Journal of Medicinal Chemistry
Article
yielding 350 mg of reaction crude. Flash chromatography with
with n-hexane/EtOAc (60:40) afforded compound 12β (40%). 12β:
colorless crystals (CH2Cl2); mp 168−170 °C; H NMR (CDCl3) δ
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n-hexane/EtOAc (40:60) afforded compound 9βr (30%). Yellow
1
amorphous powder; mp 163−165 °C; H NMR (CDCl3) δ 7.45 (s,
6.96 (s, 1H), 6.56 (s, 1H), 6.46 (s, 2H), 5.97 (s, 2H), 4.50 (d, J = 4.4
Hz, 1H), 4.40 (t, J = 8 Hz, 1H), 4.28 (t, J = 7 Hz, 1H), 3.80 (s, 3H),
3.74 (s, 6H), 3.23−3.14 (m, 1H), 3.10 (dd, J = 4.4, 14 Hz, 1H), 2.33−
2.05 (m, 4H), 1.89−1.69 (m, 2H); 13C NMR (CDCl3) δ 174.9, 152.7
(2C), 148.0, 147.7, 136.8, 134.6 (2C), 133.6, 110.8, 108.1 (2C), 105.2,
101.6, 83.1, 75.8, 68.2, 60.7, 56.1 (2C), 44.7, 42.5, 37.5, 33.0, 30.9,
15.8; [α]22 −47° (Na, 589 nm) (c 1.0%, EtOH); IR νmax = 3467, 2934,
1771, 1689, 1506, 1232, and 1127 cm−1; MS (EI) m/z = 466 (M −
18)+, 410, 242, 207, 168, 55. HPLC: 96.5%.
1H), 6.74−6.66 (m, 2H), 6.42 (s, 1H), 6.14 (s, 2H), 5.99 (bs, 2H),
5.61−5.55 (m, 1H), 4.92 (t, J = 9.7 Hz, 1H), 4.35 (t, J = 8.8 Hz, 1H),
4.13 (d, J = 6 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 6H), 3.69 (s, 6H), 3.48
(dd, J = 1.8; 6.6 Hz, 1H), 2.97−2.94 (m, 1H), 1.72 (s, 3H); 13C NMR
(CDCl3) δ 175.0, 152.3 (2C), 148.3, 148.3, 146.6, 136.9, 136.2 (2C),
135.6, 134.7, 131.9, 110.5, 109.8 (2C), 108.2 (3C), 107.9, 101.6, 80.3,
78.1, 69.0, 60.7, 56.2 (3C), 55.7, 45.5, 44.5, 42.5, 30.8; [α]22 −75°
(Na, 589 nm) (c 1.0%, EtOH); MS (ES) m/z = 617.20 [M + Na]+,
536 (40), 331 (20), 149 (35). HPLC: 98.5%.
7β-(1-Hydroxycyclopentyl)podophyllotoxin (13α) and 7α-
(1-hydroxycyclopentyl)epipodophyllotoxin (13β). Following
experimental protocol A, 1d reacted with cyclopentanone (80 μL,
0.95 mmol), yielding 250 mg of reaction crude. Flash chromatography
with n-hexane/EtOAc (60:40) afforded compounds 13β (40%) and
13α (8%). 13β: White amorphous powder; mp 117−119 °C; 1H
NMR (CDCl3) δ 7.78 (s, 1H), 6.55 (s, 1H), 6.49 (s, 2H), 6.00 (d, J =
1.3 Hz, 1H), 5.57 (d, J = 1.3 Hz, 1H), 4.57 (d, J = 4.4 Hz, 1H), 4.50 (t,
J = 7.5 Hz, 1H), 4.45 (t, J = 5.3 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 6H),
3.15 (dd, J = 4, 11.8 Hz, 1H), 2.90−2.85 (m, 1H), 1.85−1.55 (m, 8H);
13C NMR (CDCl3) δ 175.3, 152.6 (2C), 147.6, 147.3, 136.7, 135.5,
135.0, 133.3, 110.0, 108.3, 107.8 (2C), 101.6, 83.3, 77.7, 69.2, 60.8,
56.0 (2C), 44.5, 44.0, 39.6, 37.6, 36.6, 23.7, 22.4; [α]22 −87° (Na, 589
