Use of the benzyl mesylate for the synthesis of tetrahydrofuran lignan: Syntheses of 7,8-trans, 7′,8′-trans, 7,7′-cis, and 8,8′-cis-virgatusin stereoisomers

Article abstract of DOI:10.1271/bbb.70236

The benzyl mesylate was employed to construct the tetrasubstituted tetrahydrofuran lignan with avoiding Friedel-Crafts type of reaction. The optically pure 7,8-trans, 7′,8′-trans, 7,7′-cis, and 8,8′-cis-virgatusin stereoisomers were synthesized. The enant

Full text of DOI:10.1271/bbb.70236

Biosci. Biotechnol. Biochem., 71 (9), 2248–2255, 2007
Use of the Benzyl Mesylate for the Synthesis
of Tetrahydrofuran Lignan: Syntheses of 7,8-trans,
70,80-trans, 7,70-cis, and 8,80-cis-Virgatusin Stereoisomers
y
Satoshi YAMAUCHI,1; Tomofumi NAKATO,1 Masahiro TSUCHIYA,1 Koichi AKIYAMA,2
1
Masafumi MARUYAMA,1 Takuya SUGAHARA,1 and Taro KISHIDA
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 April 20, 2007; Accepted June 4, 2007; Online Publication, September 7, 2007
[doi:10.1271/bbb.70236]
The benzyl mesylate was employed to construct the
tetrasubstituted tetrahydrofuran lignan with avoiding
Friedel-Crafts type of reaction. The optically pure 7,8-
trans, 70,80-trans, 7,70-cis, and 8,80-cis-virgatusin stereo-
isomers were synthesized. The enantiomeric excess was
ꢀ99%.
giving an aryl-benzyl carbon bond has previously been
reported.12) To obtain desired 2,5-diaryltetrahydrofuran
4, etherification between the benzylic oxygen at the 70
position and the benzylic position (7 position) of benzyl
mesylate 3 is needed (Scheme 1). The Friedel-Crafts
type of cyclization reaction between the 60 position and
benzylic 7 position of 3 is not desirable in this synthesis.
When intramolecular etherification of benzyl mesylate 3
occurs prior to the Friedel-Crafts type of reaction, SN1
etherification would occur to give stable 4 because of the
existence of a benzyl cation at the 7 position. Thus, the
70 oxygen would attack the 7-position from the opposite
side of the 8 and 80 substituents. The stereoselective
synthesis of stereoisomer 4 requires one benzylic po-
sition (the 70 position) to be stereoselectively construct-
ed before attempting this benzylic oxygen-benzyl mes-
ylate etherification. On the other hand, stereoselective
construction of the stereochemistry at the 7 position is
unnecessary. An aldol condensation, using potassium
enolate,13) was employed to obtain single stereochem-
istry at the 70-benzylic position in this study. To avoid
etherification between the primary oxygen and the
benzylic position of the mesylate (the 7 position) or
another benzylic position (the 70 position) of 3, ap-
propriate protective groups for the benzyl alcohol and
the primary alcohol of compound 3 need to be selected.
This article describes using the benzyl mesylate to
synthesize 2,5-diaryltetrahydrofuran-type lignan 5 with
avoiding the Friedel-craft type of reaction.
Key words: lignan; virgatusin; tetrahydrofuran lignan
Lignans with different biological activities1,2) possess
two or three phenylpropanoid units as an important
structural feature and are widely distributed in many
plants. The bonding type of these phenylpropanoid units
and oxidation positions on the lignan structure are pre-
sumed to be responsible for their biological activities.
The many kinds of biological activity and structure of
lignan have attracted the attention of synthetic and bio-
logical chemists.2,3) One of the difficulties of a synthetic
study on lignan is constructing the chiral center. In the
field of natural products chemistry, stereoisomers are of
high interest for research about the structure-activity
relationship, and the collation of stereoisomer libraries
has proceeded.4)
The 4-substituted tetrahydrofuran lignan, (ꢀ)-virga-
tusin (1),5) has been isolated and a total synthesis
achieved.6–8) Anti-virus activity has been anticipated.9)
The antifungal activity of 110) and antibacterial activity
of 211) were discovered in the course of our biological
studies (Fig. 1). To continue these studies, syntheses of
the stereoisomers of virgatusin having four chiral centers
are important. The attractive structure of the stereo-
isomers of virgatusin and potent anti-microbiological
activity make them suitable synthetic targets. The ster-
eoselective construction of a 2,5-diaryltetrahydrofuran
moiety is important in this synthetic study, and the use
of unstable benzyl mesylate 3 has been considered. A
Friedel-Crafts type of reaction of the benzyl mesylate
Results and Discussion
Substrate 9 for the intramolecular cyclization was
prepared from lactone 614) (Scheme 2). The aldol con-
densation of lactone 6 with 3,4-dimethoxybenzaldehyde,
using potassium bis(trimethylsilyl)amide, stereoselec-
tively gave erythro aldol product 7 (erythro/threo =
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

Synthesis of Stereoisomers of Virgatusin
2249
H3CO
H3CO
H3CO
O
O
O
O
O
O
H3CO
H3CO
OCH3
HO
OH
2
(-)-virgatusin (1)
Fig. 1. (ꢀ)-Virgatusin and Its Related Compounds.
