Total Synthesis of Natural and Unnatural Lamellarins
reduced pressure to provide a crude product, which was further
purified by column chromatography on silica (70% DCM/hexanes)
to furnish the desired product 72 as a yellow solid of a 1:1 mixture
of cis and trans isomers (0.53 g, 1.15 mmol, 40%). Recrystallization
from MeOH gave an analytically pure red crystal as a single isomer.
mp (MeOH) 119.5-120 °C. IR (KBr): νmax 1722, 1609, 1526,
the desired lamellarin U 100 as a white solid (0.28 g, 0.54 mmol,
91% over two steps). A small amount of these products was
recrystallized from MeOH for melting point determination. mp
(MeOH) 247-250 °C. IR (neat): νmax 3407 (br), 3002, 2936, 2838,
1682, 1584, 1549, 1513, 1485, 1439, 1413, 1339, 1320, 1272, 1246,
1212, 1163, 1143, 1043, 1023 cm-1. 1H NMR (200 MHz, DMSO-
d6): δ 3.08 (apparent t, J ) 6.0 Hz, 2H), 3.24 (s, 3H), 3.38 (s,
3H), 3.76 (s, 3H), 3.81 (s, 3H), 4.52-4.70 (m, 2H), 6.67 (s, 2H),
6.79 (s, 1H), 6.87 (s, 1H), 6.89 (d, J ) 6.6 Hz, 1H), 6.97 (s, 1H),
7.14 (d, J ) 8.8 Hz, 1H), 9.33 (s, 1H), 9.71 (s, 1H). 13C NMR (50
MHz, DMSO-d6): δ 28.1, 42.4, 55.0, 55.6, 56.1, 56.6, 104.1, 105.7,
109.1, 109.3, 112.4, 113.0, 114.1, 114.8, 118.3, 119.8, 122.1, 127.4,
127.8, 135.8, 144.9, 146.1, 147.3, 147.5, 148.0, 148.2, 149.4, 154.7.
LRMS (EI) m/z (rel intensity) 516 (M + H+, 43), 515 (M+, 100),
258 (24). TOF-HRMS calcd for C29H26NO8 (M + H+) 516.1653,
found 516.1661. These spectroscopic data are identical to those
reported previously.2g
1
1255, 1225, 1208, 1007 cm-1. H NMR (200 MHz, CDCl3): δ
1.33 (t, J ) 7.4 Hz, 3H), 3.85 (s, 3H), 4.31 (q, J ) 7.2 Hz, 2H),
5.00 (s, 2H), 5.12 (s, 2H), 6.50 (s, 1H), 6.82 (s, 1H), 7.39-7.47
(m, 10H), 7.98 (s, 1H). 13C NMR (50 MHz, CDCl3): δ 14.0, 56.0,
62.4, 71.6, 71.8, 88.6, 110.2, 113.3, 127.2, 127.3, 127.6, 127.9,
128.2, 128.5, 128.7, 136.1, 136.4, 138.0, 142.8, 154.4, 154.7, 159.9.
LRMS (EI) m/z (rel intensity) 463 (M+, 6), 326 (11), 253 (9), 235
(7), 91 (100), 65 (14). TOF-HRMS calcd for C26H26NO7 (M +
H+) 464.1715, found 464.1714. Anal. Calcd for C26H25NO7: C,
67.38; H, 5.44; N, 3.02. Found: C, 67.13; H, 5.57; N, 2.86.