nm) (c 1.0%, EtOH); MS (EI) m/z = 480 (M − 18)+, 282, 207, 133,
73. HPLC: 96.7%. 13α: white amorphous powder; mp 120−121 °C;
1H NMR (CDCl3) δ 7.24 (s, 1H), 6.45 (s, 1H), 6.19 (s, 2H), 5.96 (bs,
2H), 4.65 (m, 1H), 4.55 (m, 1H), 4.45 (m, 1H), 3.79 (s, 3H), 3.73 (s,
6H), 3.65 (m, 1H), 3.05−2.90 (m, 1H), 1.80−1.54 (m, 4H); 13C
NMR (CDCl3) δ 174.9, 152.5 (2C), 148.0, 146.5, 137.1, 136.1, 133.8,
132.3, 110.0, 108.3 (2C), 108.2, 101.5, 88.5, 78.1, 69.7, 60.8, 56.2
(2C), 45.9, 44.5, 43.5, 37.2, 35.7, 22.3, 21.4; [α]22 −188° (Na, 589
nm) (c 0.5%, EtOH); MS (EI) m/z = 480 (M − 18)+, 282, 207, 133,
73. HPLC: 95.2%.
7α-[(1R)-1-Hydroxy-2-methyl-1-phenylpropyl]epipodophyl-
lotoxin (10β) and (E)-7-(2-Methyl-1-phenyl-1-propylidene)-
deoxypodophyllotoxin (22). Following experimental protocol B,
1d reacted with 2-methyl-1-phenylpropan-1-one (150 μL, 1.0 mmol),
yielding 340 mg of reaction crude. Flash chromatography with n-hexane/
EtOAc (80:20, 70:30, and 60:40) afforded compounds 22 (40%) and
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10β (15%). 22: colorless crystals (CH2Cl2); mp 165−166 °C; H
NMR (CDCl3) δ 7.45−7.40 (m, 2H), 7.23−7.19 (m, 2H), 6.69 (d,
J = 7.5 Hz, 1H), 6.59 (s, 1H), 6.53 (s, 2H), 6.12 (s, 1H), 5.80 (d, J =
1.3 Hz, 1H), 5.77 (d, J = 1.3 Hz, 1H), 4.76 (t, J = 8.3 Hz, 1H), 4.55
(d, J = 3.1 Hz, 1H), 4.17 (dd, J = 8; 1.8 Hz, 1H), 3.84 (s, 9H),
3.44−3.41 (m, 2H), 3.35 (dd, J = 3, 11.9 Hz, 1H), 2.96 (m, 1H),
1.18 (d, J = 7 Hz, 3H), 0.65 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3)
δ 174.0, 153.0 (2C), 147.5, 146.0, 145.5, 139.9, 137.1, 135.2, 130.5
(2C), 129.7, 128.7 (2C), 128.2, 127.1, 126.9, 111.5, 109.2, 106.6
(2C), 101.0, 71.9, 60.8, 56.2 (2C), 50.3, 45.0, 40.0, 32.4, 22.7, 20.6;
[α]22 +150° (Na, 589 nm) (c 1.0%, EtOH); MS (ES) m/z = 551.20
[M + Na]+. HPLC: 96.0%. 10β: colorless crystals; mp 115−118 °C;
1H NMR (CDCl3) δ 7.92 (s, 1H), 7.29 (m, 2H), 7.24−7.13 (m,
3H), 6.45 (s, 1H), 6.27 (s, 2H), 5.96 (d, J = 1.3 Hz, 1H), 5.93 (d,
J = 1.3 Hz, 1H), 4.41 (d, J = 4.4 Hz, 1H), 4.37 (m, 1H), 3.84 (s,
3H), 3.75 (s, 1H), 3.69 (s, 6H), 3.23−3.21 (m, 1H), 3.05 (dd, J =
4.4, 8.8 Hz, 1H), 2.48−2.44 (m, 1H), 0.98 (d, J = 6.1 Hz, 3H), 0.92
(d, J = 7 Hz, 3H); 13C NMR (CDCl3) δ 175.4, 152.6 (2C), 147.1,
146.9, 141.4, 137.4, 135.3, 134.3, 133.5, 127.6 (2C), 127.0, 126.9,
110.2, 109.1, 108.8 (2C), 101.4, 82.6, 82.1, 70.0, 60.7, 56.6 (2C),
44.3, 44.0, 39.8, 36.8, 19.2, 18.7; [α]22 −143° (Na, 589 nm) (c 1.0%,
EtOH); MS (ES) m/z = 585.21 [M + Na]+. HPLC: 96.3%.