H3CO
H3CO
6'
×
H3CO
O
6'
Ar1
Ar2
OR2
H
MsO
H
Ar2
OR2
H
SN1 ether formation
H
7
7'
+
7
H3CO
Ar2
H
H
8'
8
OR1
H
H
R1O
8'
8
4
OR1
R1O
4: R1 = protective group
5: R1 = CH3
3
OR1
R1O
H3CO
H3CO
6'
OR2
R1O
H3CO
H3CO
6'
OR2
H
MsO
H
OCH3
Ar2
OR2
Friedel-Craft type
of reaction
H
H
7
+
7
7'
Ar2
H
H
OCH3
H
H
OR1
R1O
Ar2
R1O
OR1
R1O
3
Scheme 1. Intramolecular SN1 Ether Formation and Friedel-Crafts Type Reaction of Benzyl Mesylate 3.
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
TESO
H
HO
O
O
Ar1
H
Ar1
O
O
Ar1
Ar2
a
c
H
H
H
H
OTBDPS
OTBDPS
RO
TBDPSO
OTBDPS
Ar2
6
9
7
8
: R = H
b
: R = TES
O
O
Ar2
Ar1
OR
Ar2
Ar1
e
d
RO
TBDPSO
OTBDPS
11: R = H
10
f
(-)-5: R = CH3
Scheme 2. Synthesis of Stereoisomer of Virgatusin (ꢀ)-5.
(a) KHMDS, 3,4-dimethoxybenzaldehyde, THF, ꢀ70 ꢁC, 1 h (94% yield, containing 5% of the threo isomer); (b) TESOTf, 2,6-lutidine,
CH2Cl2, r.t., 1 h (78% yield); (c) (1) LiBH4, THF, r.t., 16 h; (2) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 2 h (69% yield); (d) MsCl, Et3N, CH2Cl2,
r.t., 2 h (98% yield); (e) n-Bu4NF, THF, r.t., 2 h (62% yield); (f) NaH, CH3I, THF, r.t., 16 h (92% yield). Ar1, 3,4-methylenedioxyphenyl; Ar2,
3,4-dimethoxyphenyl

2250
S. YAMAUCHI et al.
OTES
H
H
H
HO
O
O
Ar1
1) LiBH4/THF
r.t., 16 h
Ar1
Ar2
7'
7
H
2) TBDPSCl, Et3N
DMAP/CH2Cl2
r.t., 2 h
H
TESO
OTBDPS
H
72%, 2 steps
TBDPSO
OTBDPS
Ar2
13
12
H
H
OH HO
Ar1
O
Ar2
Ar1
Ar2
+
H
H
13
TBDPSO
OTBDPS
TBDPSO
OTBDPS
14
10
Reaction conditions to 13
10
14
recovered 13
MsCl (1.1 eq.), Et3N (1.1 eq.),
CH2Cl2, r.t., 1 h
0%
52%
33%
MsCl (1.1 eq.), Et3N (1.1 eq.),
CH2Cl2, r.t., 16 h
40%
17%
98%
0%
0%
Ms2O, Et3N, CH2Cl2
r.t., 1 h
29%
0%
32%
0%
Ms2O, Et3N, CH2Cl2
r.t., 16 h
Scheme 3. Mesylation of Benzyl Alcohol 13.
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
95/5). While some of the threo isomer of 7 could be
separated in this stage, the erythro product was com-
pletely separated after triethylsilylating the benzylic
hydroxy group. After LiBH4 reduction of lactone 8 to
the corresponding butanol derivative, the primary hy-
droxy group was selectively protected as a tert-butyldi-
phenylsilyl ether, giving substrate 9 for the intramolec-
ular cyclization reaction. The benzylic triethylsilyl ether
would be selectively cleaved in the presence of the tert-
butyldiphenylsilyl ether before intramolecular cycliza-
tion of 9 occurred.
Substrate 9 was treated with methanesulfonyl chloride
in CH2Cl2 in the presence of triethylamine. Although
the benzyl mesylate was not obtained, cyclization pro-
duct 10 was obtained as a single isomer in this step in a
high yield (98%). It could be assumed that the benzyl
mesylate was produced as a first step, followed by the
emergence of a benzyl cation. The benzylic oxygen in
the triethylsilyl ether attacked this resulting benzyl
cation to stereoselectively give tetrahydrofuran ring 10.
Under theses conditions, the Friedel-Crafts type of
reaction12) between the aryl carbon and benzylic carbon
of the benzyl mesylate did not occur. The stereochem-
istry of tetrahydrofuran derivative 10 was determined
by a comparison with the literature data.2) Even if the
reaction was carried out at a lower temperature (ꢀ10
ꢁC), the benzyl mesylate could not be isolated, the use of
pyridine or N,N-diisopropylethylamine instead of trieth-
ylamine giving the same result.
Benzyl alcohol 13 was prepared from minor silylated
threo aldol product 12 (Scheme 3). Unexpectedly,
treating 13 with methanesulfonyl chloride in the pres-
ence of triethylamine also gave tetrahydrofuran deriv-
ative 10 (40%) as a single isomer after a 16-h reaction,
indicating that the benzyl cation at the 70 position had
been produced instead of at the 7 position. A 1-h
reaction enabled diol 14 (52%) to be obtained, together
with the recovery of benzyl alcohol 13 (33%). To
determine the stereochemistry of 14, the threo isomer
of lactone 7 was subjected to LiBH4 reduction and
subsequent tert-butyldiphenylsilylation to give 14,
whose NMR data agreed with those of 14 which had
been obtained after treating benzyl alcohol 13 with
methanesulfonyl chloride. The stereoisomer of benzyl
alcohol 13 was not isolated from this reaction mixture. It
could be assumed from these results that mesylation to
the benzylic hydroxy group of 13 did not occur in this
reaction. When benzyl alcohol 13 was treated only with

Synthesis of Stereoisomers of Virgatusin
2251
H
O
S
O
H2C
Cl
O
S
SiEt3
H
H
OH HO
O
HO H
H
H2C
Ar1
Ar2
H
Ar2
Ar1
O
7'
H
H
H
TBDPSO
OTBDPS
TBDPSO
OTBDPS
14
13
MsO
H
H
HO
Ar2
Ar1
O
Ar2
Ar1
7'
H
H
TBDPSO
OTBDPS
OTBDPS
TBDPSO
10
Scheme 4. Proposed Mechanism for the Production of Diol 14 and Tetrahydrofuran Derivative 10 from Benzyl Alcohol 13.
