First enantioselective synthesis of (-)- And (+)-virgatusin, tetra-substituted tetrahydrofuran lignan

Article abstract of DOI:10.1039/b501151e

The first highly enantioselective syntheses of tetra-substituted tetrahydrofuran lignan, (-)- and (+)-virgatusin, were achieved. Hemiacetal 15 was stereoselectively obtained from Evans's syn-aldol product 8 as a single isomer. This hemiacetal 15 was converted to (-)-virgatusin via hydrogenolysis. (+)-Virgatusin was also synthesized through the same process. The enantiomeric excess of the both enantiomers was determined as more than 99% ee. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b501151e

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A R T I C L E
First enantioselective synthesis of (−)- and (+)-virgatusin,
tetra-substituted tetrahydrofuran lignan
Satoshi Yamauchi,*a Momotoshi Okazaki,a Koichi Akiyama,b Takuya Sugahara,a
Taro Kishidaa and Takehiro Kashiwagia
a Department of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime, 790-8566,
Japan. E-mail: syamauch@agr.ehime-u.ac.jp; Fax: +81-89-977-4364
b Integrated Center for Sciences Tarumi Station, Ehime University, 3-5-7 Tarumi, Matsuyama,
Ehime, 790-8566, Japan
Received 24th January 2005, Accepted 9th March 2005
First published as an Advance Article on the web 24th March 2005
The first highly enantioselective syntheses of tetra-substituted tetrahydrofuran lignan, (−)- and (+)-virgatusin, were
achieved. Hemiacetal 15 was stereoselectively obtained from Evans’s syn-aldol product 8 as a single isomer. This
hemiacetal 15 was converted to (−)-virgatusin via hydrogenolysis. (+)-Virgatusin was also synthesized through the
same process. The enantiomeric excess of the both enantiomers was determined as more than 99% ee.
Introduction
(−)-Virgatusin, a tetra-substituted tetrahydrofuran lignan, was
isolated from Phylanthus amarus1 with other lignans. This
plant has been used by natives as a herbal drug for liver.
The plant extract from this species exhibited inhibition of the
endogenous DNA polymerase of the hepatitis B virus.2 Because
lignans cover a wide spectrum of biological activity,3–5 nothing
is definitively known regarding the biological activity of (−)-
virgatusin. Recently, related compounds have been isolated.6–9
Lignans are widely distributed among many kinds of plant.
Research on the biological activity of lignans is very important
for the effective utilization of this bioresource.
Since some lignans are biosynthesized as an enantiomeric
mixture,10 the synthetic study of lignans would contribute to
biological research. (−)-Virgatusin has four chiral centers on
the tetrahydrofuran ring. There is a considerable interest in
the synthesis of highly substituted tetrahydrofuran rings. In the
case of other types of tetra-substituted tetrahydrofuran lignans,
racemic syntheses are known.11–14 Only Yoda and coworkers
Fig. 1
reported the synthesis of (−)-virgatusin utilizing resolution of
the starting material.15 Our challenge is the first enantioselective
synthesis of virgatusin to give enantiomerically pure (−)- and
Results and discussion
(+)-virgatusin, respectively. This project will lead to the precise
determination of biological activity.
According to the procedure by Evans,17 syn-aldol product
8 was obtained from (R)-acyl oxazolidinone 7 and 3,4-
dimethoxybenzaldehyde in 93% yield. After protection of the
benzylic hydroxy group as the triisopropylsilyl ether by treat-
ment with triisopropylsilyl triflate and 2,6-lutidine (100% yield),
the auxiliary was reductively removed to give the primary
alcohol 10 in 62% yield. Oxidative cleavage of the olefin by
employing OsO4 and NaIO4 gave the hemiacetal, which was
exposed to pyridinium chlorochromate oxidation to afford
lactone 11 in 73% yield through 3 steps. The aldol condensation
of lactone 11 with piperonal by using KHMDS as base gave
aldol product 12 in 93% yield. Though the major product was the
erythro isomer,18 the threo isomer could been seen in the NMR
spectrum (erythro : threo = 9 : 1). Lactone 12 was reduced to
the corresponding diol by LiBH4, which led to dipivaloyl ester
13 as a single isomer by using pivaloyl chloride and pyridine
in 69% yield through 2 steps. The resulting benzyl alcohol was
converted to ketone 14 by pyridinium chlorochromate oxidation
in 94% yield (Scheme 1).
A key step is the construction of an ethereal bond between
two benzylic positions. The SN1 cyclization by benzylic cation
produced at the 7ꢀ position of 2 will predominately give
the undesired steric configuration. On the other hand, SN2
cyclization of the secondary benzyl mesylate derived from 2
will fail because of a Friedel–Craft type reaction.16 Yoda and
coworkers succeeded in the conversion of an a,b-mixture of
hemiacetal 3 to 4 by using Et3SiH and TiCl4 by control of
the temperature.15 Without temperature control, the benzylic
positions would be epimerized under this condition. If the
stereoselective preparation of hemiacetal 5 is possible, the tetra-
substituted tetrahydrofuran 6 could be obtained as a single
isomer by treatment of 5 with H2 and catalyst (Fig. 1). It could
be expected that H2 would add to the 7ꢀC and oxygen of the
hemiacetal, giving desired configuration as a hydrogenolysis
product. It is important for this project to get stereoselectively
the C7ꢀ position of hemiacetal 5.
This article describes the first highly enantioselective synthesis
of (−)- and (+)-virgatusin. In this work, the stereoselective
construction of the tetra-substituted tetrahydrofuran ring was
achieved by a new method.
