Synthesis of amino tetrahydrofuran lignan via an N,O-heterocyclic compound as an intermediate

Article abstract of DOI:10.1271/bbb.60575

Tetrahydrofuran aminolignans bearing an amino group at the 8 position were synthesized via an N,O-heterocyclic compound that had been obtained by silylnitronate cycloaddition.

Full text of DOI:10.1271/bbb.60575

Biosci. Biotechnol. Biochem., 71 (3), 741–745, 2007
Synthesis of Amino Tetrahydrofuran Lignan via an N,O-Heterocyclic
Compound as an Intermediate
y
2
Haruna HIRAO,1 Satoshi YAMAUCHI,1; and Fumio ISHIBASHI
1Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
2Faculty of Fisheries, Nagasaki University, 1-14 Bunkyo-Machi, Nagasaki 852, Japan
Received October 18, 2006; Accepted November 16, 2006; Online Publication, March 7, 2007
[doi:10.1271/bbb.60575]
Tetrahydrofuran aminolignans bearing an amino
group at the 8 position were synthesized via an N,O-
O
heterocyclic compound that had been obtained by
silylnitronate cycloaddition.
O
Key words: lignan; silylnitronate cycloaddition; amino-
lignan
OH
NH2
OH
9
7
Lignans are widely biosynthesized by plants, and
many types of biological activity have been reported
from many kinds of lignans1,2) In the case of the
cytotoxic lignan, podophyllotoxin, research on its
structure-activity relationship has been performed, and
podophyllotoxin derivatives containing nitrogen which
had strong cytotoxic activity3) have been synthesized.
The biologically active dibenzocyclooctene derivatives
containing a nitrogen atom have also been synthesized.4)
Derivatives of natural products containing nitrogen are
interesting for biological research. Although the syn-
thetic study of many kinds of lignans has also been
reported,5) there are no reports on a convenient synthesis
of aminolignans except for podophyllotoxin. Synthetic
study is important to develop research on the biological
activity of aminolignans.
8
O
H
H
1: R = H
2: R = OCH3
R
R
Fig. 1. Target Tetrahydrofuran Aminolignans 1 and 2 Bearing an
NH2 Group at the 8 Position.
In our previous study, some tetrahydrofuran lignans of
the oxidized type have been synthesized.6–11) In this
study, tetrahydrofuran aminolignans 1 and 2 were
adopted as targets (Fig. 1). Tetrahydrofuran lignans
having many kinds of biological activity are in one of
the important groups of natural lignans and oxidized
tetrahydrofuran lignans are known. These target com-
pounds have an amino group at the 8 position. The
synthesis of tetrahydrofuran lignans bearing an NH2
group attached to a primary or secondary carbon would
not be difficult to achieve by transformation from a
hydroxy group. However, a compound bearing an NH2
group attached to the tertiary carbon would be difficult.
To obtain the tetrahydrofuran aminolignan structure of 1
and 2, silylnitronate cycloaddition (Scheme 1)12) was
employed as the key reaction, giving N,O-heterocyclic
compound 4. The reduction of this N,O-heterocyclic
compound 4 was considered likely to give the target
compounds. The previous study has described the
production of an N,O-heterocyclic compound without a
1-substituent.12–15) To lead to the lignan structure, the
presence of a 1-substituent is important, this being the
reason for compound 3 being selected as a cyclization
substrate. The reaction conditions for silylnitronate
cycloaddition of olefin 3 bearing a hydroxymethyl
group needs to be considered in this study. This article
describes a convenient synthesis of an aminolignan
bearing an amino group attached to the 8 position of a
tetrahydrofuran lignan.
Results and Discussion
Substrate 8 for the silyl nitronate cycloaddition
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

742
H. HIRAO et al.
OTMS
OTMS
HO
Ar
O
OTMS
O
TMS-Cl
Ar
O
H
N+
H
N
N+
Et3N
toluene
-
O
1
-
O
O
O
Ar
H
Ar
Ar
H
H
Ar
OTMS
3
4
Scheme 1. Intramolecular Silyl Nitronate Cycloaddition Giving 1-Substituted 4,8-Diaryl-2-aza-3,7-dioxabicyclo[3.3.0]octane.
