10 min before the dropwise addition, over a period of 5 min,
of distilled N,N-diisopropylethylamine (9.14 mL, 52.5 mmol),
keeping the temperature below 2 ЊC. The mixture was stirred
at 1 ЊC for 1 h, then cooled to Ϫ78 ЊC. A solution of 3,4-
dimethoxybenzaldehyde (5.74 g, 34.5 mmol) in anhydrous
methylene dichloride (120 mL), stored over 4 Å molecular
sieves for 1 h, was then added over a period of 33 min by
cannula, keeping the temperature below Ϫ75 ЊC. The mixture
was stirred at this temperature for 1 h, then at room temper-
ature for 2 h, before quenching with 10% aq. NaH2PO4 (600
mL). The mixture was extracted with diethyl ether (800 ϩ 400
mL) and the combined organic extracts were washed with sat-
urated aq. NaCl (200 mL) and evaporated. The residue was
dissolved in methanol (810 mL), cooled to 0 ЊC, and 30% aq.
hydrogen peroxide (160 mL) was added. The mixture was
stirred for 140 min in an ice–water-bath, then concentrated in
vacuo. The resulting aqueous residue was partitioned between
diethyl ether (500 mL) and water (400 mL), and the aqueous
layer was further extracted with diethyl ether (300 mL). The
combined organic extracts were washed with saturated aq.
NaCl (200 mL), dried (MgSO4), and evaporated. The residue
was purified by flash chromatography (silica gel; 35% EtOAc–
petroleum spirit) to give 11 (16.35 g, 87%) as a white solid; mp
65–69 ЊC; [α]D ϩ81.3 (c 1.0 in CH2Cl2) (Found: C, 60.3; H, 5.25;
N, 2.5. C30H32BrNO7 requires C, 60.2; H, 5.4; N, 2.3%); νmax
(KBr)/cmϪ1 3501, 2963, 1782, 1694, 1593, 1517, 1487, 1464,
1453, 1385, 1235, 1202, 1154, 1139, 1120, 1101, 1057, 1025, 974,
859, 807, 752, 740, 697, 647; δH (360 MHz; CDCl3; Me4Si) 7.46
(1H, d, J 2.5, ArH), 7.39–7.27 (6H, m, ArH), 6.73 (1H, d, J 8.8,
ArH), 6.71 (1H, m, ArH), 6.62–6.60 (2H, m, ArH), 5.80 (1H, d,
J 6.0, CHCON), 5.23 (1H, d, J 6.0, CHOH), 4.92 (1H, d, J 11.6,
PhCHO), 4.72 (1H, d, J 11.6, PhCHO), 4.35 (1H, m, NCH),
4.09–4.07 (2H, m, CO2CH2), 3.80 (3H, s, OCH3), 3.61 (3H, s,
OCH3), 2.33 (1H, m, Me2CH), 0.86 (3H, d, J 7.0, CCH3), 0.65
(3H, d, J 6.8, CCH3); δC (90.6 MHz; CDCl3; Me4Si) 173.4
(CCON), 157.1 (Ar), 153.1 (NCOO), 148.9 (Ar), 148.8 (Ar),
137.0 (Ar), 134.3 (Ar), 132.6 (CH), 131.9 (CH), 128.8 (CH),
128.2 (CH), 127.7 (CH), 125.9 (Ar), 119.6 (CH), 114.2 (CH),
113.1 (Ar), 110.9 (CH), 109.9 (CH), 75.0 (CHOH), 71.1
(PhCH2O), 63.2 (CO2CH2), 58.7 (NCH), 56.2 (OCH3), 56.0
(OCH3), 50.0 (CHCON), 28.3 (CHMe2), 18.4 (CCH3), 14.5
(CCH3); m/z (ESϩ) 582/580 (11/12%, [M Ϫ H2O ϩ H]ϩ), 393
(13), 391 (47), 167 (100), 130 (34).
MHz; CDCl3; Me4Si) 170.0 (CCON), 158.6 (Ar), 153.8
(NCOO), 149.5 (Ar), 149.3 (Ar), 132.5 (CH), 132.0 (Ar), 128.0
(CH), 127.0 (Ar), 118.8 (CH), 112.6 (Ar), 111.6 (CH), 111.2
(CH), 109.3 (CH), 86.2 (CH), 63.8 (CH2), 58.7 (CH), 55.9
(CH3), 54.4 (CH), 28.4 (CH), 17.8 (CH3), 14.8 (CH3); m/z (ESϩ)
509/507 (64/74%, [M ϩ NH4]ϩ), 492/490 (12/13, [M ϩ H]ϩ),
214 (16), 195 (24), 172 (16), 152 (21), 147 (26), 130 (100),
118 (79).
