Didier et al.
(s, 9 H), 2.26 (s, 3 H), 7.19-7.42 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 9.6, 28.0, 83.9, 115.9, 117.6, 120.6, 123.4, 126.4, 126.5,
132.4, 135.0, 149.0; MS (CI) m/z 283 (M + NH4)+; HRMS (CI)
m/z calcd for C14H20ClN2O2 (M + NH4)+ 283.1213, found (M +
NH4)+ 283.1206. Anal. Calcd for C14H16ClNO2: C, 63.28; H,
6.07; N, 5.27. Found C, 63.27; H, 6.19; N, 5.20.
and stirred for 2 h. The solution was rotary evaporated and
chromatographed (hexanes/EtOAc 4:1) to afford the tryptophan
derivative 11 (850 mg, 84%) as a colorless oil: TLC (hexanes/
EtOAc 2:1) Rf ) 0.66; [R]22 +27.3 (c 1.00, CHCl3); IR (film)
D
3406, 1744, 1713, 1490, 1456, 1366, 1166, 1077, 1059, 863, 780,
1
734 cm-1; H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.17-
3.28 (m, 2 H), 3.67 (s, 3 H), 4.08 (s, 3 H), 4.62 (dd, 1 H, J )
13.2, 5.4 Hz), 5.07 (d, 1 H, J ) 7.8 Hz), 6.78 (s, 1 H), 6.94-
6.98 (m, 1 H), 7.12 (d, 1 H, J ) 7.2 Hz), 7.39 (d, 1 H, J ) 7.9
Hz); 13C NMR (100 MHz, CDCl3) δ 27.7, 28.3, 36.5, 52.2, 54.0,
79.8, 108.8, 117.0, 117.6, 119.8, 123.2, 130.1, 131.3, 132.1,
155.1, 172.5; MS (CI) m/z 367 (M + H)+; HRMS (CI) m/z calcd
for C18H24ClN2O4 (M + H)+ 367.1425, found (M + H)+
367.1427. Anal. Calcd for C18H23ClN2O4: C, 58.93; H, 6.32; N,
7.64. Found: C, 58.74; H, 6.47; N, 7.41.
tert-Butyl 7-Chloro-3-(5R-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2S-ylmethyl)indole-1-carboxylate 10. In-
dole 9 (7.3 g, 27.5 mmol) in CCl4 (150 mL) was heated to reflux
when an intimate mixture of recrystallized (H2O) N-bromo-
succinimide (5.9 g, 33.0 mmol, 1.2 equiv) and AIBN (290 mg,
1.8 mmol, 0.06 equiv) was added in three portions over 3 min.
The mixture was heated to reflux for 20 min, when additional
AIBN (150 mg, 0.91 mmol, 0.03 equiv) was added. The mixture
was kept at reflux for 50 min and allowed to cool. The
precipitated succinimide was filtered off and leached with
hexane (4 × 10 mL). Rotary evaporation of the combined
filtrates gave crude 3-(bromomethyl)indole (8.7 g, 92%) as a
brown oil. The crude material was flash evaporated under
reduced pressure from dry THF solution three times and used
directly in the next step without further purification. n-BuLi
(2.3M, 12.1 mL, 26.6 mmol, 1.1 equiv) was added dropwise
with stirring to 2(R)-isopropyl-3,6-dimethoxy-2,5-dihydropy-
razine (5.1 g, 27.8 mmol, 1.1 equiv) in dry THF (100 mL) under
nitrogen at -78 °C. After 30 min, crude 3-(bromomethyl)indole
(8.7 g, 25.3 mmol) in THF (50 mL) was added dropwise, and
the mixture was stirred at -78 °C for 4 days and allowed to
slowly warm to room temperature. The solution was concen-
trated under reduced pressure and diluted with saturated