Conversion of ketone 14 to hemiacetal 15 was achieved by
employing tetra-n-butylammonium fluoride and acetic acid in
87% yield (Scheme 1). Fortunately, this hemiacetal 15 was
1 6 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 1 Synthesis of (−)-virgatusin (a) (n-Bu)2BOTf, Et3N, 3,4-dimethoxybenzaldehyde, CH2Cl2, −78 to 0 ◦C, 1 h (93% yield); (b) TIPSOTf, 2,6-
lutidine, CH2Cl2, rt, 1 h (100% yield); (c) LiBH4, MeOH, THF, rt, 16 h (62% yield); (d) (1) OsO4, NMO, aq. acetone, tert-BuOH, rt, 48 h, (2) NaIO4,
MeOH, rt, 16 h, (3) PCC, CH2Cl2, rt, 16 h (73% yield, 3 steps); (e) KHMDS, piperonal, THF, −70 ◦C, 1 h (93% yield, 90% de); (f) (1) LiBH4, THF,
◦
˚
−78 to 0 C, 24 h, (2) PivCl, pyridine, rt, 30 min (69% yield, 2 steps); (g) PCC, MS 4 A, CH2Cl2, rt, 16 h (94% yield); (h) (n-Bu)4NF, AcOH, THF, rt,
16 h (87%); (i) H2, Pd(OH)2/C, EtOAc, rt, 1 h (79% yield); (j) NaOH, aq. EtOH, rt, 20 h (85% yield); (k) NaH, CH3I, THF, rt, 5 h (88% yield).
obtained as a single isomer. The stereochemistry at the 7ꢀ
position could not be determined in this work. In the case of
hemiacetal 17, a mixture of 7ꢀR : S isomer (1 : 1) was obtained
from di(tert-butyldiphenylsilyloxy)(triethylsilyloxy) ketone 16
by employing 2% HF in CH3CN (Scheme 2). This ketone
16 was prepared from alcohol 8 by the almost same process.
The benzylic hydroxy group of 8 was prepared as the TES
ether. The two primary hydroxy groups were protected as
TBDPS ethers instead of dipivaloyl esters. Treatment of this
After hydrolysis of pivaloyl ester 18 by exposure to aqueous
NaOH solution (85% yield), methylation of the resulting diol by
using methyl iodide and NaH gave (−)-virgatusin ((−)-1) in 88%
yield. The enantiomeric excess of the synthesized pivaloyl ester
18 and (−)-virgatusin ((−)-1) was determined as more than 99%
ee by a chiral column.
(+)-Virgatusin was also synthesized from (S)-acyl oxazo-
lidinone and 3,4-dimethoxybenzaldehyde through the same
procedure. The enantiomeric excess was also determined as more
than 99% ee.
15
hemiacetal 17 with Et3SiH and BF3.OEt2 or TiCl4 did not
give desired tetrahydrofuran derivative, but many unidentified
compounds were obtained. Since hemiacetal 15 was unstable
giving a highly polar compound, the next step had to be started
immediately. The conversionof hemiacetal 15 to tetrahydrofuran
The first highly enantioselective synthesis of (−)- and (+)-
virgatusin was accomplished by employing Evans’s syn-aldol
condensation and stereoselective construction of the hemiacetal,
followed by hydrogenolysis through 14 steps in 13% overall yield.
15
derivative 18 by using Et3SiH and BF3·OEt2 or TiCl4 also
failed. However, hydrogenolysis in the presence of Pd(OH)2/C
gave tetrahydrofuran derivative 18 as a single isomer in 79%
yield. The benzylic ethereal bonds on the main structure were
not cleaved in this work. Though the selective hydrogenolysis
of phenolic benzyl ether was reported,19,20 this is a first report
of the selective hydrogenolysis of a hemiacetal. A differential
NOE experiment between 7-H and 7ꢀ-H confirmed this relative
configuration. The mesylation of the benzyl hydroxy group of 13
by using methanesulfonyl chloride and triethylamine gave many
unidentified products. This fact means that SN2 etherification to
construct the tetrahydrofuran ring was not suitable in this case.
Experimental
Melting point (mp) data are uncorrected. NMR data were
measured by a JNM-EX400 spectrometer, IR spectra were deter-
mined with a Shimadzu FTIR-8100 spectrophotometer, EIMS
data were measured with a JMS-MS700V spectrometer, and op-
tical rotation values were evaluated with a HORIBA SEPA-200
instrument. The silica gel used was Wakogel C-300 (Wako, 200–
300 mesh). HPLC analyses were performed with Shimadzu LC-
6AD and SPD-6AV instruments. The numbering of compounds
was changed to follow IUPAC nomenclature rules.
Scheme 2 Conversion of di(tert-butyldiphenylsilyloxy)(triethylsilyloxy) ketone 16 to hemiacetal 17.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5
1 6 7 1

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addition of sat. aq. NH4Cl solution. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentra-
tion and subsequent silica gel column chromatography (EtOAc :
hexane = 1 : 3) gave alcohol 10 (4.50 g, 0.011 mol, 62%) as a
colorless oil, [a]D20 = +15 (c 0.85, CHCl3); mmax(CHCl3)/cm−1
3461, 2946, 1516, 1464, 1260, 1157, 1142, 1049, 1028, 884, 818;
dH(CDCl3) 0.96–1.08 (20H, m, iso-Pr), 1.15 (1H, m, iso-Pr), 1.75
(1H, m, 3-HH), 1.95 (1H, m, 3-HH), 2.27 (1H, m, 2-H), 3.28 (1H,
m, OH), 3.48 (1H, m, 1-HH), 3.62 (1H, m, 1-HH), 3.88 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.97 (1H, d, J 3.9 Hz, ArCHOTIPS),
(4R)-4-Benzyl-3-{(2R)-2-[(R)-(3,4-dimethoxyphenyl)(hydroxy)-
methyl]-4-pentenoyl}-2-oxazolidinone 8
To a solution of (R)-oxazolidinone 7 (11.6 g, 0.045 mol) in
CH2Cl2 (100 ml) was added dibutylboron triflate (49.2 ml,
1 M in CH2Cl2, 0.049 mol) and Et3N (7.20 ml, 0.052 mol)
at below 0 ◦C. After cooling to −65 ◦C, a solution of 3,4-
dimethoxybenzaldehyde (8.33 g, 0.050 mol) in CH2Cl2 (20 ml)
was added. The reaction solution was stirred at −65 ◦C for
20 min, and then warmed to 0 ◦C. After stirring at 0 ◦C for
1 h, phosphate buffer pH 7 (100 ml), MeOH (140 ml), and 2 :
1 MeOH : 30% H2O2 (140 ml) were added. The mixture was
stirred at below 10 ◦C for 1 h, and then evaporated at 30 ◦C. The
resulting residue was dissolved in CH2Cl2 and H2O. The organic
solution was separated, washed with sat. aq. NaHCO3 solution
and brine, and dried (Na2SO4). After concentration, the residue
was applied to silica gel column chromatography (EtOAc :
hexane = 1 : 3) to give aldol product 8 (17.7 g, 0.042 mol, 93%)
as a colorless oil, [a]2D0 = −93 (c 1.8, CHCl3); mmax(CHCl3)/cm−1
3675, 3013, 2967, 1779, 1692, 1516, 1385, 1264, 1238, 1196,
1140, 1028, 909; dH(CDCl3) 2.58–2.72 (3H, m, CHHAr,
=
=
5.02–5.08 (2H, m, CH CH2), 5.81 (1H, m, CH CH2), 6.79–
6.83 (2H, m, ArH), 6.98 (1H, d, J 1.5 Hz, ArH); dC(CDCl3)
12.1, 17.9, 18.0, 32.6, 46.8, 55.76, 55.79, 63.3, 77.9, 110.3, 110.4,
116.6, 119.5, 133.2, 136.8, 148.3, 148.5 (Found: C, 67.61; H,
9.76. C23H40O4Si requires C, 67.60; H, 9.87%). (−)-10: [a]D20
−15 (c 0.98, CHCl3).
