Stereoselective construction of tetra-substituted tetrahydrofuran compounds from benzylic hemiacetal in the presence 0of H2 and a Pd catalyst: Stereoselective synthesis of a stereoisomer of (-)-virgatusin and its antimicrobiological activity

Article abstract of DOI:10.1271/bbb.70554

Tetra-substituted tetrahydrofuran compounds were stereoselectively prepared from benzylic hemiacetal in the neutral condition by employing the simple reagent, H₂, and a Pd catalyst. The stereoselective conversion of benzylic hemiacetal to two different stereoisomers of the tetrasubstituted tetrahydrofuran compound was observed. One of these tetrahydrofuran compounds was converted to the virgatusin stereoisomer to estimate its antimicrobiological activity.

Full text of DOI:10.1271/bbb.70554

Biosci. Biotechnol. Biochem., 72 (1), 197–203, 2008
Stereoselective Construction of Tetra-Substituted Tetrahydrofuran Compounds
from Benzylic Hemiacetal in the Presence of H2 and a Pd Catalyst:
Stereoselective Synthesis of a Stereoisomer of (À)-Virgatusin
and Its Antimicrobiological Activity
Tomofumi NAKATO,1 Ryosuke TAGO,1 Koichi AKIYAMA,2 Masafumi MARUYAMA,1
y
1;
Takuya SUGAHARA,1 Taro KISHIDA,1 and Satoshi YAMAUCHI
1Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
2Integrated Center for Sciences, Tarumi Station, Ehime University,
3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received August 29, 2007; Accepted September 22, 2007; Online Publication, January 7, 2008
[doi:10.1271/bbb.70554]
Tetra-substituted tetrahydrofuran compounds were
stereoselectively prepared from benzylic hemiacetal in
the neutral condition by employing the simple reagent,
H2, and a Pd catalyst. The stereoselective conversion of
benzylic hemiacetal to two different stereoisomers of the
tetrasubstituted tetrahydrofuran compound was ob-
served. One of these tetrahydrofuran compounds was
converted to the virgatusin stereoisomer to estimate its
antimicrobiological activity.
(Scheme 1). Resulting tetrahydrofuran compound 3 or 4
contained two benzylic chiral centers on a benzyl ether.
It could be assumed that the neutral condition was better
for the reduction of hemiacetal 2 to avoid epimerization
of the benzylic chiral center. This article describes the
stereoselective reduction of benzylic hemiacetal under
the neutral condition using H2 and a Pd catalyst, giving a
tetra-substituted tetrahydrofuran derivative.
Results and Discussion
Key words: virgatusin; tetrahydrofuran lignan; antimi-
crobiological activity
The preparation of ketone 9 is shown in Scheme 2.
Lactone 5 was prepared from (1S,2R)-2-allyl-1-(3,4-
methylenedioxyphenyl)-1,3-propanediol9) by tritylation
of the primary hydroxy group, oxidative cleavage of the
olefin, and oxidation to the lactone. Lactone 5 was
subjected to the aldol reaction with 3,4-dimethoxyben-
zaldehyde to give the corresponding aldol product
(erythro/threo = 4/1). Pure erythro-form 6 was ob-
tained by protection of the resulting benzyl alcohol as a
TIPS ether. This lactone 6 was treated with LiBH4 to
give the corresponding diol, which was converted to a
diacetate, before detritylation was performed under a
formic acid-ether system to give 7. Detritylation without
acetylation was accompanied by desilylation. Deacety-
lation followed by protection of the primary hydroxy
groups as pivaloates gave 8, before oxidation of benzyl
alcohol 8 gave ketone 9.
After desilylation of ketone 9, resulting unstable
benzylic hemiacetal 10 was treated with H2 and a Pd
catalyst (Table 1). In entry 1, hemiacetal 10 was reacted
with H2 and Pd(OH)2 in EtOAc. Unexpectedly, this
reaction predominantly gave 11,10) which was a 2,5-cis,
3,4-trans-tetra-substituted tetrahydrofuran compound.
Two reaction mechanisms could be assumed, one being
The tetrahydrofuran structure is widely distributed
and is a synthetic target for organic chemists. The
reduction of hemiacetal has been employed to obtain
tetrahydrofuran compounds. Although stereoselectivity
is required in synthetic studies of natural products, the
stereocontrolled synthesis of a tetra-substituted tetrahy-
drofuran compound is difficult because of the existence
of four chiral centers. In previous studies, stereocon-
trolled reduction of the benzylic hemiacetal to a
substituted tetrahydrofuran compound using Lewis
acid1–7) and hydride8) has been reported. However, there
is a possibility of epimerization of the benzylic stereo-
center of benzyl ether under the Lewis acid condition
because of the occurrence of the benzyl cation. In some
cases, neutral conditions for the reduction of benzylic
hemiacetal would be important to obtain a tetrahydro-
furan compound bearing the desired stereochemistry. In
this present study, stereoselective reduction of benzylic
hemiacetal using the simple reagent, H2 gas, and a Pd
catalyst was tried. To achieve this objective, silyloxy
ketone 1 was prepared, and then unstable benzylic
hemiacetal 2 converted from 1 was used for this study
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

198
T. NAKATO et al.
OH
OTIPS
O
O
H
Ar1
RO
Ar2
OR
Ar1
RO
Ar2
OR
O
O
Ar1
Ar2
Ar1
RO
H2, Pd cat.