aqueous NaHCO3. The aqueous layer was extracted with CH2-
Cl2 (3 × 40 mL), and the combined organic layers were washed
with brine (30 mL) and dried (Na2SO4). Rotary evaporation
and chromatography (hexanes/EtOAc 4:1) gave indole 10 (8.7
g, 71%) as a yellow oil: TLC (hexanes/EtOAc 2:1) Rf ) 0.74;
[R]22D -178.0 (c 1.00, CHCl3); IR (film) 1757, 1735, 1696, 1461,
1436, 1369, 1347, 1238, 1194, 1156, 1116, 1014, 843, 774, 762
Methyl (2S,3aR,8aS)-7-Chloro-3a-hydroxy-8-methyl-3,-
3a,8,8a-tetrahydro-2H-pyrrolo[2,3-b]indole-1,2-dicarbox-
ylate 13 and Methyl (2S,3aS,8aR)-7-Chloro-3a-hydroxy-
8-methyl-3,3a,8,8a-tetrahydro-2H-pyrrolo[2,3-b]indole-
1,2-dicarboxylate 14. Indole 11 (1.5 g, 4.1 mmol) and
porphyrazine 12 (150 mg, 0.41 mmol, 0.05 equiv) in MeOH
(300 mL) was irradiated at -30 °C (temperature of the reaction
mixture) by a 500 W halogen lamp while a stream of oxygen
was bubbled through the reaction vessel. After 90 min, Me2S
(10 mL) was added, and the reaction mixture was stirred for
2 h at -30 °C. Rotary evaporation and chromatography (CH2-
Cl2/EtOAc/Et2O 15:1:1) gave alcohol 13 (463 mg, 30%) and
alcohol 14 (446 mg, 28%) both as an orange oils. Alcohol 13:
TLC (CH2Cl2/EtOAc/Et2O 8:1:1) Rf ) 0.77; [R]22D -80.9 (c 1.00,
CHCl3); IR (film) 3441, 1756, 1708, 1606, 1472, 1368, 1200,
1
1164, 1050, 969, 784, 751 cm-1; H NMR (500 MHz, (CD3)2-
SO, 413 K) δ 1.45 (s, 9 H), 2.35 (dd, 1 H, J ) 13.3, 5.6 Hz),
2.42 (dd, 1 H, J ) 13.3, 8.3 Hz), 3.30 (s, 3 H), 3.69 (s, 3 H),
4.05-4.15 (m, 1 H), 5.08 (s, 1 H), 6.81 (t, 1 H, J ) 7.5 Hz),
7.15-7.18 (m, 2 H); 13C NMR (125 MHz, (CD3)2SO, 413 K) δ
27.3, 38.5, 41.3, 50.7, 58.9, 79.5, 83.9, 91.4, 115.1, 120.2, 121.0,
130.1, 135.7, 145.7, 153.3, 171.1; MS (CI) m/z 383 (M + H)+;
HRMS (CI) m/z calcd for C18H24ClN2O5 (M + H)+ 383.1374,
found (M + H)+ 383.1376. Anal. Calcd for C18H23ClN2O5: C,
56.47; H, 6.06; N, 7.32. Found: C, 56.59; H, 5.93; N, 7.18.
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.63, 0.94 (2d, 6 H, J )
6.8 Hz), 1.62 (s, 9 H), 2.12-2.19 (m, 1 H), 3.14 (dd, 1 H, J )
14.5, 5.6 Hz), 3.20 (dd, 1 H, J ) 14.5, 3.8 Hz), 3.54-3.56 (m,
1 H), 3.65 (s, 3 H), 3.67 (s, 3 H), 4.28-4.33 (m, 1 H), 7.10-
7.14 (m, 1 H), 7.27 (d, 1 H, J ) 7.2 Hz), 7.31 (s, 1 H), 7.49 (d,
1 H, J ) 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 16.6, 18.9,
27.9, 29.1, 31.6, 52.2, 52.3, 55.9, 60.6, 83.8, 116.0, 118.2, 120.3,
123.0, 126.2, 127.8, 132.0, 134.9, 148.7, 162.4, 164.1; MS (CI)
m/z 448 (M + H)+; HRMS (CI) m/z calcd for C23H31ClN3O4 (M
+ H)+ 448.2003, found (M + H)+ 448.2002. Anal. Calcd for
C23H30ClN3O4: C, 61.67; H, 6.75; N, 9.38. Found: C, 61.62; H,
6.64; N, 9.28.