=
(3S)-3-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide 11
A reaction solution of olefin 10 (3.65 g, 8.93 mmol), 4-
methylmorpholine N-oxide (1.29 g, 11.0 mmol), and OsO4 (aq.
2% solution, 1 ml) in acetone (80 ml), tert-BuOH (20 ml), and
H2O (20 ml) was stirred at room temperature for 48 h before
addition of Na2S2O3 (1 g). After the mixture was concentrated,
the residue was dissolved in EtOAc and H2O. The organic
solution was evaporated, washed with brine, and dried (Na2SO4).
Evaporation gave crude glycol. A reaction mixture of the crude
glycol and NaIO4 (2.35 g, 11.0 mmol) in MeOH (30 ml) was
stirred at room temperature for 16 h before concentration. The
residue was dissolved in EtOAc and H2O. The organic solution
was separated, washed with brine, and dried (Na2SO4). Con-
centration and subsequent silica gel column chromatography
(EtOAc : hexane = 1 : 1) gave hemiacetal (3.38 g, 8.23 mmol,
92%) as a colorless oil. A reaction mixture of hemiacetal (3.38 g,
8.32 mmol) and PCC (2,13 g, 9.88 mmol) in CH2Cl2 (30 ml)
=
CH2CH CH2), 2.60 (1H, d, J 2.4 Hz, OH), 3.21 (1H, dd, J
13.4, 3.2 Hz, CHHAr), 3.81 (1H, d, J 9.3 Hz, 5-HH), 3.85
(3H, s, OCH3), 3.88 (3H, s, OCH3), 4.02 (1H, dd, J 9.3, 2.4 Hz,
=
5-HH), 4.38 (1H, m, O CCH), 4.51 (1H, m, 4-H), 4.89 (1H, dd,
=
J 6.6, 2.4 Hz, ArCHOH), 5.04 (1H, m, CH CHH), 5.12 (1H,
=
=
m, CH CHH), 5.80–5.91 (1H, m, CH CH2), 6.80 (1H, d, J
8.3 Hz, ArH), 6.90 (1H, dd, J 8.3, 2.0 Hz, ArH), 6.99 (1H, d, J
2.0 Hz, ArH), 7.16–7.18 (2H, m, ArH), 7.24–7.33 (3H, m, ArH);
dC(CDCl3) 32.5, 38.0, 49.4, 55.5, 55.86, 55.91, 65.8, 74.6, 109.4,
110.8, 117.2, 118.7, 127.3, 128.9, 129.3, 134.0, 135.20, 135.24,
148.6, 148.9, 153.1, 174.5 (Found: C, 67.55; H, 6.48; N, 3.30.
C24H27O6N requires C, 67.75; H, 6.40; N, 3.29%). (+)-8: [a]D20
+93 (c 1.9, CHCl3).
=
(4R)-4-Benzyl-3-{(2R)-2-[(R)-(3,4-dimethoxyphenyl)-
˚
containing MS 4 A (0.5 g) was stirred at room temperature for
(triisopropylsilyloxy)methyl-4-pentenoyl]}-2-oxazolidinone 9
16 h before addition of dry ether. After filtration, the filtrate
was concentrated. The residue was applied to silica gel column
chromatography (5% EtOAc in toluene) to give lactone 11
(2.67 g, 6.53 mmol, 79%) as colorless crystals, mp 91–92 ◦C
(iso-Pr2O), [a]D20 = +49 (c 0.55, CHCl3); mmax(CHCl3)/cm−1 2948,
1775, 1514, 1466, 1260, 1176, 1154, 1140, 1094, 1026, 1013, 909,
884; dH(CDCl3) 0.96–1.03 (21H, m, iso-Pr), 2.55 (1H, dd, J 17.6,
9.0 Hz, 2-HH), 2.66 (1H, dd, J 17.6, 7.8 Hz, 2-HH), 2.87 (1H,
ddddd, J 9.0, 7.8, 7.8, 6.8, 6.2 Hz, 3-H), 3.88 (6H, s, OCH3),
4.10 (1H, dd, J 9.3, 6.8 Hz, 4-HH), 4.15 (1H, dd, J 9.3, 7.8 Hz,
4-HH), 4.72 (1H, d, J 6.2 Hz, ArCHOTIPS), 6.78 (1H, dd, J
8.3, 2.0 Hz, ArH), 6.81 (1H, d, J 8.3 Hz, ArH), 6.87 (1H, d, J
2.0 Hz, ArH); dC(CDCl3) 12.4, 17.9, 18.0, 31.0, 44.6, 55.8, 69.7,
75.5, 109.2, 110.7, 118.7, 134.5, 148.8, 149.1, 176.8 (Found: C,
64.61; H, 8.96. C22H36O5Si requires C, 64.67; H, 8.88%). (−)-11:
[a]2D0 = −49 (c 0.98, CHCl3).