O2N
O
OH
CHO
O2N
O
a
b
c
R
R
NO2
O
O
O
O
O
O
O
5
6
7: R = H
O
10: R = OCH3
O
OTMS
OTMS
O
N
O
d
e
f
O
O
1, 2
OH
R
R
NO2
H
O
R
8: R = H
9: R = H
12: R = OCH3
R
11: R = OCH3
Scheme 2. Synthesis of Tetrahydrofuran Aminolignans 1 and 2.
(a) NaOH, CH3NO2, NaOH, aq. MeOH, 10–15 ꢀC, 1 h (67% yield); (b) KHSO4, toluene, reflux, 1 h (74% yield); (c) NaH, cinnamyl alcohol or
30,40-dimethoxycinnamyl alcohol, THF, ꢁ75 ꢀC, 2 h (7, 88% yield; 10, 62% yield); (d) (CH2O)n, KF, DMSO, r.t., 3 h (Rf 0.16-8, 12% yield; Rf
0.06-8, 36% yield; 11, 46% yield); (e) Method 1, TMSCl, Et3N, toluene, r.t., 48 h (from Rf 0.06-8, 0–68% yield; from Rf 0.16-8, 0% yield);
Method 2, N,O-bis(trimethylsilyl)acetamide, Et3N, CH3CN, toluene, 85 ꢀC, 24 h (from Rf 0.06-8, 100% yield; from Rf 0.16-8, 100% yield; from
11, 79% yield); (f) Mo(CO)6, NaBH4, aq. CH3CN, reflux, 10 min (1, 73% yield; 2, 100% yield).
reaction was prepared from piperonal (Scheme 2). After
piperonal had been exposed to a condensation reaction
with nitromethane by using sodium hydroxide (67%
yield), resulting alcohol 5 was subjected to dehydrox-
ylation by treatment with KHSO4 in refluxing toluene
to give alkene 616) in 74% yield. The 1,4-addition of
cinnamyl alcohol to nitroalkene 6 was achieved by using
NaH, giving nitro compound 7 in 88% yield. Substrate
8 for the silylnitronate cycloaddition reaction was
obtained as two separable diastereomers (Rf 0.06, silica
gel, EtOAc/hexane = 1/6; and Rf 0.16, silica gel,
EtOAc/hexane = 1/6) by the condensation reaction of
nitro compound 7 with paraformaldehyde using KF in
DMSO in 48% yield. Due to its instability, this substrate
was immediately used for the next intramolecular
cyclization reaction.
triethylamine in toluene. N,O-heterocyclic compound
9 was sometimes obtained in 68% maximum yield,
although there was little reproducibility. In most cases,
decomposed products containing piperonal were yield-
ed, giving no desired product. The other diastereomer of
8 (Rf 0.16) did not produce N,O-heterocyclic compound
9 by this method. It was assumed that the instability of
the trimethylsilyl ether of the cyclization intermediate or
desired compound caused decomposition. However,
the adoption of chlorotriethylsilane did not improve
the yield, while the use of the other bases, pyridine and
N,N,-diisopropylethylamine, did not give desired N,O-
heterocyclic compound 9. On the presumption that the
hydrochloric acid salt of the base would decompose the
intermediate or desired cyclic compound, N,O-bis(tri-
methylsilyl)acetamide was employed instead of chloro-
trimethylsilane17) as an alternative method. This attempt
succeeded, namely, the important synthetic intermedi-
ate, N,O-heterocyclic compound 9, was obtained in a
The intramolecular silylnitronate cycloaddition reac-
tion of one of the diastereomers of 8 (Rf 0.06) was
initially attempted by using chlorotrimethylsilane and

Synthesis of Aminolignan
743
quantitative yield by a treatment with N,O-bis(tri-
methylsilyl)acetamide and triethylamine in heated tol-
uene–CH3CN (10:1). Compound 9 having the same
stereochemistry was obtained from both diastereomers
of 8. The steric configuration of 9 was determined by a
differential NOE experiment. The presence of NOE
between both benzylic positions revealed the cis form,
no production of the trans form being apparent. The
silylnitronate cycloaddition which gave a 4,8-diaryl-2-
aza-3,7-dioxabicylo[3.3.0]octane structure bearing the
1-substituent was achieved stereoselectively by treat-
ment of the acyclic substance with N,O-bis(trimethylsil-
(E)-1-(3,4-Methylenedioxyphenyl)-2-nitroethene (6).
