Liermann and Opatz
55.8, 55.8, 55.8, 55.6, 55.2 (6 × OCH3), 42.8 (C-5), 29.1 (C-6),
13.9 (CH3) ppm; the spectroscopic data are in accordance with those
reported in the literature;13 IR (NaCl) ν ) 3430, 2096, 1680, 1254,
1232, 1135, 1066, 1027 cm-1; FD-MS (m/z) 573.2 (100, M+). Anal.
Calcd for C33H35NO8: C, 69.10; H, 6.15; N, 2.44. Found: C, 68.89;
H, 6.14; N, 2.29.
31.4 µmol) was dissolved in a mixture of 4 M aq NaOH (110 µL),
dioxane (1.54 mL), and MeOH (0.55 mL) and heated to reflux for
3.5 h. The solution was acidified to pH 2 with 1 N aq HCl, and
brine (10 mL) was added, followed by extraction with ethyl acetate
(10 mL). The organic extract was dried over Na2SO4 and evaporated
in vacuo to furnish the pyrrole carboxylic acid as a brown solid.
The acid was dissolved in dry benzene (2 mL), Pb(OAc)4 (41.4
mg, 93.4 µmol) was added, and the mixture was stirred at room
temperature for 2 h. CH2Cl2 (10 mL) and 1 M aq HCl (10 mL)
were added, and the organic layer was dried over Na2SO4 and
evaporated in vacuo. The crude product was purified by filtration
over silica gel (EtOAc, Rf ) 0.38) to furnish a green oil (10.0 mg,
66%): 1H NMR (400 MHz, CDCl3) δ ) 7.07 (dd, 3J ) 8.3 Hz, 4J
Ethyl 2-(2-Benzyloxy-4,5-dimethoxyphenyl)-8,9-dimethoxy-1-
(3,4-dimethoxyphenyl)-5,6-dihydropyrrolo[2,1a]isoquinoline-3-car-
boxylate (16a). Dihydroisoquinoline 7a (198 mg, 0.58 mmol) was
dissolved in dry dioxane (1 mL) under argon atmosphere. Solutions
of 15a (187 mg, 0.48 mmol) and 2,6-di-tert-butylpyridine (185 mg,
0.97 mmol, 217 µL) in dry dioxane (1 mL each) were added, and
the resulting mixture was heated to 90 °C for 20 h. Following
workup and purification were performed according to the general
procedure: yellow oil (138 mg, 42%), Rf (3:2 petroleum ether/ethyl
acetate) ) 0.16; 1H NMR, COSY (400 MHz, CDCl3) δ )
7.26-7.14 (m, 5H, Bn), 6.76-6.71 (m, 5H, H-2′′, H-5′′, H-6′′, H-7,
H-10), 6.61 (s, 1H, H-3′), 6.44 (s, 1H, H-6′), 4.83 (br s, 2H, PhCH2),
4.64 (t, J ) 6.2 Hz, 2H, H2-5), 4.05 (q, J ) 7.1 Hz, 2H, OCH2),
3.89 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.66
(s, 3H, OCH3), 3.56 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.07 (t, J
) 6.2 Hz, 2H, H2-6), 0.93 (t, J ) 7.1 Hz, 3H, CH3) ppm; 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ ) 162.0 (CdO), 150.6 (C-
2′) 148.4, 148.1, 147.9, 147.5, 147.1, 142.9 (C-OCH3), 137.9 (Bn-
C-1), 130.8 (C-10b), 128.6 (C-1′), 128.2 (3C, C-1″, 2 × Bn) 127.4
(Bn) 126.9 (2C, 2 × Bn), 125.8 (C-6a), 123.1 (C-6′′), 121.8 (C-1),
121.0 (C-10a), 119.1 (C-3), 118.1 (C-2), 115.5 (C-3′), 114.0 (C-
2′′), 110.8 (C-5′′), 110.6 (C-7), 108.7 (C-10), 100.5 (C-6′), 72.1
(PhCH2), 59.6 (OCH2), 56.2, 55.9, 55.8, 55.8, 55.6, 55.2 (6 ×
OCH3), 42.8 (C-5), 29.1 (C-6), 13.8 (CH3) ppm; the spectroscopic
data are in accordance with those reported in the literature;12 IR
(NaCl) ν ) 3529, 2936, 1685, 1610, 1517, 1465, 1336, 1260, 1154,
1064, 1027 cm-1; FD-MS (m/z) 679.4 (100, M+); ESI-HRMS calcd
for [C40H41NO9 + H+] 680.2860, found 680.2866.