To an ice-cooled solution of alcohol 8 (12.7 g, 0.030 mol), 2,6-
lutidine (5.92 ml, 0.051 mol) in CH2Cl2 (100 ml) was added
TIPSOTf (10.3 ml, 0.038 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
brine, and dried (Na2SO4). After concentration, the residue
was applied to silica gel column chromatography (EtOAc :
hexane = 1 : 3) to give silyl ether 9 (17.5 g, 0.030 mol, 100%)
as a colorless oil, [a]2D0 = −73 (c 1.1, CHCl3); mmax(CHCl3)/cm−1
2948, 1779, 1686, 1510, 1466, 1385, 1262, 1238, 1102; dH(CDCl3)
1.01–1.02 (20H, m, iso-Pr), 1.15 (1H, m, iso-Pr), 2.59 (1H,
=
dd, J 13.7, 9.8 Hz, PhCHH), 2.67 (1H, m, CHHCH CH2),
=
2.85 (1H, m, CHHCH CH2), 3.09 (1H, dd, J 13.7, 2.9 Hz,
PhCHH), 3.47 (1H, dd, J 8.3, 7.8 Hz, 5-HH), 3.82 (3H, s,
OCH3), 3.87 (3H, s, OCH3), 3.87 (1H, dd, J 8.3, 2.0 Hz, 5-
=
HH), 4.10 (1H, m, O CCH), 4.51 (1H, m, 4-H), 4.83 (1H, d,
=
J 8.3 Hz, ArCHOTIPS), 5.03 (1H, m, CH CHH), 5.13 (1H,
(2R,3S)-3-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)-
methyl]-2-[(R)-(hydroxy)(3,4-methylenedioxyphenyl)methyl]-4-
butanolide 12
=
=
m, CH CHH), 5.83–5.93 (1H, m, CH CH2), 6.71 (1H, d, J
8.3 Hz, ArH), 6.78 (1H, dd, J 8.3, 2.0 Hz, ArH), 7.00 (1H, d,
J 2.0 Hz, ArH), 7.13–7.14 (2H, m, ArH), 7.22–7.33 (3H, m,
ArH); dC(CDCl3) 12.5, 12.7, 17.9, 18.0, 34.3, 37.9, 51.9, 55.7,
55.8, 55.9, 65.6, 77.2, 109.94, 109.99, 110.1, 116.8, 119.3, 127.2,
128.8, 129.4, 135.28, 135.34, 135.7, 148.5, 152.8, 173.8 (Found:
C, 68.05; H, 8.08; N, 2.50. C33H47O6NSi requires C, 68.12; H,
8.14; N, 2.41%). (+)-9: [a]2D0 = +73 (c 0.89, CHCl3).
To a solution of KHMDS (8.47 ml, 0.5 M toluene solution,
4.24 mmol) in THF (20 ml) was added a solution of lactone 11
(1.44 g, 3.52 mmol) in THF (10 ml) at −70 ◦C. After stirring at
−70 ◦C for 15 min, piperonal (0.58 g, 3.86 mmol) in THF (5 ml)
was added, and then the reaction solution was stirred at −70 ◦C
for 1 h before addition of sat. aq. NH4Cl solution. The organic
solution was separated, washed with brine, and dried (Na2SO4).
After evaporation, the residue was applied to silica gel column
chromatography (EtOAc : hexane = 1 : 3) to give aldol product
12 (1.84 g, 3.29 mmol, 93%, a mixture of erythro : threo = 9 :
1) as a colorless oil; mmax(CHCl3)/cm−1 3497, 2946, 1759, 1516,
1256, 1240, 1042; dH(CDCl3) 0.87–1.00 (21H, m, iso-Pr), 2.73
(1H, d, J 4.4 Hz, OH), 2.79 (1H, dd, J 5.4, 2.9 Hz, 2-H), 2.88
(2S)-2-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)methyl]-
4-penten-1-ol 10
To an ice-cooled solution of LiBH4 (0.90 g, 0.041 mol) in THF
(100 ml) was added MeOH (1.49 ml) and acyloxazolidinone
9 (9.76 g, 0.017 mol) in THF (80 ml), and then the resulting
reaction solution was stirred at room temperature for 16 h before
1 6 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5

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(1H, dddd, J 8.3, 5.4, 4.6, 3.9 Hz, 3-H), 3.78 (3H, s, OCH3), 3.85
(3H, s, OCH3), 4.33 (1H, dd, J 8.8, 4.6 Hz, 4-HH), 4.40 (1H,
dd, J 8.8, 8.3 Hz, 4-HH), 4.65 (1H, d, J 3.9 Hz, ArCHOTIPS),
5.20 (1H, dd, J 4.4, 2.9 Hz, ArCHOH), 5.96 (1H, s, OCHHO),
5.97 (1H, s, OCHHO), 6.48 (1H, d, J 2.0 Hz, ArH), 6.54 (1H,
dd, J 8.3, 1.5 Hz, ArH), 6.60 (1H, d, J 1.5 Hz, ArH), 6.65–6.71
(3H, m, ArH); dC(CDCl3) 12.5, 17.90, 17.94, 43.0, 48.8, 55.58,
55.62, 70.0, 72.5, 75.5, 101.2, 105.9, 107.8, 109.1, 110.4, 118.6,
133.3, 135.0, 147.0, 147.7, 148.3, 148.6, 178.5 (Found: C, 64.35;
H, 7.62. C30H42O8Si requires C, 64.49; H, 7.58%).
