Journal of Medicinal Chemistry
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evaporated in vacuo. The crude product was purified by silica gel
preparative TLC using ethyl acetate/n-hexane (4:6) to yield the desire
product 16a as an off-white solid (0.051 g, 46%). Mp 60−62 °C; H
MHz, CDCl3): δ 0.88 (t, J = 7.3 Hz, 3H), 1.30−1.34 (m, 6H), 1.84−
1.95 (m, 2H), 3.52 (d, 2H), 5.61−5.66 (m, 1H), 7.55 (s, 1H); 13C
NMR (75.6 MHz, CDCl3): δ 13.8, 22.2, 24.4, 31.1, 32.4, 40.7, 70.2,
81.8, 135.0, 135.3, 149.1, 165.1, 165.9, 171.2; IR (neat): νmax 3104,
2926, 1750, 1698, 1609, 1421, 1405, 1335, 1208, 1147, 1027, 967, 892,
844, 775, 686, 670 cm−1; UV (MeOH): λmax 306 nm (ε 266715 M−1
cm−1); HRMS (ESI) m/z Calcd for C14H16Br2O6Na (M + Na)+
460.9211. Found 460.9212. Anal. Calcd for C14H16Br2O6: C, 38.21; H,
3.66. Found: C, 38.40; H, 3.55.
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NMR (300 MHz, CDCl3): δ 0.92 (t, J = 7.4 Hz, 3H), 1.10 (t, J = 7.1
Hz, 6H), 1.33−1.42 (m, 2H), 1.82−1.90 (m, 2H), 3.12 (q, J = 7.1 Hz,
4H), 4.82 (s, 2H), 5.70 (t, J = 6.8 Hz, 1H), 7.44 (s, 1H); 13C NMR
(75.6 MHz, CDCl3): δ 11.4, 13.4, 18.1, 34.5, 48.6, 68.9, 69.4, 82.2,
134.9, 135.3, 149.0, 165.7, 166.8; IR (neat): νmax 3108, 2957, 2931,
2875, 1775, 1752, 1604, 1513, 1450, 1261, 1204, 1098, 1033, 1005,
964, 951, 843, 776, 725, 660 cm−1; UV (MeOH): λmax 307 nm (ε
314073 M−1 cm−1); HRMS (ESI) m/z Calcd for C15H21Br2N3O6Na
(M + Na)+ 519.9695. Found 519.9692.
3-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-3-yl)-
dodecyloxy)-3-oxopropanoic Acid (18c). The desired compound
was synthesized using malonyl dichloride (0.40 g, 2.85 mmol),
hydroxyfimbrolide 7c (0.5 g, 1.14 mmol), and pyridine (0.27 mL, 3.42
mmol) as described for the compound 18a to yield the title compound
18c as an off-white solid (0.47 g, 79%). Mp 46−48 °C; 1H NMR (300
MHz, CDCl3): δ 0.88 (t, J = 7.3 Hz, 3H), 1.23−1.30 (m, 18H), 1.84−
1.89 (m, 2H), 3.45 (d, 2H), 5.61−5.66 (m, 1H), 7.55 (s, 1H); 13C
NMR (75.6 MHz, CDCl3): δ 14.1, 22.6, 24.9, 29.0, 29.3, 29.5, 29.6,
31.9, 32.5, 40.8, 70.3, 77. 2, 82.2, 135.1, 135.5, 149.2, 165.3, 166.0,
171.1; IR (neat): νmax 3092, 2919, 2850, 1759, 1699, 1608, 1423, 1334,
1266, 1152, 1040, 1026, 966, 850, 774, 684, 670 cm−1; UV (MeOH):
λmax 307 nm (ε 290145 M−1 cm−1); HRMS (ESI) m/z Calcd for
C20H28Br2O6Na (M + Na)+ 545.0150. Found 545.0146. Anal. Calcd
for C20H28Br2O6: C, 45.82; H, 5.38. Found: C, 45.52; H, 5.30.
4-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-3-yl)-
dodecyloxy)-4-oxobutanoic Acid (18d). The desired compound
was synthesized using succinyl dichloride (0.31 mL, 2.85 mmol),
hydroxyfimbrolide 7c (0.5 g, 1.14 mmol) and pyridine (0.27 mL, 3.42
mmol) as described for the compound 18a to yield the title compound
18d as an off-white solid (0.50 g, 83%). Mp 58−60 °C; 1H NMR (300
MHz, CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.23−1.30 (m, 18H), 1.83−
1.88 (m, 2H), 2.69−2.73 (m, 4H), 5.59 (t, J = 5.3 Hz, 1H), 7.55 (s,
1H); 13C NMR (75.6 MHz, CDCl3): δ 14.1, 22.6, 24.9, 28.5, 28.7,
29.1, 29.3, 29.5, 29.6, 31.9, 32.6, 69.2, 77. 2, 81.7, 135.1, 135.7, 149.2,
166.0, 171.1, 176.3; IR (neat): νmax 3086, 2924, 2852, 1759, 1740,
1709, 1608, 1417, 1322, 1162, 1045, 965, 913, 847, 774, 684 cm−1; UV
(MeOH): λmax 307 nm (ε 223431 M−1 cm−1); HRMS (ESI) m/z
Calcd for C21H30Br2O6Na (M + Na)+ 559.0307. Found 559.0304.