A reaction mixture of benzyl alcohol 5 (4.43 g, 0.021
mmol) and KHSO4 (2.85 g, 0.021 mol) in toluene
(80 ml) was heated under refluxing for 1 h before
addition of H2O. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by recrystallization (MeOH) gave alkene 6
(3.09 g, 0.016 mol, 74%) as yellowish crystals, mp 140–
141 ꢀC. NMR ꢀH (acetone-d6): 6.13 (2H, s, OCH2O),
6.97 (1H, d, J ¼ 8:3 Hz, ArH), 7.33–7.39 (2H, m, ArH),
7.87 (1H, d, J ¼ 13:7 Hz, 1-H), 8.01 (1H, d, J ¼ 13:7
Hz, 2-H). NMR ꢀC (CDCl3): 103.6, 108.5, 110.1, 126.0,
128.5, 137.3, 140.2, 150.2, 152.7. Anal. Found: C,
55.86; H, 3.68; N, 7.24%. Calcd. for C9H7NO4: C,
55.96; H, 3.65; N, 7.25%.
yl)acetamide and triethylamine. Finally, reduction with
18,19)
Mo(CO)6 and NaBH4
gave aminolignan 1 in 71%
yield. Aminolignan 2 was also obtained by the same
synthetic method. In this synthetic process, substrate 11
for cyclization was obtained as a single isomer. The
production of many by-products was observed in the
reaction of 10 with formaldehyde.
Aminolignans 1 and 2 were synthesized by 7 steps in
15% and 11% overall yields, respectively. As the key
reaction, silyl nitronate cycloaddition was employed,
giving the important intermediate, N,O-heterocyclic
compound 4. This is first example of silylnitronate
cycloaddition giving 4,8-diaryl-2-aza-3,7-dioxabicy-
lo[3.3.0]octane bearing the 1-substituent. This is also a
convenient new synthetic method for producing an
amino tetrahydrofuran lignan, in which the amino group
is attached to the tertiary carbon (8 position).
1-Cinnamyloxy-1-(3,4-methylenedioxyphenyl)-2-nitro-
ethane (7). To a suspension of NaH (0.20 g, 60% in
mineral oil, 5.00 mmol), which was washed with hexane,
in THF (10 ml) was added a solution of cinnamyl
alcohol (0.70 g, 5.22 mmol) in THF (20 ml) at 10–15 ꢀC,
and then the mixture was stirred for 1 h at room
temperature. After the solution was cooled to ꢁ75 ꢀC,
alkene 6 (0.50 g, 2.59 mmol) in THF (20 ml) was added.
The reaction mixture was stirred for 2 h at ꢁ78 ꢀC, and
then sat. aq. NH4Cl was added. The aqueous solution
was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc/hexane = 1/6) gave nitro compound
7 (0.75 g, 2.29 mmol, 88%) as a yellowish oil. NMR
ꢀH (CDCl3): 3.97 (1H, dd, J ¼ 12:5, 6.6 Hz, ArCH=
CHCHHO), 4.14 (1H, ddd, J ¼ 12:5, 5.4, 1.5 Hz,
ArCH=CHCHHO), 4.37 (1H, dd, J ¼ 12:7, 3.4 Hz,
CHHNO2), 4.63 (1H, dd, J ¼ 12:7, 9.8 Hz, CHHNO2),
5.09 (1H, dd, J ¼ 9:8, 3.4 Hz, ArCH), 5.98 (2H, s,
OCH2O), 6.18 (1H, m, ArCH=CH), 6.50 (1H, d, J ¼
15:6 Hz, ArCH=CH), 6.81–6.87 (3H, m, ArH), 7.22–
7.36 (5H, m, ArH). NMR ꢀC (CDCl3): 69.4, 77.0, 80.3,
101.4, 106.9, 108.6, 120.8, 124.9, 126.5, 127.8, 128.5,
130.0, 133.1, 136.4, 148.3, 148.4. Anal. Found: C,
66.32; H, 5.29; N, 4.17%. Calcd. for C18H17NO5: C,
66.05; H, 5.23; N, 4.28%.
