Synthesis and SAR Study of Lam-D Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3265
122.2 (d); 123.5 (d); 124.0 (s); 129.1 (s); 130.9 (s); 144.9 (s); 145.9
(s); 146.5 (s); 146.7 (s); 161.8 (s). MS (EI) m/z 393 (M, 100); 394
(M + 1, 12). HRMS m/z calcd for C27H19N3O8, 393.1212; found,
393.1215.
with hexane/AcOEt (60:40 to 40:60) gave a yellowish oil (10 mg,
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49%). IR (film) ν 3342, 1599 cm-1. H NMR (CDCl3, 400 MHz)
δ 3.47 (s, 3H, OMe); 3.68 (s, 3H, OMe); 3.70 (s, 3H, OMe); 3.71
(s, 3H, OMe); 3.87 (s, 3H, OMe); 3.88 (s, 3H, OMe); 5.79 (bs,
1H, OH); 6.70-6.78 (m, 4H); 6.85 (s, 2H); 6.92 (d, J ) 7.6 Hz,
1H, H6); 7.11 (s, 1H); 7.12 (s, 1H); 9.29 (d, J ) 7.6 Hz, 1H, H5).
13C NMR (CDCl3, 100 MHz) δ 50.7 (q); 55.3 (q); 55.6 (q); 55.7
(q); 55.8 (q); 55.9 (q); 104.8 (d); 109.9 (d); 110.3 (d); 111.1 (d);
111.9 (s); 112.1 (d); 114.2 (d); 115.0 (d), 118.3 (s); 119.3 (s), 123.2
(d); 123.7 (d); 124.2 (d); 124.3 (s); 127.8 (s); 128.7 (s); 130.6 (s);
135.7 (s); 145.9 (s); 146.5 (s); 147.5 (s); 147.5 (s); 148.0 (s); 148.9
(s); 162.6 (s). MS (MALDI-TOF) m/z 543 (M); 544 (M + 1).
HRMS m/z calcd for C31H29NO8, 543.1893; found, 543.1888.
Methyl 8-Hydroxy-9-methoxy-1,2-bis(4-methoxyphenyl)pyr-
rolo[2,1-a]isoquinoline-3-carboxylate (17g). Following general
procedure G and starting with 11g (42 mg, 0.08 mmol), elution
with hexane/AcOEt (60:40 to 40:60) gave a pale solid (27 mg,
Methyl 1-(2,5-Dimethoxyphenyl)-8-hydroxy-9-methoxypyr-
rolo[2,1-a]isoquinoline-3-carboxylate (16e). Following general
procedure G and starting with 10e (26 mg, 0.06 mmol), elution
with hexane/AcOEt (80:20 to 70:30) gave a yellow solid (14 mg,
57%). Mp (MeCN) 198-199 °C. IR (film) ν1690, 1465, 1206 cm-1
.
1H NMR (CDCl3, 400 MHz) δ 3.53 (s, 3H, OMe); 3.64 (s, 3H,
OMe); 3.79 (s, 3H, OMe); 3.90 (s, 3H, OMe); 5.80 (s, 1H, OH);
6.93 (d, J ) 7.6 Hz, 1H, H6); 6.94 (dd, J ) 8.4, 2.8 Hz, 1H, H4′);
6.97 (d, J ) 8.4 Hz, 1H, H3′); 6.99 (d, J ) 2.8 Hz, 1H, H6′); 7.12
(s, 1H); 7.14 (s, 1H); 7.43 (s, 1H); 9.23 (d, J ) 7.6 Hz, 1H, H5).
13C NMR (CDCl3, 100 MHz): δ 51.1 (q); 55.4 (q); 55.8 (q); 56.3
(q); 104.4 (d); 110.2 (d); 112.1 (d); 112.4 (d); 113.4 (s); 114.0 (d);
114.3 (s); 117.9 (d); 120.0 (s); 122.4 (d); 123.6 (d); 124.0 (s); 127.0
(s); 131.5 (s); 145.8 (s); 146.8 (s); 152.2 (s); 153.6 (s); 161.8 (s).