Anal. Calcd for C20H28Br2O6: C, 46.86; H, 5.62. Found: C, 47.12; H,
5.48.
(Z)-2-(2-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-
3-yl)butoxy)-2-oxoethoxy)-1-(4-(ethoxycarbonyl)piperazin-1-
yl)diazene Oxide (16b). The title compound was synthesized
following the procedure described for compound 16a using the 2-
bromoacetyl ester derivative 11a (0.2 g, 0.44 mmol) and piperazine
diazeniumdiolate derivative 15b (0.12 g, 0.53 mmol) to give the
desired product 16b as a white solid (0.15 g, 58%). Mp 84−86 °C; 1H
NMR (300 MHz, CDCl3): δ 0.93 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1
Hz, 3H), 1.30−1.38 (m, 2H), 1.83−1.91 (m, 2H), 3.40 (t, J = 4.9 Hz),
3.64 (t, J = 4.9 Hz), 4.13 (q, J = 7.1 Hz, 2H), 4.78 (s, 2H), 5.69 (t, J =
6.7 Hz, 1H), 7.43 (s, 1H); 13C NMR (75.6 MHz, CDCl3): δ 13.4,
14.5, 18.1, 34.5, 42.2, 50.8, 61.8, 69.0, 69.3, 82.3, 134.8, 135.4, 149.0,
154.9, 165.7, 166.9; IR (neat): νmax 3099, 2957, 2932, 2862, 1773,
1697, 1504, 1473, 1421, 1248, 1215, 1196, 1183, 1096, 1057, 1041,
968, 947, 921, 894, 854, 835, 780, 682 cm−1; UV (MeOH): λmax 308
nm (ε 311580 M−1 cm−1); HRMS (ESI) m/z Calcd for
C18H24Br2N4O8Na (M + Na)+ 604.9859. Found 604.9855.
(Z)-2-(2-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-
3-yl)butoxy)-2-oxoethoxy)-1-morpholinodiazene Oxide (16c).
The title compound was synthesized following the procedure
described for compound 16a using the 2-bromoacetyl ester derivative
11a (0.25 g, 0.55 mmol) and morpholine diazeniumdiolate derivative
15c (0.11 g, 0.67 mmol) to give the desired product 16c as a sticky oil
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(0.11 g, 40%). H NMR (300 MHz, CDCl3): δ 0.93 (t, J = 7.4 Hz),
1.27−1.31 (m, 2H), 1.77−1.85 (m, 2H), 3.42−3.46 (m, 4H), 3.82−
3.85 (m, 4H), 4.78 (s, 2H), 5.71 (t, J = 6.7 Hz, 1H), 7.45 (s, 1H); 13C
NMR (75.6 MHz, CDCl3): δ 13.5, 18.2, 34.6, 51.4, 65.6, 69.1, 69.4,
82.4, 134.9, 135.5, 149.1, 165.8, 167.0; IR (neat): νmax 2962, 2929,
2865, 1767, 1611, 1500, 1456, 1267, 1228, 1194, 1099, 1036, 963, 927,
848, 728, 681 cm−1; UV (MeOH): λmax 308 nm (ε 270071 M−1 cm−1);
HRMS (ESI) m/z Calcd for C15H21Br2N3O7Na (M + Na)+ 533.9487
Found 533.9487.