Experimental
All melting point (mp) data are uncorrected. NMR
data were measured by a JNM-EX400 spectrometer, and
EIMS data were measured with a JMS-MS700V
spectrometer. The silica gel used was Wakogel C-300
(Wako, 200–300 mesh). The numbering of compounds
follows the IUPAC nomenclatural rules.
1-(3,4-Methylenedioxyphenyl)-2-nitro-1-ethanol (5).
To an ice-cooled solution of piperonal (54.0 g, 0.36
mol) in methanol (300 ml) was added an aqueous
solution of sodium hydroxide (17.3 g, 0.43 mol) in
H2O (35 ml) and nitromethane (25.0 ml, 0.46 mol) at
10–15 ꢀC. The reaction solution was stirred at 10–15 ꢀC
for 1 h, and then a sat. aq. NH4Cl solution was added.
After the resulting mixture was filtered, the crude
crystals were washed with water, dried, and then
recrystallized from benzene to give nitro compound 5
(50.3 g, 0.24 mol, 67%) as yellowish crystals, mp 85–
86 ꢀC. NMR ꢀH (CDCl3): 2.81 (1H, d, J ¼ 3:4 Hz, OH),
4.46 (1H, dd, J ¼ 13:3, 3.2 Hz, CHHNO2), 4.57 (1H, dd,
J ¼ 13:3, 9.3 Hz, CHHNO2), 5.37 (1H, m, ArCHOH),
5.98 (2H, s, OCH2O), 6.80–6.89 (3H, m, ArH). NMR ꢀC
(CDCl3): 70.8, 81.2, 101.4, 106.3, 108.6, 119.6, 132.0,
148.1, 148.2. Anal. Found: C, 51.14; H, 4.25; N, 6.72%.
Calcd. for C9H9NO5: C, 51.19; H, 4.30; N, 6.63%.
1-[(E)-3-(3,4-Dimethoxyphenyl)-2-propenyloxy]-1-(3,
4-methylenedioxyphenyl)-2-nitroethane (10). 62% yield,
a yellowish oil. NMR ꢀH (CDCl3): 3.87 (3H, s, OCH3),
3.89 (3H, s, OCH3), 3.89–3.98 (1H, overlapped, ArCH=
CHCHH), 4.13 (1H, m, ArCH=CHCHHO), 4.37 (1H,
dd, J ¼ 12:7, 3.4 Hz, CHHNO2), 4.62 (1H, dd, J ¼ 12:7,
10.4 Hz, CHHNO2), 5.09 (1H, dd, J ¼ 9:8, 3.4 Hz,
ArCHOR), 5.98 (2H, s, OCH2O), 6.05 (1H, m, ArCH=
CH), 6.44 (1H, d, J ¼ 15:6 Hz, ArCH=CH), 6.79–6.92
(6H, m, ArH). NMR ꢀC (CDCl3): 55.8, 55.9, 69.5, 76.9,
80.4, 101.4, 106.9, 108.6, 108.9, 111.1, 119.8, 120.8,
121.9, 122.9, 129.5, 130.1, 133.1, 148.4, 149.0, 149.1.
Anal. Found: C, 61.85; H, 5.47; N, 3.59%. Calcd. for
C20H21NO7: C, 62.01; H, 5.46; N, 3.62%.

