A convenient synthesis of (±)-3-methoxybenzodioxane-4,9,9'-triol neolignan, and methyl ethers of isoamericanol A and isoamericanin A

Article abstract of DOI:10.1039/a807191h

The (±)-3-methoxybenzodioxane-4,9,9'-triol neolignan 9, and methyl ethers of isoamericanol A 8 and isoamericanin A 7 were synthesized from the readily available materials caffeic acid and ferulic acid, using a coupling reaction as a key step.

Full text of DOI:10.1039/a807191h

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1
00 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
999, 100±101$
A Convenient Synthesis of (2)-3-Methoxybenzodioxane- 1
0
4,9,9 -triol Neolignan, and Methyl Ethers of
Isoamericanol A and Isoamericanin A$
Xuegong She, Wenxin Gu, Tongxing Wu and Xinfu Pan*
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou Gansu 730000, P.R. China
The (2)-3-methoxybenzodioxane-4,9,9'-triol neolignan 9, and methyl ethers of isoamericanol A 8 and isoamericanin A 7
were synthesized from the readily available materials caffeic acid and ferulic acid, using a coupling reaction as a key
step.
Isoamericanol A, isoamericanin
A
and (2)-3-methoxy-
In order to study methods of construction of the 1,4-
benzodioxane ring and the structure±activity relationship,
we developed a facile synthetic route to (2)-3-methoxy-
benzodioxane-4,9,9'-triol neolignan 9, and methyl ethers of
isoamericanol A 7 and isoamericanin A 8, in which use of
silver carbonate as the oxidizing agent resulted in higher
regioselectivity (ca. 30:1) than that obtained with silver
benzodioxane-4,9,9'-triol neolignan are three neolignans iso-
lated from phytocaccaceae and Juniperns chinesis and were
1
,2
0
0
assigned structure 7 , 8 and 9 respectively through spectral
studies. In the literature it is reported that natural products
containing the 1,4-benzodioxane ring have cytotoxic and
3
hepatoprotective, and other biological activity associated
4
with the 1,4-benzodioxane group, but no syntheses of these
particular natural products have been reported.
5
oxide (ca. 20:1) by Merlini et al.
As shown in Scheme 1, 3-(3,4-dihydroxy)phenylprop-2-
enoate 5 and ferulic alcohol 3 were synthesized from the
starting materials ca€eic acid and ferulic acid based on an
3
earlier report, then compounds 3 and 5 were converted into
key intermediate 6 by a coupling reaction, which was then
reduced with LiAlH
7
4
±AlCl
was hydrogenated to get the target compound 9 and was
3
(3:1) to a€ord alcohol 7. Then
2 2
oxidized with MnO ±SiO to obtain compound 8.
Experimental
Melting points were measured on a Ko¯er apparatus and were
uncorrected. Mass spectra were recorded on a ZAB-HS spec-
trometer. Elemental analyses were performed on a Carlo-Erba 1106
instrument. IR spectra were recorded on a Nicolet 170 SXFT-IR
1
spectrometer. H NMR spectra were recorded on a Bruker Ac-80
3 2 4 4 3 2 3
Scheme 1 Reagents and conditions: i: CH OH, H SO , reflux; ii; LiAlH , AlCl room temp.; iii, Ag CO , acetone±benzene (1:2), room
temp.; iv, MnO ±SiO , CH Cl room temp.; v: H
2
2
2
2
2
, Pd/C (10%)
*To receive any correspondence.
4
and AM-400 instrument. Chemical shifts are referenced to Me Si on
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
the d scale. J values are in Hz. Standard ¯ash chromatography was
employed to purify the crude reaction mixture using ca. 2000300
mesh silica gel under positive nitrogen pressure.