7β-(1-Hydroxycyclohexyl)podophyllotoxin (14α) and 7α-(1-
Hydroxycyclohexyl)epipodophyllotoxin (14β). Following exper-
imental protocol A, 1d reacted with cyclohexanone (100 μL, 0.97
mmol), yielding 280 mg of reaction crude. Flash chromatography with
n-hexane/EtOAc (60:40) afforded compounds 14β (40%) and 14α
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(7%). 14β: colorless crystals (CDCl3); mp 106−108 °C; H NMR
(CDCl3) δ 7.95 (s, 1H), 6.52 (s, 1H), 6.44 (s, 2H), 5.98 (d, J = 1.6 Hz,
1H), 5.94 (d, J = 1.6 Hz, 1H), 4.54 (d, J = 4,4 Hz, 1H), 4.50 (t, J = 10
Hz, 1H), 4.42 (t, J = 8 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 6H), 3.13 (dd,
J = 4; 13.6 Hz, 1H), 2.63 (ddd, J = 3, 6, 11 Hz, 1H), 1.68−1.55 (m,
4H), 1.28−1.20 (m, 4H), 1.07−1.02 (m, 2H); 13C NMR (CDCl3) δ
175.2, 152.6 (2C), 147.4, 147.3, 136.8, 135.1 (2C), 133.2, 109.8, 108.9,
107.7 (2C), 101.4, 78.7, 77.8, 69.2, 60.7, 56.8 (2C), 44.5, 44.1, 39.1,
34.5, 33.0, 25.2, 21.7, 21.3; [α]22 −190° (Na, 589 nm) (c 1.0%,
EtOH); IR νmax = 3502, 2934, 1772, 1589, 1506, 1483, 1232, and 1128
cm−1; MS (ES) m/z = 535.19 [M + Na]+, 530 (85), 477 (35), 399
(30). HPLC: 99.1%. 14α: white amorphous powder; mp 102−104 °C;
1H NMR (CDCl3) δ 7.08 (s, 1H), 6.51 (s, 1H), 6.40 (s, 2H), 5.96 (d,
J = 2.4 Hz, 1H), 5.93 (d, J = 2.4 Hz, 1H), 4.42 (d, J = 4.8 Hz, 1H),
4.28 (t, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 6H), 3.50 (dd, J = 4.8;
12.8 Hz, 1H), 3.46 (dd, J = 5, 9.6 Hz, 1H), 2.95−2.85 (m, 1H), 1.76−
1.66 (m, 4H), 1.43 (m, 4H), 0.95−0.85 (m, 2H); 13C NMR (CDCl3)
δ 175.7, 152.7 (2C), 147.5, 147.3, 136.7, 135.4, 132.7, 129.9, 108.5,
106.7 (2C), 106.3, 101.2, 88.0, 82.3, 68.3, 60.7, 56.0 (2C), 50.6, 48.3,
45.4, 31.4, 31.3, 25.6, 22.9, 21.5; [α]22 −110° (Na, 589 nm) (c 0.5%,
EtOH); IR νmax = 3467, 2934, 1771, 1589, 1506, 1483, 1232, and 1127
cm−1; MS, m/z (%) = 494 (M − 18)+, 367 (34), 282 (60), 201 (53),
67 (43). HPLC: 95.1%.
