430
J. Zhang et al. / European Journal of Medicinal Chemistry 121 (2016) 422e432
CDCl3)
d
: 7.87 (d, 2H, R2-H2, H6, J ¼ 8.4 Hz), 7.40e7.19 (m, 5H, R1-
intermediate 8 (0.21 g, 0.25 mmol), triethylamine (0.50 mmol), and
DMAP (0.01 mmol) in dichloromethane (8 mL). The mixture was
stirred at room temperature for 8 h. The reaction mixture was
poured into water and extracted with dichloromethane
(3 ꢂ 10 mL). The organic layer was washed with 5% dilute hydro-
H2, H3, H4, H5, H6), 6.93 (d, 2H, R2-H3, H5, J ¼ 8.4 Hz), 5.84 (m, 1H,
H9), 5.78e5.70 (m, 3H, H23, H10, H11), 5.54 (d, 1H, H22, J ¼ 8.4 Hz),
5.42e5.39 (m, 3H, H19, H100, H3), 5.06 (m, 1H, H15), 4.96 (br. s, 1H,
eNHe), 4.73e4.68 (m, 3H, H10, H8a), 4.51 (d, 1H, eCH2C]Ne,
J ¼ 8.0 Hz), 4.35e4.25 (m, 2H, H5, eCH2C]Ne), 4.03 (s, 1H, 7-OH),
3.98e3.75 (m, 8H, H6, H13, H50, H17, H500, R2-OCH3), 3.59e3.44 (m,
3H, H30, H25, H300), 3.38 (s, 3H, 300-OCH3), 3.28 (s, 3H, 30-OCH3), 3.07
(t, 1H, H40, J ¼ 9.2 Hz), 2.50 (m, 1H, H12), 2.36e2.17 (m, 6H, 5-OH,
H16, H24, H20), 2.01 (d, 1H, H20, J ¼ 8.8 Hz), 1.87 (s, 3H, 4-Me), 1.76
(d, 1H, H18, J ¼ 11.2 Hz), 1.59e1.43 (m, 9H, H20, H26, H27, 14-Me,
H200), 1.25e0.86 (m, 19H, 60-Me, 600-Me, 12-Me, 27-Me, 24-Me, 26-
chloric acid (3
ꢂ
10 mL), 5% aqueous sodium bicarbonate
(3 ꢂ 10 mL), and saturated sodium chloride solution (3 ꢂ 10 mL),
dried over anhydrous sodium sulfate, filtered. The organic phase
was evaporated under reduced pressure, and the residue was
subjected to flash chromatography on silica gel, eluting with pe-
troleum ether/ethyl acetate (10:1e20:1) to afford target products
16aef.
Me, H18). 13C NMR (100 MHz, CDCl3)
d: 173.6, 167.6, 162.0, 139.6,
137.9, 137.7, 136.2, 135.0, 129.9, 129.3 (2C), 128.6 (2C), 128.3 (2C),
128.1, 127.6, 124.7, 120.2, 118.2, 117.9 (2C), 113.6, 113.5, 98.3, 95.7,
94.8, 81.9, 81.1, 80.3, 79.1, 77.3, 77.0, 76.6, 74.8, 73.4, 68.2, 67.6, 66.8,
64.8, 56.4, 55.4, 50.3, 45.6, 40.3, 39.7, 39.6, 36.5, 35.0, 34.3, 34.1,
31.6, 30.4, 29.6, 27.4, 20.0, 19.8, 18.0, 16.9, 16.2, 15.0, 12.8, 11.9. Anal.
Calcd. For C63H86N2O16S: C, 65.26; H, 7.48; N, 2.42. Found: C, 65.24;
H, 7.48; N, 2.40. ESI-MS m/z: 1159.40 [MþH]þ.