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
H
H
OH HO
Ar1
O
7
7'
Ar2
Ar1
MsCl, Et3N
CH2Cl2
Ar2
7
7'
+
7,7'-trans-compound (13%)
H
H
r.t., 15 min
TBDPSO
OTBDPS
TBDPSO
OTBDPS
14
10 (83%)
Scheme 5. Reaction of Diol 14 with Methanesulfonyl Chloride.
Ar1, 3,4-methylenedioxyphenyl; Ar2, 3,4-dimethoxyphenyl
triethylamine, no reaction occurred. It might be assumed
from this that interaction between the Si atom and Cl
atom took place by the treatment with methanesulfonyl
chloride, desilylation occurring to give diol 14 having
the same stereochemistry. Since the stereochemistry of
diol 14 was not changed and no salt was produced in this
reaction, it could be assumed that direct mesylation to 7-
OH did not occur. Selective mesylation to the 70-
hydroxy group of diol 14 then took place to give the
benzyl mesylate which was subsequently transformed to
tetrahydrofuran derivative 10 by SN1 intramolecular
cyclization (Scheme 4). The Friedel-Crafts type of re-
action product did not result in this reaction. The reac-
tion of benzyl alcohol 13 with methanesulfonic anhy-
dride was also tried. In a short reaction (1 h), tetrahy-
drofuran derivative 10 (17%) and diol 14 (29%) were
obtained, together with the recovery of benzyl alcohol
13 (32%). A longer reaction (16 h) gave tetrahydrofuran
derivative 10 in a higher yield (98%) than the reaction
using methanesulfonyl chloride (Scheme 3). Mesylation
to diol 14 was examined by using methanesulfonyl chlo-
ride (Scheme 5), the reaction proceeding quickly to give
tetrahydrofuran derivative 10 (83%) and the 7,70-trans-
compound (13%). Although selective mesylation to the
70-hydroxy group of diol 14 was also observed, the
selectivity was decreased. The presence of the triethyl-
silyl ether increased this selectivity, meaning that
erythro or threo selectivity in the aldol condensation
of lactone 6 was not necessary to give the stereo-
chemistry of 10.
Tetrahydrofuran derivative 10 was converted to ster-
eoisomer of virgatusin 5 by desilylation and subsequent
methylation of the resulting hydroxy groups. The enan-
tiomer of 5 was also synthesized by employing the same
synthetic method. The optical purity of both (+)-5 and
(ꢀ)-5 was determined as ꢂ99%ee by using a chiral
column.
The 7,8-trans,70,80-trans,7,70-cis,8,80-cis-virgatusin ster-
eoisomers were stereoselectively synthesized by an SN1
intramolecular cyclization reaction of benzyl mesylate,
avoiding the Friedel-Crafts type of reaction. This is a
new example of the use of benzyl mesylate.

2252
S. YAMAUCHI et al.
Experimental
[(R)-(3,4-dimethoxyphenyl)(triethylsilyloxy)methyl]-4-(3,
4-methylenedioxyphenyl)-4-butanolide (8) and (2R,3R,
4S)-3-[(tert-butydiphenylsilyloxy)methyl]-2-[(S)-(3,4-di-
methoxyphenyl)(triethylsilyloxy)methyl]-4-(3,4-methyl-
enedioxyphenyl)-4-butanolide (12). To an ice-cooled
solution of aldol product 7 (4.01 g, 6.26 mmol) contain-
ing 5% of threo isomer and 2,6-lutidine (1.46 ml, 12.5
mmol) in CH2Cl2 (100 ml) was added TESOTf (1.55 ml,
6.85 mmol). The reaction solution was stirred at room
temperature for 1 h before addition of sat. aq. NH4Cl
solution. The organic solution was separated, washed
with sat. aq. CuSO4 solution, sat. aq. NaHCO3 solution,
and brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane =
Optical rotation values were measured by 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), and
the HPLC analysis was performed with Shimadzu LC-
6AD and SPD-6AV instruments. The numbering of
compounds follows the IUPAC nomenclatural rules.
