd for C20H26O5: 346.1780, found:
346.1780. >99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1
mL/min, 280 nm, tR6.6 min). (2R,3S)-(4). 71% yield,
20
[(2S,3R,4S)]-(21). 43% yield, ½aꢀD +11 (c 0.9, CHCl3).
(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-dim
ethyl-4-(triisopropylsilyloxy)-1-butanol (23). The title
compound was obtained from 21 by the same synthetic
method as that of compound 22 in 80% yield as a col-
20
orless oil; ½aꢀD +40 (c 1.4, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 0.94–0.99 (27H, m, TIPSi, CH3 × 2),
1.29 (1H, m, 3-H), 1.61 (1H, br. s, OH), 1.71 (1H, m,
2-H), 3.29 (1H, dd, J = 10.4, 7.3 Hz, 1-H), 3.48 (1H,
dd, J = 10.4, 5.9 Hz, 1-H), 3.87 (3H, s, OCH3), 4.74
(1H, d, J = 6.2 Hz, 4-H), 5.12 (2H, s, OCH2Bn), 6.73
(1H, dd, J = 8.1, 1.4 Hz, ArH), 6.79 (1H, d, J = 8.1 Hz,
ArH), 6.94 (1H, d, J = 1.4 Hz, ArH), 7.27–7.37 (3H, m,
ArH), 7.42–7.44 (2H, m, ArH); 13C NMR (100 MHz,
CDCl3) δ: 11.5, 12.7, 16.7, 18.1, 18.2, 36.1, 45.9, 56.0,
65.4, 71.2, 77.9, 110.7, 113.5, 119.3, 127.4, 127.8,
128.5, 137.3, 138.1, 147.2, 149.4; IR (CHCl3) cm−1:
3560, 2945, 1505, 1452, 1258, 1140, 1059, 1025. MS
(EI) m/z: 486 (M+, 9), 400 (100); Anal. Calcd for
C29H46O4Si: C, 71.56; H, 9.53%. Found: C, 71.43; H,
20
½aꢀD −10 (c 1.0, CHCl3),>99%ee (AD-H, iso-PrOH/
hexane = 1.7/1, 1 mL/min, 280 nm, tR9.4 min).
(4R)-4-Benzyl-3-[(3S,4R)-4-(4-benzyloxy-3-methoxy-
phenyl)-3-methyl-4-(triisopropylsilyloxy)butanoyl]-2-ox
azolidinone (19)
The title compound was obtained from 17 by the
same synthetic method as that of compound 18 by
using (R)-4-benzyloxazolidinone in 72% yield as a col-
20
1
orless oil; ½aꢀD −7 (c 1, CHCl3); H NMR (400 MHz,
CDCl3) δ: 0.93 (3H, d, J = 6.7 Hz, CH3), 0.97–1.02
(21H, m, TIPSi), 2.50 (1H, m, CHCH3), 2.61–2.74
(2H, m, C = OCH2), 3.24 (2H, d, J = 14.0 Hz, CH2Bn),
3.91 (3H, s, OCH3), 4.08–4.15 (2H, m, 5-H), 4.62 (1H,
m, 4-H), 4.73 (1H, d, J = 4.9 Hz, ArCHOTIPS), 5.12
(2H, s, OCH2Bn), 6.73 (1H, d, J = 8.2 Hz, ArH), 6.80
(1H, d, J = 8.2 Hz, ArH), 7.01 (1H, s, ArH), 7.19–7.25
(2H, m, ArH), 7.27–7.36 (6H, m, ArH), 7.42–7.43
(2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ: 12.5,
16.0, 18.05, 18.12, 37.6, 37.9, 38.1, 55.2, 55.9, 66.1,
71.1, 78.2, 110.9, 113.1, 119.4, 127.3, 127.4, 127.7,
128.5, 128.9, 129.4, 135.4, 136.0, 137.3, 147.2, 149.2,
153.3, 172.8; IR (CHCl3) cm−1: 2940, 1782, 1698,
1508, 1456, 1384, 1261,1090. MS (EI) m/z: 645 (M+,
4), 399 (100), 290 (57); HRMS (M+) m/z calcd for
C38H51O6NSi: 645.3485, found: 645.3456. (4S)-3-
20
9.59%. (2S,3R,4S)-(23). 74% yield, ½aꢀD −40 (c 0.9,
CHCl3).