5.3.1. Data for compound 16a
Yield ¼ 45%; white solid; mp: 163e165 ꢃC; 1H NMR (400 MHz,
CDCl3) d: 5.86 (m, 1H, H9), 5.79e5.72 (m, 3H, H23, H10, H11), 5.55
(d, 1H, H22, J ¼ 9.2 Hz), 5.43e5.36 (m, 3H, H19, H100, H3), 4.98 (m,
1H, H15), 4.77e4.67 (m, 3H, H10, H8a), 4.51 (d, 1H, H5), 4.07 (s, 1H,
7-OH), 3.99e3.81 (m, 5H, H6, H13, H50, H17, H500), 3.62e3.44 (m,
3H, H30, H25, H300), 3.43 (s, 6H, 300-OCH3, 30-OCH3), 3.30 (s, 1H, H2),
3.22 (t, 1H, H40, J ¼ 8.8 Hz), 3.10 (s, 3H, ReCH3), 2.53 (m, 1H, H12),
2.36e2.22 (m, 6H, 5-OH, H16, H24, H20), 2.18 (s, 1H, H20), 1.88 (s,
3H, 4-Me), 1.77 (d, 1H, H18, J ¼ 9.2 Hz), 1.55e1.43 (m, 9H, H20, H26,
H27, 14-Me, H200), 1.26e1.15 (m, 6H, 60-Me, 600-Me), 0.96e0.87 (m,
13H, 12-Me, 27-Me, 24-Me, 26-Me, H18ax). 13C NMR (100 MHz,
5.2.2. Data for compound 12a
Yield ¼ 36%; white solid; mp: 148e150 ꢃC; 1H NMR (400 MHz,
CDCl3) d: 7.42e7.27 (m, 5H, AreH), 5.84 (m, 1H, H9), 5.82e5.67 (m,
3H, H23, H10, H11), 5.54 (d, 1H, H22, J ¼ 9.2 Hz), 5.42 (s, 1H, H3),
5.38e5.32 (m, 1H, H19), 4.93 (d, 1H, H15, J ¼ 7.2 Hz), 4.66 (m, 2H,
H8a), 4.50 (t, 1H, eCH2C]Ne), 4.52e4.48 (m, 1H, H40), 4.37 (m, 1H,
H5), 4.29 (m, 1H, eCH2C]Ne), 4.13e4.10 (m, 1H, eNHe), 4.03 (s,
1H, 7-OH), 3.97e3.81 (m, 3H, H50, H6, H13), 3.70e3.67 (m, 2H, H17,
H30), 3.48 (s, 3H, 30-OCH3), 3.04 (s, 3H, R2-CH3), 3.11 (m, 2H, H25,
H2), 2.48 (m,1H, H12), 2.35e1.99 (m, 7H, 5-OH, H16, H24, H20, H20),
1.87e1.71 (m, 4H, 4-Me, H18), 1.60e1.26 (m, 7H, H20, H26, H27, 14-
Me), 1.12e0.95 (m, 6H, 60-Me, 12-Me), 0.91e0.81 (m, 10H, 27-Me,
CDCl3) d: 173.7, 139.6, 137.9, 136.2, 135.1, 127.6, 124.7, 120.3, 118.2,
117.9, 98.5, 95.7, 94.9, 81.9, 80.9, 80.3, 79.1, 77.3, 77.0, 76.6, 74.8, 74.5,
68.2, 67.6, 67.0, 65.7, 56.5, 56.0, 54.7, 45.6, 42.9, 40.3, 39.6, 36.5, 35.1,
34.3, 34.1, 30.8, 30.5, 29.6, 27.4, 20.1, 19.9, 18.2, 17.1, 16.3, 15.0, 12.9,
12.0. Anal. Calcd For C49H75NO15S: C, 61.94; H, 7.96; N, 1.47. Found:
C, 61.95; H, 7.95; N, 1.47. ESI-MS m/z: 972.45 [MþNa]
þ
.
5.4. General procedure for the preparation of target compounds
17aed
24-Me, 26-Me, H18). 13C NMR (100 MHz, CDCl3)
d
: 173.5, 167.5,
139.8, 137.8, 137.3, 136.3, 134.8, 132.7, 130.0, 129.3 (2C), 128.9 (2C),
128.2, 127.5, 124.9, 120.1, 118.4, 117.9, 95.6, 94.9, 82.3, 80.2, 78.9,
77.3, 76.6, 74.7, 73.5, 70.2, 68.3, 67.5, 64.8, 59.0, 56.5, 50.3, 45.5, 43.1,
40.3, 39.4, 36.4, 35.0, 34.1, 31.3, 30.4, 27.4, 19.8, 17.0, 16.3, 14.9, 12.9,
11.9. Anal. Calcd For C50H70N2O12S: C, 65.05; H, 7.64; N, 3.03. Found:
Intermediate 8 (0.2 mmol) was added dropwise to a solution of
0.4 mmol of sulfonylcarbamate in dry toluene (20 mL). The reaction
mixture was refluxed for 2e4 h and then concentrated. The residue
was purified by chromatography on silica gel using petroleum
ether/ethyl acetate (10:1e20:1) as eluant to give target products
17aed.
C, 65.06; H, 7.64, N, 3.02. ESI-MS m/z: 945.43 [MþNa] þ
.