(2R,3R,4S)-3-[(tert-Butyldiphenylsilyloxy)methyl]-2-
[(R)-(hydroxy)(3,4-dimethoxyphenyl)methyl]-4-(3,4-meth-
ylenedioxyphenyl)-4-butanolide (7). To a solution of
KHMDS (50.1 ml, 0.5 M in toluene, 0.025 mol) in THF
(150 ml) was added a solution of lactone 6 (7.69 g, 0.016
mol) in THF (50 ml) at ꢀ70 ꢁC. After the mixture was
stirred at ꢀ70 ꢁC for 15 min, a solution of 3,4-dime-
thoxybenzaldehyde (2.94 g, 0.018 mol) in THF (20 ml)
was added. The resulting 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). Concentration followed
by silica gel column chromatography (EtOAc/hexane =
1/4) gave aldol product 7 (9.30 g, 0.015 mol, 94%)
containing 5% of the threo isomer as a colorless oil. ꢀH
(CDCl3) 1.01 (9H, s, tert-BuSi), 2.78 (1H, m, 3-H), 2.98
(1H, dd, J 10.7, 3.9 Hz, 2-H), 3.23 (1H, d, J 9.8 Hz,
CHHOSi), 3.43 (1H, dd, J 9.8, 2.4 Hz, CHHOSi), 3.75
(3H, s, OCH3), 3.82 (3H, s, OCH3), 5.07 (1H, d, J
8.8 Hz, 4-H), 5.56 (1H, br. s, ArCHOH, d, J ¼ 2:2 Hz,
by D2O exchange), 5.81 (2H, s, OCH2O), 6.30 (1H, d, J
7.8 Hz, ArH), 6.53 (1H, d, J 7.8 Hz, ArH), 6.63 (1H, s,
ArH), 6.72 (1H, d, J 8.3 Hz, ArH), 6.90 (1H, d, J 8.3 Hz,
ArH), 6.93 (1H, s, ArH), 7.27–7.38 (8H, m, ArH), 7.54–
7.56 (2H, m, ArH); ꢀC (CDCl3) 18.9, 26.7, 45.3, 49.0,
55.48, 55.54, 59.8, 69.8, 81.4, 100.8, 106.8, 107.5,
108.0, 110.8, 117.0, 120.6, 127.5, 127.6, 127.7, 129.6,
129.8, 132.3, 132.4, 132.5, 133.8, 135.2, 135.3, 148.0,
148.8, 177.3. Anal. Found: C, 69.37; H, 6.36. Calcd. for
1/7) gave TES ether 8 (3.71 g, 4.91 mmol, 78%) as a
20
colorless oil, ½ꢁꢃ
¼ þ19 (c 0.9, CHCl3); ꢀH (CDCl3)
D
0.60–0.67 (6H, m, (CH3CH2)3Si), 0.93 (9H, t, J 7.8 Hz,
(CH3CH2)3Si), 0.97 (9H, s, tert-BuSi), 2.83 (1H, m, 3-
H), 2.91 (1H, dd, J 10.7, 3.9 Hz, 2-H), 3.18 (1H, dd, J
9.8, 2.0 Hz, CHHOSi), 3.27 (1H, dd, J 9.8, 2.0 Hz,
CHHOSi), 3.79 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.06
(1H, d, J 8.8 Hz, 4-H), 5.56 (1H, d, J 2.0 Hz, ArCHOSi),
5.93 (2H, s, OCH2O), 6.36 (1H, dd, J 7.8, 1.5 Hz, ArH),
6.61 (1H, d, J 7.8 Hz, ArH), 6.65 (1H, d, J 1.5 Hz, ArH),
6.72 (1H, d, J 8.8 Hz, ArH), 6.84–6.86 (2H, m, ArH),
7.21–7.23 (2H, m, ArH), 7.29–7.47 (6H, m, ArH), 7.51–
7.53 (2H, m, ArH); ꢀC (CDCl3) 4.7, 6.8, 19.1, 26.8, 45.1,
50.2, 55.67, 55.70, 60.2, 71.6, 81.2, 101.1, 106.8, 107.8,
108.0, 110.8, 117.2, 120.6, 127.6, 127.8, 129.8, 129.9,
132.5, 132.8, 133.1, 134.8, 135.4, 135.7, 147.7, 147.9,
148.1, 148.9, 176.7. Anal. Found: C, 68.70; H, 7.32.
Calcd. for C43H54O8Si2: C, 68.40; H, 7.21%. (ꢀ)-8:
20
½ꢁꢃ
¼ ꢀ19 (c 1.4, CHCl3). Threo isomer 12 (0.18 g,
D
0.24 mmol, 4%) was obtained as a colorless oil,
20
½ꢁꢃ
¼ ꢀ20 (c 2.5, CHCl3). ꢀH (CDCl3) 0.48–0.60
D
(6H, m, Si(CH2CH3)3), 0.87 (9H, t,
J 7.8 Hz,
Si(CH2CH3)3), 1.08 (9H, s, tert-BuSi), 3.38 (1H, m, 3-
H), 3.39 (1H, dd, J 8.8, 3.9 Hz, 2-H), 3.72 (1H, dd, J
10.5, 2.7 Hz, CHHOSi), 3.77 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 3.88 (1H, dd, J 10.5, 4.9 Hz, CHHOSi), 5.07
(1H, d, J 7.8 Hz, 4-H), 5.46 (1H, d, J 4.4 Hz, ArCHOSi),
5.74 (1H, d, J 2.0 Hz, ArH), 5.85 (1H, d, J 5.9 Hz,
OCHHO), 5.86 (1H, d, J 5.9 Hz, OCHHO), 5.97 (1H,
dd, J 8.1, 2.0 Hz, ArH), 6.47 (1H, d, J 8.3 Hz, ArH), 6.79
(1H, d, J 8.3 Hz, ArH), 6.84–6.88 (2H, m, ArH), 7.37–
7.42 (4H, m, ArH), 7.44–7.48 (2H, m, ArH), 7.61–7.63
(4H, m, ArH); ꢀC (CDCl3) 4.6, 6.8, 19.3, 26.9, 46.7,
50.6, 55.76, 55.80, 62.6, 72.8, 81.6, 101.0, 106.2, 107.6,
109.9, 110.7, 118.9, 119.9, 127.7, 127.8, 129.86, 129.94,
132.98, 133.01, 133.1, 133.2, 135.6, 135.7, 147.4, 147.7,
148.6, 148.7, 175.9. Anal. Found: C, 68.68; H, 7.30.