(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-2,3-di-
methyl-4-(triisopropylsilyloxy)butyl benzoate (25).
The title compound was obtained from 23 by the same
synthetic method as that of compound 24 in 85% yield
20
1
as a colorless oil; ½aꢀD +3 (c 1.4, CHCl3); H NMR
(400 MHz, CDCl3) δ: 0.94–0.99 (21H, m. TIPSi), 1.04
(3H, d, J = 6.8 Hz, CH3), 1.08 (3H, d, J = 7.0 Hz,
CH3), 1.79 (1H, m, 3-H), 1.87 (1H, m, 2-H), 3.83 (3H,
s, OCH3), 4.06 (1H, dd, J = 10.9, 7.5 Hz, 1-H), 4.22
(1H, dd, J = 10.9, 4.9 Hz, 1-H), 4.74 (1H, d, J = 6.8 Hz,
4-H), 5.11 (2H, s, OCH2Bn), 6.75 (1H, dd, J = 8.2, 1.4
Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.94 (1H, d,
20
[(3R,4S)]-(19). 75% yield, ½aꢀD +7 (c 1, CHCl3).

26
S. Yamauchi et al.
J = 1.4 Hz, ArH), 7.25–7.36 (3H, m, ArH), 7.40–7.44
(4H, m, ArH), 7.54 (1H, m, ArH), 8.01–8.03 (2H, m,
ArH); 13C NMR (100 MHz, CDCl3) δ: 11.6, 12.7,
17.4, 18.1, 18.2, 32.8, 46.3, 55.9, 67.3, 71.2, 77.8,
110.7, 113.6, 119.3, 127.4, 127.8, 128.3, 128.5, 129.5,
130.5, 132.8, 137.3, 137.9, 147.3, 149.4, 166.6; IR
(CHCl3) cm−1: 2945, 1711, 1504, 1460, 1279, 1137,
1116, 1063. MS (EI) m/z: 590 (M+, 16), 547 (100);
Anal. Calcd for C36H50O5Si: C, 73.18; H, 8.53%.
Found: C, 72.95; H, 8.63%. (2S,3R,4S)-(25). 87%
(2R,3R)-4,4-Bis(4-hydroxy-3-methoxyphenyl)-2,3-
dimethyl-1-butanol (5). The title compound was
obtained from 29 by the same synthetic method as that
of compound 3 in 64% yield as a colorless oil through
20
two steps; ½aꢀD +24 (c 0.8, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 0.72 (3H, d, J = 6.9 Hz, CH3), 0.92
(3H, d, J = 6.9 Hz, CH3), 1.20 (1H, br. s, 1-OH), 1.80
(1H, m, 3-H), 2.28 (1H, m, 2-H), 3.34 (1H, dd, J =
10.4, 7.8 Hz, 1-H), 3.66 (1H, dd, J = 10.4, 5.4 Hz, 1-
H), 3.70 (1H, d, J = 11.7 Hz, 4-H), 3.826 (3H, s,
OCH3), 3.834 (3H, s, OCH3), 5.56 (1H, s, ArOH),
5.58 (1H, s, ArOH), 6.72 (1H, d, J = 1.8 Hz, ArH),
6.75 (1H, d, J = 1.4 Hz, ArH), 6.78 (1H, dd, J = 8.2,
1.8 Hz, ArH), 6.80 (1H, d, J = 8.2 Hz, ArH), 6.80–6.84
(2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ: 13.3,
16.6, 36.5, 40.9, 55.9, 56.1, 64.6, 110.6, 110.7, 114.4,
114.5, 120.1, 120.2, 136.9, 137.2, 143.8, 143.9, 146.4,
146.6; IR (CHCl3) cm−1: 3560, 3019, 2980, 1511,
1269, 1219, 1036. MS (EI) m/z: 346 (M+, 53), 260
(100), 229 (60); HRMS (EI) m/z calcd for C20H26O5:
346.1780, found: 346.1770. >99%ee (AD-H, iso-PrOH/
hexane = 1.7/1, 1 mL/min, 280 nm, tR4.2 min). (2S,3S)-
20
yield, ½aꢀD −3 (c 0.9, CHCl3).