5.2.3. Data for compound 15a
Yield ¼ 48%; pale yellow solid; mp: 159e161 ꢃC; 1H NMR
5.4.1. Data for compound 17a
(400 MHz, CDCl3)
d
: 7.92 (d, 2H, R2-H2, H6, J ¼ 6.4 Hz), 7.53 (m, 3H,
Yield ¼ 30%; white solid; mp: 145e147 ꢃC; 1H NMR (400 MHz,
R2-H2, H5, R1-H4), 7.27e7.08 (m, 4H, R1-H2, H3, H5, H6), 5.73 (m,
1H, H9), 5.70e5.66 (m, 3H, H23, H10, H11), 5.53 (d, 1H,H22,
J ¼ 11.2 Hz), 5.41 (s, 1H, H3), 5.30e5.23 (m, 2H, H19, H15),
4.64e4.56 (m, 3H, H8a, eNHe), 4.51e4.49 (m, 1H, eCH2C]Ne),
4.44e4.35 (m, 2H, H5, eCH2C]Ne), 4.03 (s, 1H, 7-OH), 4.00e3.60
(m, 4H, H6, H13, H17, H25), 3.23 (m, 1H, H2), 2.62 (m, 1H, H12),
2.37e2.13 (m, 4H, 5-OH, H16, H24), 2.05 (s, 1H, H20), 1.87 (s, 3H, 4-
Me), 1.60e1.21 (m, 7H, H20, H26, H27, 14-Me), 0.95e0.78 (m, 10H,
CDCl3)
d
: 8.02 (dd, 2H, ReH2, H6, J ¼ 8.0 Hz, 14.4 Hz), 7.66e7.54 (m,
3H, ReH3, H4, H5), 5.84e5.68 (m, 4H, H9, H23, H10, H11), 5.56 (d,
1H, H22, J ¼ 8.0 Hz), 5.43e5.39 (m, 3H, H3, H19, H100), 4.99 (m, 1H,
H15), 4.77 (s, 1H, H10), 4.58e4.47 (m, 2H, H8a), 4.21 (d, 1H, H5), 4.07
(s, 1H, 7-OH), 3.98e3.50 (m, 8H, H6, H13, H50, H17, H500, H30, H25,
H300), 3.38 (s, 3H, 300-OCH3), 3.30 (s, 3H, 30-OCH3), 2.52 (m, 1H, H12),
2.29e2.01 (m, 7H, 5-OH, H16, H24, H20, H20), 1.88 (s, 3H, 4-Me),
1.75 (m, 1H, H18), 1.68e1.49 (m, 9H, H20, H26, H27, 14-Me, H200),
1.25e1.05 (m, 9H, 60-Me, 600-Me, 12-Me), 0.96e0.87 (m, 10H, 27-Me,
27-Me, 24-Me, 26-Me, H18). 13C NMR (100 MHz, CDCl3)
d: 173.3,
165.4, 141.5, 137.8, 134.7, 133.8, 132.6, 129.9 (2C), 129.7 (2C), 128.8
(2C), 126.2, 119.3, 117.9 (2C), 117.8, 115.6, 97.6, 80.2, 78.9, 77.3, 77.0,
76.6, 71.6, 68.2, 67.5, 67.0, 59.9, 56.5, 45.3, 41.4, 40.0, 38.3, 38.1, 36.6,
36.2, 35.5, 34.1, 29.6, 27.2, 19.8, 18.7, 15.4, 13.1, 12.5, 11.4. Anal. Calcd
For C48H59FN2O9S: C, 67.11; H, 6.92; N, 3.26. Found: C, 67.10; H, 6.93;
24-Me, 26-Me, H18). 13C NMR (100 MHz, CDCl3)
d: 173.0, 139.6,
138.6, 138.1, 136.2, 135.1, 133.6, 132.5, 129.2, 128.8 (2C), 128.2, 127.5
(2C), 127.0, 124.0, 121.7, 120.5, 118.2, 98.5, 95.7, 94.9, 81.0, 80.6, 79.1,
77.3, 77.0, 76.6, 74.8, 73.3, 72.3, 68.6, 68.2, 67.0, 65.2, 56.6, 55.8, 50.8,
49.9, 45.5, 40.4, 39.6, 35.1, 34.1, 31.6, 30.9, 30.5, 29.6, 27.4, 20.1, 19.4,
18.2, 16.9, 16.3, 15.0, 12.9, 12.0. Anal. Calcd For C55H78N2O16S: C,
N, 3.26. ESI-MS m/z: 881.19 [MþNa] þ
.
62.60; H, 7.45; N, 2.65. Found: C, 62.62; H, 7.44; N, 2.65. ESI-MS m/z:
þ
5.3. General procedure for the preparation of target compounds
16aef
1055.19 [MþH]
.
5.5. Biological assay
A solution of sulfony chloride (0.50 mmol) in dried dichloro-
methane (5 mL) at 0 ꢃC was added dropwise to a solution of
Bioassays were conducted with three insect species, Tetranychus