(2R,3S,4S,5S)-2-(3,4-Dimethoxyphenyl)-5-(3,4-
methylenedioxyphenyl)-3,4-bis(pivaloyloxymethyl)-
tetrahydrofuran 18
To an ice-cooled solution of silyl ether 14 (0.98 g, 1.23 mmol) in
THF (20 ml) was added AcOH (93 ll) and (n-Bu)4NF (1.48 ml,
1 M THF solution, 1.48 mmol). The reaction solution was
stirred at room temperature for 16 h before addition of sat. aq.
NaHCO3 solution. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration and subsequent
silica gel column chromatography (EtOAc : hexane = 3 : 1) gave
unstable hemiacetal 15 (0.61 g, 1.07 mmol, 87%) as a colorless
oil; dH(CDCl3) 1.196 (9H, s, Piv), 1.203 (9H, s, Piv), 3.34 (1H,
m, 4-H), 3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.81–3.91 (1H,
m, 3-H), 4.26 (1H, dd, J 11.2, 6.8 Hz, CHHOPiv), 4.36 (1H, dd,
J 11.2, 4.2 Hz, CHHOPiv), 4.77 (1H, d, J 12.7 Hz, CHHOPiv),
4.83 (1H, d, J 12.7 Hz, CHHOPiv), 5.33 (1H, d, J 4.4 Hz, 5-H),
5.99 (2H, s, OCH2O), 6.83–6.86 (2H, m, ArH), 6.90–6.92 (2H, m,
ArH), 7.08 (1H, d, J 1.5 Hz, ArH), 7.12 (1H, dd, J 8.3, 1.5 Hz,
ArH); dC(CDCl3) 27.1, 27.2, 38.8, 54.1, 55.8, 55.9, 59.8, 65.0,
84.1, 101.3, 102.2, 107.9, 108.3, 108.6, 111.2, 117.8, 122.0, 123.9,
134.6, 147.7, 148.6, 148.9, 149.2, 178.3, 178.5. A reaction mixture
of hemiacetal (0.39 g, 0.68 mmol) and Pd(OH)2 (0.30 g) in EtOAc
(10 ml) was stirred at ambient temperature under H2 gas for
1 h. After filtration, the filtrate was concentrated. The residue
was applied to silica gel column chromatography (EtOAc :
hexane = 3 : 1) to give tetra-substituted tetrahydrofuran 18
(0.30 g, 0.54 mmol, 79%) as a colorless oil, [a]2D0 = −19 (c 0.82,
CHCl3), more than 99% ee (HPLC, DAICEL chiral column OD-
H, detected at 280 nm, 1 ml min−1, 10% iso-PrOH in hexane, tR
16 min); mmax(CHCl3)/cm−1 2966, 1721, 1524, 1262, 1160, 1043;
dH(CDCl3) 1.17 (9H, s, Piv), 1.18 (9H, s, Piv), 2.37 (1H, m, 3-H),
2.73 (1H, m, 4-H), 3.79–3.86 (2H, m, 4-CH2OPiv), 3.89 (3H, s,
OCH3), 3.93 (3H, s, OCH3), 4.21 (1H, dd, J 11.2, 5.1 Hz, 3-
CHHOPiv), 4.29 (1H, dd, J 11.2, 4.4 Hz, 3-CHHOPiv), 4.67
(1H, d, J 8.3 Hz, 2-H), 5.12 (1H, d, J 7.3 Hz, 5-H), 5.95 (2H, s,
OCH2O), 6.78 (1H, d, J 7.8 Hz, ArH), 6.84–6.91 (3H, m, ArH),
7.00–7.01 (2H, m, ArH); dC(CDCl3) 27.06, 27.15, 38.6, 38.9,
45.5, 50.4, 55.9, 56.0, 63.7, 64.7, 81.2, 82.8, 101.0, 106.9, 108.1,
109.8, 111.2, 119.1, 119.6, 131.7, 132.4, 147.0, 147.7, 149.0,
149.2, 178.2, 178.3 (Found: C, 66.56; H, 7.20. C31H40O9 requires
C, 66.89; H, 7.24%). (+)-18: [a]2D0 = +19 (c 1.1, CHCl3), more
than 99% ee (tR 12 min).
(2S,3S)-2-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)-
methyl]-3-[(R)-(hydroxy)(3,4-methylenedioxyphenyl)methyl]-
tetramethylene dipivaloate 13
To a solution of LiBH4 (0.59 g, 27.1 mmol) in THF (10 ml)
was added a solution of lactone 12 (1.96 g, 3.51 mmol) in THF
(10 ml) at −10 ◦C. After the reaction solution was stirred at
0 ◦C for 24 h, sat. aq. NH4Cl solution was added at below 0 ◦C,
and then concentrated. The residue was dissolved in EtOAc and
H2O. The organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration gave crude diol. To an ice-
cooled solution of crude diol in pyridine (5 ml) was added PivCl
(0.56 ml, 4.53 mmol), and then the reaction mixture was stirred
at room temperature for 30 min. After additions of CH2Cl2
and H2O, the organic solution was separated, washed with 1 M
aq. HCl solution, sat. aq. NaHCO3 solution, and brine, and
dried (Na2SO4). Evaporation and subsequent silica gel column
chromatography (EtOAc : hexane = 1 : 5) gave pivaloyl ester
13 (1.77 g, 2.42 mmol, 69%) as a colorless oil, [a]2D0 = +58 (c
0.57, CHCl3); mmax(CHCl3)/cm−1 3629, 2975, 1723, 1626, 1254,
1157, 1042, 930; dH(CDCl3) 0.97–1.02 (21H, m, iso-Pr), 1.21
(9H, s, Piv), 1.24 (9H, s, Piv), 2.12 (1H, m, 2-H), 2.46 (1H,
m, 3-H), 2.77 (1H, d, J 4.4 Hz, OH), 3.76 (3H, s, OCH3),
3.87 (3H, s, OCH3), 4.17 (1H, dd, J 11.2, 8.3 Hz, PivOCHH),
4.24 (1H, dd, J 11.2, 3.4 Hz, PivOCHH), 4.38–4.43 (2H, m,
PivOCH2), 4.80 (1H, dd, J 4.4, 3.5 Hz, 1-H), 4.99 (1H, d, J
4.4 Hz, ArCHOTIPS), 5.91 (1H, d, J 8.8 Hz, OCHHO), 5.92
(1H, d, J 8.8 Hz, OCHHO), 6.40 (1H, s, ArH), 6.52 (1H, s, ArH),
6.58–6.65 (3H, m, ArH), 6.80 (1H, d, J 8.3 Hz, ArH); dC(CDCl3)
12.7, 18.1, 27.2, 27.3, 38.75, 38.81, 41.7, 43.8, 55.4, 55.7, 63.3,
63.4, 73.0, 74.8, 101.0, 106.1, 107.6, 109.0, 110.3, 118.5, 118.7,
135.6, 136.6, 146.4, 147.5, 148.0, 148.5, 178.3, 178.7 (Found: C,
65.96; H, 8.58. C40H62O10Si requires C, 65.72; H, 8.55%). (−)-13:
[a]2D0 = −58 (c 1.4, CHCl3).