Calcd. for C43H54O8Si2: C, 68.40; H, 7.21%.
C37H40O8Si: C, 69.35; H, 6.29%. Some of threo isomer
20
was purified to give a colorless oil, ½ꢁꢃ
¼ þ99 (c 1.6,
D
CHCl3). ꢀH (CDCl3) 1.06 (9H, s, tert-Bu), 2.16 (1H, m,
2-H), 2.94 (1H, dd, J 10.9, 3.6 Hz, CHHOTBDPS), 3.25
(1H, dd, J 10.8, 2.5 Hz, CHHOTBDPS), 3.35 (1H, dd, J
10.1, 8.5 Hz, 2-H), 3.81 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 4.50 (1H, d, J 1.9 Hz, OH), 4.91 (1H, dd, J 8.2,
1.9 Hz, ArCHOH), 5.07 (1H, d, J 8.9 Hz, 4-H), 5.91 (2H,
s, OCH2O), 6.09 (1H, d, J 8.1 Hz, ArH), 6.28 (1H, s,
ArH), 6.54 (1H, d, J 8.1 Hz, ArH), 6.73 (1H, d, J 8.2 Hz,
ArH), 6.82 (1H, d, J 8.2 Hz, ArH), 7.00 (1H, s, ArH),
7.29–7.47 (6H, m, ArH), 7.56–7.58 (4H, m, ArH); ꢀC
(CDCl3) 19.2, 26.9, 47.9, 49.2, 55.7, 55.8, 59.5, 74.5,
81.4, 101.2, 106.2, 108.0, 109.3, 110.8, 119.1, 120.1,
127.7, 128.0, 130.0, 130.2, 131.6, 132.48, 132.52, 132.6,
135.5, 135.8, 147.8, 148.0, 149.2, 149.4, 178.3.
(1S,2R,3S,4R)-2,3-Bis[(tert-butyldiphenylsilyloxy)meth-
yl]-4-(3,4-dimethoxyphenyl)-1-(3,4-methylenedioxyphen-
yl)-4-triethylsilyloxy-1-butanol (9). To an ice-cooled
solution of LiBH4 (1.08 g, 0.050 mol) in THF (10 ml)
was added a solution of lactone 8 (3.77 g, 4.99 mmol) in
(2R,3R,4S)-3-[(tert-Butyldiphenylsilyloxy)methyl]-2-

Synthesis of Stereoisomers of Virgatusin
2253
THF (10 ml), and then the reaction solution was stirred
at room temperature for 16 h before addition of sat. aq.
NH4Cl solution. After the mixture was concentrated,
the residue was dissolved in H2O and EtOAc. The
organic solution was separated, washed with brine, dried
(Na2SO4), and concentrated to give crude diol. A re-
action solution of this crude diol, Et3N (0.89 ml, 6.39
mmol), DMAP (29 mg, 0.24 mmol), and TBDPSCl (1.48
ml, 5.69 mmol) in CH2Cl2 (10 ml) was stirred at room
temperature for 2 h before additions of H2O and EtOAc.
The organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane = 1/7)
(53), 135 (100). HRFABMS (Mþ þ 1): Calcd. for
C53H61O7Si2, 865.3956. Found: 865.3956. (+)-10:
20
½ꢁꢃ
¼ þ3 (c 1.8, CHCl3).
D
(2R,3S,4R,5S)-3,4-Bis(hydroxymethyl)-2-(3,4-dimeth-
oxyphenyl)-5-(3,4-methylenedioxyphenyl)tetrahydrofuran
(11). A reaction solution of diTBDPS ether 10 (0.39 g,
0.45 mmol) and n-Bu4NF (0.99 ml, 1 M in THF, 0.99
mmol) in THF (5 ml) was stirred at room temperature
for 2 h before additions of sat. aq. NH4Cl solution and
EtOAc. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane =
gave diTBDPS ether 9 (3.43 g, 3.44 mmol, 69%) as a
20
1/9 and 1/4) gave diol 11 (0.11 g, 0.28 mmol, 62%) as a
20
colorless oil, ½ꢁꢃ
¼ þ36 (c 1.0, CHCl3). ꢀH (CDCl3)
colorless oil, ½ꢁꢃ
¼ ꢀ5 (c 0.66, CHCl3). ꢀH (CDCl3)
D
D
0.40–0.55 (6H, m, (CH3CH2)3Si), 0.82 (9H, t, J 8.1 Hz,
(CH3CH2)3Si), 0.90 (9H, s, tert-BuSi), 1.08 (9H, s, tert-
BuSi), 2.33 (1H, m, CH), 2.67 (1H, m, CH), 3.17 (1H,
m, CHHOSi), 3.43 (1H, m, CHHOSi), 3.70–3.80 (2H,
m, CH2OSi), 3.80 (3H, s, OCH3), 3.85 (3H, s, OCH3),
4.34 (1H, br. s, OH), 5.15 (1H, br. s, ArCHOH), 5.82
(2H, s, OCH2O), 5.83 (1H, d, J 7.3 Hz, ArCHOSi),
6.45–6.51 (2H, m, ArH), 6.57–6.62 (2H, m, ArH), 6.74
(1H, d, J 6.8 Hz, ArH), 6.93 (1H, s, ArH), 7.24–7.44
(16H, m, ArH), 7.59–7.64 (4H, m, ArH); ꢀC (CDCl3)
4.5, 6.7, 19.0, 19.2, 26.8, 26.9, 46.9, 55.5, 55.8, 63.1,
71.2, 74.0, 100.6, 106.7, 107.5, 109.8, 110.7, 119.2,
119.8, 127.3, 127.4, 127.6, 127.7, 129.4, 129.5, 129.6,
133.3, 133.4, 133.47, 133.54, 135.4, 135.47, 135.50,