(2R,3S,4R)-4-(4-Benzyloxy-3-methoxyphenyl)-4-hydro
xy-2,3-dimethylbutyl benzoate (27).
The title com-
pound was obtained from 25 by the same synthetic
method as that of compound 26 in 94% yield as a col-
20
orless oil; ½aꢀD −22 (c 1.1, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 0.99 (3H, d, J = 7.0 Hz, CH3), 1.11
(3H, d, J = 6.8 Hz, CH3), 1.82 (1H, m, 3-H), 1.97 (1H,
m, 2-H), 3.79 (1H, br. s, OH), 3.83 (3H, s, OCH3),
4.14 (1H, dd, J = 10.9, 7.3 Hz, 1-H), 4.40 (1H, dd, J =
10.9, 5.2 Hz, 1-H), 4.77 (1H, d, J = 4.7 Hz, 4-H), 5.12
(2H, s, OCH2Bn), 6.79 (1H, dd, J = 8.2, 1.4 Hz, ArH),
6.83 (1H, d, J = 8.2 Hz, ArH), 6.89 (1H, d, J = 1.4 Hz,
ArH), 7.26–7.36 (3H, m, ArH), 7.41–7.45 (4H, m,
ArH), 7.55 (1H, m, ArH), 8.01–8.03 (2H, m, ArH);
13C NMR (100 MHz, CDCl3) δ:10.3, 16.4, 34.8, 43.5,
56.0, 67.5, 71.1, 75.6, 109.92, 109.95, 109.96, 113.8,
113.89, 113.91, 118.2, 127.3, 127.8, 128.4, 128.5,
129.5, 130.4, 132.9, 137.2, 137.4, 147.4, 149.7, 166.6;
IR (CHCl3) cm−1: 3619, 1976, 1716, 1520, 1452,
1277, 1138, 1026. MS (EI) m/z: 434 (M+, 20), 243
(100); HRMS (EI) m/z calcd for C27H35O5: 434.2093,
20
(6). 62% yield, two steps, ½aꢀD −24 (c 0.6, CHCl3),
>99%ee (AD-H, iso-PrOH/hexane = 1.7/1, 1 mL/min,
280 nm, tR4.7 min).
(2S,3S)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-3-hydr
oxymethyl-2-methyl-N,N-diethylbutanamide (30).
To
an ice-cooled solution of AlMe3 (1.40 mL, 0.98 M in
hexane, 1.37 mmol) in CH2Cl2 (2 mL) were added
Et2NH (0.15 mL, 1.45 mmol) and lactone 15 (0.36 g,
0.67 mmol) in CH2Cl2 (1mL) under N2 gas. The result-
ing reaction solution was stirred at room temperature
for 72 h before pouring into an ice-cooled H2O. The
mixture was dissolved in EtOAc and H2O. The organic
solution was separated and washed with sat. aq.
NaHSO4 solution. After further washing with brine, the
organic solution was dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/
hexane = 1/1) gave hydroxyamide 30 (0.29 g, 0.47
20
found: 434.2094. (2S,3R,4S)-(27). 96% yield, ½aꢀD +23
(c 1.2, CHCl3).
