Total synthesis of (±)-Eusiderin K and (±)-Eusiderin J

Article abstract of DOI:10.1081/SCC-100103321

(±)-Eusiderin K and (±)-Eusiderin J were first synthesized from pyrogallol, in which the Claisen Rearrangement was used to afford two important C₆-C₃ units.

Full text of DOI:10.1081/SCC-100103321

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TOTAL SYNTHESIS OF (±)-
EUSIDERIN K AND (±)-
EUSIDERIN J
Xiaobi Jing a , Wenxin Gu a , Pingyan Bie a
Xinfeng Ren a & Xinfu Pan b
,
a Department of Chemistry, National Laboratory
of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P. R. China
b Department of Chemistry, National Laboratory
of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P. R. China
Version of record first published: 09 Nov 2006.
To cite this article: Xiaobi Jing , Wenxin Gu , Pingyan Bie , Xinfeng Ren & Xinfu
Pan (2001): TOTAL SYNTHESIS OF (±)-EUSIDERIN K AND (±)-EUSIDERIN J, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:6, 861-867
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SYNTHETIC COMMUNICATIONS, 31(6), 861–867 (2001)
TOTAL SYNTHESIS OF (ꢀ)-EUSIDERIN K
AND (ꢀ)-EUSIDERIN J
Xiaobi Jing, Wenxin Gu, Pingyan Bie, Xinfeng Ren,
and XinfuPan *
Department of Chemistry, National Laboratory of
Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
ABSTRACT
(ꢀ)-Eusiderin K and (ꢀ)-Eusiderin J were first synthe-
sized from pyrogallol, in which the Claisen Rearrangement
was used to afford two important C6-C3 units.
(ꢀ)-Eusiderin K and (ꢀ)-Eusiderin J (Fig. 1) are two neolignans iso-
lated from the bark and calyx of Licaria chrysophylla.1 This type of natural
products containing the 1,4-benzodioxane ring have cytotoxic, hepatopro-
tective,2 and other biological activity.3
Figure 1.
* Corresponding author.
861
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

862
JING ET AL.
Although many syntheses of 1,4-benzodioxane neolignans have been
reported,4–6 the synthesis of l,4-benzodioxane neolignans that have
4-hydroxy-3,5-dimethoxy aryl groups have not been reported, because it is
difficult to synthesize the C6-C3 units of 4-hydroxy-3,5-dimethoxy aryl
group. Herein, we developed a facile synthetic route to (ꢀ)-Eusiderin K
and (ꢀ)-Eusiderin J, in which the Claisen Rearrangement reaction was
used to afford the 4-hydroxy-3,5-dimethoxy aryl group (5) and 3,4-dihy-
droxy-5-methoxy aryl group (9).
As shown in Scheme 1, pyrogallol was easily converted into trimethyl
pyrogallol (2). Treatment of 2 with ZnCl2 and propionic acid gave 2,6-
dimethoxy phenol (3) in 81% yield.7 Compound 4, readily available in
rear quantitative yield by the reaction of 3 with allyl bromide, was submitted
to a Claisen Rearrangement in a sealed tube to give (5) in >99% yield.
Compound 5 was treated with PdCl2 in methanol to afford compound (6) in
88% yield.
Reagents and Conditions i: NaOH, (CH3)2SO4, 98%; ii: ZnCl2, propionic acid, reflux,
81%; iii: K2CO3, Allyl bromide, 90%; iv: Claisen Rearrangement, >99%; v: PdCl2,
methanol, 88%; vi: Na2B4O7Á10H2O, K2CO3, (CH3)2SO4, 85%; vii: Ag2O, benzene/
acetone(5:1, v/v), 40%; viii: KOH, CH3I, acetone, 95%.
Scheme 1.
Synthesis of the other unit (9) also began from pyrogallol, which was
selectively protected by (CH3)2SO4 under the protection of Na2B4O7ꢁ10H2O