135.6, 138.2, 146.3, 147.4, 148.1, 148.6. Anal. Found:
2.53 (2H, m, 3,4-H), 3.63 (2H, br. s, OH), 3.71–3.78
(2H, m, CH2OH), 3.82–3.90 (2H, m, CH2OH), 3.87 (3H,
s, OCH3), 3.89 (3H, s, OCH3), 4.60 (1H, d, J 7.3 Hz,
ArCH), 4.61 (1H, d, J 7.3 Hz, ArCH), 5.95 (2H, s,
OCH2O), 6.77–6.80 (2H, m, ArH), 6.84–6.88 (2H, m,
ArH), 6.94–6.97 (2H, m, ArH); ꢀC (CDCl3) 51.6, 51.8,
55.89, 55.91, 60.06, 60.15, 82.1, 101.0, 106.7, 108.1,
109.7, 111.1, 118.8, 120.0, 133.6, 135.0, 147.3, 147.9,
148.8, 149.1. Anal. Found: C, 64.57; H, 6.33. Calcd. for
20
C21H24O7: C, 64.94; H, 6.23%. (+)-11: ½ꢁꢃ
¼ þ5 (c
D
1.2, CHCl3).
(2R,3S,4R,5S)-3,4-Bis(methoxymethyl)-2-(3,4-dimeth-
oxyphenyl)-5-(3,4-methylenedioxyphenyl)tetrahydrofuran
(5). To an ice-cooled suspension of NaH (22 mg, 60% in
oil, 0.55 mmol) in THF (1 ml) was added a solution of
diol 11 (0.10 g, 0.26 mmol) in THF (2 ml). The resulting
mixture was stirred at room temperature for 30 min
before addition of CH3I (40 ml, 0.64 mmol). The result-
ing reaction solution was stirred at room temperature for
16 h before additions of 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 stereo-
C, 71.34; H, 7.89. Calcd. for C59H76O8Si3: C, 71.04; H,
20
7.68%. (ꢀ)-9: ½ꢁꢃ
¼ ꢀ36 (c 2.5, CHCl3).
D
(2R,3S,4R,5S)-3,4-Bis[(tert-butyldiphenylsilyloxy)meth-
yl]-2-(3,4-dimethoxyphenyl)-5-(3,4-methylenedioxyphen-
yl)tetrahydrofuran (10). To an ice-cooled solution of
benzyl alcohol 9 (0.72 g, 0.72 mmol) and Et3N (0.11 ml,
0.79 mmol) in CH2Cl2 (4 ml) was added MsCl (62 ml,
0.80 mmol). The reaction solution was stirred at room
temperature for 2 h before additions of sat. aq. NaHCO3
solution and CH2Cl2. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography
isomer of virgatusin 5 (0.10 g, 0.24 mmol, 92%) as a
20
colorless oil, ½ꢁꢃ
¼ ꢀ10 (c 0.81, CHCl3), ꢂ99%ee
D
(HPLC, DAICEL OD-H chiral column, detected at 280
nm, 1 ml minꢀ1, 10% iso-PrOH in hexane, tR 32 min. ꢀH
(CDCl3) 2.56 (2H, m, 3,4-H), 3.34 (6H, s, OCH3), 3.48–
3.52 (2H, m, CH2OCH3), 3.54–3.58 (2H, m, CH2-
OCH3), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.81
(1H, d, J 6.8 Hz, ArCH), 4.82 (1H, d, J 6.8 Hz, ArCH),
5.94 (2H, s, OCH2O), 6.78 (1H, d, J 7.8 Hz, ArH), 6.85
(1H, d, J 7.8 Hz, ArH), 6.90 (1H, dd, J 7.8, 1.7 Hz,
ArH), 6.96–7.00 (3H, m, ArH); ꢀC (CDCl3) 49.1, 49.3,
55.8, 55.9, 58.83, 58.85, 70.53, 70.54, 82.9, 100.9,
106.9, 108.0, 109.8, 111.0, 118.7, 119.9, 134.5, 136.0,
147.0, 147.7, 148.5, 148.9; EIMS m=z (%): 416 (Mþ,
88), 224 (86), 208 (97), 192 (82), 189 (94), 173 (98), 84
(EtOAc/hexane = 1/7) gave tetrahydrofuran compound
20
10 (0.61 g, 0.71 mmol, 98%) as a colorless oil, ½ꢁꢃ
¼
D
ꢀ3 (c 1.1, CHCl3). ꢀH (CDCl3) 0.97 (9H, s, tert-BuSi),
0.98 (9H, s, tert-BuSi), 2.53 (2H, m, 3, 4-H), 3.79 (3H, s,
OCH3), 3.82–3.97 (4H, m, 3,4-CH2OSi), 3.87 (3H, s,
OCH3), 4.90 (1H, d, J 6.8 Hz, ArCH), 4.95 (1H, d, J
6.4 Hz, ArCH), 5.93 (1H, d, J 5.4 Hz, OCHHO), 5.94
(1H, d, J 5.4 Hz, OCHHO), 6.68–6.71 (2H, m, ArH),
6.76–6.81 (2H, m, ArH), 6.83–6.87 (2H, m, ArH), 7.25–
7.33 (10H, m, ArH), 7.37–7.40 (4H, m, ArH), 7.54–7.57
(6H, m, ArH); ꢀC (CDCl3) 19.06, 19.10, 26.8, 51.0, 51.3,
55.7, 55.9, 61.8, 61.9, 82.8, 82.9, 100.9, 107.0, 107.9,
109.7, 111.0, 118.7, 120.3, 127.6, 127.7, 129.6, 133.2,
133.3, 134.7, 135.50, 135.53, 135.6, 136.0, 146.9, 147.7,
148.4, 148.8; FAB m=z (%) 865 (Mþ þ 1, 2%), 197
(100). HREIMS (Mþ): Calcd. for C23H28O7, 416.1835.