(2R,3R)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2,3-
dimethylbutyl benzoate (29). The title compound was
obtained from 27 by the same synthetic method as that
of compound 28 in 52% yield as a colorless oil
20
mmol, 70%) as a colorless oil; ½aꢀD −30 (c 1.4,
1
CHCl3); H NMR (400 MHz, C5D5 N) δ: 0.64 (3H, t,
20
1
J = 6.9 Hz, CH2CH3), 1.11 (3H, t, J = 6.9 Hz, CH2CH3),
1.33 (3H, d, J = 7.3 Hz, CH3), 2.49 (1H, m, CHHCH3),
2.57 (1H, m, CHHCH3), 2.74 (1H, m, 3-H), 3.14 (1H,
m, CHHCH3), 3.36 (1H, m, 2-H), 3.51 (1H, m,
CHHCH3), 3.75 (3H, s, OCH3), 3.75–3.84 (1H, over-
lapped, CHHOH), 3.84 (3H, s), 4.15 (1H, dd, J = 11.6,
1.4 Hz, CHHOH), 4.61 (1H, d, J = 12.4 Hz, 4-H), 5.00
(1H, br. s, OH), 5.11 (2H, s, OCH2Bn), 5.22 (2H, s,
OCH2Bn), 7.08 (1H, d, J = 8.3 Hz, ArH), 7.14 (1H, d,
J = 8.3 Hz, ArH), 7.18 (1H, dd, J = 8.2, 1.9 Hz, ArH),
7.25 (1H, dd, J = 8.3, 1.9 Hz, ArH), 7.28–7.40 (5H, m,
ArH), 7.44 (1H, d, J = 1.9 Hz, ArH), 7.55–7.61 (6H, m,
ArH); 13C NMR (100 MHz, CDCl3) δ: 12.8, 13.7,
18.2, 36.8, 41.0, 42.2, 47.5, 50.2, 56.0, 56.2, 57.7,
70.9, 71.0, 112.2, 112.8, 114.0, 114.5, 119.5, 119.9,
127.09, 127.14, 127.6, 127.8, 128.4, 128.5, 136.5,
137.2, 137.4, 146.56, 146.62, 149.3, 149.9, 175.8; IR
(CHCl3) cm−1: 3629, 3021, 1625. MS (EI) m/z: 611
(M+, 9), 129 (100); HRMS (EI) m/z calcd for
through three steps; ½aꢀD −5 (c 0.6, CHCl3); H NMR
(400 MHz, CDCl3) δ: 0.83 (3H, d, J = 7.0 Hz, CH3),
1.09 (3H, d, J = 6.9 Hz, CH3), 2.07 (1H, m, 3-H), 2.33
(1H, m, 2-H), 3.71 (1H, d, J = 11.5 Hz, 4-H), 3.80 (3H,
s, OCH3), 3.85 (3H, s, OCH3), 4.10 (1H, dd, J = 10.9,
7.9 Hz, 1-H), 4.37 (1H, dd, J = 10.9, 5.1 Hz, 1-H), 5.07
(2H, s, OCH2Bn), 5.08 (2H, s, OCH2Bn), 6.75 (1H,
dd, J = 8.3, 1.9 Hz, ArH), 6.77–6.80 (5H, m, ArH),
7.26–7.36 (6H, m, ArH), 7.39–7.45 (6H, m, ArH), 7.55
(1H, m, ArH), 8.01–8.03 (2H, m, ArH); 13C NMR
(100 MHz, CDCl3) δ: 13.3, 17.2, 33.1, 41.2, 55.99,
56.03, 56.1, 66.4, 71.1, 112.0, 112.1, 114.1, 114.3,
119.5, 119.8, 127.25, 127.27, 127.29, 127.7, 128.4,
128.45, 128.49, 129.5, 130.5, 132.9, 137.37, 137.40,
137.5, 137.9, 146.66, 146.70, 149.5, 149.6, 166.7; IR
(CHCl3) cm−1: 3012, 2960, 1714, 1510, 1277. MS (EI)
m/z: 630 (M+, 7), 204 (100); HRMS (EI) m/z calcd for
C41H42O6: 630.2981, found: 630.3001. (2S,3S)-(29).
20
49% yield, ½aꢀD +6 (c 0.7, CHCl3).

1,7-seco-2,7′-cyclolignane
27
C38H45O6 N: 611.3247, found: 611.3252. (2R,3R)-(30).
76% yield, ½aꢀD +30 (c 0.5, CHCl3).
reaction solution was stirred at room temperature for
1.5 h before the addition of sat. aq, NH4Cl solution.