Alcohol 14: TLC (CH2Cl2/EtOAc/Et2O 8:1:1) Rf ) 0.67; [R]22
D
+83.5 (c 1.00, CHCl3); IR (film) 3418, 1739, 1706, 1681, 1606,
1
1475, 1393, 1368, 1310, 1164, 1121, 1051, 965, 751 cm-1; H
NMR (500 MHz, (CD3)2SO, 373 K) δ 1.46 (s, 9 H), 2.23 (dd, 1
H, J ) 13.1, 5.1 Hz), 2.57 (dd, 1 H, J ) 13.1, 8.8 Hz), 3.27 (s,
3 H), 3.39 (s, 3 H), 4.58 (dd, 1 H, J ) 8.8, 5.1 Hz), 5.08 (s, 1
H), 5.83 (s, 1 H), 6.69 (t, 1 H, J ) 7.5 Hz), 7.07-7.10 (m, 2 H);
13C NMR (125 MHz, (CD3)2SO, 373 K) δ 27.5, 36.0, 41.6, 50.9,
59.0, 79.5, 84.0, 90.6, 113.6, 119.1, 121.3, 130.4, 134.8, 145.1,
153.4, 170.8; MS (CI) m/z 383 (M + H)+; HRMS (CI) m/z calcd
for C18H24ClN2O5 (M + H)+ 383.1374, found (M + H)+
383.1376. Anal. Calcd for C18H23ClN2O5: C, 56.47; H, 6.06; N,
7.32. Found: C, 56.54; H, 6.06; N, 7.23.
Methyl (2S)-2-tert-Butoxycarbonylamino-3-(7-chloro-
1-methyl-1H-indol-3-yl)propanoate 11. Carbamate 10 (5.6
g, 12.5 mmol) in xylenes (300 mL) was degassed and heated
at reflux for 36 h. After rotary evaporation, the residue was
flash evaporated under reduced pressure with dry THF three
times and used directly in the next step without further
purification. MeI (940 µL, 15.0 mmol, 1.2 equiv) was added to
the crude product in dry DMF (100 mL) at 0 °C. NaH (360
mg, 15.0 mmol, 1.2 equiv) was added slowly, and the reaction
mixture was stirred at 0 °C for 2 h. Cold H2O (30 mL) and
EtOAc (150 mL) were added sequentially, and the organic
layer was washed with H2O (4 × 50 mL) and dried (Na2SO4).
Rotary evaporation and chromatography (hexanes/EtOAc 4:1)
gave (3S,6R)-3-[(1-methyl-7-chloro-3-indolyl)methyl]-3,6-dihy-
dro-6-isopropyl-2,5-dimethoxypyrazine (4.1 g) as a yellow oil,
which was used directly without further purification. HCl in
H2O (2M; 8 mL) was added to an aliquot of the oil (1.0 g, 2.8
mmol) in THF (25 mL) at 0 °C. The mixture was stirred and
allowed to warm to room temperature. After 1.5 h, the mixture
was concentrated by evaporation under reduced pressure and
the residue dissolved in 1,4-dioxane (25 mL) and cooled to 0
°C. Di-tert-butyl dicarbonate (1.3 g, 6.1 mmol, 2.2 equiv) and
iPr2NEt (1.45 mL, 8.3 mmol, 3.0 equiv) were added, and the
reaction mixture was allowed to warm to room temperature
Methyl (2S,3aR,9bR)-6-Chloro-9b-hydroxy-5-methyl-
1,2,3,3a,5,9b-hexahydro-4-oxa-3,5-diazacyclopenta[a]naph-
thalene-2-carboxylate 15. m-CPBA (61 mg, 0.33 mmol, 1.0
equiv) in CH2Cl2 (1 mL) was added dropwise with stirring to
amine 13 (100 mg, 0.35 mmol) in CH2Cl2 (2 mL) at 0 °C. After
30 min, additional m-CPBA (61 mg, 0.35 mmol, 1.0 equiv) in
CH2Cl2 (1 mL) was added dropwise and stirring continued at
0 °C for a further 30 min. The solution was diluted with CH2-
Cl2 (5 mL), washed with 10% aqueous Na2CO3, dried (Na2SO4),
and rotary evaporated. HCl in EtOAc (1 M; 5 mL) was added
with stirring to the residue. After 1 h, the solution was
concentrated under reduced pressure, and saturated aqueous
NaHCO3 was added to pH 8. The mixture was extracted with
CH2Cl2 (2 × 10 mL), and the organic layer was dried (Na2-
SO4). Rotary evaporation and chromatography (hexanes/EtOAc
1:1) gave ester 15 (64 mg, 61% yield) as a yellow oil: TLC
(hexanes/EtOAc 1:1) Rf ) 0.13; [R]22 +19.6 (c 1.00, CHCl3);
D
IR (film) 3381 (br), 1737, 1568, 1438, 1334, 1235, 1219, 1070,
1
1006, 934, 791, 759 cm-1; H NMR (500 MHz, acetone-d6) δ
7878 J. Org. Chem., Vol. 69, No. 23, 2004