1202 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 5
Burke and Koch
hexanes), providing 90.4 mg (68%) of 8a as a clear, colorless
oil. TLC (SiO2, 4:1 ethyl acetate/hexanes): Rf ) 0.55. 1H NMR
(500 MHz, CDCl3): δ 0.92 (3H, dt, J ) 7.3 Hz, TAM 4), 1.48
(1H, m, 10b), 1.74 (1H, m, 10a), 2.46 (5H, m, TAM 3, N-Me),
2.89 (3H, m, -CH2-N-CH2-CH2-O-Ar, -CH2-N-CH2-
CH2-O-Ar diast. 1), 2.99 (1H, t, J ) 5.3 Hz, -CH2-N-CH2-
CH2-O-Ar diast. 2), 3.16 (2H, m, 1, 7), 3.40 (2H, m, 2, 6),
3.94 (1H, t, J ) 5.5 Hz, -N-O-CH2- diast. 2), 4.11 (3H, m,
Ar-O-CH2-, -N-O-CH2- diast. 1), 6.11 (2H, dt, J ) 2.0
Hz, 8, 9), 6.45 (2H, dd, J ) 8.8, 8.6 Hz, RO-Ph 2), 6.71 (2H,
dd, J ) 8.8 Hz, HO-Ph 3), 6.80 (2H, dd, J ) 8.8, 8.6 Hz, RO-
Ph 3), 7.10 (7H, m, HO-Ph 2, phenyl). HRMS [M + Na]+
calculated 601.2673, found 601.2692.
a round-bottom flask and concentrated in vacuo. The crude
product was purified via flash chromatography on silica gel
(90% chloroform/10% methanol), providing 16.9 mg (71%) of
9a as
a clear, colorless oil. TLC (SiO2, 9:1 chloroform/
methanol): Rf ) 0.17. 1H NMR (500 MHz, CD3CN): δ 0.87
(3H, dt, J ) 7.3 Hz, 4), 2.25 (1.5H, s, N-Me diast. 1), 2.32
(1.5H, s, N-Me diast. 2), 2.42 (2H, dq, J ) 7.3 Hz, 3), 2.59
(1H, t, J ) 5.7 Hz, H2N-O-CH2-CH2-N-CH2- diast. 1), 2.65
(1H, t, J ) 5.7 Hz, H2N-O-CH2-CH2-N-CH2- diast. 2), 2.69
(1H, t, J ) 5.9 Hz, H2N-O-CH2-CH2-N-CH2- diast. 1), 2.79
(1H, t, J ) 5.9 Hz, H2N-O-CH2-CH2-N-CH2- diast. 2), 3.64
(1H, t, J ) 5.7 Hz, H2N-O-CH2- diast. 1), 3.69 (1H, t, J )
5.7 Hz, H2N-O-CH2- diast. 2), 3.90 (1H, t, J ) 5.9 Hz, Ar-
O-CH2- diast. 1), 4.06 (1H, t, J ) 5.9 Hz, Ar-O-CH2- diast.
2), 6.45 (1H, d, J ) 8.6 Hz, HO-Ph 3 diast. 2), 6.54 (1H, d, J
) 9.0 Hz, HO-Ph 3 diast. 1), 6.70 (1H, d, J ) 8.6 Hz, RO-Ph
3 diast. 2), 6.77 (1H, d, J ) 8.8 Hz, RO-Ph 3 diast. 1), 6.79
(1H, d, J ) 8.6 Hz, HO-Ph 2 diast. 2), 6.88 (1H, d, J ) 8.8
Hz, HO-Ph 2 diast. 1), 7.05 (1H, d, J ) 8.6 Hz, RO-Ph 2
diast. 2), 7.13 (6H, m, RO-Ph 2 diast. 1, phenyl). HRMS [M
+ Na]+ calculated 455.2305, found 455.2275.