Ethyl 2-[2,4-Bis(benzyloxy)-5-methoxyphenyl]-8,9-dimethoxy-
1-(3-hydroxy-4-methoxyphenyl)-2-(5,6-dihydropyrrolo[2,1a]is-
oquinoline-3-carboxylate (16b). The title compound was prepared
from 7b (167 mg, 0.45 mmol) and 15b (174 mg, 0.38 mmol)
according the general procedure. The MOM group was cleaved by
dissolving the crude product in ethyl acetate (5 mL) and adding 2
M hydrogen chloride in ethanol (1 mL). The solution was stirred
at room temperature for 40 min, washed with saturated aq NaHCO3,
dried over Na2SO4, and evaporated in vacuo. Purification by column
chromatography (3:2 petroleum ether/ethyl acetate, Rf ) 0.29)
furnishes the product as a yellow oil (96 mg, 41%): 1H NMR (400
MHz, CDCl3) δ ) 7.36-7.21 (m, 8H, Bn), 7.13-7.10 (m, 2H,
Bn), 6.82-6.79 (m, 1H, H-2″), 6.73-6.67 (m, 3H, H-5′′, H-6′′,
H-6′), 6.65 (s, 1H, H-7), 6.59 (s, 1H, H-10), 6.44 (s, 1H, H-3′),
5.47 (s, 1H, OH), 5.02 (br s, 2H, PhCH2), 4.78 (s, 2H, PhCH2),
4.63 (br s, 2H, H2-5), 3.99 (q, J ) 7.2, 2H, OCH2), 3.88 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.37 (s, 3H,
OCH3), 3.05 (t, J ) 6.6 Hz, 2H, H2-6), 0.83 (t, J ) 7.2 Hz, 3H,
CH3) ppm; 13C NMR (100.6 MHz, CDCl3) δ ) 162.0 (CdO), 150.6
(C-2′), 147.9, 147.2, 146.9, 145.3, 145.3, 143.5 (6 × C-OR), 137.9,
137.2 (2 × Bn-C-1), 130.9 (C-10b), 129.1 (C-1′), 128.4 (2C, 2 ×
Bn), 128.3 (C-1′′), 128.2 (2C, 2 × Bn), 127.7, 127.4 (2 × Bn),
127.3 (2C, 2 × Bn), 126.9 (2C, 2 × Bn), 125.7 (C-6a), 122.7 (C-
6′′), 121.6 (C-1), 121.1 (C-10a), 119.1 (C-3), 118.8 (C-2), 117.3
(C-3′), 116.0 (C-2′′), 110.6 (C-5′′), 110.4 (C-7), 108.8 (C-10), 103.2
(C-6′), 71.9 (PhCH2), 71.2 (PhCH2), 59.6 (OCH2), 56.4, 56.0, 55.9,
55.1 (4 × OCH3), 42.8 (C-5), 29.1 (C-6), 13.7 (CH3) ppm; although
the presence of an impurity could be detected in the NMR spectra,
debenzylation and lactonization of 16b furnished analytically pure
lamellarin U without further purification; IR (NaCl) ν ) 3424, 2936,
1684, 1610, 1499, 1464, 1336, 1255, 1213, 1176, 1025 cm-1; FD-
MS (m/z) 741.4 (100, M+); ESI-HRMS calcd for [C45H43NO9 +
H+] 742.3016, found 742.3019.
3
4
) 1.5 Hz, 1H, H-6′′), 7.03 (dd, J ) 8.5 Hz, J ) 2.0 Hz, 1H,
4
4
H-6′), 6.99 (d, J ) 2.0 Hz, 1H, H-2′), 6.94 (d, J ) 1.5 Hz, 1H,
H-2′′), 6.90 (d, J ) 8.3 Hz, 1H, H-5′′), 6.68 (d, J ) 8.5 Hz, 1H,
H-5′), 6.59 (s, 1H, H-10), 6.46 (s, 1H, H-7), 4.43-4.37 (m, 1H,
Ha-5), 3.90 (s, 3H, OCH3), 3.82 (s, 6H, OCH3), 3.71 (s, 3H, OCH3),
2
3
3.62 (s, 3H, OCH3), 3.36 (dt, J ) 12.7 Hz, J ) 3.9 Hz, 1H, Hb-
2
5), 3.30 (s, 3H, OCH3), 3.06-2.97 (m, 1H, Ha-6), 2.65 (dd, J )
16.3 Hz, J ) 2.8 Hz, 1H, Hb-6) ppm; 13C NMR, HSQC, HMBC
3
(100.6 MHz, CDCl3) δ ) 169.7 (CdO), 152.9 (C-1), 149.3, 149.0,
148.8, 148.8, 148.0, 146.9 (C-OCH3), 130.1 (C-2), 127.4 (C-10a),
126.5 (C-6a), 126.3 (C-1′′), 123.0 (C-1′), 122.6 (C-6′′), 122.6 (C-
6′), 113.0 (C-2′), 112.5 (C-2′′), 111.1 (C-5′′), 111.0 (C-10), 110.8
(C-7), 110.5 (C-5′), 86.8 (C-10b), 56.0, 56.0, 55.8, 55.7, 55.5, 55.1
(6 × OCH3), 35.7 (C-5), 29.2 (C-6) ppm; the compound is unstable
1
in CDCl3 solution, and both H and 13C NMR spectra show the
presence of decomposition products; IR (NaCl) ν ) 3360, 2926,
2852, 1678, 1516, 1464, 1260, 1142, 1026 cm-1; ESI-HRMS calcd
for [C30H31NO8 + H+] 534.2128, found 534.2133.