Conversion of (1S,2R,3R)-2,3-bis[(tert-butyldiphenylsilyloxy)-
methyl]-1-(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxybenzoyl)-
1-(triethylsilyloxy)propane 16 to hemiacetal 17
(2S,3S)-2-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsilyloxy)-
methyl]-3-(3,4-methylenedioxybenzoyl)tetramethylene
dipivaloate 14
To an ice-cooled solution of alcohol 8 (21.8 g, 0.051 mol) and
2,6-lutidine (11.8 ml, 0.10 mol) in CH2Cl2 (200 ml) was added
TESOTf (17.1 ml, 0.076 mol). The reaction solution was stirred
in ice bath for 1 h before addition of sat. aq. NaHCO3 solution.
The organic solution was separated, washed with brine, and
dried (Na2SO4). The organic solution was evaporated, and then
the residue was applied to silica gel column chromatography
(EtAOc : hexane = 1 : 3) to give oxazolidinone-TES ether (24.7 g,
0.046 mol, 90%) as a colorless oil. To an ice-cooled solution of
LiBH4 (4.00 g, 0.18 mol) in THF (200 ml) containing MeOH
(3.79 ml) was added a solution of the oxazolidinone-TES ether
(24.7 ml, 0.046 mol) in THF (50 ml). After the reaction solution
was stirred at room temperature for 12 h, sat. aq. NH4Cl solution
was added. The mixture was concentrated, and then the residue
was dissolved in EtOAc and H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4). After the
solution was evaporated, the residue was purified with silica gel
column chromatography (EtOAc : hexane = 1 : 4) to give olefin-
alcohol (6.52 g, 0.019 mol, 41%) as a colorless oil. A reaction
solution of the olefin-alcohol (6.52 g, 0.019 mol), NMO (2.77 g,
0.024 mol), and 2% OsO4 (3.5 ml) in acetone (140 ml), tert-
BuOH (35 ml), and H2O (35 ml) was stirred at room temperature
for 20 h before addition of Na2S2O3. After the mixture was
A reaction mixture of benzyl alcohol 13 (0.51 g, 0.70 mmol),
˚
PCC (0.19 g, 0.88 mmol), and MS 4 A (0.2 g) in CH2Cl2 (20 ml)
was stirred at room temperature for 16 h before addition of dry
ether. After concentration of the filtrate, the residue was applied
to silica gel column chromatography (5% EtOAc in toluene) to
give ketone 14 (0.48 g, 0.66 mmol, 94%) as a colorless oil, [a]D20
=
+14 (c 0.80, CHCl3); mmax(CHCl3)/cm−1 3021, 1725, 1676, 1516,
1443, 1256, 1157, 1042; dH(CDCl3) 0.99–1.04 (21H, m, iso-Pr),
1.19 (18H, s, Piv), 2.52 (1H, m, 3-H), 3.79 (3H, s, OCH3), 3.87
(3H, s, OCH3), 3.97 (1H, dd, J 11.7, 4.9 Hz, CHHOPiv), 4.13
(1H, dd, J 11.7, 4.4 Hz, CHHOPiv), 4.13–4.18 (1H, m, 2-H),
4.45 (1H, dd, J 10.7, 9.8 Hz, CHHOPiv), 4.53 (1H, dd, J 10.7,
3.4 Hz, CHHOPiv), 4.95 (1H, d, J 6.4 Hz, 4-H), 6.05 (2H, s,
OCH2O), 6.66 (1H, dd, J 8.3, 2.0 Hz, ArH), 6.75 (1H, d, J 8.3 Hz,
ArH), 6.80 (1H, d, J 8.3 Hz, ArH), 6.87 (1H, d, J 2.0 Hz, ArH),
7.36 (1H, d, J 1.5 Hz, ArH), 7.46 (1H, dd, J 8.3, 1.5 Hz, ArH);
dC(CDCl3) 12.5, 18.0, 18.1, 27.0, 27.1, 38.5, 38.7, 43.7, 46.7, 55.7,
55.9, 61.5, 62.8, 73.7, 101.9, 107.8, 108.4, 109.8, 110.6, 119.1,
124.9, 131.2, 134.8, 148.3, 148.7, 148.9, 151.9, 177.8, 178.0, 197.6
(Found: C, 65.65; H, 8.30. C40H60O10Si requires C, 65.90; H,
8.30%). (−)-14: [a]2D0 = −14 (c 0.82, CHCl3).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5
1 6 7 3

View Article Online
concentrated, the residue was dissolved in EtOAc and H2O. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Evaporation gave crude glycol. A reaction mixture of
the crude glycol and NaIO4 (4.95 g, 0.023 mol) in MeOH (100 ml)
was stirred at room temperature for 2 h before concentration.