744
H. HIRAO et al.
3-Cinnamyloxy-3-(3,4-methylenedioxyphenyl)-2-nitro-
brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (5% EtOAc/hexane)
gave N,O-hetero compound 9 (1.50 g, 2.99 mmol, 68%)
as colorless crystals, mp 108–110 ꢀC (iso-Pr2O). Method
2: A reaction solution of hydroxymethyl nitro compound
8 (Rf 0.06, 0.30 g, 0.84 mmol), N,O-bis(trimethylsilyl)-
acetamide (0.80 ml, 3.27 mmol), and Et3N (0.08 ml,
0.57 mmol) in toluene (5 ml) and MeCN (0.5 ml) was
stirred at 85 ꢀC for 24 h under N2 gas. After additions of
H2O and EtOAc, the organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (5%
EtOAc/hexane) gave 9 (0.42 g, 0.84 mmol, 100%).
From diastereomer 8 (Rf 0.16), 9 was also obtained in
100% yield. NMR ꢀH (CDCl3): ꢁ0:10 (9H, s, Si(CH3)3),
0.14 (9H, s, Si(CH3)3), 3.38 (1H, d, J ¼ 10:1 Hz,
TMSOCHH), 3.46 (1H, m, 5-H), 3.69 (1H, d, J ¼
10:1 Hz, TMSOCHH), 4.20 (1H, d, J ¼ 8:3 Hz, 6-HH),
4.46 (1H, dd, J ¼ 8:3, 5.9 Hz, 6-HH), 5.03 (1H, s, 8-H),
5.27 (1H, d, J ¼ 5:4 Hz, 4-H), 5.91 (1H, d, J ¼ 14:2 Hz,
OCHHO), 5.96 (1H, d, J ¼ 14:2 Hz, OCHHO), 6.77
(1H, d, J ¼ 7:8 Hz, ArH), 6.91 (1H, d, J ¼ 8:8 Hz,
ArH), 7.00 (1H, s, ArH), 7.25–7.36 (3H, m, ArH), 7.52–
7.54 (2H, m, ArH). NMR ꢀC (CDCl3): ꢁ1:09, ꢁ0:46,
56.5, 60.9, 73.6, 84.0, 89.4, 92.9, 100.7, 107.2, 107.5,
119.2, 127.3, 127.5, 128.1, 132.6, 141.9, 146.5, 147.0.
Anal. Found: C, 59.90; H, 6.90; N, 2.81%. Calcd. for
C25H35NO6Si2: C, 59.85; H, 7.03; N, 2.79%.
1-propanol (8). A reaction mixture of nitro compound 7
(1.00 g, 3.05 mmol), KF (0.18 g, 3.10 mmol), and paraf-
ormaldehyde (0.60 g) in DMSO (20 ml) was stirred at
room temperature for 3 h, and then sat. aq. NH4Cl and
EtOAc were added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/
hexane = 1/6) gave hydroxymethyl nitro compound 8
(Rf 0.16, silica gel, EtOAc/hexane = 1/6, 0.13 g, 0.36
mmol, 12%) as a yellowish oil and 8 (Rf 0.06, silica gel,
EtOAc/hexane = 1/6, 0.39 g, 1.09 mmol, 36%) as a
yellowish oil. Because both diastereomers were unsta-
ble, these compounds were immediately used for the