MS (MALDI-TOF) m/z 407 (M, 100); 408 (M + 1, 40). HRMS
m/z calcd for C23H21NO6, 407.1369; found, 407.1363.
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71%). Mp (MeCN) 241-4 °C. IR (film) ν 2951, 1676 cm-1. H
NMR (DMSO-d6, 400 MHz) δ 3.28 (s, 3H, OMe); 3.54 (s, 3H,
OMe); 3.71 (s, 3H, OMe); 3.74 (s, 3H, OMe); 6.77 (d, J ) 8.6 Hz,
2H); 6.80 (s, 1H); 6.96 (d, J ) 8.6 Hz, 2H); 7.08-7.11 (m, 3H);
7.11 (s, 1H); 7.19 (d, J ) 8.5 Hz, 2H); 9.14 (d, J ) 7.6 Hz, 1H,
H5); 9.67 (bs, 1H, OH). 13C NMR (DMSO-d6, 100 MHz) δ 50.5
(q); 54.3 (q); 54.7 (q); 55.0 (q); 104.7 (d), 111.1 (d); 111.9 (d);
112.3 (2d); 113.8 (2d); 117.6 (s); 117.8 (s), 122.5 (s); 123.4 (d);
126.9 (s); 127.4 (s); 130.0 (s); 131.3 (2d); 132.8 (2d); 134.9 (s);
147.2 (s); 148.0 (s); 157.6 (s); 158.3 (s); 161.6 (s). MS (MALDI-
TOF) m/z 483 (M). HRMS m/z calcd for C29H25NO6, 483.1682,
found. 483.1676.
Methyl 8-Hydroxy-9-methoxy-1-(2-thienyl)-5,6-dihydropyr-
rolo[2,1-a]isoquinoline-3-carboxylate (16n). Following general
procedure G and starting with 6n (15 mg, 0.04 mmol), elution with
hexane/AcOEt (90:10) gave a white solid (6 mg, 45%). Mp (MeCN)
1
134-136 °C. IR (film) ν 3420, 1693, 1466, 1207 cm-1. H NMR
(CDCl3, 200 MHz) δ 3.62 (s, 3H, OMe); 3.91 (s, 3H, OMe); 5.82
(s, 1H, OH); 6.95 (d, J ) 7.5 Hz, 1H, H6); 7.14 (s, 1H); 7.16 (s,
1H); 7.17 (d, J ) 2.0 Hz, 1H); 7.34-7.35 (bd, 1H); 7.44 (dd, J )
4.1, 2.0 Hz, 1H); 7.48 (s, 1H); 9.22 (d, J ) 7.5 Hz, 1H, H5). 13C
NMR (CDCl3, 100 MHz): δ 51.2 (q); 55.5 (q); 104.3 (d); 109.1
(s); 110.4 (d); 112.7 (d); 114.3 (s); 119.3 (s); 123.4 (d); 123.5 (d);
124.2 (s); 126.2 (d); 127.3 (d); 128.0 (d); 132.0 (s); 138.3 (s); 146.2
(s); 146.9 (s); 161.7 (s). MS (MALDI-TOF) m/z 353 (M, 100).
MS (ESI-TOF) m/z 354 (M + 1, 100). HRMS m/z calcd for C19H16-
NO4S, 354.0795; found, 354.0795.
