158 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 158±159$
Facile Total Synthesis of Isopregomisin$
Wang Mingyi, Yang Hongfang, Wu Anxin and Pan Xinfu*
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P.R. China
Isopregomisin, a diarylbutane-lignan, has been synthesized by a short and efficient route starting from pyrogallol; the
synthesis involves a novel selective demethylation reaction and the coupling reaction of the Grignard reagent produced
from an aryl bromopropane with (E)-2-tert-butyl-3-phenyloxaziridine.
Isopregomisin,
a diarylbutane-lignan, isolated from the
twigs of Prolieria chilensis Johnston (Zygophyllaceae) in
1989,1 has good antioxidant activity.2 In this paper, we
report a new short synthetic route to isopregomisin.
Our synthetic strategy (outlined in Scheme 1) started from
pyrogallol 2, which was easily converted into trimethyl
pyrogallol 3. Treatment of 3 with ZnCl2/propionic acid gave
2,6-dimethoxyphenol (4) in a yield of 71%.3 Previously, the
most eective method to prepare this compound has been
the methylation of pyrogallol 2 with CH3Br, whose products
were complicated and the yield of 4 rather low.4 However,
when ZnCl2/propionic acid was used as a demethylation
agent, 4 can be easily obtained in a higher yield from
trimethyl pyrogallol 3 and was almost the sole product.
Compound 5, readily available in near quantitative yield by
the reaction of 4 with allyl bromide, was submitted to a
Claisen rearrangement in a sealed tube to give 6 in 88%
yield (lit.5 48%). Reaction of 6 with HBr (40%, in acetic
acid) led to the bromide 7 in a yield of 84%. According to
the published report,6 isopregomisin (1) could be directly
synthesized by treatment of 7 with Mg/I2, but the yield
was only 8%. Fortunately, compound 8, readily obtained
by protection of 7 with acetyl chloride in 95% yield, was
coupled with magnesium and (E)-tert-butyl-3-phenyl-
oxaziridine7 followed by hydrolysis with a 10% ammonia
solution to give the target molecule 1 in a yield of 51%.
The spectra and elemental analysis of 1 are compatible with
those reported.
Scheme 1 Reagents: i, (CH3)2SO4; ii, ZnCl2/C2H5CO2H;
iii, CH2CHCH2Br/K2CO3; iv, 170±180 8C; v, HBr/CH3CO2H;
vi, CH3COCl/pyr; vii, Mg/(E)-2-tert-butyl-3-phenyloxaziridine;
viii, 10% NH3, H2O; ix, Mg/I2
crude product obtained was then puri®ed by column chromatog-
pale-yellow oil (5.3 g, 88%) (lit.5 54%): m/z
raphy to give
a
(FABMS) 195 (M 1), 194 (M ); ꢀH 3.33 (d, J 7.0 Hz, 2 H,
Experimental
.
CH2), 3.83 (s, 6 H, ArOCH3), 4.8±5.3 (m, 3 H, CH CH2), 5.5 (bs,
1
ArOH, D2O exchanged), 6.36 (s, 2 H, ArH); ꢁmax/cm (®lm) 3521,
3451, 2973, 1613, 1513, 1214.
Melting points were determined with a Ko¯er micro-melting
point apparatus and are uncorrected. Mass spectra were recorded
on a ZAB-HS spectrometer, NMR spectra were taken on a FT-80A
and a Bruker 400 instrument in CDCl3 with Me4Si as internal
standard, and IR spectra were obtained on a FT-170SX spec-
trometer. Elemental analysis were performed on a Carlo-Erba-1106
instrument. All compounds were puri®ed by column chromatog-
raphy on silica gel H, from the Qingdo Marine Chemical Factory,
eluting with the solvent mixture of light petroleum (bp 60±90 8C)
and ethyl acetate.
1-(3,5-Dimethoxy-4-hydroxyphenyl)-2-bromopropane 7.ÐA mixture
of compound 6 (2.5 g, 13 mmol), HBr (40%, in glacial acetic acid,
15 ml) was shaken and placed in a darkroom for a week. Then the
bulk of the acetic acid was removed under reduced pressure and
the remaining acetic acid was removed by co-distillation with
ethanol. The residue was cooled in a ice-bath and slowly mixed
with anhydrous K2CO3 (1±2 g), and the resultant mixture was
puri®ed by column chromatography to obtain 7 as a colourless
oil (3 g, 84%): m/z (EIMS) 276, 274 (M, 21), 195(32), 167(100);
ꢀH 1.68 (d, J 6.3 Hz, 3 H, CH3), 2.9±3.2 (m, 2 H, ArCH2), 3.87
(s, 6 H, ArOCH3), 4.3 (m, 1 H, CHBr), 5.30 (s, 1 H, ArOH, D2O
Allyl 2,6-dimethoxyphenyl Ether 5.ÐA mixture of compound 4
(7.7 g, 0.05 mol), allyl bromide (9.0 g, 0.075 mol) and NaH (1.2 g,
0.05 mol) in dry acetone (50 ml) was stirred at room temp. for
24 h. The solvent and excess allyl bromide were removed with a
rotary evaporator. The residue was puri®ed by column chromatog-
raphy to aord 5 as a pale-yellow oil (14.4 g, 99%) (lit.5 88%): m/z
exchanged), 6.42 (s,
11H15BrO3 requires C, 48.0; H, 5.5%).
1-(4-Acetoxy-3,5-dimethoxyphenyl)-2-bromopropane 8.ÐTo
2 H, ArH); (Found: C, 48.0; H, 5.34.
C
a
solution of compound 7 (1.1 g, 4 mmol) in anhydrous THF (20 ml)
was added pyridine (20 ml), cooled to 30 8C. Subsequently acetyl
chloride (1 ml) was added dropwise and the mixture was stirred at
30 8C for 1 h, and then at room temp. overnight. The resulting
mixture was washed with ice±water and aq. HCl (10%) to remove
the pyridine. The standard ethereal workup followed by puri®cation
by FCG aorded the desired product 8 as a white solid (1.2 g,
(EIMS) 194 (M , 56), 167 (5), 153 (100), 125 (95); ꢀH 3.73 (s, 6 H,
ArOCH3); 4.46 (d, J 8.0 Hz, 2 H, OCH2), 5.0±5.9 (m, 3 H,
1
.
CH CH2, 6.0±7.1 (m, 3 H, ArH); ꢁmax/cm (®lm) 2942, 1594, 1479,
1112.
4-Allyl-2,6-dimethoxyphenol 6.ÐAn ampoule charged with
compound 5 (6.0 g, 0.031 mol) was sealed and placed in an anti-
pressure tube followed by further sealing. This doubly-sealed tube
was soaked in a oil-bath and heated at 170±180 8C for 7 h. The
95%): mp 78±80 8C; m/z (EIMS) 318, 316 (M ), 276, 237 (6) 274
(36), 195 (23), 167 (100); ꢀH 1.69(d, J 6.8 Hz, 3 H, CH3), 2.33 (s,
3 H, CH3CO), 2.9±3.2 (m, 2 H, ArCH2), 3.80 (s, 6 H, ArOCH3),
4.3 (m, 1 H, CHBr), 6.45 (s, 2 H, ArH); (Found C, 49.2; H, 5.4.
C13H17BrO4 requires C, 49.2; H, 5.4%).
*To receive any correspondence.
Isopregomisin 1.ÐTo the Grignard reagent made from magnesium
turnings (72 mg, 3 mmol) and compound 8 (640 mg, 2 mmol) in dry
THF (10 ml) was added dropwise a solution of (E)-2-tert-butyl-3-
$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).
Mingyi, Wang