General Procedure for the Lactonization. Pyrroles were dis-
solved in EtOH (1 mL/µmol). Acetic acid (0.1 mL/µmol) and
palladium (3 mg/µmol, 10% on charcoal) were added, and the
resulting mixture was stirred for 2 h under hydrogen atmosphere
at room temperature. The mixture was filtered through a plug of
Celite with ethyl acetate, and the combined filtrates were washed
with saturated aq NaHCO3, dried over Na2SO4, and evaporated in
vacuo. The oily residue was dissolved in toluene (5 mL), and few
drops of DBU (approximately 50 µL) were added and the solution
was heated to 80 °C for 40 min. The solution was washed with 2
M aq HCl, dried over Na2SO4, and evaporated in vacuo to furnish
the lamellarins.
Lamellarin G Trimethyl Ether (11a): Colorless solid (24 mg,
79%); mp 235-239 °C (lit.1 235 °C); 1H NMR, COSY (400 MHz,
3
4
CDCl3) δ ) 7.11 (dd, J ) 8.1 Hz, J ) 1.8 Hz, 1H, H-12), 7.07
(d, J ) 8.1 Hz, 1H, H-15), 7.05 (d, J ) 1.8 Hz, 1H, H-16), 6.90 (s,
1H, H-22), 6.76 (s, 1H, H-7), 6.71 (s, 1H, H-10), 6.66 (s, 1H, H-19),
4.85-4.73 (m, 2H, H2-5), 3.95 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
3.87 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 3.36
(s, 3H, OCH3), 3.12 (t, J ) 6.8 Hz, 2H, H2-6) ppm; 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ ) 155.5 (CdO), 149.7,
149.0, 148.8, 148.8, 147.5 (5 x C-OCH3), 146.1 (C-18), 145.5 (C-
OCH3), 135.9 (C-10b), 128.2 (C-17), 128.0 (C-11), 126.6 (C-6a),
123.6 (C-16), 120.0 (C-10a), 114.7 (C-1), 114.0 (C-12), 113.7 (C-
3), 111.9 (C-15), 111.0 (C-7), 110.3 (C-2), 108.7 (C-10), 104.5
(C-19), 100.5 (C-22), 56.2, 56.1, 56.0, 55.9, 55.5, 55.2 (6 × OCH3),
42.4 (C-6), 28.7 (C-5) ppm; the spectroscopic data are in accordance
with those reported in the literature;1,14 IR (NaCl) ν ) 3424, 2925,
1703, 1515, 1463, 1416, 1264, 1166, 1041 cm-1; FD-MS (m/z)
543.2 (100, M+); ESI-HRMS calcd for [C31H29NO8 + H+]
544.1971, found 544.1980.
Lamellarin U (11b): Colorless solid (20 mg, 85%); mp 198-200
°C (lit.36 200-204 °C); 1H NMR, COSY (400 MHz, CDCl3) δ )
4
7.13 (d, J ) 1.6 Hz, 1H, H-12), 7.04 (d, J ) 8.2 Hz, 1H, H-15),
6.99 (dd, 3J ) 8.2 Hz, 4J ) 1.6 Hz, 1H, H-16), 6.94 (s, 1H, H-22),
1,2-Bis(3,4-dimethoxyphenyl)-8,9-dimethoxy-10b-hydroxy-6,10b-
dihydro-5H-pyrrolo[2,1a]isoquinolin-3-one (10). Pyrrole 9 (18 mg,
(36) Reddy, M. V. R.; Faulkner, D. J.; Venkateswarlu, Y.; Rao, M. R.
Tetrahedron 1997, 53, 3457–3466.
4530 J. Org. Chem. Vol. 73, No. 12, 2008