20
Found: 416.1834. (+)-5: ½ꢁꢃ
ꢂ99%ee (tR 20 min).
¼ þ10 (c 0.94, CHCl3),
D

2254
S. YAMAUCHI et al.
(1S,2R,3S,4S)-2,3-Bis[(tert-butyldiphenylsilyloxy)meth-
yl]-4-(3,4-dimethoxyphenyl)-1-(3,4-methylenedioxyphen-
17%), diol 14 (11 mg, 0.012 mmol, 29%), and recovered
13 (13 mg, 0.013 mmol, 32%). In the case of 16 h
reaction, tetrahydrofuran derivative 10 (35 mg, 0.040
mmol, 98%) was obtained.
yl)-4-triethylsilyloxy-1-butanol (13). Colorless oil,
20
½ꢁꢃ
¼ ꢀ18 (c 0.9, CHCl3). ꢀH (CDCl3) 0.37–0.43
D
(6H, m, Si(CH2CH3)3), 0.78 (9H, t, J 7.9 Hz, Si(CH2-
CH3)3), 0.95 (9H, s, tert-BuSi), 1.03 (9H, s, tert-BuSi),
2.05 (1H, m, CH), 2.46 (1H, m, CH), 3.32 (1H, dd, J 7.4,
6.4 Hz, CHHOSi), 3.41 (1H, dd, J 7.4, 7.4 Hz, CHHO-
Si), 3.65 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.88 (1H,
dd, J 10.4, 4.6 Hz, CHHOSi), 4.01 (1H, dd, J 10.4,
8.2 Hz, CHHOSi), 4.26 (1H, d, J 2.3 Hz, OH), 4.77 (1H,
dd, J 8.2, 2.3 Hz, ArCHOH), 5.00 (1H, d, J 5.9 Hz,
ArCHOSi), 5.89 (2H, s OCH2O), 6.57–6.72 (5H, m,
ArH), 6.78 (1H, d, J 8.2 Hz, ArH), 7.21–7.31 (8H, m,
ArH), 7.34–7.39 (4H, m, ArH), 7.42–7.44 (4H, m, ArH),
7.54 (2H, d, J 6.8 Hz, ArH), 7.60 (2H, d, J 6.6 Hz, ArH);
ꢀC (CDCl3) 4.7, 6.8, 19.06, 19.10, 26.8, 26.9, 47.5, 49.5,
55.5, 55.7, 62.4, 63.9, 72.9, 75.6, 100.7, 106.9, 107.7,
109.9, 110.4, 119.3, 119.8, 127.4, 127.5, 127.56, 127.61,
129.4, 129.57, 129.62, 133.1, 133.2, 133.5, 133.6,
135.38, 135.41, 135.6, 135.7, 135.8, 138.2, 146.4,
147.5, 147.9, 148.3. Anal. Found: C, 71.26; H, 7.78.
Calcd. for C59H76O8Si3: C, 71.04; H, 7.68%.
Determination of the stereochemistry of diol 14. To an
ice-cooled solution of LiBH4 (48 mg, 3.58 mmol) in
THF (10 ml) was added a solution of the threo isomer of
7 (0.13 g, 0.20 mmol) in THF (10 ml). The resulting
reaction mixture was stirred at 0 ꢁC for 13 h before
addition of sat. aq. NH4Cl solution. After concentration,
the residue was dissolved in H2O and EtOAc. The
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude triol. After
a reaction solution of this crude triol, TBDPSCl (10 ml,
0.038 mmol), Et3N (6.0 ml, 0.043 mmol), and DMAP
(0.2 mg, 0.0016 mmol) in CH2Cl2 (2 ml) was stirred at
room temperature for 30 min, H2O and CH2Cl2 were
added. The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (EtOAc/hexane =
1/3) gave 14 (0.10 g, 0.11 mmol, 55%).
Treatment of diol 14 with methanesulfonyl chloride.
To an ice-cooled solution of diol 14 (16 mg, 0.018
mmol) and Et3N (3 ml, 0.022 mmol) in CH2Cl2 (2 ml)
was added MsCl (23 ml, 0.30 mmol). After stirring at
room temperature for 15 min, H2O and CH2Cl2 were
added. The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (EtOAc/hexane = 1/
9) gave tetrahydrofuran derivative 10 (13 mg, 0.015
mmol, 83%) and 7,70-trans-compoud (2 mg, 0.0023
Reaction of benzyl alcohol 13 with methanesulfonyl
chloride. Reaction for 1 h: recovered 13 (33%) and diol
20
14 (52%) as a colorless oil, ½ꢁꢃ
¼ þ7 (c 0.8, CHCl3).