next reaction. Rf (0.16)-8, NMR ꢀH (CDCl3): 2.38 (1H,
br. s, OH), 3.95 (1H, ddd, J ¼ 12:5, 6.8, 1.5 Hz, ArCH=
CHCHH), 4.10 (1H, m, HOCHH), 4.15 (1H, ddd, J ¼
12:5, 5.5, 1.5 Hz, ArCH=CHCHH), 4.30 (1H, m,
HOCHH), 4.67 (1H, m, CHNO2), 4.99 (1H, d, J ¼ 6:8
Hz, ArCHOR), 5.98 (2H, s, OCH2O), 6.17 (1H, m,
ArCH=CH), 6.51 (1H, d, J ¼ 15:6 Hz, ArCH=CH),
6.75–6.89 (3H, m, ArH), 7.23–7.42 (5H, m, ArH). NMR
ꢀC (CDCl3): 60.4, 69.8, 78.9, 92.4, 101.4, 107.0, 108.5,
121.0, 124.4, 126.5, 127.8, 128.5, 128.6, 129.7, 133.6,
136.2, 148.2. Rf (0.06)-8. NMR ꢀH (CDCl3): 1.99 (1H,
br. s, OH), 3.71 (2H, m, HOCH2), 3.90 (1H, dd, J ¼
12:2, 6.8 Hz, ArCH=CHCHHO), 4.10 (1H, dd, J ¼
12:2, 5.1 Hz, ArCH=CHCHHO), 4.77 (1H, ddd, J ¼
9:8, 6.3, 3.4 Hz, CHNO2), 4.89 (1H, d, J ¼ 9:8 Hz,
ArCHOR), 6.00 (2H, s, OCH2O), 6.12 (1H, m,
ArCH=CH), 6.46 (1H, d, J ¼ 16:1 Hz, ArCH=CH),
6.69–6.90 (3H, m, ArH), 7.22–7.36 (5H, m, ArH). NMR
ꢀC (CDCl3): 61.1, 69.2, 78.1, 93.1, 101.4, 107.3, 108.6,
121.6, 124.8, 126.6, 127.8, 128.5, 133.2, 136.4, 148.5.
(1Rꢂ,4Sꢂ,5Rꢂ,8Rꢂ)-4-(3,4-Dimethoxyphenyl)-8-(3,4-
methylenedioxyphenyl)-2-(trimethylsilyloxy)-1-(trimethyl-
silyloxy)methyl-2-aza-3,7-dioxabicyclo[3.3.0]octane (12).
79% yield, colorless crystals, mp 105 ꢀC (iso-Pr2O).
NMR ꢀH (CDCl3): ꢁ0:08 (9H, s, Si(CH3)3), 0.17 (9H, s,
Si(CH3)3), 3.40 (1H, d, J ¼ 10:1 Hz, TMSOCHH), 3.41
(1H, m, 5-H), 3.71 (1H, d, J ¼ 10:1 Hz, TMSOCHH),
3.88 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.19 (1H, d,
J ¼ 8:4 Hz, 6-HH), 4.42 (1H, dd, J ¼ 8:4, 5.5 Hz, 6-
HH), 5.04 (1H, s, 8-ArCH), 5.20 (1H, d, J ¼ 6:2 Hz, 4-
ArCH), 5.93 (1H, d, J ¼ 5:8 Hz, OCHHO), 5.94 (1H, d,
J ¼ 5:8 Hz, OCHHO), 6.77 (1H, d, J ¼ 8:1 Hz, ArH),
6.81 (1H, d, J ¼ 8:2 Hz, ArH), 6.92 (1H, d, J ¼ 7:8 Hz,
ArH), 6.97–7.00 (2H, m, ArH), 7.24 (1H, d, J ¼ 1:8 Hz,
ArH). NMR ꢀC (CDCl3): ꢁ1:13, ꢁ0:39, 55.8, 55.9,
56.6, 60.8, 73.2, 83.7, 89.2, 93.3, 100.7, 107.2, 107.4,
110.4, 110.9, 119.2, 119.8, 132.4, 134.0, 146.5, 147.0,
148.7, 149.0. EIMS m=z: 561 (Mþ, 73), 239 (100).
HRMS (EI) m=z (Mþ): calcd. for C27H39NO8Si2,
561.2214; found, 561.2213.