(Z)-1-(4-(4-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofur-
an-3-yl)butoxy)-4-oxobutanoyl)piperazin-1-yl)-2-methoxydia-
zene Oxide (20a). To a solution of fimbrolide monoacid 18a (0.2 g,
0.47 mmol) and piperazine diazeniumdiolate 19 (0.09 g, 0.56 mmol)
in DCM was added EDC (0.13 g, 0.70 mmol), and the mixture was
stirred for 7 h at room temperature. The organic layer was successively
washed with water (2 × 20 mL) and brine, dried over sodium sulfate,
and evaporated to dryness followed by vacuum chromatography using
ethyl acetate/n-hexane (50:50) to yield the title compound 20a as
4-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-3-yl)-
butoxy)-4-oxobutanoic Acid (18a). To a solution of succinyl
dichloride (0.42 mL, 3.83 mmol) at 0 °C was added a solution of
hydroxyfimbrolide 7a (0.5 g, 1.53 mmol) and pyridine (0.36 mL, 4.60
mmol) in DCM slowly over a period of 45 min. The reaction mixture
was stirred further for 10 min at 0 °C and then at room temperature
for 2 h. The organic layer was washed with 1 M HCl (2 × 20 mL),
water (2 × 20 mL), and brine (20 mL). The organic layer was dried
and evaporated, and the crude product was purified by vacuum
chromatography using ethyl acetate/n-hexane (4:6) to give the title
1
sticky brown oil (0.15 g, 57%). H NMR (300 MHz, CDCl3): δ 0.92
(t, J = 7.4 Hz, 3H), 1.36−1.41 (m, 2H), 1.78−1.85 (m, 2H), 2.60−
2.75 (m, 4H), 3.35−3.43 (m, 4H), 3.65 (t, J = 5.2 Hz, 2H), 3.76 (t, J =
5.2 Hz, 2H), 4.00 (s, 3H), 5.61 (m, 1H), 7.61 (s, 1H); 13C NMR (75.6
MHz, CDCl3): δ 13.6, 18.3, 27.9, 29.0, 29.6, 34.6, 40.3, 43.7, 51.0,
51.2, 61.2, 69.0, 81.3, 135.3, 135.9, 149.5, 166.2, 169.5, 172.0; IR
(neat): νmax 2933, 2871, 1769, 1736, 1645, 1496, 1440, 1214, 1156,
1066, 1030, 965, 912, 847, 725, 683 cm−1; UV (MeOH): λmax 307 nm
(ε 174472 M−1 cm−1); HRMS (ESI) m/z Calcd for C18H24Br2N4O7Na
(M + Na)+ 588.9909. Found 588.9911.
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compound 18a as a white solid (0.56 g, 86%). Mp 130−132 °C; H
NMR (300 MHz, CDCl3): δ 0.93 (t, J = 7.3 Hz, 3H), 1.33−1.41 (m,
2H), 1.81−1.89 (m, 2H), 2.68−2.73 (m, 4H), 5.61 (t, J = 6.7 Hz, 1H),
7.42 (s, 1H); 13C NMR (75.6 MHz, CDCl3): δ 13.5, 18.2, 28.6, 28.7,
34.6, 68.9, 81.8, 135.1, 135.7, 149.2, 166.0, 171.1, 177.2; IR (neat):
νmax 3095, 2974, 1768, 1731, 1712, 1409, 1234, 1204, 1169, 1035, 968,
905, 843, 771, 678 cm−1; UV (MeOH): λmax 307 nm (ε 217372 M−1
cm−1); HRMS (ESI) m/z Calcd for C13H14Br2O6Na (M + Na)+
446.9055. Found 446.9051. Anal. Calcd for C13H14Br2O6: C, 36.65; H,
3.31. Found: C, 36.90; H, 3.28.
(Z)-1-(4-(3-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofur-
an-3-yl)hexyloxy)-3-oxopropanoyl)piperazin-1-yl)-2-methoxy-
diazene Oxide (20b). The title compound was synthesized following
the procedure described for compound 20a using the monoacid
fimbrolide derivative 18b (0.2 g, 0.454 mmol), piperazine
diazeniumdiolate derivative 19 (0.08 g, 0.496 mmol), and EDC
(0.11 g, 0.59 mmol) to give desired product 20b as a yellow sticky oil
3-(1-(5-(Dibromomethylene)-2-oxo-2,5-dihydrofuran-3-yl)-
hexyloxy)-3-oxopropanoic Acid (18b). The desired compound
was synthesized using malonyl dichloride (0.35 mL, 3.53 mmol),
hydroxyfimbrolide 7b (0.5 g, 1.41 mmol), and pyridine (0.34 mL, 4.23
mmol) as described for the compound 18a to yield the title compound
18b as an off-white solid (0.46 g, 75%). Mp 74−76 °C; 1H NMR (300
1
(0.21 g, 79%). H NMR (300 MHz, CDCl3): δ 0.88 (t, J = 7.3 Hz,
3H), 1.28−1.33 (m, 6H), 1.85−1.89 (m, 2H), 3.40−3.48 (m, 4H),
3.53 (d, J = 2.8 Hz, 2H), 3.63 (t, J = 5.4 Hz, 2H), 3.82 (t, J = 5.7 Hz,
2H), 4.02 (s, 3H), 5.58−5.62 (m, 1H), 7.62 (s, 1H); 13C NMR (75.6
K
dx.doi.org/10.1021/jm400951f | J. Med. Chem. XXXX, XXX, XXX−XXX