After concentration, the residue was dissolved in
CHCl3 and H2O. The organic solution was separated
and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/6) gave
32 (57 mg, 0.083 mmol, 52%, four steps) as a colorless
20
(2S,3S)-4,4-Bis(4-benzyloxy-3-methoxyphenyl)-2-meth
yl-3-(triisopropylsilyloxy)methyl-N,N,-diethylbutanamide
(31). To an ice-cooled solution of amide 30 (94 mg,
0.12 mmol) and 2,6-lutidine (0.045 mL, 0.39 mmol) in
CH2Cl2 (5 mL) was added TIPSOTf (0.050 mL, 0.19
mmol). After the resulting reaction solution was stirred
at room temperature for 6 h, sat. aq. NaHCO3 solution
was added. The organic solution was separated and
washed with sat. aq CuCO4 solution. After further
washing with sat. aq. NaHCO3 solution, the organic
solution was dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane =
1/3) gave silyl ether 31 (0.12 g, 0.16 mmol, 75%) as a
20
oil; ½aꢀD −3 (c 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 0.88 (3H, d, J = 7.3 Hz, CH3), 0.90–0.94
(21H, m, TIPSi), 1.02 (3H, d, J = 6.9 Hz, CH3), 1.75
(1H, m, 3-H), 2.22 (1H, m, 2-H), 3.61 (1H, dd, J =
10.3, 6.4 Hz, TIPSOCHH), 3.65 (1H, dd, J = 10.3, 3.2
Hz, TIPSOCHH), 3.77 (1H, d, J = 11.5 Hz, 1-H), 3.84
(3H, s, OCH3), 3.86 (3H, s, OCH3), 5.08 (4H, s,
OCH2Bn), 6.74 (1H, d, J = 8.2 Hz, ArH), 6.78–6.82
(5H, m, ArH), 7.26–7.30 (2H, m, ArH), 7.33–7.36
(4H, m, ArH), 7.39–7.42 (4H, m, ArH); 13C NMR
(100 MHz, CDCl3) δ: 11.9, 17.2, 18.0, 18.1, 22.7, 27.7,
49.0, 51.6, 56.0, 56.1, 61.9, 71.1, 71.2, 112.1, 114.0,
114.3, 119.7, 120.0, 121.9, 127.2, 127.3, 127.7, 128.5,
137.5, 138.1, 146.6, 149.4; IR (CHCl3) cm−1: 2941,
2851, 1508, 1465, 1263, 1148. MS (EI) m/z: 682 (M+,
16), 439 (100); HRMS (EI) m/z calcd for C43H58O5Si:
682.4054, found: 682.4042. (2S)-(32). 63% yield, four
20
colorless oil; ½aꢀD −1 (c 2, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 0.78 (3H, t, J = 7.1 Hz, CH2CH3),
0.90–0.93 (21H, m, TIPSi), 1.03 (3H, t, J = 6.9 Hz,
CH2CH3), 1.19 (3H, d, J = 7.1 Hz, CH3), 2.54 (1H, m,
3-H), 2.73 (2H, m, CH2CH3), 2.89 (1H, m, 2-H), 3.08
(1H, m, CHHCH3), 3.35 (1H, m, CHHCH3), 3.59 (1H,
dd, J = 10.5, 2.8 Hz, TIPSOCHH), 3.83 (6H, s, OCH3 ×
2), 3.85 (1H, d, J = 13.6 Hz, 4-H), 4.27 (1H, dd, J =
10.5, 5.6 Hz, TIPSOCHH), 5.06 (2H, s, OCH2Bn),
5.08 (2H, s, OCH2Bn), 6.72–6.77 (4H, m, ArH), 6.83–
6.84 (2H, m, ArH), 7.24–7.27 (2H, m, ArH), 7.30–7.34
(4H, m, ArH), 7.38–7.40 (4H, m, ArH); 13C NMR
(100 MHz, CDCl3) δ: 12.0, 13.1, 14.2, 17.1, 18.2,
35.6, 40.0, 41.6, 49.6, 52.4, 56.0, 56.2, 63.4, 71.1,
71.3, 112.5, 112.7, 114.2, 114.3, 120.0, 120.1, 127.2,
127.3, 127.75, 127.82, 128.6, 137.4, 137.6, 137.7,
137.9, 146.6, 146.7, 149.4, 149.7, 175.3; IR (CHCl3)
cm−1: 2940, 1626, 1512, 1464, 1261, 1141. MS (EI)
m/z: 768 (M+, 0.6), 131 (100). Anal. Calcd for
C46H63O6NSi: C, 73.27; H, 8.42%. Found: C, 73.33;
20
steps, ½aꢀD +3 (c 1, CHCl3).