1-[(E)-3-(3,4-Dimethoxyphenyl)-2-propenyloxy]-1-(3,
4-methylenedioxyphenyl)-2-nitro-1-propanol (11). 46%
yield, a yellowish oil. NMR ꢀH (CDCl3): 1.98 (1H, br.
s), 3.70–3.73 (2H, m, HOCH2), 3.86–3.92 (1H, over-
lapped, ArCH=CHCHHO), 3.87 (3H, s, OCH3), 3.89
(3H, s, OCH3), 4.08 (1H, ddd, J ¼ 12:5, 5.6, 1.0 Hz,
ArCHCHCHHO), 4.76 (1H, ddd, J ¼ 9:8, 6.4, 3.4 Hz,
CHNO2), 4.88 (1H, d, J ¼ 9:8 Hz, ArCHOR), 5.99 (2H,
s, OCH2O), 5.94–6.03 (1H, overlapped, ArCH=CH),
6.39 (1H, d, J ¼ 15:9 Hz, ArCH=CH), 6.79–6.91 (6H,
m, ArH). NMR ꢀC (CDCl3): 55.9, 56.0, 61.2, 69.5, 78.2,
93.2, 101.5, 107.4, 108.7, 109.0, 111.2, 120.0, 121.7,
122.9, 129.6, 129.6, 133.2, 148.6, 149.1.
(1Rꢂ,4Sꢂ,5Rꢂ,8Rꢂ)-8-(3,4-Methylenedioxyphenyl)-4-
phenyl-2-(trimethylsilyloxy)-1-(trimethylsilyloxy)methyl-
2-aza-3,7-dioxabicyclo[3.3.0]octane (9). Method 1: A
reaction mixture of a solution of hydroxymethyl nitro
compound 8 (Rf 0.06, 1.56 g, 4.37 mmol), TMSCl
(3.12 ml, 24.4 mmol), and Et3N (2.80 ml, 20.1 mmol)
in toluene (20 ml) was stirred at room temperature for
48 h under N2 gas, and then H2O and EtOAc were
added. The organic solution was separated, washed with
(2Rꢂ,3Rꢂ,4Rꢂ)-3-Amino-3-hydroxymethyl-4-[(Sꢂ)-(hy-
droxy)(phenyl)methyl]-2-(3,4-methylenedioxyphenyl)tet-
rahydrofuran (1). To a solution of 2-aza-3,7-dioxabicy-
clo[3.3.0]octane 9 (1.00 g, 1.99 mmol) in MeCN (20 ml)
and H2O (1 ml) were added Mo(CO)6 (0.20 g, 0.76
mmol) and NaBH4 (0.30 g, 7.93 mmol). After the
reaction mixture was heated under refluxing for 10
min, the mixture was cooled by ice for 1 h. The resulting

Synthesis of Aminolignan
745
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active olivil type of lignan from L-arabinose using threo-
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synthesis of (+)-magnostellin C, a tetrahydrofuran type
of lignan bearing a chiral secondary benzyl alcohol.
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solid inorganic by-products were filtered off. Concen-
tration of the filtrate, followed by silica gel column
chromatography (EtOAc) gave aminolignan 1 (0.50 g,
1.46 mmol, 73%) as colorless crystals, mp 132–134 ꢀC
(CHCl3). NMR ꢀH (C5D5N): 2.97 (1H, ddd, J ¼ 10:0,
10.0, 7.8 Hz, 4-H), 3.61 (1H, d, J ¼ 10:5 Hz, CHHOH),
3.68 (1H, d, J ¼ 10:5 Hz, CHHOH), 3.79 (1H, dd, J ¼
10:7, 8.8 Hz, 5-HH), 3.89 (1H, dd, J ¼ 10:7, 8.8 Hz, 5-
HH), 5.04 (1H, s, 2-H), 5.21 (1H, d, J ¼ 9:8 Hz,
ArCHOH), 5.93 (2H, s, OCH2O), 6.90 (1H, d, J ¼
8:3 Hz, ArH), 7.09 (1H, dd, J ¼ 8:3, 1.5 Hz, ArH), 7.27
(1H, d, J ¼ 1:5 Hz, ArH), 7.30–7.34 (1H, m, ArH),
7.38–7.57 (2H, m, ArH), 7.62–7.64 (2H, m, ArH). NMR
ꢀC (C5D5N): 55.0, 65.7, 68.9, 70.3, 72.0, 91.8, 101.4,
107.7, 108.1, 120.2, 127.3, 127.9, 128.7, 134.0, 145.2,
147.3, 147.9. Anal. Found: C, 66.23; H, 6.18; N, 4.05%.