E/Z-4-{2-{2-[(2-{4-[1-(4-Hyd r oxyp h en yl)-2-p h en ylbu t-1-
e n yl]p h e n oxy}e t h yl)m e t h yla m in o]e t h oxy}e t h oxy)-4-
a za tr icyclo[5.2.1.02,6]d ec-8-en e-3,5-d ion e (8b). A solution
of 7b (223 mg, 0.6 mmol) in dry THF (4.0 mL) was added to 6
(297 mg, 0.9 mmol). Diisopropylethylamine (157 µL, 0.9 mmol)
was added. The reaction and workup were performed exactly
as described for 8a above. The crude material was purified
via flash chromatography on silica gel (98:2 to 100:0 ethyl
acetate/hexanes), providing 205 mg (55%) of 8b as a light-
yellow oil. TLC (SiO2, 4:1 chloroform/methanol): Rf ) 0.54.
1H NMR (500 MHz, CDCl3): δ 0.92 (3H, dt, J ) 7.3 Hz, TAM
4), 1.45 (1H, m, 10b), 1.73 (1H, m, 10a), 2.46 (5H, m, TAM 3,
N-Me), 2.78 (1H, t, J ) 5.6 Hz, -CH2-N-CH2-CH2-O-Ar
diast. 1), 2.85 (1H, t, J ) 5.6 Hz, -CH2-N-CH2-CH2-O-Ar
diast. 2), 2.90 (1H, t, J ) 5.6 Hz, -CH2-N-CH2-CH2-O-Ar
diast. 1), 3.00 (1H, t, J ) 5.6 Hz, -CH2-N-CH2-CH2-O-Ar
diast. 2), 3.15 (2H, m, 1, 7), 3.38 (2H, m, 2, 6), 3.65 (4H, m,
-N-O-CH2-CH2-O-CH2-CH2-N-), 3.95 (1H, t, J ) 5.6
Hz, -N-O-CH2- diast. 2), 4.08 (3H, m, Ar-O-CH2-, -N-
O-CH2- diast. 1), 6.12 (2H, m, 8. 9), 6.42 (1H, d, J ) 8.7 Hz,
RO-Ph 2 diast. 2), 6.46 (1H, d, J ) 8.7 Hz, RO-Ph 2 diast.
1), 6.67 (1H, d, J ) 8.7 Hz, HO-Ph 3 diast. 1), 6.72 (1H, d, J
) 8.9 Hz, HO-Ph 3 diast. 2), 6.78 (2H, m, RO-Ph 3), 7.10
(7H, m, HO-Ph 2, phenyl). HRMS [M + H]+ calculated
623.3116, found 623.3133.
E/Z-1-[4-(2-{[2-(2-Am in ooxyeth oxy)eth yl]m eth ylam in o}-
eth oxy)ph en yl]-1-(4-h ydr oxyph en yl)-2-ph en ylbu ten e (9b).
To a solution of 8b (45.7 mg, 73.4 µmol) dissolved in 1.0 mL of
95% ethanol was added hydrazine hydrate (11.5 µL, 367 µmol).
The reaction was performed exactly as described for 9a above.
The crude product was purified via flash chromatography on
silica gel (98:2 to 92:8 chloroform/methanol), providing 23.5
mg (67%) of 9b as a clear, colorless oil. TLC (SiO2, 9:1 chloro-
form/methanol): Rf ) 0.12. 1H NMR (500 MHz, CD3CN): δ
0.87 (3H, dt, J ) 7.3 Hz, TAM 4), 2.26 (1.5H, s, N-Me diast.
1), 2.33 (1.5H, s, N-Me diast. 2), 2.42 (2H, dq, J ) 7.3 Hz,
TAM 3), 2.58 (1H, t, J ) 5.8 Hz, Ar-O-CH2-CH2-N-CH2-
diast. 1), 2.64 (1H, t, J ) 5.8 Hz, Ar-O-CH2-CH2-N-CH2-
diast. 2), 2.71 (1H, t, J ) 5.8 Hz, Ar-O-CH2-CH2-N-CH2-
diast. 1), 2.81 (1H, t, J ) 5.8 Hz, Ar-O-CH2-CH2-N-CH2-
diast. 2), 3.52 (4H, m, -N-O-CH2-CH2-O-CH2-), 3.66 (2H,
m, -N-O-CH2-), 3.90 (1H, t, J ) 5.6 Hz, Ar-O-CH2- diast.