Ar2
or
OR
RO
OR
1
2
3
4
Scheme 1. Reduction of the Benzylic Hemiacetal.
OH
O
O
O
Ar1
O
Ar1
b
a
c
HO
Ar1
H
OTr
H
Ar2
OTr
OTIPS
5
6
H
O
R2O
H
R3O
H
PivO
Ar2
Ar1
Ar1
e
H
H
H
H
Ar2
OR1
OPiv
OTIPS
OTIPS
9
7: R1 = H, R2 = Ac, R3 = Ac
8: R1 = Piv, R2 = Piv, R3 = H
d
Scheme 2. Preparation of Ketone 9.
(a) (1) TrCl, 4-DMAP, pyridine, r.t., 1 h (92% yield); (2) OsO4, NMO, aq. acetone, tert-BuOH, r.t., 13 h; (3) NaIO4, MeOH, r.t., 2 h (85%, 2
steps); (4) PCC, CH2Cl2, MS 4A, r.t., 13 h (90% yield); (b) (1) KHMDS, 3,4-dimethoxybenzaldehyde, THF, ꢀ70 ꢁC, 1 h (68% yield, mixture of
erythro/threo = 4/1); (2) TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 2 h (46% yield, 2 steps); (c) (1) LiBH4, THF, 60 ꢁC, 14 h; (2) Ac2O, pyridine,
DMAP, r.t., 13 h; (3) HCO2H, Et2O, 0 ꢁC 1 h (53% yield, 3 steps); (d) (1) K2CO3, MeOH, r.t., 12 h; (2) PivCl, pyridine, r.t., 11 h (85%, 2 steps);
(e) PCC, MS 4A, CH2Cl2, r.t., 16 h (83% yield). Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl.
Table 1. Reaction of Benzylic Hemiacetal 10 with H2 and a Pd Catalyst
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
OH
OTIPS
O
O
2
3
H
5
Ar2
Ar1
Ar2
Ar1
O
2
3
5
O
Ar2
Ar1
Ar2
Ar1
H2
n-Bu4NF, AcOH
4
4
condition
THF
PivO
OPiv
PivO
OPiv
PivO
OPiv
PivO
OPiv
9
10
11
12
Entry
Catalyst
Solvent
Time (min)
11 (%)
12 (%)
1
2
3
4
5
6
7
8
9
Pd(OH)2/C
Pd/C
EtOAc
THF
THF
5
30
60
5
44
0
0
0
Pd(OH)2/C
Pd
0
0
EtOAc
3
26
17
16
28
25
53
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
EtOAc, AcOH (4 eq)
EtOAc, AcOH (23 eq)
EtOH
10
10
15
15
4
20
39
0
EtOAc-EtOH (1:1)
EtOAc-EtOH (1:1)
0
0
production of a dihydrofuran, and the other being
epimerization at the 4 position. It could be assumed
that the dihydrofuran had been formed from hemiacetal
10 by dehydration, and then hydrogenation occurred
from the opposite side of the aryl group at the 2 position
(Ar2).11) To ascertain the validity of this reaction

Stereoisomer of (ꢀ)-Virgatusin
199
O
O
O
Ar2
Ar1
Ar2
Ar1
Ar2
Ar1
a
b
H3CO
OCH3
PivO
OPiv
HO
OH
12
(+)-13
(+)-14
Scheme 3. Synthesis of Virgatusin Stereoisomer (+)-14.
(a) aq. NaOH, EtOH, r.t., 5 h (63% yield); (b) NaH, MeI, r.t., 5 h (66% yield). Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
Table 2. Antibacterial Activity [MIC values (mM)] of (+)- and (ꢀ)-13, (+)- and (ꢀ)-15, and (+)-17
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
O
O
O
Ar2
Ar1
Ar2
Ar1
Ar2
Ar1
HO
OH
HO
OH
HO
OH
(+)-15
(-)-15
(+)-17
(+)-13
(ꢀ)-13
>50
25
(+)-15
(ꢀ)-15
>50
12.5
>50
(+)-17
Bacillus subtilis NBRC 13719T
Listeria denitrificans JCM 11481
Staphylococcus aureus subsp. aureus NBRC 14462
>50
>50
>50
>50
50
12.5
>50
>50
>50
>50
mechanism, hemiacetal 10 was treated with Pd(OH)2/C
in EtOAc under N2 gas; however, the hemiacetal was
recovered and no products were yielded. The unstable
dihydrofuran, which was easily transformed to a high
polar compound, was prepared from hemiacetal 10 by
treating with mesyl chloride and Et3N. The reaction of
this dihydrofuran with H2 and Pd(OH)2 in EtOAc did
not give 11. The reaction mechanism giving 11 could
consequently not be determined.