Representative Example for Pyrrole Formation via Mi-RC
(Ethyl 1-(3-Benzyloxy-4-methoxyphenyl)-2-(2,4-dibenzyloxy-5-
methoxyphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinoline-3-carboxylate (88)). To a stirred solution of benzyldihy-
droisoquinoline 66 (0.50 g, 1.23 mmol) in anhydrous acetonitrile
(13 mL) at room temperature were added sodium bicarbonate (0.10
g, 1.23 mmol) and R-nitrocinnamate 71 (0.38 g, 0.82 mmol). The
mixture was heated to reflux for 18 h. At that time, the reaction
was cooled to room temperature, and sodium bicarbonate was
filtered off. Successive washings (3×) with EtOAc followed by
concentration under reduced pressure of the combined organic
materials furnished crude product, which was further purified by
column chromatography on silica (30% EtOAc/hexanes) to provide
the desired product 2-carboethoxypyrrole 88 as a sticky gum (0.53
g, 0.64 mmol, 78%). IR (neat): νmax 2933, 2900, 2833, 2091, 1683,
1609, 1531, 1497, 1480, 1454, 1396, 1383, 1333, 1251, 1210, 1173,
1127, 1062, 1022 cm-1. 1H NMR (200 MHz, CDCl3): δ 0.83 (t, J
) 8.0 Hz, 3H), 3.05 (apparent t, J ) 6.4 Hz, 2H), 3.30 (s, 3H),
3.64 (s, 3H), 3.83 (s, 3H), 3.88 (s, 3H), 3.97 (q, J ) 8.0 Hz, 2H),
4.61 (br m, 2H), 4.72 (s, 2H), 4.76 (s, 2H), 5.01 (s, 2H), 6.43 (s,
1H), 6.59 (d, J ) 8.0 Hz), 6.76 (s, 3H), 7.02-7.10 (m, 1H), 7.20-
7.32 (m, 10H). 13C NMR (50 MHz, CDCl3): δ 13.9, 29.3, 43.0,
55.3, 56.1, 56.3, 56.8, 59.7, 71.2, 71.6, 72.0, 103.7, 107.4, 109.0,
111.0, 112.0, 116.7, 116.8, 117.2, 119.3, 121.3, 121.9, 123.4, 124.0,
125.9, 126.9, 127.3, 127.4, 127.5, 127.9, 128.4, 128.5, 128.6, 131.1,
137.3, 137.4, 138.1, 144.0, 147.5, 148.2, 148.6, 150.9, 162.2. LRMS
(EI) m/z (rel intensity) 832 (M + H+, 11), 831 (M+, 15), 741 (15),
651 (11), 650 (12), 91 (100), 65 (33). TOF-HRMS calcd for C52H50-
NO9 (M + H+) 832.3480, found 832.3466.
Representative Example for Hydrogenolysis/NaH-Mediated
Lactonization (14-(3-Hydroxy-4-methoxyphenyl)-3-hydroxy-2,-
11,12-trimethoxy-8,9-dihydro-6H-chromeno[4′,3′:4,5]pyrrolo-
[2,1-a]isoquinolin-6-one (100; Lamellarin U)). A high-pressure
Paar apparatus was charged with 2-carboethoxypyrrole 88 (0.50 g,
0.60 mmol), EtOAc (10 mL), and palladium on activated charcoal
(Pd/C; ca. 0.05 g) at room temperature. The reaction was flushed
with hydrogen and kept under hydrogen atmosphere (75 psi).
Progress of the reaction was monitored by TLC until all starting
material was consumed (20 h). Palladium was filtered off using
Celite. After concentration under reduced pressure and removal of
trace solvent under vacuum, the crude material (0.34 g, 0.60 mmol)
was dissolved in anhydrous THF (60 mL) at room temperature.