(R)-2-Bis(4-benzyloxy-3-methoxyphenyl)methyl-3-
methy-1-butanol (33). To a solution of silyl ether 32
(57 mg, 0.083 mmol) in THF (5 mL) was added
(n-Bu)4NF (0.17 mL, 1 M in THF, 0.17 mmol). After
stirring at room temperature for 2 h, sat. aq. NH4Cl
solution and EtOAc were added. The organic solution
was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 1/3) gave alcohol 33 (40
20
mg, 0.078 mmol, 94%) as a colorless oil, ½aꢀD −43 (c
20
1
H, 8.48%. (2R,3R)-(31). 73% yield, ½aꢀD +1 (c 0.8,
0.5, CHCl3); H NMR (400 MHz, CDCl3) δ: 0.83 (3H,
CHCl3).
d, J = 6.9 Hz, CH3), 1.01 (3H, d, J = 6.9 Hz, CH3), 1.76
(1H, m, 3-H), 2.21 (1H, m, 2-H), 3.57–3.66 (2H, m, 1-
H2), 3.79 (1H, d, J = 11.4 Hz, Ar2CH), 3.85 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 5.08 (2H, s, OCH2Bn),
5.09 (2H, s, OCH2Bn), 6.77–6.86 (6H, m, ArH), 7.25–
7.26 (2H, m, ArH), 7.28–7.36 (4H, m, ArH), 7.39–7.42
(4H, m, ArH); 13C NMR (100 MHz, CDCl3) δ: 16.5,
22.1, 27.6, 49.8, 52.8, 55.9, 56.0, 61.7, 71.0, 111.7,
111.8, 113.9, 114.2, 119.6, 127.2, 127.67, 127.70,
128.4, 137.1, 137.2, 137.3, 146.6, 147.8, 149.5, 149.6;
IR (CHCl3) cm−1: 3735, 3025, 3000, 1508, 1261,
1141, 1036. MS (EI) m/z: 526 (M+, 18), 439 (100);
HRMS (EI) m/z calcd for C34H38O5: 526.2720, found:
(2R)-1,1-Bis(4-benzyloxy-3-methoxyphenyl)-3-methyl-
2-(triisopropylsilyloxy)methylbutane (32). To a solu-
tion of silyl ether 31 (0.12 g, 0.16 mmol) in toluene (5
mL) was added DIBAL-H (0.91 mL, 1 M in toluene,
0.91 mmol) at 0 °C. After the reaction solution was stir-
red at 0 °C for 13 h, sat. aq. NH4Cl solution was added.
The organic solution was separated, washed with brine,
and dried (Na2SO4). The concentration gave crude
aldehyde. To an ice-cooled solution of aldehyde in
EtOH (8 mL) was added NaBH4 (20 mg, 0.53 mmol),
and then the reaction mixture was stirred at room tem-
perature for 0.5 h before additions of sat. aq. NH4Cl
solution and EtOAc. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). Concen-
tration gave crude alcohol. To an ice-cooled solution
of alcohol and Et3 N (36 μL, 0.26 mmol) in CH2Cl2
(5 mL) was added MsCl (20 μL, 0.26 mmol). After the
reaction mixture was stirred at room temperature for
0.5 h, H2O and CH2Cl2 were added. The organic solu-
tion was separated and dried (Na2SO4). Concentration
gave crude mesylate. To an ice-cooled solution of mes-
ylate in THF (10 mL) was added Super-Hydride
(5.00 mL, 1.00 M in THF, 5.00 mmol), and then the
20
526.2735. (2S)-(33). 97% yield, ½aꢀD +43 (c 0.8,
CHCl3).