Compound 12 was converted to virgatusin stereo-
isomer (+)-14 by hydrolysis followed by methylation
(Scheme 3). Enantiomer (ꢀ)-14 was also synthesized
from (1R,2S)-2-allyl-1-(3,4-methylenedioxyphenyl)-1,3-
propanediol by the same synthetic method as that just
described. The optical purity was determined as being
more than 99% ee. Stereoisomer 11 has been reported as
an important synthetic intermediate to (ꢀ)-virgatusin.10)
The highly stereoselective syntheses of the two tetra-
substituted tetrahydrofuran compounds were achieved
by using the simple reagent, H2, and a Pd catalyst in a
suitable solvent.
The antimicrobiological activity of synthesized (+)-
and (ꢀ)-13 and of (+)- and (ꢀ)-14 was examined with
previously synthesized (+)- and (ꢀ)-15 and (+)- and
(ꢀ)-16.12) The antibacterial activity of (+)-17 against
Bacillus subtilis has been reported in our previous study
(MIC of 12.5 mM).13) Compounds (ꢀ)-13, (+)-15 and
(ꢀ)-15 showed antibacterial activity against Listeria
denitrificans instead of Bacillus subtilis, the activity of
(ꢀ)-15 being strongest (Table 2). The activity of (ꢀ)-16
against Colletotrichum lagenarium was observed in the
antifungal test (growth %: 80:9 ꢂ 3:06), although the
activity was weaker than that of natural (ꢀ)-virgatusin
(18; growth %: 49:4 ꢂ 3:92)14) (Table 3).
The reaction conditions were examined to obtain the
other stereoisomer. Although the reaction conditions of
H2, Pd/C-THF and H2, and Pd(OH)2/C-THF did not
yield any product (entries 2 and 3), employing Pd-black
in EtOAc under H2 gas gave different stereoisomer 12
together with 11 (11/12 = 1/9, entry 4). In this case,
2,5-trans, 3,4-cis form 12 was favored. For the next step,
a reaction under acidic conditions was examined. In
entries 5 and 6, the selectivity between 11 and 12 was
decreased. Complete selectivity for stereoisomer 12 was
achieved by employing Pd(OH)2 in ethanol as a protic
solvent under H2 gas (entry 7). The application of the
EtOAc-EtOH solvent also gave only 12 as a single
isomer (entry 8), and the yield was increased by a
shorter reaction time (entry 9). The stereochemistry of
12 was confirmed by a differential NOE experiment.
Upon irradiation at 5-H, NOEs were observed at 3-H
and 4-H. Hemiacetal 10 did not give any product by
treatment with Pd(OH)2/C and N2 in EtOAc and EtOH.
The unstable dihydrofuran prepared from hemiacetal 10
could not be converted to a tetrahydrofuran compound
by a reaction with Pd(OH)2/C and H2 in EtOAc-EtOH.
The reaction mechanism could not be determined in this
experiment.
Experimental
Optical rotation values were measured with a Horiba
SEPA-200 instrument. NMR data were obtained with a
JNM-EX400 spectrometer, and EIMS data were meas-
ured with a JMS-MS700V spectrometer. The silica gel
used was Wakogel C-300 (Wako, 200-300 mesh). HPLC

200
T. NAKATO et al.
Table 3. Antifugal Activity (growth % against control) of (+)- and (ꢀ)-14, (+)- and (ꢀ)-16, and (ꢀ)-Virgatusin (18) against C. lagenarium
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
O
O
O
Ar2
Ar1
Ar2
Ar1
Ar2
Ar1
H3CO
OCH3 H3CO
OCH3 H3CO
OCH3
(-)-virgatusin (18)
(+)-16
(-)-16
(+)-14
>1 mM
(ꢀ)-14
>1 mM
(+)-16
>1 mM
(ꢀ)-16
0.25 mM
(ꢀ)-Virgatusin (18)
0.25 mM
80:9 ꢂ 3:06 (growth %)
49:4 ꢂ 3:92 (growth %)
analyses were performed with Shimadzu LC-6AD and
SPD-6AV instruments. The numbering of compounds
follows IUPAC nomenclatural rules.
