W. Fan et al. / European Journal of Medicinal Chemistry 46 (2011) 3651e3661
3659
CH2CH2OH, J ¼ 6.4 Hz), 2.84e2.79 (m, 1H, SCH(CH3)3), 1.78 (s, 3H,
CCH3), 1.56 (d, 3H, CHCH3, J ¼ 7.2 Hz), 1.21 (d, 6 H, SCH(CH3)2,
J ¼ 6.8 Hz); MS (m/z): 506 ([M þ 1]þ).
4.08 (t, 1H, H-2, J ¼ 5.6 Hz), 4.07e4.04 (m, 2H, COCH2),
3.95e3.93 (m, 1H, H-60), 3.91 (s, 3H, OCH3), 3.82 (s, 2H, CH2Ar),
3.81e3.79 (m, 1H, CHCH3), 3.78 (t, 1H, H-3, J ¼ 4.8 Hz), 3.41 (t,
1H, H-4, J ¼ 9.2 Hz), 3.36 (dd, 1H, H-5, J1 ¼ 3.2 Hz, J2 ¼ 9.2 Hz),
2.68 (t, 2H, CH2CH2OH, J ¼ 6.4 Hz), 1.78 (s, 3H, CCH3), 1.56 (d, 3H,
CHCH3, J ¼ 6.8 Hz), 0.17e0.13 (m, 36H, Si(CH3)3); MS (m/z): 1004
([M þ 1]þ).
5.1.7.3. (S)-2-(N-(3-(Benzyldisulfanyl)-5-(2-(6-methoxynaphthalen-2-
yl)propanoyloxy)pent-2-en-2-yl)formamido) acetic acid (14c). Yield:
75.9%. 1H NMR (CDCl3, ppm): 7.77 (s, 1 H, CHO), 7.68 (dd, 2H, AreH,
J1 ¼ 4.8 Hz, J2 ¼ 8.4 Hz), 7.62 (s, 1H, AreH), 7.35 (dd, 1H, AreH,
J1 ¼ 1.4 Hz, J2 ¼ 8.4 Hz), 7.26e7.10 (m, 7H, AreH), 4.15 (t, 2H,
CH2CH2O, J ¼ 6.0 Hz), 3.90 (s, 3H, OCH3), 3.85 (s, 2H, CH2Ar), 3.82 (s,
2H, COCH2), 3.79e3.77 (m, 1H, CHCH3), 2.66 (t, 2H, CH2CH2OH,
J ¼ 6.4 Hz), 1.69 (s, 3H, CCH3), 1.55 (d, 3H, CHCH3, J ¼ 6.8 Hz); MS (m/
z): 554 ([M þ 1]þ).
5.1.9. General procedure for synthesis of compounds 1ae1c
The prepared ester (15ae15c) (2.0 mmol) was dissolved in
dichlormethane (30 mL), which was cooled to 0 ꢀC. To the vigor-
ously stirred solution was dropped in trifluoroacetic acid (1.8 mL,
24 mmol) and kept for 1.5 h. Solvent and excess reagents were
evaporated under reduced pressure. The resulting syrup was
purified by the column chromatography with dichlormethane-
methanol (40:1) to yield 1ae1c as a pale-yellow solid.
5.1.8. General procedure for synthesis of compounds 15ae15c
A mixture of the prepared acid (14ae14c) (3.60 mmol), DCC
(0.97 g, 4.68 mmol) and DMAP (12 mg, 0.1 mmol) in dry tetrahy-
drofuran (40 mL) was stirred for 0.5 h. The solution of trimethylsilyl
glucopyranose 6 (1.69 g, 3.60 mmol) in tetrahydrofuran (20 mL)
was dropped into the reaction system, and then the temperature
was slowly raised to 60 ꢀC and the solution was stirred overnight.
Solvent was evaporated under reduced pressure to result a yellow
syrup. The desired derivative was purified by the column chro-
matography with petroleumeacetone (20:1) as eluent to give
a colorless oil.