The reaction mixture was cooled to 0 °C, and NaH (70% dispersion
in paraffin; 1.5 equiv/each hydroxy group) was added. The reaction
was stirred at 0 °C for 0.5 h, and slowly warmed to room
temperature at which the reaction was stirred for 4 h. At that time,
a saturated solution of NH4Cl (15 mL) and EtOAc (25 mL) was
added. The two layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 25 mL). The aqueous phase was allowed
to stir with EtOAc (20 mL) for 6 h to ensure that all lamellarins
partitioned into the organic layer. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure
to give crude product, which was triturated with MeOH to furnish
Representative Example for Acetylation (14-(3-Acetoxy-4-
methoxyphenyl)-3-acetoxy-2,11,12-tetramethoxy-8,9-dihydro-
6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one (114;
Lamellarin U Diacetate)). To a mixture of lamellarin U 100 (51.5
mg, 0.10 mmol) in DCM (9 mL) at room temperature were added
Et3N (40 µL, 0.30 mmol), DMAP (30 mg, 0.25 mmol), and acetyl
chloride (20 µL, 0.30 mmol). The reaction was monitored by TLC
until all starting material was consumed (4 h). At that time, water
(10 mL) was added, and the two layers were separated. The aqueous
phase was extracted with DCM (3 × 5 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure to give crude product, which was purified
by recrystallization (MeOH) to furnish lamellarin U diacetate 114
as a white solid (56.7 mg, 0.095 mmol, 95%). mp (MeOH) >250
°C. IR (neat): νmax 2987, 2939, 2841, 1766, 1717, 1547, 1519,
1
1484, 1439, 1414, 1369, 1267, 1203, 1131, 1041, 1010 cm-1. H
NMR (200 MHz, CDCl3): δ 2.30 (s, 3H), 2.31 (s, 3H), 3.03-3.25
(m, 2H), 3.43 (s, 3H), 3.47 (s, 3H), 3.90 (s, 6H), 4.57-4.71 (m,
1H), 4.90-5.02 (m, 1H), 6.63 (s, 1H), 6.75 (d, J ) 3.6 Hz, 2H),
7.10 (d, J ) 8.8 Hz, 1H), 7.16 (s, 1H), 7.25 (d, J ) 2.2 Hz, 1H),
7.33 (dd, J ) 8.0, 2.2 Hz, 1H). 13C NMR (50 MHz, CDCl3): δ
20.7, 20.8, 28.8, 42.6, 55.5, 55.8, 56.1, 56.4, 105.6, 108.7, 111.1,
112.0, 113.2, 114.3, 114.5, 116.4, 119.9, 125.7, 126.7, 127.5, 127.9,
129.8, 136.4, 138.9, 140.9, 145.1, 147.7, 149.2, 151.5, 155.3, 168.7,
169.0. TOF-LRMS m/z (rel intensity) 600 (M + H+, 100). TOF-
HRMS calcd for C33H30NO10 (M + H+) 600.1864, found 600.1866.
Representative Example for DDQ Oxidation (14-(3-Acetoxy-
4-methoxyphenyl)-3-acetoxy-2,11,12-tetramethoxy-6H-chromeno-
[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-6-one (128; Lamellarin r
Diacetate)). To a solution of lamellarin U diacetate 114 (20 mg,
0.033 mmol) in DCM (3.5 mL) at room temperature was added
DDQ (23 mg, 0.083 mmol). The resulting mixture was stirred at
room temperature for 18 h. At that time, water (5 mL) was added,
and the two layers were separated. The aqueous phase was extracted
with DCM (3 × 5 mL), and the combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure to
give crude product, which was purified by column chromatography
on silica (1% MeOH/CH2Cl2) to furnish lamellarin R diacetate 128
as a white solid (18.5 mg, 0.031 mmol, 94%). mp (EtOAc/hexanes)
193-198 °C. IR (neat): νmax 2938, 2840, 1766, 1706, 1616, 1540,
1
1512, 1486, 1418, 1369, 1266, 1194, 1139, 1082, 1042 cm-1. H
NMR (200 MHz, CDCl3): δ 2.25 (s, 6H), 3.41 (s, 3H), 3.46 (s,
3H), 3.86 (s, 3H), 3.90 (s, 3H), 6.71 (s, 1H), 6.97-7.06 (m, 3H),
7.15 (d, J ) 8.0 Hz, 1H), 7.19 (s, 1H), 7.25 (d, J ) 1.4 Hz, 1H),
7.36 (dd, J ) 8.0, 1.4 Hz, 1H), 9.14 (d, J ) 7.4 Hz, 1H). 13C NMR
(50 MHz, CDCl3): δ 20.4, 20.5, 55.4, 55.7, 56.0, 56.4, 105.3, 106.4,
107.6, 108.4, 110.4, 112.1, 112.9, 113.3, 115.9, 119.1, 123.1, 124.7,
126.1, 128.2, 128.6, 130.2, 134.5, 139.8, 141.1, 145.6, 147.7, 149.6,
150.4, 151.7, 155.0, 168.4, 168.6. LRMS (EI) m/z (rel intensity)
598 (M + H+, 10), 597 (M+, 41), 556 (34), 555 (100), 43 (20).
TOF-HRMS calcd for C33H28NO10 (M + H+) 598.1708, found
598.1717.
J. Org. Chem, Vol. 71, No. 25, 2006 9447