ture of this hemiacetal (7.01 g, 14.6 mmol) and PCC
(4.03 g, 18.7 mmol) in CH2Cl2 (20 ml) containing MS
4A (0.3 g) was stirred at room temperature for 13 h
before addition of dry ether. After filtration, the resulting
filtrate was concentrated. The residue was applied to
silica gel column chromatography (EtOAc-hexane =
(3R,4S)-4-(3,4-Methylenedioxyphenyl)-3-trityloxymeth-
yl-4-butanolide (5). A reaction solution of (1S,2R)-
2-allyl-1-(3,4-methylenedioxyphenyl)-1,3-propanediol9)
(4.40 g, 18.6 mmol), trityl chloride (5.19 g, 18.6 mmol),
and 4-DMAP (0.10 g) in pyridine (25 ml) was stirred at
room temperature for 1 h before additions of H2O and
EtOAc. The organic solution was separated, washed
with sat. aq. CuSO4 solution, sat. aq. NaHCO3 solution,
and brine, and dried (Na2SO4). After evaporation, the
organic residue was applied to silica gel column
chromatography (EtOAc-hexane = 93:7) to give trityl
1:9) to give lactone 5 (6.33 g, 13.2 mmol, 90%) as a
20
colorless oil, ½ꢀꢃ
¼ þ0:9 (c 2.0, CHCl3); ꢁH(CDCl3)
D
2.56 (1H, m, 3-H), 2.61–2.73 (2H, m, 2-H2), 3.22 (1H,
dd, J 9.8, 3.9 Hz, TrOCHH), 3.27 (1H, dd, J 9.8, 5.4 Hz,
TrOCHH), 5.24 (1H, d, J 7.3 Hz, 4-H), 5.94 (2H, s,
OCH2O), 6.60 (1H, dd, J 7.8, 2.0 Hz, ArH), 6.68 (1H, d,
J 2.0 Hz, ArH), 6.71 (1H, d, J 7.8 Hz, ArH), 7.22–7.31
(9H, m, ArH), 7.37–7.39 (6H, m, ArH); ꢁC(CDCl3) 31.8,
44.7, 61.8, 83.5, 86.9, 101.2, 106.3, 108.2, 119.7, 127.2,
127.9, 128.5, 132.4, 143.4, 147.8, 148.1, 175.8. Anal.
ether (7.20 g, 17.2 mmol, 92%) as a colorless oil,
20
½ꢀꢃ
¼ ꢀ3:1 (c 2.8, CHCl3); ꢁH(CDCl3) 1.98 (1H,
Found: C, 77.51; H, 5.71. Calcd. for C31H26O5: C,
20
D
m, CH2=CHCH2CH), 2.13–2.17 (2H, m, CH2=
CHCH2), 3.10 (1H, s, OH), 3.19 (2H, d, J 4.9 Hz,
CH2OTr), 4.82–4.90 (3H, m, ArCH(OH), CH2=CH),
5.58 (1H, m, CH=CH2), 5.88 (2H, s, OCH2O), 6.67
(2H, s, ArH), 6.75 (1H, s, ArH), 7.20–7.30 (9H, m,
ArH), 7.40–7.42 (6H, m, ArH); ꢁC(CDCl3) 30.4, 45.7,
63.9, 75.5, 87.3, 100.8, 106.9, 107.7, 116.3, 119.5,
127.0, 127.8, 128.6, 136.6, 136.9, 143.7, 146.4, 147.4.
77.81; H, 5.48%. (3S,4R)-5: ½ꢀꢃ
¼ ꢀ1:0 (c 1.1,
D
CHCl3).
(2R,3R,4S)-2-[(R)-(3,4-Dimethoxyphenyl)(triisoprop-
ylsilyloxy)methyl]-4-(3,4-methylenedioxyphenyl)-3-trityl-
oxymethyl-4-butanolide (6). To a solution of KHMDS
(18.0 ml, 0.5 M toluene solution, 9.00 mmol) in THF
(20 ml) was added a solution of lactone 5 (3.33 g, 6.96
mmol) in THF (10 ml) at ꢀ70 ꢁC. After stirring at
ꢀ70 ꢁC for 15 min, 3,4-dimethoxybenzaldehyde (1.35 g,
8.12 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
a diastereomeric mixture of aldol product (erythro/
threo = 4/1, 3.04 g, 4.72 mmol, 68%) as a colorless oil.
To an ice-cooled solution of this diastereomeric mixture
of aldol product (3.04 g, 4.72 mmol), 2,6-lutidine (1.37
ml, 11.8 mmol) in CH2Cl2 (20 ml) was added TIPSOTf
(1.58 ml, 5.88 ml). After the reaction solution was stirred
at room temperature for 2 h, sat. aq. NaHCO3 solution
was added. The organic solution was separated, washed
with sat. aq. CuSO4 solution, sat. aq. NaHCO3 solution,
and brine, and dried (Na2SO4). After concentration, the
residue was applied to silica gel column chromatography
Anal. Found: C, 79.93; H, 6.42. Calcd. for C32H30O4: C,
20
80.31; H, 6.32%. (+)-Trityl ether: ½ꢀꢃ
¼ þ3:0 (c 1.1,
D
CHCl3) A reaction solution of trityloxy olefin (7.20 g,
17.2 mmol), 4-methylmorpholine N-oxide (2.40 g, 20.5
mmol), and OsO4 (aq. 2% solution, 1.5 ml) in acetone
(140 ml), tert-BuOH (35 ml), and H2O (35 ml) was
stirred at room temperature for 13 h before addition of
sat. aq. Na2S2O3 solution. After the mixture was con-
centrated, 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 (4.32 g,
20.2 mmol) in MeOH (70 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).