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J. CHEM. RESEARCH (S), 1999 101
Methyl (E)-3-[2-Hydroxymethyl-3-(4-hydroxy-3-methoxyphenyl)-1,4-
benzodioxan-6-yl] propenoate 6.ÐSilver carbonate (270 mg) was
added to a solution of 190 mg of methyl 3-(3,4-dihydroxy)phenyl-
prop-2-enoate 5 and 180 mg of ferulic alcohol 3 in acetone±benzene
3
5.0, H-9), 3.74 (s, 3H, OCH ), 4.04 (m, 1H, H-7), 4.92 (d, 1H, J 8,
H-8), 4.11 (d, 1H, J 16, H-7'), 7.48 (d, 1H, J 16, H-8'), 6.80±7.22
(m, 6H, Ar-H), 9.53 (d, 1H, J 7.6, CHO); MS, m/z: 342 (M , 100),
‡
324 (45), 137 (30), 124 (20).
(2)-3-Methoxybenzodioxane-4,9,9'-triol Neolignan 9.ÐA solution
of 8 (30 mg) in methanol (30 ml) was hydrogenated over 10% Pd/C
(
®
1:2; 50 ml; the mixture was stirred for 20 h at room temperature,
ltered through silica gel, the solvent evaporated in vacuum and
the residue ¯ash chromatographed using light petroleum and ethyl
(5 mg) under H
through silica gel and preparative TLC a€orded 9 as a colorless oil,
2
for 40 min. Then the reaction mixture was ®ltered
acetate (2:1, v/v) as eluent to a€ord 6 as a white powder, 150 mg,
2
2
yield 40%, Mp 135±137 8C.
ꢀ
H
(400 MHz, [ H
6
]acetone); 3.50
), 3.84 (s, 3H,
), 4.30 (m, 1H, H-8), 4.98 (d, 1H, J 8, H-7), 6.40 (d, 1H,
29 mg, 97% yield; ꢀ
H 6
(400 MHz, [ H ]acetone): 1.78 (m, 2H, H-8'),
and 3.77 (dd, 2H, J 12, 4, H-9), 3.70 (s, 3H, OCH
3
2.58 (t, 2H, J 7.7, H-9'), 3.47 and 3.69 (dd, 1H, J 12, 4, H-9), 3.55
COOCH
3
(t, 2H, J 6.5, H-7'), 3.85 (s, SH, OCH
3
), 4.00 (m, 1H, H-8), 4.86
(d, 1H, J 8, H-7), 6.69±6.98 (m, 6H, Ar-H); MS, m/z: 346 (M , 89),
‡
J 16, H-7'), 6.65±6.96 (m, 3H, Ar-H), 7.58 (d, 1H, J 16, H-8'); MS,
m/z: 372 (M , 100), 354 (69), 205 (25), 137 (46), 124 (22).
Methyl Ether of Isoamericanol A 7.ÐCompound 6 (600 mg in
‡
328 (55), 180 (69), 166 (72), 137 (100), 123 (40).
All the spectral data were in good agreement with those
reported.
2
3
0 ml of THF) was added to a solution of stirred LiAlH
and AlCl 9220 mg) in 40 ml of diethyl ether. The mixture was
stirred at room temperature for 2 h, then saturated NH Cl was
4
(200 mg)
3
4
We are grateful to the National Science Foundation of
China for ®nancial support.
added, and the mixture stirred, extracted with ethyl acetate and
dried, the solvent was evaporated o€ and the crude product was
puri®ed by ¯ash chromatography using light petroleum and ethyl
acetate (2:1, v/v) as eluent to give a white powder of 7 (416 mg,
Received, 15th September 1998; Accepted, 19th October 1998
Paper E/8/07191H
7
5% yield), Mp 171±172 8C. Elemental analysis: C19
C, 66.27, H, 5.85. Found C, 66.7, H, 5.9%.
CD CN):3.38 and 3.57 (dd, 2H, J 12.4, 5.1, H-9), 3.60 (s, 3H,
OCH ), 4.10 (m, 2H, J 5.4, H-9'), 4.30 (m, 1H, J 8, 5.1, H-8), 4.87
d, 1H, J 8, H-7), 6.20 (m, 1H, J 16, H-8'), 6.46 (d, 1H, J 16, H-7'),
H
20
O
6
requires
ꢀ
H
(400 MHz,
3
3
(
‡
References
6
.80±7.20 (m, 6H, Ar-H); MS, m/z: 344 (M , 44), 326 (80), 180
(
60), 162 (73), 137 (100), 124 (60).
Methyl Ether of Isoamericanin A 8.ÐTo a solution of 70 mg of 7
1 Y. Fukuyama, T. Hasegawa, M. Kodama and H. Okazaki,
Chem. Pharm. Bull., 1992, 40(1), 252.
in 50 ml diethyl ether was added activated MnO
2
±SiO
2
(m/m 1:1);
00 mg; the mixture was stirred at room temperature for 24 h and
2 J.-M. Fang, C.-K. Lee and Y.-S. Cheng, Photochemistry, 1992,
31, 3659.
3 S. Antus, E. Baitz-Gacs, R. Bauer and H. Wagner, Liebigs Ann.
Chem., 1989, 1147.
6
®
¯
ltered through silica gel, the crude product was puri®ed by
ash chromatography using light petroleum and ethyl acetate (2:1,
v/v) as eluent to obtain 8 (55 mg) in 80% yield, Mp 165±167 8C.
4 (a) S. Yamauchi and E. Taniguchi, Biosci. Biotech. Biochem.,
1992, 56, 1751; (b) 1992, 50, 630.
5 L. Merlini and A. Zanarotti, J. Chem. Soc., Perkin Trans. 1,
1980, 775.
Elemental analysis: C19
H
18
O
8
requires C, 66.66, H, 5.30. Found
�
1
C, 66.5, H, 5.3%. ꢁ/cm (KBr): 3375, 2924, 2852, 1697, 1661, 1609,
2
1
H 6
578; ꢀ (400 MHz, [ H ]acetone): 3.38 and 3.60 (dd, 2H, J 12.3,