Calcd. for C19H21NO5: C, 66.46; H, 6.16; N, 4.08%.
10) Yamauchi, S., Hayashi, Y., Kirikihira, T., and Masuda,
T., Synthesis and antioxidant activity of olivil-type
lignans. Biosci. Biotechnol. Biochem., 69, 113–122
(2005).
11) Yamauchi, S., Okazaki, M., Akiyama, K., Sugahara, T.,
Kishida, T., and Kashiwagi, T., First enantioselective
synthesis of (ꢁ)- and (+)-virgatusin, tetra-substituted
tetrahydrofuran lignan. Org. Biomol. Chem., 3, 1670–
1675 (2005).
12) Huang, K. S.-L., Lee, E. H., Olmstead, M. M., and
Kurth, M. J., Sequential 1,3-dipolar cycloadditions in the
synthesis of bis-isoxazolo substituted piperidinones.
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13) Jiang, S., Singh, G., and Batsanov, A. S., Synthesis of a
difluorinated carbasugar from D-ribose via intramolecu-
lar nitrone cycloaddition reaction. Tetrahedron: Asym-
metry, 11, 3873–3877 (2000).
(2Rꢂ,3Rꢂ,4Rꢂ)-3-Amino-3-hydroxymethyl-4-[(Sꢂ)-(hy-
droxy)(3,4-dimethoxyphenyl)methyl]-2-(3,4-methylenedi-
oxyphenyl)tetrahydrofuran (2). 100% yield, colorless
crystals, mp 130–131 ꢀC (acetone). NMR ꢀH (C5D5N):
3.05 (1H, ddd, J ¼ 10:0, 10.0, 7.9 Hz, 4-HH), 3.62 (1H,
d, J ¼ 10:5 Hz, CHHOH), 3.70 (1H, d, J ¼ 10:5 Hz,
CHHOH), 3.74 (3H, s, OCH3), 3.77 (3H, s, OCH3),
3.88–3.97 (2H, m, 5-H2), 5.07 (1H, s, 2-H), 5.23 (1H, d,
J ¼ 9:7 Hz, ArCHOH), 5.95 (2H, s, OCH2O), 6.91 (1H,
d, J ¼ 7:9 Hz, ArH), 6.96 (1H, d, J ¼ 8:2 Hz, ArH), 7.12
(1H, dd, J ¼ 7:9, 1.3 Hz, ArH), 7.18 (1H, dd, J ¼ 8:2,
1.9 Hz, ArH), 7.29 (1H, d, J ¼ 1:3 Hz, ArH), 7.37 (1H,
d, J ¼ 1:9 Hz, ArH). NMR ꢀC (C5D5N): 55.0, 55.8, 55.9,
65.6, 69.0, 70.4, 72.0, 91.9, 101.4, 107.8, 108.1, 111.3,
112.2, 119.5, 120.3, 134.0, 137.8, 147.4, 148.0, 149.5.
EIMS m=z: 403 (Mþ, 81), 235 (97), 167 (100), 139 (71).
HRMS (EI) m=z (Mþ): calcd. for C21H25NO7, 403.1632;
found, 403.1635.
14) Zhao, Q., Han, F., and Romero, D., A stereoselective
intermediate 1,3-dipolar nitrone cycloaddition for the
synthesis of substituted chromanes. J. Org. Chem., 67,
3317–3322 (2002).
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Alexander, R., Highly diastereoselective nitrone cyclo-
addition onto a chiral ketene equivalent: asymmetric
synthesis of cispentacin. Org. Lett., 4, 1227–1229
(2002).
16) Kamlet, M. J., The Michael reaction in non-alkaline
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trolled synthesis of trans-2-hydroxymethyl-3-methylcy-
clopentanone from (S)-(+)-citronellene. Russ. Chem.
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Acknowledgments
We measured the 400 MHz NMR and MS data at
INCS of Ehime University. We are grateful to
Marutomo Co. for financial support.
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