Evaporation and subsequent silica gel column chroma-
tography (EtOAc-hexane = 1:4) gave hemiacetal (7.01
g, 14.6 mmol, 85%) as a colorless oil. A reaction mix-

Stereoisomer of (ꢀ)-Virgatusin
201
(1% EtOAc in toluene) to give pure erythro product 6
(2.54 g, 3.17 mmol, 46%, 2 steps) as a colorless oil,
135.5, 147.3, 147.8, 148.7, 149.0, 169.3, 170.9. Anal.
Found: C, 63.74; H, 7.96. Calcd. for C34H50O10Si: C,
20
20
½ꢀꢃ
¼ þ64 (c 1.8, CHCl3); ꢁH(CDCl3) 1.01–1.06
68.13; H, 7.79%. (ꢀ)-7: ½ꢀꢃ
¼ þ3:8 (c 1.3, CHCl3).
D
D
(18H, m, CH(CH3)2), 1.08–1.17 (3H, m, CH(CH3)2,
2.80 (1H, dd, J 9.8, 4.9 Hz, CHHOTr), 2.86 (1H, dd, J
9.8, 2.4 Hz, CHHOTr), 3.03 (1H, m, 3-H), 3.26 (1H, dd,
J 9.8, 2.0 Hz, 2-H), 3.77 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 4.90 (1H, d, J 8.8 Hz, 4-H) 5.67 (1H, d, J 2.0 Hz,
ArCHOTIPS), 5.93 (2H, s, OCH2O), 6.30 (1H, dd, J 8.3,
2.0 Hz, ArH), 6.57 (1H, d, J 2.0 Hz, ArH), 6.63 (1H, d, J
7.8 Hz, ArH), 6.67 (1H, d, J 8.3 Hz, ArH), 6.89–6.91
(2H, m, ArH), 7.10–7.15 (6H, m, ArH), 7.19–7.22 (9H,
m, ArH); ꢁC(CDCl3) 12.6, 18.0, 18.1, 43.1, 51.4, 55.6,
55.8, 59.9, 72.6, 82.0, 86.5, 101.1, 107.1, 107.7, 108.4,
110.8, 117.7, 120.8, 127.0, 127.7, 128.5, 132.9, 135.2,
143.3, 147.7, 147.9, 148.2, 148.8, 176.6. Anal. Found:
(2R,3S)-3-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsi-
lyloxy)methyl]-2-[(S)-(hydroxy)(3,4-methylenedioxyphen-
yl)methyl]tetramethylene dipivaloate (8). A reaction
mixture of alcohol 7 (1.09 g, 1.68 mmol) and K2CO3
(0.54 g, 3.91 mmol) in MeOH (10 ml) was stirred for
12 h at room temperature before additions of CHCl3 and
H2O. The organic solution was separated, washed with
brine, and dried (Na2SO4). Evaporation gave crude triol.
To an ice-cooled solution of the crude triol in pyridine
(7 ml) was added PivCl (0.44 ml, 3.57 mmol), and then
the reaction mixture was stirred at room temperature for
11 h. After additions of EtOAc and H2O, the organic
solution was separated, washed with 1 M aq. HCl
solution, sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). After evaporation, the residue was applied to
silica gel column chromatography (EtOAc-hexane =
C, 73.18; H, 6.94. Calcd. for C49H56O8Si: C, 73.47; H,
20
7.05%. (ꢀ)-6: ½ꢀꢃ
¼ ꢀ64 (c 0.7, CHCl3).
D
(1S,2R,3S)-3-[(R)-(3,4-Dimethoxyphenyl)(triisopropyl-
silyloxy)methyl]-2-hydroxymethyl-1-(3,4-methylenedioxy-
phenyl)tetramethylene diacetate (7). To a solution of
LiBH4 (1.41 g, 6.47 mmol) in THF (40 ml) was added a
solution of silyloxy lactone 6 (2.54 g, 3.17 mmol) in
THF (10 ml) at room temperature. After the reaction
solution was stirred for 14 h at 60 ꢁC, sat. aq. NH4Cl
solution was added, and then the mixture was concen-
trated. 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 pyridine (2.4 ml) and Ac2O (2.4 ml) con-
taining 4-DMAP (20 mg). After the reaction solution
was stirred at room temperature for 13 h, ice was added.