The residue was dissolved in EtOAc and H2O. The organic
solution was separated, washed with brine and dried (Na2SO4).
Concentration gave crude hemiacetal. A reaction mixture of
(2R,3S,4S,5S)-2-(3,4-Dimethoxyphenyl)-3,4-bis(hydroxymethyl)-
5-(3,4-methylenedioxyphenyl)tetrahydrofuran 19
A reaction solution of pivaloyl ester 18 (0.29 g, 0.52 mmol) in
EtOH (6 ml) and 1 M aq. NaOH solution (4 ml) was stirred
at room temperature for 20 h before additions of CHCl3 and
H2O. The organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration and subsequent silica gel
column chromatography (EtOAc : hexane = 6 : 1) gave diol
19 (0.17 g, 0.44 mmol, 85%) as a colorless oil, [a]2D0 = −31 (c
0.85, CHCl3); mmax(CHCl3)/cm−1 3500, 3000, 1515, 1258, 1031;
dH(CDCl3) 2.22 (1H, m, 3-H), 2.54 (1H, m, 4-H), 3.11 (1H, dd,
J 10.3, 10.3 Hz, 4-CHHOH), 3.31 (1H, dd, J 10.3, 4.6 Hz, 4-
CHHOH), 3.55 (1H, dd, J 10.3, 8.8 Hz, 3-CHHOH), 3.71 (1H,
dd, J 10.3, 3.9 Hz, 3-CHHOH), 3.88 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 4.46 (1H, d, J 9.8 Hz, 2-H), 5.08 (1H, d, J 8.8 Hz, 5-H),
5.95 (2H, s, OCH2O), 6.76–6.82 (2H, m, ArH), 6.86–6.88 (2H,
m, ArH), 6.88–7.01 (2H, m, ArH); dC(CDCl3) 50.9, 55.1, 55.9,
62.8, 63.6, 81.2, 82.5, 101.0, 107.0, 108.0, 110.0, 111.1, 119.1,
119.8, 132.3, 132.8, 147.0, 147.6, 149.0, 149.1; m/z (EI) 388 (M+,
74%), 222 (37), 207 (72), 189 (92), 174 (100), 149 (41), 135 (55),
115 (31) [Found (HRMS): M+, 388.1521. C21H24O7 requires M+,
388.1522]. (+)-19: [a]2D0 = +31 (c 0.38, CHCl3).
˚
the crude hemiacetal, PCC (4.15 g, 0.019 mol), and MS 4 A
(0.3 g) in CH2Cl2 (80 ml) was stirred at room temperature for
16 h before addition of dry ether. After filtration, the filtrate
was concentrated. The residue was applied to silica gel column
chromatography (EtOAc : hexane = 1 : 3) to give lactone (3.77 g,
0.010 mol, 53%, 3 steps) as a colorless oil. To a solution of
KHMDS (24.7 ml, 0.5 M toluene solution, 0.012 mol) was added
a solution of the lactone (3.77 g, 10.0 mmol) in THF (25 ml) at
−70 ◦C. After 15 min, a solution of piperonal (1.72 g, 0.011 mol)
in THF (10 ml) was added. The reaction solution was stirred at
−70 ◦C for 1 h before addition of sat. aq. NH4Cl solution.
The organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration, the residue was applied to
silica gel column chromatography (EtOAc : hexane = 1 : 3) to
give aldol product (4.69 g, 9.08 mmol, a mixture of erythro :
threo = 9 : 1) as a colorless oil. To a solution of LiBH4
(1.54 g, 70.7 mmol) in THF (50 ml) was added a solution
of the aldol product (4.69 g, 9.08 mmol) in THF (20 ml) at
below 0 ◦C. The resulting reaction solution was stirred at 0 ◦C
for 16 h before addition of sat. aq. NH4Cl solution. After
concentration, the residue was dissolved in EtOAc and H2O. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration gave crude triol. A reaction solution
of the resulting crude triol, Et3N (3.01 ml, 21.6 mmol), DMAP
(94 mg, 0.77 mmol), and TBDPSCl (4.64 ml, 17.8 mmol) in
CH2Cl2 (10 ml) was stirred at room temperature for 4 h before
additions of sat. aq. NaHCO3 solution and CH2Cl2. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Evaporation and silica gel column chromatography (5% EtOAc
in hexane) gave diTBDPSoxy-benzyl alcohol (7.02 g, 7.03 mmol,
77%, 2 steps) as a colorless oil. A reaction mixture of the benzyl
alcohol (2.03 g, 2.03 mmol), PCC (0.48 g, 2.23 mmol), and MS
(2R,3S,4S,5S)-2-(3,4-Dimethoxyphenyl)-3,4-bis-
(methoxymethyl)-5-(3,4-methylenedioxyphenyl)tetrahydrofuran
((−)-virgatusin (1))
To an ice-cooled suspension of NaH (29 mg, 60% oil suspension,
0.73 mmol) in THF (5 ml) was added a solution of diol 19 (0.13 g,
0.33 mmol) in THF (10 ml). After the resulting solution was
stirred at 0 ◦C for 30 min, MeI (1.00 ml, 16.1 mmol) was added,
and then the reaction solution was stirred at room temperature
for 5 h before addition of sat. aq. HN4Cl solution and EtOAc.
The organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration, the residue was applied
to silica gel column chromatography (EtOAc : hexane = 2 :
1) to give (−)-virgatusin ((−)-1) (0.12 g, 0.29 mmol, 88%) as a
colorless oil, [a]2D0 = −19 (c 0.48, CH2Cl2), more than 99% ee
(HPLC, DAICEL chiral column OD-H, detected at 280 nm,
1 ml min−1, 10% iso-PrOH in hexane, tR 14 min), Lit.1: [a]2D0
−12.7 (c 0.5, CH2Cl2). The spectral data agreed with those of
the natural product. (+)-virgatusin: [a]2D0 = +19 (c 0.32, CH2Cl2),
more than 99% ee (tR 16 min).