5.1.9.1. (S)-4-(N-(2-(
3-(ethyldisulfanyl)pent-3-enyl
anoate (1a). Yield: 90.2%. Mp: 64e66 ꢀC; IR (KBr pellets cmꢂ1):
a
-
D
-Glucopyranose-6-yl)-2-oxoethyl)formamido)-
2-(6-methoxynaphthalen-2-yl)prop-
y
3421, 2960, 2932, 1733, 1666, 1453, 1266; 1H NMR (DMSO-d6, ppm):
7.85 (s, 1H, CHO), 7.78(dd, 2H, AreH, J1 ¼7.6 Hz, J2 ¼ 8.4 Hz), 7.71(s,1H,
AreH), 7.37 (dd, 1H, AreH, J1 ¼1.6 Hz, J2 ¼ 8.4 Hz), 7.29 (d, 1H, AreH,
J ¼ 2.0), 7.16 (dd, 1H, AreH, J1 ¼ 2.4 Hz, J2 ¼ 8.8 Hz), 4.91 (d, 1H, H-1,
J ¼ 3.2 Hz), 4.40e4.31 (m, 1H, H-6), 4.21 (t, 2H, CH2CH2O, J ¼ 6.4 Hz),
4.08 (t, 1H, H-2, J ¼ 6.4 Hz), 4.05 (s, 2H, COCH2), 3.91 (q, 1H, CHCH3,
J ¼ 7.2 Hz), 3.86 (s, 3H, OCH3), 3.83e3.79 (m,1H, H-60), 3.45 (t,1H, H-3,
J ¼ 8.8 Hz), 3.15 (dd,1H, H-5, J1 ¼ 3.6 Hz, J2 ¼ 9.6 Hz), 3.06 (t, 1H, H-4,
J ¼ 9.2 Hz), 2.83 (t, 2H, CH2CH2OH, J ¼ 6.4 Hz), 2.60 (q, 2H, SCH2CH3,
J ¼ 7.2 Hz),1.88 (s, 3H, CCH3),1.46 (d, 3H, CHCH3, J ¼ 6.8 Hz),1.13 (t, 3H,
SCH2CH3, J ¼ 6.8 Hz); 13C NMR (DMSO-d6, ppm): 174.3 (1C, COCH),
168.5 (1C, COCH2),162.6 (1C, CHO),157.4 (1C, AreCO),138.3 (1 C, NC]
C), 135.7 (1C, AreC), 133.6 (1C, AreC), 129.4 (1C, AreC), 128.6
(1C, AreC), 127.3 (1C, AreC), 126.4 (1C, AreC), 125.9 (1C, AreC),
119.1 (1C, AreC), 105.9 (1C, AreC), 97.3 (1C, C]CS), 92.6 (1C,
HOCHO), 76.6 (1C, COH), 72.7 (1C, COH), 70.7 (1C, COH), 69.3 (1C,
COH), 65.3 (1C, CHCH2O), 62.4 (1C, CH2CH2O), 55.4 (1C, OCH3), 45.2
(1C, SC), 44.7 (1C, COCH2N), 40.3 (1C, COCH), 29.5 (1C, C]CCCH2),
18.6 (C]CCH3), 18.5 (1 C, CHCH3), 14.1 (1C, SCCH3); MS (m/z): 654
([M þ 1]þ).