2), 4.06 (1H, t, J ) 5.6 Hz, Ar-O-CH2- diast. 1), 6.45 (1H, d,
J ) 8.5 Hz, HO-Ph 3 diast. 2), 6.53 (1H, d, J ) 8.7 Hz, HO-
Ph 3 diast. 1), 6.70 (1H, d, J ) 8.5 Hz, RO-Ph 3 diast. 2),
6.77 (1H, d, J ) 8.7 Hz, RO-Ph 3 diast. 1), 6.79 (1H, d, J )
8.5 Hz, HO-Ph 2 diast. 2), 6.88 (1H, d, J ) 8.7 Hz, HO-Ph 2
diast. 1), 7.05 (1H, d, J ) 8.5 Hz, RO-Ph 2 diast. 2), 7.14 (6H,
m, RO-Ph 2 diast. 1, phenyl). HRMS [M + Na]+ calculated
499.2567, found 499.2545.
E/Z-1-{4-[2-({2-[2-(2-Am in ooxyet h oxy)et h oxy]et h yl}-
m e t h yla m in o)e t h oxy]p h e n yl}-1-(4-h yd r oxyp h e n yl)-2-
p h en ylbu ten e (9c). To a solution of 8c (135 mg, 203 µmol)
dissolved in 2.6 mL of 95% ethanol was added hydrazine
hydrate (31.8 µL, 1.02 mmol). The reaction was performed
exactly as described for 9a above. The crude product was
purified via flash chromatography on silica gel (98:2 to 90:10
chloroform/methanol), providing 78.4 mg (74%) of 9c as a clear,
colorless oil. TLC (SiO2, 4:1 chloroform/methanol): Rf ) 0.16.
1H NMR (500 MHz, CD3CN): δ 0.87 (3H, dt, J ) 7.3 Hz, 4),
2.25 (1.5H, s, N-Me diast. 1), 2.32 (1.5 H, s, N-Me diast. 2),
2.42 (2H, dq, J ) 7.3 Hz, 3), 2.57 (1H, t, J ) 5.7 Hz, -O-
CH2-CH2-N-CH2-CH2-O-Ar diast. 1), 2.64 (1H, t, J ) 5.9
Hz, -O-CH2-CH2-N-CH2-CH2-O-Ar diast. 2), 2.70 (1H,
t, J ) 5.9 Hz, -O-CH2-CH2-N-CH2-CH2-O-Ar diast. 1),
2.80 (1H, t, J ) 5.7 Hz, -O-CH2-CH2-N-CH2-CH2-O-Ar
diast. 2), 3.52 (8H, m, H2N-O-CH2-CH2-O-CH2-CH2-O-
CH2-CH2-N-), 3.67 (2H, m, H2N-O-CH2-), 3.89 (1H, t, J
) 5.9 Hz, Ar-O-CH2- diast. 1), 4.05 (1H, t, J ) 5.7 Hz, Ar-
O-CH2- diast. 2), 6.45 (1H, d, J ) 8.8 Hz, HO-Ph 3 diast.
2), 6.53 (1H, d, J ) 8.8 Hz, HO-Ph 3 diast. 1), 6.69 (1H, d, J
) 8.8 Hz, RO-Ph 3 diast. 2), 6.76 (1H, d, J ) 8.8 Hz, RO-Ph
3 diast. 2), 6.79 (1H, d, J ) 8.6 Hz, HO-Ph 2 diast. 2), 6.87
(1H, d, J ) 8.6 Hz, HO-Ph diast. 1), 7.04 (1H, d, J ) 8.6 Hz,
RO-Ph 2 diast. 1), 7.14 (6H, m, RO-Ph 2 diast. 2, phenyl).