The mixture was stood at room temperature for 6 h, and
then the mixture was dissolved in EtOAc and H2O. The
organic solution was separated, washed with 6 M aq. HCl
solution, sat aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Evaporation gave crude diacetate. To a
solution of this crude diacetate in ether (90 ml) was
added formic acid (135 ml) at below 0 ꢁC. The resulting
reaction solution was stirred at below 0 ꢁC for 1 h before
addition of CHCl3. The organic solution was separated,
washed with sat. aq. NaHCO3 solution and brine, and
dried (Na2SO4). Concentration and subsequent silica gel
column chromatography (EtOAc-hexane = 1:5) gave
1:5) to give dipivaloate 8 (1.04 g, 1.42 mmol, 85%, 2
20
steps) as a colorless oil, ½ꢀꢃ
¼ þ44 (c 1.1, CHCl3);
D
ꢁH(CDCl3) 1.04–1.14 (21H, m, iso-Pr), 1.04 (9H, s, Piv),
1.24 (9H, s, Piv), 2.38 (1H, m, CH), 2.42 (1H, m, CH),
3.40 (1H, dd, J 11.2, 3.9 Hz, CHHOPiv), 3.61 (1H, dd, J
11.2, 7.3 Hz, CHHOPiv), 3.88 (3H, s, OCH3), 3.93 (3H,
s, OCH3), 4.36 (1H, dd, J 11.2, 8.8 Hz, CHHOPiv), 4.45
(1H, d, J 8.8 Hz, ArCHOH), 4.59 (1H, dd, J 11.2, 5.4 Hz,
CHHOPiv), 5.29 (1H, d, J 3.9 Hz, ArCHOTIPS), 5.36
(1H, s, OH), 5.92 (2H, s, OCH2O), 6.71 (2H, s, ArH),
6.82–6.85 (3H, m, ArH), 7.01 (1H, s, ArH); ꢁC(CDCl3)
12.5, 18.0, 27.0, 27.2, 38.5, 38.7, 42.6, 47.3, 55.7, 55.8,
62.9, 65.9, 71.6, 74.8, 100.9, 106.7, 108.0, 109.8, 110.9,
118.8, 120.4, 134.8, 137.1, 147.2, 147.9, 148.4, 148.7,
177.9. Anal. Found: C, 65.93; H, 8.55. Calcd. for
20
C40H62O10Si: C, 65.72; H, 8.55%. (ꢀ)-8: ½ꢀꢃ
¼ ꢀ44
D
(c 1.6, CHCl3).
(2S,3R)-2-[(R)-(3,4-Dimethoxyphenyl)(triisopropylsi-
lyloxy)methyl]-3-(3,4-methylenedioxybenzoyl)tetrameth-
ylene dipivaloate (9). A reaction mixture of benzyl
alcohol 8 (1.13 g, 1.55 mmol), PCC (0.41 g, 1.90 mmol),
and MS 4A (50 mg) in CH2Cl2 (10 ml) was stirred at
room temperature for 16 h before addition of dry ether.
The mixture was filtered, and then the filtrate was
concentrated. The residue was applied to silica gel
column chromatography (EtOAc-hexane = 1:6) to give
hydroxy diacetate 7 (1.09 g, 1.68 mmol, 53%, 3 steps) as
20
a colorless oil. (+)-7: ½ꢀꢃ
¼ þ3:7 (c 0.9, CHCl3);
D
ꢁH(CDCl3) 1.02–1.03 (21H, m, iso-Pr), 1.91 (3H, s, Ac),
2.03 (3H, s, Ac), 2.38 (1H, m, OH), 2.51 (1H, m, CH),
2.63 (1H, m, CH), 3.36 (1H, m, CHHOH), 3.50 (1H, m,
CHHOH), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.98
(1H, dd, J 11.5, 6.1 Hz, CHHOAc), 4.06 (1H, dd, J 11.5,
7.6 Hz, CHHOAc), 5.06 (1H, d, J 7.8 Hz, ArCHOTIPS),
5.68 (1H, d, J 10.7 Hz, ArCHOAc), 5.95 (2H, s,
OCH2O), 6.75–6.79 (3H, m, ArH), 6.83–6.85 (2H, m,
ArH), 6.92 (1H, s, ArH); ꢁC(CDCl3) 12.7, 18.07, 18.10,
20.8, 21.4, 44.9, 47.6, 55.8, 55.9, 63.2, 63.7, 75.9, 76.2,
101.1, 107.2, 108.2, 109.7, 110.5, 119.3, 121.0, 133.7,
ketone 9 (0.94 g, 1.29 mmol, 83%) as a colorless oil,
20
½ꢀꢃ
¼ þ36 (c 0.8, CHCl3); ꢁH(CDCl3) 0.92–0.93
D
(21H, m, iso-Pr), 0.98 (9H, s, tert-Bu), 1.02 (9H, s, tert-
Bu), 2.37 (1H, m, 2-H), 3.85 (3H, s, OCH3), 3.89 (3H, s,
OCH3), 4.03 (1H, m, 3-H), 4.26 (1H, dd, J 11.9, 6.8 Hz,
CHHOPiv), 4.35 (1H, dd, J 10.5, 8.3 Hz, CHHOPiv),
4.41 (1H, dd, J 10.5, 6.6 Hz, CHHOPiv), 4.51 (1H, dd, J
11.9, 4.1 Hz, CHHOPiv), 5.07 (1H, d, J 3.9 Hz, ArCH-
OTIPS), 6.03 (2H, s, OCH2O), 6.81–6.83 (3H, m, ArH),
6.93 (1H, s, ArH), 7.42 (1H, d, J 2.1 Hz, ArH), 7.51 (1H,
dd, J 8.3, 2.1 Hz, ArH); ꢁC(CDCl3) 12.4, 17.89, 17.93,