7β-(1-Hydroxy-1,1-diphenylmethyl)podophyllotoxin (11α)
and 7α-(1-Hydroxy-1,1-diphenylmethyl)epipodophyllotoxin
(11β). Following experimental protocol A, 1d reacted with
benzophenone (178.5 mg, 0,97 mmol), yielding 365 mg of reaction
crude. Flash chromatography with n-hexane/EtOAc (70:30) afforded
compounds 11β (35%) and 11α (5%). 11β: colorless crystals
(CH2Cl2); mp 168−170 °C; 1H NMR (CDCl3) δ 7.94 (bs, 2H),
7.77 (dd, J = 2.2, 6.6 Hz, 4H), 7.38−7.29 (m, 6H), 7.29 (s, 1H), 6.55
(s, 2H), 6.53 (s, 1H), 5.87 (d, J = 1.3 Hz, 1H), 5.81 (d, J = 1.3 Hz,
1H), 4.45 (bs, 1H), 3.95 (m, 1H), 3.84 (s, 10H), 3.13 (dd, J = 1.8, 3.5
Hz, 1H), 2.52 (bs, 1H); 13C NMR (CDCl3) δ 175.0, 152.6 (2C),
147.9, 147.1, 145.4, 143.6, 137.4, 135.2, 134.5, 133.5, 128.6 (2C),
128.3, 127.7 (2C), 126.8 (5C), 110.9, 108.8 (2C), 107.2, 101.6, 82.6,
80.8, 68.5, 60.7, 56.5 (2C), 44.9, 43.0, 40.5; [α]22 −100° (Na, 589 nm)
(c 1.0%, EtOH); MS (EI) m/z = 619.19 [M + Na]+, 605 (20), 308
(30), 217 (30). HPLC: 96.0%. 11α: white amorphous powder;
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mp 163−165 °C; H NMR (CDCl3) δ 7.58−7.56 (m, 2H), 7.48−
7.39 (m, 2H), 7.38−7.32 (m, 6H), 6.46 (s, 1H), 6.20 (s, 2H), 5.90
(d, J = 1.3 Hz, 1H), 5.82 (d, J = 1.3 Hz, 1H), 5.66 (s, 1H), 4.48 (t,
J = 7 Hz, 1H), 4.44 (d, J = 5.7 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 6H),
3.48 (t, J = 8 Hz, 1H), 3.12 (dd, J = 3.8; 10 Hz, 1H), 2.45 (m, 1H);
13C NMR (CDCl3) δ 174.8, 152.3 (2C), 148.2, 146.3, 143.0, 139.9,
138.0, 135.5, 134.3, 131.1, 128.8, 128.5, 128.2, 128.1, 127.2 (3C),
126.8, 126.3, 125.6, 109.6, 108.2 (3C), 101.4, 83.7 (2C), 79.7, 69.1,
60.7, 56.1 (2C), 45.9, 43.4; [α]22 −40° (Na, 589 nm) (c 0.5%,
EtOH); MS (EI) m/z = 619.19 [M + Na]+, 605 (20), 308 (30), 217
(30). HPLC: 96.4%.
7α-(1-Hydroxycyclohexyl)epipicropododophylloxin (14βp).
To a solution of 30 mg of compound 14β (0.07 mmol) in 3 mL of
methanol, an amount of 3 mL of KOH (5%) in methanol was added.
The mixture was maintained with stirring for 30 min at room
temperature. Then the solvent was removed, water was added and
neutralized with HCl, 2 N, and finally extracted with EtOAc. After the
organic phase was washed with an aqueous solution saturated with
NaCl, it was dried with Na2SO4. After removal of the solvent,
7α-(1-Hydroxycyclobutyl)epipodophyllotoxin (12β). Follow-
ing experimental protocol A, 1d reacted with cyclobutanone (67.9 mg,
0.97 mmol), yielding 260 mg of reaction crude. Flash chromatography
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dx.doi.org/10.1021/jm2017573 | J. Med. Chem. 2012, 55, 6724−6737