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X. Wang et al. / Bioorg. Med. Chem. 17 (2009) 1898–1904
5.2.1. 2-Hexyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (10a)
1H NMR (400 MHz, CDCl3) d 4.12 (m, 1H), 3.09 (m, 1H), 2.84–
3.04 (m, 2H), 1.1–2.1 (m, 10H), 0.86 (t, 3H, J = 6.86 Hz); FAB
MS(m/e) [M]+ 230.3.
2.04 Hz), 1.1–2.1 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz); 13C NMR
(100 MHz, CDCl3) d 14.0, 22.6, 27.6, 29.2, 29.3, 29.4, 29.6, 31.8,
37.0, 47.1, 53.0, 120.0, 142.1, 175.6, 195.4; FAB MS(m/z) [M+1]+
285.1. Anal. Calcd for C15H24O3S: C, 63.35; H, 8.51; O, 16.88; S,
11.27. Found: C, 63.37; H, 8.51; S, 11.23.
5.2.2. 2-Octyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (10c)
1H NMR (400 MHz, CDCl3) d 4.13 (m, 1H), 3.10 (m, 1H), 2.83–
3.04 (m, 2H), 1.1–2.1 (m, 14H), 0.86 (t, 3H, J = 6.88 Hz); FAB
MS(m/e) [M]+ 258.1.
5.3.4. 2-Decyl-4-methylene-5-oxo-tetrahydro-thiophene-3-
carboxylic acid (1e)
1H NMR (400 MHz, CD3Cl) d 6.18 (d, 1H, J = 2.48 Hz), 5.61 (d, 1H,
J = 2.28 Hz), 4.08 (dt, 1H, J = 9.28, 5.32 Hz), 3.71 (dt, 1H, J = 5.42,
2.14 Hz), 1.1–2.1 (m, 18H), 0.89 (t, 3H, J = 6.68 Hz); 13C NMR
(100 MHz, CDCl3) d 14.1, 22.6, 27.6, 29.2, 29.3, 29.4, 29.5, 29.6,
31.8, 37.0, 47.1, 53.1, 120.0, 142.2, 175.5, 195.5; FAB MS(m/z)
[M+1]+ 299.1. Anal. Calcd for C16H26O3S: C, 64.39; H, 8.78; O,
16.08; S, 10.74. Found: C, 64.34; H, 8.80; S, 10.77.
5.2.3. 2-Nonyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (10d)
1H NMR (400 MHz, CDCl3) d 4.13 (m, 1H), 3.10 (m, 1H), 2.84–
3.05 (m, 2H), 1.1–2.1 (m, 16H), 0.86 (t, 3H, J = 6.88 Hz); FAB
MS(m/e) [M]+ 272.2.
5.2.4. 2-Decyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid
(10e)
5.3.5. 2-Undecyl-4-methylene-5-oxo-tetrahydro-thiophene-3-
carboxylic acid (1f)
1H NMR (400 MHz, CDCl3) d 4.14 (m, 1H), 3.12 (m, 1H), 2.84–
3.05 (m, 2H), 1.1–2.1 (m, 18H), 0.86 (t, 3H, J = 6.89 Hz); FAB
MS(m/e) [M]+ 286.1.
1H NMR (400 MHz, CD3Cl) d 6.18 (d, 1H, J = 2.4 Hz), 5.59 (d, 1H,
J = 2.12 Hz), 4.08 (dt, 1H, J = 9.28, 5.32 Hz), 3.71 (dt, 1H, J = 2.12,
5.32 Hz), 1.1–2.1 (m, 20H), 0.86 (t, 3H, J = 6.64 Hz); 13C NMR
5.2.5. 2-Undecyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid
(10f)
(100 MHz, CDCl3)
d
14.1, 22.6, 27.6, 29.1, 29.3(ꢁ2), 29.4,
29.5(ꢁ2), 31.8, 37.0, 47.0, 52.9, 120.1, 142.0, 175.4, 195.2; FAB
MS(m/z) [M+1]+ 313.1. Anal. Calcd for C17H28O3S: C, 65.35; H,
9.03; O, 15.35; S, 10.26. Found: C, 65.39; H, 8.99; S, 10.22.
1H NMR (400 MHz, CDCl3) d 4.14 (m, 1H), 3.13 (m, 1H), 2.84–
3.05 (m, 2H), 1.1–2.1 (m, 20H), 0.86 (t, 3H, J = 6.90 Hz); FAB
MS(m/e) [M]+ 300.1.
5.4. 2-Isopropylidene-succinic acid (13)
5.3. General procedures for 1a–f
Potassium (4.73 g, 0.12 mol) was added into dry t-butyl alcohol
(120 ml) stirring, and it was warmed up to 60–65 °C slowly. A clear
liquid was obtained and diethyl succinate (30.8 g 0.177 mol), ace-
tone (7 g 0.12 mol) and t-butyl alcohol (10 ml) was added. The
reaction solution was refluxed for 20 min diluted with water
(100 ml) and the aqueous layer was separated and acidified with
concd HCl. The solution was extracted with ether and evaporated
yielding red oil, and then it was refluxed with NaOH solution
(2 M, 100 ml) overnight. The mixture was acidified with HCl and
extracted with acetic ether. The organic phase was evaporated un-
der reduced pressure and 13 was obtained as a white solid in 82%
yield. Mp 159–162 °C, 1H NMR (400 Hz, CDCl3) d 1.99 (s, 3H), 2.27
(s, 3H), 3.58 (s, 2H); FAB MS(m/z) [M+1]+ 159.1.