D
ꢀH (CDCl3) 0.99 (9H, s, tert-BuSi), 1.04 (9H, s, tert-
BuSi), 2.17 (1H, m, CH), 2.56 (1H, m, CH), 3.33 (1H,
dd, J 10.3, 4.3 Hz, CHHOSi), 3.55 (1H, dd, J 10.3,
7.6 Hz, CHHOSi), 3.75 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 3.97 (1H, dd, J 11.0, 3.7 Hz, CHHOSi), 4.09
(1H, dd, J 11.0, 7.0 Hz, CHHOSi), 4.67 (1H, d, J 8.9 Hz,
ArCHOH), 5.19 (1H, d, J 5.3 Hz, ArCHOH), 5.89 (2H,
s, OCH2O), 6.50 (1H, d, J 7.9 Hz, ArH), 6.57 (1H, d, J
7.9 Hz, ArH), 6.63 (1H, s, ArH), 6.75 (1H, d, J 8.2 Hz,
ArH), 6.89 (1H, s, ArH), 6.92 (1H, d, J 8.2 Hz, ArH),
7.26–7.49 (16H, m, ArH), 7.56 (2H, d, J 6.9 Hz, ArH),
7.62 (2H, d, J 6.9 Hz, ArH); ꢀC (CDCl3) 19.08, 19.10,
26.9, 46.7, 48.6, 55.7, 55.9, 62.1, 64.3, 73.7, 75.3, 100.8,
106.8, 107.8, 109.5, 110.8, 118.5, 120.0, 127.57, 127.59,
127.69, 127.73, 129.64, 129.76, 129.81, 132.6, 132.8,
132.9, 133.0, 135.46, 135.51, 135.6, 136.3, 136.9, 146.9,
147.7, 147.8, 148.6; EIMS m=z (%): 882 (Mþ, 4), 448
(39), 253 (47), 199 (100), 135 (90). HREIMS (Mþ):
Calcd. for C53H62O8Si2, 882.3980. Found: 882.3977.
Reaction for 16 h: tetrahydrofuran derivative 10 (40%).
mmol, 13%) as a colorless oil. 7,70-trans-compound,
20
½ꢁꢃ
¼ ꢀ36 (c 0.1, CHCl3). ꢀH (CDCl3) 0.91 (9H, s,
D
tert-Bu), 0.93 (9H, s, tert-Bu), 2.33 (1H, m, 4-H), 2.68
(1H, m, 3-H), 3.49 (2H, d, J 5.2 Hz, CH2OTBDPS), 3.66
(3H, s, OCH3), 3.79–3.84 (1H, overlapped, CHHO-
TBDPS), 3.84 (3H, s, OCH3), 4.02 (1H, dd, J 10.3,
6.2 Hz, CHHOTBDPS), 5.13 (1H, d, J 6.7 Hz, ArCH),
5.37 (1H, d, J 6.0 Hz, ArCH), 5.93 (1H, s, OCHHO),
5.96 (1H, s, OCHHO), 6.66 (1H, d, J 8.3 Hz, ArH),
6.72–6.78 (3H, m, ArH), 6.81 (1H, s, ArH), 6.85 (1H, s,
ArH), 7.20–7.42 (16H, m, ArH), 7.48–7.71 (4H, m,
ArH); ꢀC (CDCl3) 18.95, 19.04, 26.77, 26.84, 47.8, 53.5,
55.6, 55.8, 60.5, 62.6, 82.2, 83.3, 100.9, 106.7, 108.0,
109.1, 110.8, 118.1, 119.6, 121.3, 122.3, 127.45, 127.48,
127.58, 127.59, 129.46, 129.52, 129.6, 132.3, 133.1,
133.2, 133.5, 135.4, 135.48, 135.50, 135.56, 137.7,
147.7, 148.6. EIMS m=z (%) 864 (Mþ, 0.3%), 433 (49),
252 (52), 199 (100). HREIMS (Mþ): Calcd. for
C53H60O7Si2, 864.3878. Found, 864.3881.
Reaction of benzyl alcohol 13 with methanesulfonic
anhydride. To an ice-cooled solution of benzyl alcohol
13 (41 mg, 0.041 mmol) and Et3N (7 ml, 0.050 mmol) in
CH2Cl2 (2 ml) was added Ms2O (8 mg, 0.046 mmol).
After the reaction solution was stirred at room temper-
ature for 1 h, H2O and CH2Cl2 were added. The organic
solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/hexane = 1/9 and 1/3) gave
tetrahydrofuran derivative 10 (6 mg, 0.0069 mmol,
Acknowledgments
Our thanks to the president of Ehime University for
supporting this project. The 400 MHz NMR data were
measured at INCS in Ehime University. We thank the

Synthesis of Stereoisomers of Virgatusin
2255
Stereocontrolled assembly of tetrasubstituted tetrahydro-
furans: a concise synthesis of virgatusin. Org. Lett., 7,
3685–3688 (2005).
staff at this center for the EIMS and FABMS measure-
ments. We are also grateful to Marutomo Co. (Iyo,
Ehime, Japan).
9) Thyagarajan, S. P., Subramanian, S., Thirunalasundari,
T., Venkateswaran, P. S., and Blumberg, B. S., Effect of
Phyllanthus amarus on chronic carriers of hepatitis B
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