5.1.8.1. (S)-4-(N-(2-(1,2,3,4-tetra-O-Trimethylsilyl-a-D-glucopyr-
anosyl)-2-oxoethyl)formamido)-3-(ethyldisulfanyl)pent-3-enyl 2-
(6-methoxynaphthalen-2-yl)propanoate (15a). Yield: 55.4%. 1H
NMR (CDCl3, ppm): 7.91 (s, 1 H, CHO), 7.70 (dd, 2H, AreH,
J1 ¼ 3.2 Hz, J2 ¼ 8.4 Hz), 7.64 (s, 1H, AreH), 7.37 (dd, 1H, AreH,
J1 ¼1.6 Hz, J2 ¼ 8.4 Hz), 7.15 (dd, 1H, AreH, J1 ¼ 2.4 Hz, J2 ¼ 8.8 Hz),
7.12 (s, 1H, AreH), 4.99 (d, 1H, H-1, J ¼ 2.8 Hz), 4.41 (dd, 1H, H-6,
J1 ¼ 2.0 Hz, J2 ¼ 11.6 Hz), 4.23 (t, 2H, CH2CH2O, J ¼ 6.4 Hz), 4.12
(t, 1H, H-2, J ¼ 5.6 Hz), 4.10e4.09 (m, 2H, COCH2), 3.96e3.94
(m,1H, H-60), 3.92 (s, 3H, OCH3), 3.82 (q,1H, CHCH3, J ¼ 7.2 Hz), 3.79
(t, 1H, H-3, J ¼ 9.2 Hz), 3.41 (t, 1H, H-4, J ¼ 9.2 Hz), 3.36 (dd, 1H, H-
5, J1 ¼ 3.2 Hz, J2 ¼ 9.2 Hz), 2.87 (t, 2H, CH2CH2OH, J ¼ 6.8 Hz),
2.58 (q, 2H, SCH2CH3, J ¼ 7.2 Hz), 1.86 (s, 3H, CCH3), 1.57 (d, 3H,
CHCH3, J ¼ 8.0 Hz), 1.22 (t, 3H, SCH2CH3, J ¼ 7.6 Hz), 0.19e0.09 (m,
36H, Si(CH3)3); MS (m/z): 942 ([M þ 1]þ).
5.1.9.2. (S)-4-(N-(2-(
3-(isopropyldisulfanyl)pent-3-enyl 2-(6-methoxynaphthalen-2-yl)prop-
anoate (1b). Yield: 83.6%. Mp: 56e58 ꢀC; IR (KBr pellets cmꢂ1):
a-D-Glucopyranose-6-yl)-2-oxoethyl)formamido)-
5.1.8.2. (S)-4-(N-(2-(1,2,3,4-tetra-O-Trimethylsilyl-a-D-glucopyranos-
yl)-2-oxoethyl)formamido)-3-(isopropyldisulfanyl)pent-3-enyl 2-(6-
methoxynaphthalen-2-yl)propanoate (15b). Yield: 53.4%. 1H NMR
(CDCl3, ppm): 7.92 (s, 1 H, CHO), 7.70 (dd, 2H, AreH, J1 ¼ 2.8 Hz,
J2 ¼ 8.4 Hz), 7.64 (s, 1H, AreH), 7.36 (d, 1H, AreH, J ¼ 8.4 Hz), 7.14
(dd,1H, AreH, J1 ¼ 2.4 Hz, J2 ¼ 8.8 Hz), 7.12 (s,1H, AreH), 4.99 (d,1H,
H-1, J ¼ 3.2 Hz), 4.40 (d, 1H, H-6, J ¼ 11.2 Hz), 4.23 (t, 2H,
CH2CH2O, J ¼ 6.4 Hz), 4.11 (t, 1H, H-2, J ¼ 5.6 Hz), 4.09e4.05 (m,
2H, COCH2), 3.96e3.94 (m, 1H, H-60), 3.91 (s, 3H, OCH3), 3.82 (q,
1H, CHCH3, J ¼ 6.8 Hz), 3.78 (t, 1H, H-3, J ¼ 8.8 Hz), 3.40 (t, 1H, H-
4, J ¼ 9.2 Hz), 3.36 (dd, 1H, H-5, J1 ¼ 3.2 Hz, J2 ¼ 9.2 Hz), 2.86 (t,