(Æ)-EUSIDERIN K AND (Æ)-EUSIDERIN J
863
to afford compound (7), which was converted into compound (8) and (9) in
high yield by a procedure similar to that used for 5.
Compounds 6 and 9 were converted into (ꢀ)-Eusiderin K as a mixture
1
of isomer (cis and trans ca. 1:7 by HMR)8 with silver oxide as a oxidizing
reagent. Then (ꢀ)-Eusiderin K was protected by CH3I in a base condition to
afford trans-(ꢀ)-Eusiderin J. In this reaction, cis isomer was converted to
trans isomer exclusively in a base condition.5
EXPERIMENTAL
Melting points were measured on a Kofler apparatus and were uncor-
rected. Mass spectra were recorded on a ZAB-HS spectrometer. Elemental
analyses were performed on a Carlo-Erba 1106 instruments. 1H NMR spec-
tra were recorded on a Bruker AC-80 and AM-400 instruments. 13C NMR
spectra were recorded on a Bruker AM-400 instrument. Chemical shifts are
referenced to TMS on the ‘‘ꢀ’’ scale. Standard flash chromatography was
employed to purify the crude reaction mixture using 200–300 mesh silica gel
under a positive nitrogen pressure.
1,2,3-Trimethoxy-benzene 2
To a stirred solution of pyrogallol 1 (2.00 g, 15.9 mmol) in 25 mL
acetone was added NaOH (1.9 g). The mixture was stirred at room tempera-
ture for 30 m under the atmosphere of nitrogen and (CH3)2SO4 (4.6 mL,
47.6 mmol) was added dropwise over 15 m. The mixture was stirred for
10 h at room temperature. The solvent was evaporated in vacuum. Crude
products were dissolved in water and then extracted with Et2O (50 mLꢂ3).
The combined extracts were dried (Na2SO4), the Et2O was distilled off, and
the residue was flash chromatographed using petroleum ether and ethyl
acetate (50:1, v/v) as eluent to afford 2 (2.6 g, yield 98%) as a white solid,
m.p. 41ꢃ–42ꢃC; EI-MS (m/z): 168 (Mþ, 100), 153(70), 125 (47), 110 (55),
1H NMR (80 MHz, DCCl3): ꢀ 3.81 (s, 9H, -Me), 6.39–7.09 (m, 3H, Ar-H).
1,3-Dimethoxy-2-hydroxy-benzene 3
To a stirred solution of anhydrous ZnCl2 (3g, 0.022 mol) in 20 mL
propionic acid was added dropwise the solution of 2 (2.5 g, 0.015 mol) in
10 mL propionic acid over 5 m. Then the solution was refluxed for 2 h under
the atmosphere of nitrogen. The solvent was evaporated in vacuo. Crude

864
JING ET AL.
products were dissolved in water and then extracted with Et2O (20 mLꢂ3).
The combined extracts were dried (Na2SO4). The Et2O was distilled off. The
residue was flash chromatographed using petroleum ether and ethylacetate
(6:1, v/v) as eluent to afford the white solid of 3 (1.86 g) m.p. 46ꢃ–47ꢃC;
EI-MS (m/z): 154 (Mþ, 100), 139 (55), 114 (45), 96 (40); 1H NMR (80 MHz,
DCCl3): ꢀ 3.86 (s, 6H, -Me), 6.71–7.10 (m, 3H, Ar-H).
2-Allyoxy-1,3-dimethoxy-benzene 4
Under nitrogen atmosphere, the solution of 3 (1.5 g, 0.0097 mol) in
20 mL acetone was added NaOH (0.39 g, 0.0097 mol). After stirring for
30 m to the mixture was added allyl bromide (0.84 mL, 0.0097 mol) over
30 m. The mixture was then stirred for 6 h at room temperature. The solvent
was evaporated in vacuo. Crude products were dissolved in water and then
extracted with Et2O (50 mLꢂ3). The combined extracts were dried
(Na2SO4). The Et2O was distilled off. The residue was flash chromato-
graphed using petroleum ether as eluent to afford a yellow liquid 4
(1.86 g). EI-MS (m/z): 194 (Mþ, 24), 153(100), 110 (49), 95 (39), 65 (17),
39 (60); 1H NMR (80 MHz, CDCl3): ꢀ 3.88 (s, 6H, Ar-OMe), 4.46 (d,
J¼8.0 Hz, 2H, -CH2CH ¼ CH2), 5.0–5.9 (m, 3H, -CH2CH ¼ CH2), 6.42 (s,
3H, Ar-H).
2,6-Dimethoxy-3-allyl-phenol 5
4 (1.5 g, 0.0077 mol) was put into a tube, then it was sealed on fire. The
tube was put in hot oil (150ꢃC) for a week. Compound 5 was afforded as a
yellow liquid, quantitatively. EI-MS(m/z): 194 (Mþ, 76), 167 (29), 151 (26),
1
119 (47), 91 (96), 77 (69), 39 (100); H NMR (80 MHz, CDCl3): ꢀ 3.36 (d,
J¼6.51 Hz, 2H, -CH2CH ¼ CH2), 3.88 (s, 6H, Ar-OMe), 5.16 (d, J¼13.8 Hz,
2H, -CH ¼ CH2), 5.93(m, 1H, -C H ¼ CH2), 6.42 (s, 2H, Ar-H).
1-(3,5-Dimethoxy-4-hydroxy-phenol)propene 6
Compound 5 (2 g) was stirred for 24 h with a catalytic amount of
PdCl2 in methanol (80 mL). Filtration, evaporation, and the residue was
flash chromatographed using petroleum ether and ethyl acetate (6:1, v/v)
as eluent to afford the yellow liquid 6 (1.76 g). EI-MS (m/z): 194 (Mþ, 76),
1
167 (29), 151 (26), 119 (47), 91 (96), 77 (69), 39 (100); H NMR (400 MHz,
CDCl3): ꢀ 1.85 (dd, J¼1.63, 6.60 Hz, 3H, -CH ¼ CHCH3), 3.86 (s, 3H,