(؊)-Methyl (2R,3R)-5-bromo-2-(3,4-dimethoxyphenyl)-2,3-
dihydrobenzofuran-3-carboxylate 13
To
a solution of (4R)-(Ϫ)-3-{[(2R,3R)-5-bromo-2-(3,4-di-
methoxyphenyl)-2,3-dihydrobenzofuran-3-yl]carbonyl}-4-iso-
propyloxazolidin-2-one 12 (0.1062 g, 0.217 mmol) in anhydrous
methanol (5 mL), cooled under nitrogen to 0 ЊC, was added
dropwise a 30 wt% solution of sodium methoxide in methanol
(41.3 µL, 0.217 mmol), and the mixture was stirred at 0 ЊC for
2 h. The mixture was then partitioned between 0.05 M aq. HCl
(15 mL) and diethyl ether (20 mL). The organic layer was
washed with saturated aq. NaCl (10 mL), dried (MgSO4), and
evaporated. The residue was purified by flash chromatography
(silica gel; 25% EtOAc–petroleum spirit) to afford 13 (66.6 mg,
78%) as a white solid; mp 95.5–96 ЊC (from EtOAc–hexane);
[α]D Ϫ92.0 (c 1.0 in CH2Cl2) (Found: C, 55.1; H, 4.4.
C18H17BrO5 requires C, 55.0; H, 4.4%); νmax (KBr)/cmϪ1 2957,
2835, 1735, 1605, 1594, 1521, 1467, 1440, 1432, 1348, 1330,
1295, 1284, 1261, 1244, 1232, 1205, 1167, 1144, 1118, 1064,
1031, 998, 964, 896, 856, 842, 824, 813, 763, 662, 647; δH (360
MHz; CDCl3; Me4Si) 7.47 (1H, fine m, ArH), 7.34 (1H, m,
ArH), 6.94 (1H, dd, J 8.4 and 2.1, ArH), 6.89 (1H, d, J 2.1,
ArH), 6.85 (1H, d, J 8.4, ArH), 6.78 (1H, d, J 8.5, ArH), 6.05
(1H, d, J 8.0, CHO), 4.28 (1H, d, J 8.0, CHCO2Me), 3.88 (3H,
s, OCH3), 3.87 (3H, s, OCH3), 3.84 (3H, s, OCH3); δC (90.6
MHz; CDCl3; Me4Si) 170.6 (CCOO), 158.3 (Ar), 149.3 (Ar),
132.5 (CH), 132.3 (Ar), 128.1 (CH), 126.2 (Ar), 118.4 (CH),
112.6 (Ar), 111.4 (CH), 111.2 (CH), 108.9 (CH), 86.3 (CH),
55.9 (CH3), 55.3 (CH3), 52.9 (CH); m/z (ESϪ) 393/391 (32/35%,
[M Ϫ H]Ϫ), 367 (100), 281 (40), 255/253 (53/39, [M Ϫ (Me-
O)2C6H3 Ϫ 2H]Ϫ).
(؊)-Methyl (2R,3R)-5-[2-(tert-butoxycarbonyl)vinyl]-2-(3,4-
dimethoxyphenyl)-2,3-dihydrobenzofuran-3-carboxylate 14
Into a 15 mL pressure tube were placed (Ϫ)-methyl (2R,3R)-
5-bromo-2-(3,4-dimethoxyphenyl)-2,3-dihydrobenzofuran-3-
carboxylate 13 (0.4672 g, 1.19 mmol), palladium() acetate (5.4
mg, 0.024 mmol), tri(o-tolyl)phosphine (22.4 mg, 0.074 mmol),
tert-butyl acrylate (0.522 mL, 3.56 mmol) and anhydrous tri-
ethylamine (0.497 mL, 3.57 mmol). The tube was flushed with
argon, capped, and heated at 100 ЊC for 16 h. After cooling, the
mixture was partitioned between water (20 mL) and diethyl
ether (40 mL). The organic layer was washed with saturated aq.