HRMS [M + Na]+ calculated 543.2829, found 543.2796.
E/Z-4-[2-(2-{2-[(2-{4-[1-(4-Hyd r oxyp h en yl)-2-p h en ylbu t-
1-e n yl]p h e n oxy}e t h yl)m e t h yla m in o]e t h oxy}e t h oxy)-
eth oxy]-4-a za tr icyclo[5.2.1.02,6]d ec-8-en e-3,5-d ion e (8c). A
solution of 7c (190 mg, 0.57 mmol) in dry THF (2.5 mL) was
added to 6 (143 mg, 0.38 mmol). Diisopropylethylamine (100
µL, 0.57 mmol) and sodium iodide (114 mg, 0.76 mmol) were
added, and the reaction mixture was transferred to a sealed
tube and heated to 60 °C for 24 h. Analytical HPLC revealed
that the reaction had proceeded to 90% consumption of starting
material. The reaction workup was performed exactly as
describe above for 8a . The crude material was purified via
flash chromatography on silica gel (98% ethyl acetate/2%
methanol to 92% ethyl acetate/8% methanol), providing 154
mg (61%) of 8c as a light-yellow oil. TLC (SiO2, 4:1 ethyl
1
acetate/methanol): Rf ) 0.14. H NMR (500 MHz, CDCl3): δ
0.91 (3H, dt, J ) 7.3 Hz, TAM 4), 1.47 (1H, m, 10b), 1.73 (1H,
m, 10a), 2.42 (3H, ds, N-Me), 2.47 (2H, q, J ) 7.3 Hz, TAM
3), 2.75 (1H, t, J ) 5.7 Hz, -CH2-N-CH2-CH2-O-Ar diast.
1), 2.81 (1H, t, J ) 5.7 Hz, -CH2-N-CH2-CH2-O-Ar diast.
2), 2.86 (1H, t, J ) 5.5 Hz, -CH2-N-CH2-CH2-O-Ar diast.
1), 2.96 (1H, t, J ) 5.5 Hz, -CH2-N-CH2-CH2-O-Ar diast.
2), 3.15 (2H, m, 1, 7), 3.39 (2H, m, 2, 6), 3.63 (8H, m, -N-
O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-N-), 3.94 (1H, t,
J ) 5.7 Hz, -N-O-CH2- diast. 2), 4.10 (3H, m, Ar-O-CH2-,
-N-O-CH2- diast. 1), 6.12 (2H, m, 8, 9), 6.41 (1H, d, J )
9.0 Hz, RO-Ph 2 diast. 2), 6.47 (1H, d, J ) 8.8 Hz, RO-Ph
diast. 1), 6.68 (2H, dd, J ) 8.8, 9.0 Hz, HO-Ph 3), 6.79 (2H,
dd, J ) 8.8, 8.6 Hz, RO-Ph 3), 7.10 (7H, m, HO-Ph 2, phenyl).
HRMS [M + Na]+ calculated 689.3197, found 689.3203.
E/Z-1-(4-{2-[(2-Am in ooxyeth yl)m eth yla m in o]eth oxy}-
p h en yl)-1-(4-h yd r oxyp h en yl)-2-p h en ylbu ten e (9a ). To a
solution 8a (22.7 mg, 39 µmol) dissolved in 0.5 mL of 95%
ethanol was added hydrazine monohydrate (7 µL, 195 µmol).
The reaction mixture was transferred to a sealed tube and
heated to 60 °C. After 2 h, TLC revealed complete consumption
of starting material. The reaction mixture was transferred to
E/Z-2-Hydr oxy-5-({2-[(2-{4-[1-(4-h ydr oxyph en yl)-2-ph en -
ylbu t-1-en yl]p h en oxy}eth yl)m eth yla m in o]eth oxyim in o}-