(Æ)-EUSIDERIN K AND (Æ)-EUSIDERIN J
865
Ar-OMe), 3.87 (s, 3H, Ar-OMe), 6.05–6.14 (m, 2H, CH ¼ CHMe), 6.41 (s,
1H, Ar-H), 6.57 (s, 1H, Ar-H).
3-Methoxy-1,2-benzene-diol 7
To a stirred solution of pyrogallol (4 g, 31.7 mmol) in 50 mL ethanol
was added dropwise the solution of 12.1 g Na2B4O7ꢁ10H2O in 20 mL H2O.
After stirring for 30 m, to the solution was added 4.38 g K2CO3 and 3.1 mL
(CH3)2SO4. The mixture was stirred over night. Then H2O (10 mL) was
added and the mixture was extracted with CH2Cl2 (25 mLꢂ3). The com-
bined extracts were dried (Na2SO4, the CH2Cl2 was distilled off, and the
residue was flash chromatographed using petroleum ether and ethyl acetate
(4:1, v/v) as eluent to afford the liquid 7 (3.8 g). 1H NMR (80 MHz, CDCl3):
ꢀ 3.81 (s, 3H, -Me), 6.71–7.10 (m, 3H, Ar-H).
2-Allyoxy-3-methoxy-phenol 8
The synthesis of 8, which was a yellow liquid, was the same as 4 EI-
MS (m/z): 180 (Mþ, 4), 153 (100), 139 (25), 125 (43), 110 (46), 93 (35), 65
1
(15), 39 (53); H NMR (80 MHz, DCCl3): ꢀ 3.85 (s, 3H, Ar-OMe), 1.46 (d,
J¼6.8 Hz, 2H, -CH2CH ¼ CH2), 5.0–5.9 (m, 3H, -CH2CH ¼ CH2), 5.87–5.97
(m,1H, -CH2-CH ¼ CH2), 6.3–6.45 (m, 3H, Ar-H).
3-Methoxy-5-allyl-1,2-benzene-diol 9
The synthesis of 9, which was a yellow liquid, was the same as 5.
EI-MS (m/z): 180 (Mþ, 86), 165 (19), 147 (39), 119 (51), l03 (21), 91 (100),
65 (61), 39 (84); 1H NMR (80 MHz, DCCl3): ꢀ 3.27 (d, 6.8 Hz, 2H,
-CH2CH ¼ CH2), 3.85 (s, 3H, Ar-OMe), 5.0–5.3(m, 3H, -CH 2CH ¼ CH2),
6.30 (s, 1H, Ar-H), 6.45 (s, 1H, Ar-H).
(Æ)-Eusiderin K
Silver oxide (168 mg) was added to a solution of 6 (140 mg, 0.72 mmol)
and 9 (130 mg, 0.72 mmol) in benzene/acetone (5:1, v/v, 25 mL). The sol-
ution was stirred for 24 h at room temperature, then it was filtered. The
benzene/acetone was distilled off. Then the residue was flash chromato-
graphed using petroleum ether and ethyl acetate (3:1, v/v) as eluent.
Then 108 mg yellow solid of (ꢀ)-Eusiderin K was obtained. M.p. 85ꢃ–87ꢃC;