=
˚
4 A (0.2 g) in CH2Cl2 (40 ml) was stirred at room temperature for
48 h at 0 ◦C. After filtration, the filtrate was concentrated. The
residue was applied to silica gel column chromatography (1%
EtOAc in toluene) to give ketone 16 (0.40 g, 0.40 mmol, 20%) as
a colorless oil, [a]D20 = +44 (c 1.2, CHCl3); dH(CDCl3) 0.36 (6H,
q, J 8.3 Hz, SiCH2CH3), 0.78 (9H, t, J 8.3 Hz, SiCH2CH3),
0.85 (9H, s, tert-Bu), 0.96 (9H, s, tert-Bu), 2.15 (1H, m, 2-H),
3.48 (1H, dd, J 10.8, 4.2 Hz, CHHOTBDPS), 3.62 (1H, dd, J
10.8, 6.6 Hz, CHHOTBDPS), 3.67 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 4.05–4.13 (3H, m, CHHOTBDPS, 2-H), 4.18 (1H, dd,
J = 9.6, 9.6 Hz, CHHOTBDPS), 5.01 (1H, d, J 5.4 Hz, 1-H),
6.01 (2H, s, OCH2O), 6.53 (1H, d, J 6.8 Hz, ArH), 6.61 (1H,
d, J 7.8 Hz, ArH), 6.69–6.71 (2H, m, ArH), 7.20–7.40 (15H,
m, ArH), 7.41–7.49 (3H, m, ArH), 7.55–7.57 (3H, m, ArH),
7.72 (1H, d, J 8.8 Hz, ArH); dC(CDCl3) 19.0, 19.1, 26.6, 26.9,
46.3, 50.3, 55.6, 55.8, 60.9, 62.9, 73.3, 101.5, 107.4, 108.7, 109.6,
110.5, 118.9, 124.7, 127.5, 129.3, 129.4, 129.5, 132.5, 133.3,
133.47, 133.55, 133.9, 135.5, 135.6, 135.7, 136.3, 147.7, 148.0,
148.6, 151.0, 199.3 3 (Found: C, 71.08; H, 7.41. C59H74O8Si3
requires C, 71.19; H, 7.49%). A reaction solution of TES ether
16 (90 mg, 0.090 mmol) in MeCN (5 ml) containing 2% HF
(1 ml) was stirred at room temperature for 24 h before additions
of H2O and EtOAc. The organic solution was separated, washed
with sat. aq. NaHCO3 solution and brine, and dried (Na2SO4).
After concentration, the residue was applied to silica gel column
chromatography (EtOAc : hexane = 1 : 6) to give unstable
hemiacetal 17 (45 mg, 0.051 mmol, 57%) as a colorless oil.
Hemiacetal 17 gave complicated spectrum data. The ratio of
7ꢀR : 7ꢀS was determined by 5.30 (0.5H, d, J 9.3 Hz, 7-H) and
5.56 (0.5H, d, J 4.4 Hz, 7-H).
Acknowledgements
We measured the 400 MHz NMR and MS data at INCS,
Ehime University. We are grateful to Marutomo Co. for financial
support.
References
1 Y.-L. Huang, C.-C. Chen, F.-L. Hsu and C.-F. Chen, J. Nat Prod.,
1996, 59, 520–521.
2 S. P. Thyagarajan, S. Subramanian, T. Thirunalasundari, P. S.
Venkateswaran and B. S. Blumberg, Lancet, 1988, 1, 764–766.
3 W. D. MacRae and G. H. N. Towers, Phytochemistry, 1984, 23, 1207–
1220.
4 D. C. Ayres and J. D. Loike, Lignans, Cambridge University Press,
1990.
5 R. S. Ward, Nat. Prod. Rep., 1999, 16, 75–96.
6 A. Hernandez, C. Pascual and S. Valverde, Phytochemistry, 1981, 20,
181–182.
7 M. Scho¨ttner, J. Reiner and F. S. K. Tayman, Phytochemistry, 1997,
46, 1107–1109.
8 Y.-C. Shen, C.-Y. Chen, Y.-M. Lin and Y.-H. Kuo, Phytochemistry,
1997, 46, 1111–1113.
9 C.-C. Chang, Y.-C. Lien, K. C. S. C. Liu and S.-S. Lee, Phytochem-
istry, 2003, 63, 825–833.
10 J. Ralph, J. Peng, F. Lu, R. D. Hatfield and R. F. Helm, J. Agric. Food
Chem., 1999, 47, 2991–2996.
11 R. Ahmed, F. G. Schreiber, R. Stevenson, J. R. Williams and H. M.
Yeo, Tetrahedron, 1976, 32, 1339–1344.
12 R. Stevenson and J. R. Williams, Tetrahedron, 1977, 33, 285–288.
1 6 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5

View Article Online
13 T. Biftu, B. G. Hazra and R. Stevenson, J. Chem. Soc., Perkin Trans.
1, 1978, 1147–1150.
14 K. V. Rao and F. M. Alvarez, J. Nat. Prod., 1985, 48, 592–597.
15 H. Yoda, M. Mizutani and K. Takabe, Tetrahedron Lett., 1999, 40,
4701–4702.
17 J. R. Gage, D. A. Evans, Org. Synth., Coll. Vol. 8, 339, 1993.
18 S. Yamauchi, M. Machi and Y. Kinoshita, Biosci. Biotechnol.
Biochem., 1999, 63, 1453–1462.
19 S. Yamauchi, T. Ina, T. Kirikihira and T. Masuda, Biosci. Biotechnol.
Biochem., 2004, 68, 183–192.
20 S. Yamauchi, Y. Hayashi, T. Kirikihira and T. Masuda, Biosci.
Biotechnol. Biochem., 2005, 69, 113–122.
16 J.-C. Galland, S. Dias, M. Savignac and J.-P. Geneˆet, Tetrahedron,
2001, 57, 5137–5148.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 6 7 0 – 1 6 7 5
1 6 7 5