A solution of 10a–f (10 mmol) in methyl methoxymagnesium
carbonate in DMF (20 mmol) was stirred under argon at 135–
140 °C for 3 days. The reaction mixture was then added to 10%
aqueous HCl in the presence of CH2Cl2, and the CH2Cl2 layer was
separated, dried, and evaporated below 30 °C. The crude diacid
11a–f was obtained and it was treated with 2.0 ml of stock solution
(prepared from 20 ml of acetic acid, 15 ml of 37% formaldehyde in
water, 5.20 ml of N-methylaniline and 600 mg of sodium acetate)
and stirred under argon at 20 °C for 2 h. The crude product was ex-
tracted with ether and purified by column silica gel chromatogra-
phy (ethyl acetate/hexanes/acetic acid 2:10:0.05) to give the
products 1a–f as white solid in 29–50.4% yield.
5.3.1. 2-Hexyl-4-methylene-5-oxo-tetrahydro-thiophene-3-
carboxylic acid (1a)
5.5. 2-Isopropylidene-succinic acid 4-(4-methoxy-benzyl) ester
(15)
1H NMR (400 MHz, CD3Cl) d 6.18 (d, 1H, J = 2.24 Hz), 5.61 (d, 1H,
J = 2.0 Hz), 4.08 (dt, 1H, J = 9.04, 5.28 Hz), 3.71 (dt, 1H, J = 2.0,
5.32 Hz), 1.1–2.1 (m, 10H), 0.88 (t, 3H, J = 6.56 Hz); 13C NMR
(100 MHz, CDCl3) d 14.0, 22.4, 27.6, 28.7, 31.5, 37.0, 47.0, 53.01,
120.1, 142.0, 175.8, 195.3; FAB MS(m/z) [M+1]+ 243.1. Anal. Calcd
for C12H18O3S: C, 59.48; H, 7.49; O, 19.81; S, 13.23. Found: C,
59.45; H, 7.51; S 13.25.
Compound 13 (0.063 mol) was dissolved in 25 ml acetic anhy-
dride and refluxed for 5–6 h 14 was obtained at 125–130 °C by
distilled under 5 mmHg as a white solid (yield of 84.5%, mp 161–
163 °C). A mixture of 14 and p-methoxybenzyl alcohol (15 ml)
was stirred at 55–60 °C for 40 h. The reaction mixture was diluted
with ether and the solution was poured into saturated aqueous
NaHCO3. The aqueous layer was separated and acidified with concd
HCl. The product 15 was obtained in 55.3% yield by filtration and
recrystallization from ethyl acetate–hexane as a white solid.
5.3.2. 2-Octyl-4-methylene-5-oxo-tetrahydro-thiophene-3-
carboxylic acid (1c)
1H NMR (400 MHz, CD3Cl) d 6.18 (d, 1H, J = 2.36 Hz), 5.60 (d, 1H,
J = 2.12 Hz), 4.08 (dt, 1H, J = 5.08, 9.28 Hz), 3.71 (dt, 1H, J = 2.28,
5.32 Hz), 1.1–2.1 (m, 14H), 0.86 (t, 3H, J = 6.68 Hz); 13C NMR
(100 MHz, CDCl3) d 14.0, 22.6, 27.6, 28.3, 29.1, 29.2, 31.7, 36.9,
47.0, 53.0, 120.1, 142.1, 175.3, 195.4; FAB MS(m/z) [M+1]+ 271.1.
Anal. Calcd for C14H22O3S: C, 62.19; H, 8.20; O, 17.75; S, 11.86.
Found: C, 62.21; H, 8.17; S 11.81.
Mp 80–81 °C, 1H NMR (400 MHz, CD3Cl)
d 7.25 (d, 2H,
J = 8.96 Hz), 6.87 (dd, 2H, J = 1.96, 8.68 Hz), 5.03 (s, 2H), 3.78 (s,
3H), 2.62 (s, 2H), 1.28 (s, 6H); FAB MS(m/z) [M+1]+ 279.1.
5.6. General procedures for 2a–f
Lithiumdiisopropyl amide (40 mmol) was added to a solution of
20 mmol of 15 in anhydrous THF cooled at ꢀ78 °C. After stirring for
1 h, the aldehyde (20 mmol) in anhydrous THF was added and the
solution was stirred at ꢀ78 °C for another 4 h. The solution was
quenched with 6 N H2SO4 and extracted with ether. The ether layer
was dried over anhydrous MgSO4 and evaporated under reduced
5.3.3. 2-Nonyl-4-methylene-5-oxo-tetrahydro-thiophene-3-
carboxylic acid (1d)
1H NMR (400 MHz, CD3Cl) d 6.17 (d, 1H, J = 2.48 Hz), 5.59 (d, 1H,
J = 2.28 Hz), 4.08 (dt, 1H, J = 9.28, 5.32 Hz), 3.72 (dt, 1H, J = 5.52,