866
JING ET AL.
EI-MS (m/z): 372 (Mþ, 15), 194 (100), 179 (9); 1H NMR (400 MHz, DCCl3):
ꢀ 1.24 (d, J¼6.71 Hz, 3H, 9-H), 3.30 (d, J¼6.40 Hz, 2H, 70-H), 3.64 (s, 3H,
-OMe), 3.91 (s, 6H, -OMe), 4.05–4.13 (m, 1H, 8-H), 4.52 (d, J¼7.70 Hz, 1H,
7-H), 5.16 (d, J¼13.8 Hz, 2H, -CH2CH ¼ CH2), 5.87–5.97 (m, 1H, -CH2-
CH ¼ CH2), 6.35–6.63 (m, 4H, Ar-H); 13C NMR (400 MHz): ꢀ 132.3 (1-C),
104.2 (2-C), 147.2 (3-C), 135.3 (4-C), 147.2 (5-C), 104.2 (6-C), 81.1 (7-C),
0
74.2 (8-C), 17.3(9-C), 132.1 (1 0-C), 109.6 (20-C), 144.3(3 -C), 131.3 (40-C),
148.5 (50-C), 102.9 (60-C), 44.6 (70-C), 137.3 (80-C), 115.8 (90-C), 56.4, 56.1
(OMe); Found: C, 67.55; H, 6.48. C21H24O6 requires C, 67.67; H, 6.50%.
The above data were consistent with the literature1
(Æ)-Eusiderin J
(ꢀ)-Eusiderin K (300 mg) was added to a flask. Then 25 mL acetone,
45 mg KOH, and 0.5 mL (CH3)2SO4 was added. After stirring for 8 h, the
solution was filtered and the acetone was distilled off. Then the residue was
flash chromatographed using petroleum ether and ethyl acetate (3:1, v/v) as
eluent. A yellow liquid (296 mg) (ꢀ)-Eusiderin J was obtained. IR(ꢁ, cmꢄ1
,
film): 623, 725.4, 831.7, 916.8, 1003.4, 1039.8, 1129.3, 1186.8, 1232.1, 1330.3,
1424.2, 1459.6, 1504.8, 1593.5, 1691.3, 2836.6, 2938.1; EI-MS (m/z): 386
1
(Mþ), 344, 302, 208, 193, 151, 149, 105; H NMR (400 MHz, DCCl3): ꢀ
1.24 (d, J¼6.10 Hz, 3H, 9-H), 3.30 (d, J¼6.13Hz, 2H, 7 0-H), 3.64 (s, 3H,
-OMe), 3.91 (s, 9H, -OMe), 4.05–4.13 (m, 1H, 8-H), 4.52 (d, J¼7.71 Hz, 1H,
7-H), 5.23(d, J ¼13.8 Hz, 2H, -CH2CH ¼ CH2), 5.87–5.97 (m, 1H, -CH2-
CH ¼ CH2), 6.35–6.63 (m, 4H, Ar-H); 13C NMR (400 MHz): ꢀ 131.2 (1-C),
100.3(2-C), 148.6 (3-C), 137.3(4-C), 144.3(5-C), 106.8 (6-C), 76.9 (7-C),
0
74.1 (8-C), 12.6 (9-C), 131.3 (10-C), 109.6 (20-C), 144.3(3 -C), 132.5 (40-C),
153.5 (50-C), 104.6 (60-C), 40.0 (70-C), 137.3 (80-C), 115.8 (90-C), 56.3, 56.2
(OMe). Found: C, 68.33; H, 6.70. C22H26O6 requires C, 68.38; H, 6.78%.
The above data were consistent with the literature.1
ACKNOWLEDGMENTS
We are grateful to the National Nature Science Foundation of China
(No. 29772012) for financial support.
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(Æ)-EUSIDERIN K AND (Æ)-EUSIDERIN J
867
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Received in Japan April 10, 2000