202
T. NAKATO et al.
26.90, 26.94, 38.5, 38.6, 42.1, 47.9, 55.7, 55.9, 62.2,
64.9, 73.8, 101.8, 107.7, 108.3, 109.6, 110.7, 118.6,
124.9, 132.5, 135.3, 148.2, 148.3, 148.7, 151.8, 177.9,
residue was applied to silica gel column chromatography
(EtOAc-hexane = 1:1) to give corresponding diol 13
20
(94 mg, 0.24 mmol, 63%) as a colorless oil, ½ꢀꢃ
¼
D
178.0, 197.9. Anal. Found: C, 65.77; H, 8.21. Calcd. for
20
þ74 (c 1.0, CHCl3); ꢁH(CDCl3) 2.70 (2H, m, 3-H, 4-H),
2.93 (1H, s, OH), 3.29 (1H, m, OH), 3.58–3.69 (2H, m,
CH2OH), 3.73–3.86 (2H, m, CH2OH), 3.86 (3H, s,
OCH3), 3.88 (3H, s, OCH3) 4.91 (1H, d, J 8.9 Hz), 5.42
(1H, d, J 4.9 Hz), 5.94 (2H, s, OCH2O), 6.79 (2H, s,
ArH), 6.81–6.85 (2H, m, ArH), 6.89 (1H, dd, J 8.2,
1.8 Hz, ArH), 6.93 (1H, d, J 1.8 Hz, ArH); ꢁC(CDCl3)
48.3, 54.0, 55.8, 55.9, 59.6, 59.7, 80.9, 82.9, 100.9,
106.2, 108.1, 108.9, 111.1, 118.3, 118.7, 132.9, 134.7,
146.7, 147.7, 148.6, 149.1. EIMS m=z (%): 388 (88), 207
(93), 194 (100), 189 (97), 151 (61). HREIMS (Mþ):
C40H60O10Si: C, 65.90; H, 8.30%. (ꢀ)-9: ½ꢀꢃ
¼ ꢀ36
D
(c 1.6, CHCl3).
(2R,3S,4S,5S)-2-(3,4-Dimethoxyphenyl)-5-(3,4-methyl-
enedioxyphenyl)-3,4-bis(pivaloyloxymethyl)tetrahydro-
furan (11). To an ice-cooled solution of silyloxy ketone
9 (0.80 g, 1.10 mmol) in THF (20 ml) containing AcOH
(0.22 ml) was added TBAF (8.80 ml, 1 M in THF, 8.80
mmol). The reaction solution was stirred at room tem-
perature for 30 min before addition of sat. aq. NaHCO3
solution and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc-
hexane = 1:3) gave unstable hemiacetal 10 (0.55 g,
0.96 mmol, 87%) as a colorless oil. The reaction mixture
of unstable hemiacetal 10 (50 mg, 0.087 mmol) and 20%
Pd(OH)2/C (50 mg) in EtOAc (20 ml) was stirred at
ambient temperature under H2 gas for 5 min. After
filtration, the resulting filtrate was concentrated. The
residue was applied to silica gel column chromatography
(EtOAc-hexane = 1:7) to give tetrahydrofuran deriva-
calcd. for C21H24O7, 388.1522; found, 388.1522. (ꢀ)-
20
13: ½ꢀꢃ
¼ ꢀ74 (c 0.9, CHCl3).