(R)-2-Bis(4-hydroxy-3-methoxyphenyl)methyl-3-methy
l-1-butanol (7). A reaction mixture of benzyl ether
33 (40 mg, 0.078 mmol) and 5% Pd/C (0.10 g) in
EtOAc (10 mL) was stirred under H2 gas at ambient
temperature for 2 h before filtration. After the filtrate
was concentrated, the residue was applied to a silica
gel column chromatography (EtOAc/hexane = 1/1) to
give secocyclolignane 7 (23 mg, 0.066 mmol, 85%) as
20
a colorless oil, ½aꢀD −55 (c 0.3, CHCl3); 1H NMR

28
S. Yamauchi et al.
(400 MHz, CDCl3) δ: 0.82 (3H, d, J = 6.9 Hz, CH3),
1.02 (3H, d, J = 6.9 Hz, CH3), 1.78 (1H, m, 3-H), 2.22
(1H, m, 2-H), 3.64 (2H, s, 1-H2), 3.78 (1H, d, J = 11.5
Hz, Ar2CH), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3),
5.49 (1H, s, ArOH), 5.52 (1H, s, ArOH), 6.77 (1H, s,
ArH), 6.81 (1H, d, J = 1.9 Hz, ArH), 6.82 (1H, d, J =
8.2 Hz, ArH), 6.84 (2H, s, ArH), 6.87 (1H, dd, J = 8.2,
1.9 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ: 16.6,
22.2, 27.7, 49.9, 53.0, 55.8, 55.9, 61.8, 110.46, 110.54,
114.5, 114.7, 120.1, 120.3, 136.2, 136.3, 143.9, 144.2,
146.5, 146.7; IR (CHCl3) cm−1: 3571, 3000, 1511,
1269, 1036. MS (EI) m/z: 346 (M+, 7), 259 (100);
HRMS (EI) m/z calcd for C20H26O5: 346.1780, found:
346.1774. > 99%ee (AD-H, iso-PrOH/hexane = 1.7/1,
Acknowledgments
Part of this study was performed at INCS (Johoku
station) of Ehime University. We are grateful to Maru-
tomo Co. for financial support.
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20
20
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6519–6522.
(2R,3R)-4,4-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-1-
butanol (36). The title compound was obtained from
5 by the same synthetic method as that of compound 34
20
in 68% yield as colorless powders, ½aꢀD +18 (c 0.1,
1
MeOH); H NMR (400 MHz, CDCl3) δ: 0.78 (3H, d, J
= 6.9 Hz, CH3), 0.99 (3H, d, J = 6.9 Hz, CH3), 1.57 (1H,
br. s, OH), 1.82 (1H, m, 3-H), 2.31 (1H, m, 2-H), 3.37
(1H, dd, J = 10.5, 7.3 Hz, 1-H), 3.67 (1H, dd, J = 10.5,
6.0 Hz, 1-H), 3.75 (1H, d, J = 11.5 Hz, 4-H), 3.82 (6H, s,
OCH3 × 2), 3.83 (6H, s, OCH3 × 2), 6.76 (1H, d, J = 8.3
Hz, ArH), 6.77–6.78 (1H, overlapped, ArH), 6.79 (1H,
d, J = 8.3 Hz, ArH), 6.80 (1H, d, J = 2.3 Hz, ArH), 6.83
(1H, dd, J = 8.3, 1.9 Hz, ArH), 6.86 (1H, dd, J = 8.3, 2.3
Hz, ArH); 13C NMR (100 MHz, CDCl3) δ: 13.3, 16.6,
36.6, 40.9, 55.8, 55.87, 55.90, 56.0, 64.7, 111.2, 111.4,
119.6, 137.4, 137.8, 147.3, 147.4, 148.8, 149.0. MS (EI)
m/z: 374 (M+, 11), 287 (100); HRMS (EI) m/z calcd for
C22H30O5: 374.2094, found: 374.2088. (2S,3S)-37. 67%
20
yield, ½aꢀD −18 (c 0.1, MeOH).
Enantiomeric excess of butane-type secocyclolignane
1 and 2. 1: >99%ee, AD-H, iso-PrOH/hexane = 1/2,
1 mL/min, 271 nm, tR10 min. 2: >99%ee, AD-H, iso-
PrOH/hexane = 1/2, 1 mL/min, 271 nm, tR8 min.
[18] Rye CE, Barker D. Asymmetric synthesis of (+)-galbelgin,
(-)-kadangustin J, (-)-cyclogalgravin and (-)-pycnanthulignenes A
and B, three structurally distinct lignan classes, using a common
chiral precursor. J. Org. Chem. 2011;76:6636–6648.