2H, CH2CH2OH, J ¼ 6.8 Hz), 2.84e2.81 (m, 1H, SCH(CH3)3), 1.90 (s,
3H, CCH3), 1.56 (d, 3H, CHCH3, J ¼ 7.2 Hz), 1.21 (d, 6H, SCH(CH3)2,
y
3418, 2962, 2930, 1733, 1669, 1454, 1266; 1H NMR (CDCl3, ppm): 7.86
(s, 1H, CHO), 7.78 (dd, 2H, AreH, J1 ¼ 7.2 Hz, J2 ¼ 8.4 Hz), 7.71 (s, 1H,
AreH), 7.37 (d, 1H, AreH, J ¼ 7.2 Hz), 7.28 (d, 1H, AreH, J ¼ 2.0), 7.15
(dd, 1H, AreH, J1 ¼ 2.4 Hz, J2 ¼ 8.8 Hz), 4.91 (d, 1H, H-1, J ¼ 3.4 Hz),
4.32 (d, 1H, H-6, J ¼ 11.2 Hz), 4.17 (t, 2H, CH2CH2O, J ¼ 6.4 Hz), 4.09 (t,
1H, H-2, J ¼ 5.2 Hz), 4.06 (m, 2H, COCH2), 3.91 (q, 1H, CHCH3,
J ¼ 6.8 Hz), 3.86 (s, 3H, OCH3), 3.83e3.79 (m, 1H, H-60), 3.45 (t, 1H, H-
3, J ¼ 9.2 Hz), 3.14 (dd,1H, H-5, J1 ¼ 5.2 Hz, J2 ¼ 8.8 Hz), 3.06 (t, 1H, H-
4, J ¼ 9.6 Hz), 2.93e2.89 (m, 1H, SCH(CH3)3), 2.83 (t, 2H, CH2CH2OH,
J ¼ 6.8 Hz), 1.87 (s, 3H, CCH3), 1.46 (d, 3H, CHCH3, J ¼ 7.2 Hz), 1.15 (d,
6H, SCH(CH3)2, J ¼ 6.8 Hz); 13C NMR (DMSO-d6, ppm): 174.3 (1C,
COCH), 168.5 (1C, COCH2), 162.6 (1C, CHO), 157.4 (1C, AreCO), 137.4
(1C, NC]C), 135.8 (1C, AreC), 133.6 (1C, AreC), 129.4 (1C, AreC),
128.5 (1C, AreC), 127.3 (1C, AreC), 126.4 (1 C, AreC), 125.9 (1C,
AreC), 119.1 (1C, AreC), 105.9 (1 C, AreC), 97.1 (1C, C]CS), 92.6 (1C,
HOCHO), 76.6 (1C, COH), 72.7 (1C, COH), 70.7 (1C, COH), 69.3 (1C,
COH), 65.3 (1C, CHCH2O), 62.3 (1C, CH2CH2O), 55.4 (1C, OCH3), 45.2
(1C, SC), 44.7 (1C, COCH2N), 40.9 (1C, COCH), 29.2 (1C, C]CCCH2),
22.1 (2 C, SC(CH3)2), 18.6 (2C, C]CCH3, CHCH3); MS (m/z): 668
([M þ 1]þ).
J
¼
6.8 Hz), 0.18e0.13 (m, 36H, Si(CH3)3); MS (m/z): 956
([M þ 1]þ).
5.1.8.3. (S)-4-(N-(2-(1,2,3,4-tetra-O-Trimethylsilyl-a-D-glucopyr-
anosyl)-2-oxoethyl)formamido)-3-(benzyldisulfanyl)pent-3-enyl
2-(6-methoxynaphthalen-2-yl)propanoate (15c). Yield: 35.8%.
1H NMR (CDCl3, ppm): 7.85 (s, 1 H, CHO), 7.69 (dd, 2H, AreH,
J1 ¼ 3.6 Hz, J2 ¼ 8.4 Hz), 7.63 (s, 1H, AreH), 7.36 (d, 1H, AreH,
J ¼ 8.4 Hz), 7.28e7.11 (m, 7H, AreH), 4.99 (d, 1H, H-1, J ¼ 2.8 Hz),
4.40 (d, 1H, H-6, J ¼ 11.2 Hz), 4.14 (t, 2H, CH2CH2O, J ¼ 6.4 Hz),