D
(2R,3S,4R,5R)-3,4-Bis(methoxymethyl)-2-(3,4-dimeth-
oxyphenyl)-5-(3,4-methylenedioxyphenyl)tetrahydrofuran
(14). To an ice-cooled suspension of NaH (25 mg, 60%
oil suspension, 0.63 mmol) in THF (4 ml) was added a
solution of (+)-diol 13 (50 mg, 0.13 mmol) in THF
(5 ml). After the resulting solution was stirred at 0 ꢁC for
30 min, MeI (0.50 ml, 8.03 mmol) was added, and then
the reaction mixture was stirred at room temperature for
5 h before additions of sat. aq. NH4Cl solution and
EtOAc. The organic solution was separated, washed
with brine, and dried (Na2SO4). After concentration, the
resulting residue was applied to silica gel column
chromatography (EtOAc-hexane = 1:2) to give virga-
tive 11 (21 mg, 0.038 mmol, 44%) as a colorless oil,
20
½ꢀꢃ
¼ ꢀ20 (c 0.3, CHCl3). NMR data agreed with
D
those in the literature.10)
(2R,3S,4R,5R)-2-(3,4-Dimethoxyphenyl)-5-(3,4-methyl-
enedioxyphenyl)-3,4-bis(pivaloyloxymethyl)tetrahydro-
furan (12) and conversion to (2R,3S,4R,5R)-3,4-bis(hy-
droxymethyl)-2-(3,4-dimethoxyphenyl)-5-(3,4-methylene-
dioxyphenyl)tetrahydrofuran (13). A reaction mixture of
unstable hemiacetal 10 (0.41 g, 0.72 mmol) and 20% Pd
(OH)2/C (0.50 g) in EtOAc (60 ml) and EtOH (60 ml)
was stirred at ambient temperature under H2 gas for
4 min. After filtration, the resulting filtrate was con-
centrated. The residue was applied to silica gel column
chromatography (EtOAc-hexane = 1:6) to give unstable
tusin stereoisomer 14 (36 mg, 0.086 mmol, 66%) as a
20
colorless oil, ½ꢀꢃ
¼ þ42 (c 0.8, CHCl3); ꢁH(CDCl3)
D
2.68 (1H, m, 3-H), 2.75 (1H, m, 4-H), 3.12 (1H, dd, J
9.8, 5.4 Hz, CHHOCH3), 3.13 (3H, s, OCH3), 3.22 (1H,
d, J 9.8, 4.3 Hz, CHHOCH3), 3.31 (3H, s, OCH3), 3.44
(1H, dd, J 9.3, 5.8 Hz, CHHOCH3), 3.62 (1H, dd, J 9.3,
8.4 Hz, CHHOCH3), 3.87 (3H, s, OCH3) 3.89 (3H, s,
OCH3), 4.99 (1H, d, J 8.3 Hz, 2-H), 5.42 (1H, d, J
6.0 Hz, 4-H), 5.95 (2H, s, OCH2O), 6.79 (1H, d, J
8.1 Hz, ArH), 6.83–6.86 (2H, m, ArH), 6.91–6.96 (3H,
m, ArH); ꢁC(CDCl3) 46.0, 51.4, 55.8, 55.9, 58.5, 58.8,
69.2, 70.4, 82.6, 83.4, 100.8, 107.0, 107.7, 109.2, 110.9,
118.3, 119.4, 133.7, 135.7, 146.4, 147.4, 148.4, 149.0;
m=z (EI) 416 (40), 384 (32), 224 (53), 189 (100), 165
(55), 149 (53). HREIMS (Mþ): calcd. for C23H28O7,
416.1835; found, 416.1832. ꢄ99% ee (HPLC, DAICEL
tetrahydrofuran 12 (0.21 g, 0.38 mmol, 53%) as a color-
20
less oil, ½ꢀꢃ
¼ þ22 (c 1.8, CHCl3); ꢁH(CDCl3) 1.09
D
(9H, s, Piv), 1.17 (9H, s, Piv), 2.83 (1H, m, 4-H), 2.95
(1H, m, 3-H), 3.88 (3H, s, OCH3), 3.89–3.94 (2H,
overlapped, CH2OPiv), 3.90 (3H, s, OCH3), 4.22 (1H,
dd, J 11.6, 7.2 Hz, CHHOPiv), 4.27 (1H, dd, J 11.6,
7.7 Hz, CHHOPiv), 5.04 (1H, d, J 9.2 Hz), 5.51 (1H, d, J
5.6 Hz), 5.94 (2H, s, OCH2O), 6.77 (1H, d, J 8.0 Hz,
ArH), 6.84–6.94 (5H, m, ArH); ꢁC(CDCl3) 27.0, 27.2,
38.5, 45.5, 50.2, 55.9, 56.0, 61.0, 62.2, 82.7, 82.8, 101.0,
OD-H chiral column, detected at 280 nm, 1 ml minꢀ1
,
20
10% iso-PrOH in hexane, tR 24 min). (ꢀ)-14: ½ꢀꢃ
¼
D
ꢀ42 (c 0.6, CHCl3), ꢄ99% ee (tR 19 min).
106.6, 108.2, 109.1, 111.2, 118.6, 119.1, 132.3, 134.7,
20
Antibacterial and antifungal activity test. The anti-
microbiological test was performed by the same method
as that previously described.13,14)
146.9, 147.7, 148.9, 149.3, 178.1. (ꢀ)-12:, ½ꢀꢃ
¼
D
ꢀ22 (c 1.6, CHCl3). A reaction solution of unstable
pivaloyl ester 12 (0.21 g, 0.38 mmol) in EtOH (4.3 ml)
and 1 M aq. NaOH solution (5.5 ml) was stirred at room
temperature for 5 h before additions of CHCl3 and H2O.
The organic solution was separated, washed with brine,
and dried (Na2SO4). After evaporation, the resulting
Acknowledgments
Our thanks to the president of Ehime University for
supporting this project. The 400 MHz NMR data were

Stereoisomer of (ꢀ)-Virgatusin
203
virgatusin. Tetrahedron Lett., 40, 4701–4702 (1999).
measured in INCS at Ehime University. We thank the
staff at this Center for the EIMS and FABMS measure-
ments. We are also grateful to Marutomo Co. (Iyo,
Ehime, Japan).
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