NaCl (15 mL), dried (MgSO4), and evaporated. The residue was
purified by flash chromatography (alumina; 40–70% CH2Cl2–
hexane) to give 14 (0.4470 g, 85%) as a yellow oil; [α]D Ϫ121.7 (c
1.0 in CH2Cl2) (Found: C, 68.2; H, 6.25. C25H28O7 requires C,
68.2; H, 6.4%); νmax (film)/cmϪ1 2975, 2838, 1740, 1700, 1633,
1606, 1517, 1467, 1464, 1439, 1391, 1367, 1328, 1240, 1151,
1113, 1027, 982, 907, 859, 817, 762, 735, 703; δH (360 MHz;
(4R)-(؊)-3-{[(2R,3R)-5-Bromo-2-(3,4-dimethoxyphenyl)-2,3-
dihydrobenzofuran-3-yl]carbonyl}-4-isopropyloxazolidin-2-one
12
To a stirred solution of (4R)-(ϩ)-3-{(2R,3R)-2-[2-(benzyl-
oxy)-5-bromophenyl]-3-(3,4-dimethoxyphenyl)-3-hydroxyprop-
anoyl}-4-isopropyloxazolidin-2-one 11 (6.10 g, 10.2 mmol) in
anhydrous methylene dichloride (400 mL) under argon was
added dropwise, over a period of 3 min, iodotrimethylsilane
(3.2 mL, 22.5 mmol) and the resulting red-brown solution was
stirred at room temperature for 77 min. Methanol (100 mL) was
then added and the mixture was stirred for 10 min. The solvents
were evaporated off and the residue was purified by flash chro-
matography (silica gel; 2–4% EtOAc–CH2Cl2 then 70–80%
Et2O–hexane) to give 12 (3.56 g, 71%) as a colourless solid; mp
61–63 ЊC; [α]D Ϫ235.8 (c 1.0 in CH2Cl2) (Found: C, 56.55; H,
5.0; N, 3.1. C23H24BrNO6 requires C, 56.3; H, 4.9; N, 2.9%); νmax
(KBr)/cmϪ1 2963, 1778, 1697, 1518, 1472, 1387, 1374, 1302,
1261, 1206, 1160, 1142, 1111, 1026, 811; δH (360 MHz; CDCl3;
Me4Si) 7.41 (1H, fine m, ArH), 7.33 (1H, dd, J 8.4 and 2.1,
ArH), 6.90 (1H, dd, J 8.2 and 1.9, ArH), 6.86 (1H, d, J 1.9,
ArH), 6.83 (1H, d, J 8.2, ArH), 6.80 (1H, d, J 8.4, ArH), 6.22
(1H, d, J 6.6, CHO), 5.64 (1H, d, J 6.6, CHCON), 4.52 (1H, m,
NCH), 4.35 (1H, t, J 9.2, CO2CH), 4.30 (1H, dd, J 9.2 and 3.5,
CO2CH), 3.87 (3H, s, OCH3), 3.85 (3H, s, OCH3), 2.32 (1H, m,
Me2CH), 0.91 (3H, s, CCH3), 0.85 (3H, s, CCH3); δC (90.6
CDCl ; Me Si) 7.56 (1H, d, J 15.9, C᎐CHCO But), 7.55 (1H,
᎐
3
4
2
s, ArH), 7.41 (1H, d, J 8.3, ArH), 6.95 (1H, dd, J 8.3 and 2.0,
ArH), 6.90–6.88 (2H, m, ArH), 6.86 (1H, d, J 8.3, ArH), 6.25
(1H, d, J 15.9, CH᎐CCOO), 6.09 (1H, d, J 7.8, CHO), 4.29 (1H,
᎐
d, J 7.8, CHCO2Me), 3.88 (3H, s, OCH3), 3.86 (3H, s, OCH3),
3.85 (3H, s, OCH3), 1.53 [9H, s, C(CH3)3]; δC (125.8 MHz;
CDCl ; Me Si) 170.8 (CO Me), 166.6 (C᎐CCOO), 160.8 (Ar),
᎐
3
4
2
149.3 (COMe × 2), 143.1 (CH᎐CCO), 132.3 (Ar), 130.6 (CH),
᎐
128.2 (Ar), 125.0 (Ar), 124.6 (CH), 118.4 (CH), 117.8
(C᎐CHCO), 111.2 (CH), 110.2 (CH), 108.9 (CH), 86.5 (CH),
᎐
J. Chem. Soc., Perkin Trans. 1, 2000, 893–899
897