Methyl 8-Hydroxy-9-methoxy-1,2-bis(4-trifluoromethoxy-
phenyl)pyrrolo[2,1-a]isoquinoline-3-carboxylate (17i). Following
general procedure G and starting with 11i (29 mg, 0.05 mmol),
elution with hexane/AcOEt (60:40 to 40:60) gave a reddish oil (8
mg, 30%). IR (film) ν 1727 cm-1. 1H NMR (Acetone-d6, 400 MHz)
δ 3.26 (s, 3H, OMe); 3.46 (s, 3H, OMe); 6.75 (s, 1H); 7.01 (d,
J ) 7.6 Hz, 1H, H6); 7.06 (d, J ) 8.0 Hz, 2H); 7.09 (s, 1H); 7.23
(d, J ) 8.7 Hz, 2H); 7.26 (d, J ) 8.0 Hz, 2H); 7.36 (d, J ) 8.7 Hz,
2H); 8.23 (bs, 1H, OH); 9.18 (d, J ) 7.6 Hz, 1H, H5). 13C NMR
(Acetone-d6, 100 MHz) δ 49.4 (q); 53.5 (q); 103.9 (d), 110.6 (d);
111.5 (q); 111.9 (d); 116.0 (q); 117.7 (s); 118.8 (2d); 120.6 (2d);
122.2 (s); 123.6 (s); 129.7 (d); 131.6 (s); 133.1 (2d); 133.5 (2d);
133.9 (s); 134.7 (s); 146.9 (s); 147.1 (s); 147.5 (s); 147.6 (s); 161.0
(s). MS (MALDI-TOF) m/z 591 (M). HRMS m/z calcd for C29H19F6-
NO6, 591.1117, found. 591.1111.
Methyl 8-Hydroxy-1,2-bis(4-hydroxyphenyl)-9-methoxypyr-
rolo[2,1-a]isoquinoline-3-carboxylate (17j). Following general
procedure G and starting with 11j (77 mg, 0.18 mmol), elution
with hexane/AcOEt (60:40 to 40:60) gave a pale solid (32 mg,
53%). Mp (MeCN) 280-284 °C. IR (film) ν 3373, 1684 cm-1. 1H
NMR (DMSO-d6, 400 MHz) δ 3.29 (s, 3H, OMe); 3.54 (s, 3H,
OMe); 6.58 (d, J ) 8.5 Hz, 2H); 6.77 (d, J ) 8.5 Hz, 2H); 6.90 (s,
1H); 6.95 (d, J ) 8.5 Hz, 2H); 7.03 (s, 1H); 7.05-7.08 (m, 3H);
9.12 (d, J ) 7.6 Hz, 1H, H5); 9.22 (bs, 1H, OH); 9.42 (bs, 1H,
OH); 9.64 (bs, 1H, OH). 13C NMR (DMSO-d6, 100 MHz) δ 50.4
(q); 54.3 (q); 104.9 (d); 110.9 (d); 111.7 (d); 113.8 (2d); 115.2
(2d); 117.9 (s); 118.0 (s), 122.5 (s); 123.3 (d); 125.3 (s); 125.7 (s);
130.0 (s); 131.3 (2d); 132.7 (2d); 135.5 (s); 147.1 (s); 147.9 (s);
155.7 (s); 156.4 (s); 161.7 (s). MS (MALDI-TOF) m/z 455 (M,
100). HRMS m/z calcd for C27H21NO6, 455.1369; found, 455.1363.
Methyl 8-Hydroxy-1,2-bis(3-hydroxyphenyl)-9-methoxypyr-
rolo[2,1-a]isoquinoline-3-carboxylate (17k, R3 ) OH). Following
general procedure G and starting with 11k (67 mg, 0.12 mmol),
elution with hexane/AcOEt (60:40 to 40:60) gave a pale solid (24
Methyl 8-Hydroxy-9-methoxy-1,2-bis(3,4,5-trimethoxyphen-
yl)pyrrolo[2,1-a]isoquinoline-3-carboxylate (17a). Following gen-
eral procedure G and starting with 11a (41 mg, 0.06 mmol), elution
with hexane/AcOEt (60:40 to 40:60) gave a reddish oil (25 mg,
65%). IR (film) ν 3404, 1682, 1377, 1235 cm-1. 1H NMR (CDCl3,
400 MHz) δ 3.51 (s, 3H, OMe); 3.69 (s, 6H, 2OMe); 3.70 (s, 6H,
2OMe); 3.72 (s, 3H, OMe); 3.84 (s, 3H, OMe); 3.85 (s, 3H, OMe);
5.82 (bs, 1H, OH); 6.46 (s, 2H); 6.53 (s, 2H); 6.95 (d, J ) 7.6 Hz,
1H, H6); 7.14 (s, 1H); 7.15 (s, 1H); 9.30 (d, J ) 7.6 Hz, 1H, H5).
13C NMR (CDCl3, 100 MHz) δ 50.9 (q); 55.3 (q); 56.0 (2q); 56.2
(2q); 60.88 (q); 60.92 (q); 104.8 (d); 108.3 (2d); 108.9 (2d); 110.4
(d); 111.8 (s); 112.4 (d); 118.2 (s); 119.0 (s); 123.6 (d); 124.4 (s);
126.9 (s); 130.5 (s); 131.7 (s); 135.3 (s); 136.8 (s); 137.1 (s); 146.0
(s); 146.7 (s); 152.0 (2s); 153.2 (2s); 162.4 (s). MS (MALDI-TOF)
m/z 603 (M, 100); 604 (M + 1, 80). HRMS m/z calcd for C33H33-
NO10, 603.2105; found, 603.2099.
Methyl 8-Hydroxy-1,2-bis(4-hydroxy-3-methoxyphenyl)-9-
methoxypyrrolo[2,1-a]isoquinoline-3-carboxylate (17c). Follow-
ing general procedure G and starting with 11c (46 mg, 0.08 mmol),
a yellow solid (26 mg, 61%). Mp (MeCN) 235-237 °C. IR (film)
1
ν 3415, 1680, 1376, 1211 cm-1. H NMR (CDCl3, 400 MHz) δ
3.49 (s, 3H, OMe); 3.67 (s, 3H, OMe); 3.68 (s, 3H, OMe); 3.69 (s,
3H, OMe); 5.50 (bs, 1H, OH); 5.58 (bs, 1H, OH); 5.79 (bs, 1H,
OH); 6.66 (d, J ) 1.6 Hz, 2H, H2′, H2′′); 6.72-6.77 (m, 2H, H6′,
H6′′); 6.80 (d, J ) 8.0 Hz, 1H, H6); 6.91 and 6.92 (2d, J ) 8.6
Hz, 2H, H5′, H5′′); 7.12 (s, 1H); 7.13 (s, 1H); 9.30 (d, J ) 8.0 Hz,
1H, H5). 13C NMR (CDCl3, 100 MHz): δ 50.8 (q); 55.4 (q); 55.8
(q); 56.0 (q); 104.8 (d); 110.3 (d); 112.1 (d); 113.2 (d); 113.5 (d);
114.2 (d); 114.4 (d); 118.4 (s); 119.3 (s); 123.7 (d); 124.1 (d); 124.3
(s); 125.0 (d); 127.2 (s); 128.0 (s); 130.6 (s); 135.8 (s); 144.2 (s);
144.7 (s); 145.3 (s); 145.9 (s); 146.4 (s); 146.5 (s); 162.6 (s). MS
(MALDI-TOF) 515 (M, 100); 516 (M + 1, 80). HRMS m/z calcd
for C29H25NO8, 515.1580; found, 515.1575.
mg, 46%). Mp (MeCN) 260-265 °C. IR (film) ν 3384, 1653 cm-1
.
1H NMR (DMSO-d6, 400 MHz) δ 3.29 (s, 3H, OMe); 3.53 (s, 3H,
CO2Me); 6.66-6.76 (m, 3H); 6.72 (t, J ) 1.8 Hz, 1H); 6.70-6.72
(dd, J ) 7.8, 1.9 Hz, 2H); 6.90 (s, 1H); 6.98-7.02 (dd, J ) 8.7,
9.0 Hz, 1H); 7.10 (s, 1H); 7.11 (d, J ) 7.6 Hz, 1H, H6); 7.19 (t,
J ) 8.0 Hz, 1H); 9.11 (d, J ) 7.6 Hz, 1H, H5); 9.17 (bs, 1H, OH);
9.27 (bs, 1H, OH); 9.40 (bs, 1H, OH). 13C NMR (DMS-d6, 100
MHz) δ 50.6 (q); 54.3 (q); 104.9 (d), 111.1 (d); 112.1 (d); 113.4
Methyl 1,2-Bis(3,4-dimethoxyphenyl)-8-hydroxy-9-methoxy-
pyrrolo[2,1-a]isoquinoline-3-carboxylate (17f). Following general
procedure G and starting with 11f (22 mg, 0.04 mmol), elution