H. Tokuyama et al.
dry THF (10 mL). NaH (186 mg, 60% in mineral oil, 4.65 mmol) was
added to the solution at 08C. The solution was stirred for 30 min at the
same temperature. To the reaction mixture were added DMAP (75.7 mg,
0.620 mmol) and the acid chloride in THF (6.0 mL). The solution was
stirred for 0.5 h, after which time TLC (hexanes/EtOAc=17:3) indicated
complete consumption of 19. The reaction was quenched with saturated
aqueous NH4Cl at 08C and extracted with EtOAc. The combined organic
extracts were washed with brine, dried over anhydrous sodium sulfate,
and filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexanes/
EtOAc=19:1 to 9:1) to afford amide 26 (903 mg, 1.80 mmol, 58%) as a
sulting suspension was vigorously stirred for 5 h, after which time TLC
(hexanes/EtOAc=3:1) indicated complete consumption of 27. The reac-
tion mixture was filtered through celite pad. The filter cake was washed
with EtOAc, and the filtrate was concentrated under reduced pressure to
afford a crude acid 28 as a colorless oil, which was used to the next reac-
tion without further purification. A 10 mL screw-top test tube equipped
with a magnetic stirring bar was charged with the crude acid 28. To the
test tube was added Eatonꢀs reagent, which was prepared from P2O5
(57.5 mg, 0.405 mmol) and MsOH (0.40 mL) at 808C for 0.5 h. After the
solution was stirred for 20 min at 808C, the reaction mixture was poured
into ice-water and extracted with CHCl3 three times. The combined ex-
tracts were washed with brine and dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was puri-
fied by preparative TLC (hexanes/EtOAc=1:1) to afford ketone 29
1
yellow oil; H NMR (400 MHz, CDCl3): d=7.98 (d, J=8.8 Hz, 1H), 7.46
(d, J=6.8 Hz, 1H), 7.40–7.28 (m, 5H), 7.28–7.18 (m, 2H), 7.02 (s, 1H),
5.31 (q, J=6.8 Hz, 1H), 5.10 (s, 2H), 3.22 (t, J=8.0 Hz, 2H), 2.62–2.35
(m, 6H), 1.58 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
173.0, 172.7, 137.9, 135.60, 135.95, 131.1, 128.5, 128.21, 128.17, 124.7,
123.5, 123.2, 121.6, 119.6, 114.8, 73.2, 66.2, 38.5, 33.1, 31.6, 25.3, 13.3 ppm;
IR (neat): n˜ =2922, 2860, 1733, 1438, 1355, 1282, 1163, 747, 698 cmÀ1; MS
(EI): m/z: 501 [M+]; HRMS (EI): m/z calcd for C24H24INO3: 501.0801
[M+]; found: 501.0807.
(5.88 mg, 0.0220 mmol, 68% for 2 steps, 16% ee) as a yellow oil. [a]D26
À13.9 (c=0.588, CHCl3).
=
ACHUTNGRENUN(G 3aR)-(+)-1,2,3,3a,4,5-Hexahydro-3a-ethyl-6H-pyridoACHTUNGTRNE[NUGN 3,2,1-jk]-carbazol-
6-one (30): A two-necked 20 mL round-bottomed flask equipped with a
magnetic stirring bar was charged with ketoester 33 (162.2 mg,
0.764 mmol), phenylhydrazine hydrogen chloride salt (168.3 mg,
1.16 mmol), and acetic acid (2.5 mL). The reaction mixture was heated at
1208C for 13 h, after which time TLC (hexanes/EtOAc=3:1) indicated
complete consumption of 33. The reaction was quenched with saturated
aqueous NaHCO3. The resulting mixture was extracted with EtOAc
three times. The combined organic extracts were washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated under reduced pressure. The resi-
due was purified by silica gel column chromatography (hexanes/EtOAc=
17:3) to afford indole 30 (177.0 mg, 0.699 mmol, 91%) as an orange oil.
[a]2D5 = +74.6 (c=1.00, CHCl3); 1H NMR (600 MHz, CDCl3): d=8.38
(dd, J=7.2, 1.2 Hz, 1H), 7.39 (dd, J=7.2, 1.2 Hz, 1H), 7.29 (ddd, J=7.2,
7.2, 1.2 Hz, 1H), 7.26 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 2.87 (ddd, J=18.6,
13.8, 5.4 Hz, 1H), 2.78–2.72 (m, 1H), 2.70 (ddd, J=18.6, 4.8, 1.8 Hz, 1H),
2.55 (ddd, J=16.8, 10.2, 7.8 Hz, 1H), 2.13 (ddd, J=13.2, 5.4, 1.8 Hz, 1H),
2.10 (ddd, J=13.2, 3.6, 3.6 Hz, 1H), 2.04–1.94 (m, 2H), 1.75 (dq, J=15.6,
7.8 Hz, 1H), 1.71 (dq, J=15.6, 7.8 Hz, 1H), 1.65 (ddd, J=13.8, 13.2,
4.8 Hz, 1H), 1.34 (ddd, J=13.2, 12.6, 5.4 Hz, 1H), 0.92 ppm (dd, J=7.8,
7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=168.8, 141.1, 135.0, 130.0,
124.1, 123.6, 117.9, 116.2, 113.3, 33.2, 31.7, 30.9, 30.6, 26.3, 19.8, 18.3,
8.1 ppm; IR (neat): n˜ =2937, 1697, 1631, 1454, 1368, 1331, 1314, 1187,
1156, 750 cmÀ1; HRMS (EI): calcd for C17H19NO: 253.1467 [M+]; found:
253.1462.
Benzyl 2-(6-oxo-9-vinyl-6,7,8,9-tetrahydropyrido
nate (27): (see Table 1, entry 4): A 10 mL screw-top test tube equipped
with a magnetic stirring bar was charged with [Pd2A(dba)3·CHCl3] (2.2 mg,
ACHTUNGTNER[NUNG 1,2-a]indol-9-yl)propio-
CTHUNGTRENNUNG
2.1 mmol), (S)-BINAP (2.9 mg, 4.7 mmol), and degassed DMF (0.3 mL).
The solution was heated at 1008C for 12 h. To the solution were added
N-acyl-2-iodoindole 26 (10.8 mg, 0.0215 mmol) in DMF (0.1 mL) and
1,2,2,6,6-pentamethylpiperidine (20 mL, 0.11 mmol) at room temperature.
The solution was stirred for 1 h, after which time TLC (hexanes/EtOAc=
3:1) indicated complete consumption of 26. The reaction mixture was di-
luted with EtOAc, washed with water and brine, dried over anhydrous
sodium sulfate, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by preparative TLC (hexanes/
EtOAc=3:1) to afford lactam 27 (7.2 mg, 0.019 mmol, 90%) as a pale-
1
yellow oil; H NMR (500 MHz, CDCl3): d=8.47 (d, J=8.5 Hz, 1H), 7.50
(dd, J=8.5, 8.5 Hz, 1H), 7.36–7.25 (m, 7H), 6.43 (s, 1H), 5.88 (dd, J=
17.5, 10.5 Hz, 1H), 5.19 (d, J=10.5 Hz, 1H), 5.10 (s, 2H), 4.83 (d, J=
17.5 Hz, 1H), 2.82 (ddd, J=17.5, 11.0, 5.0 Hz, 1H), 2.75 (ddd, J=17.5,
5.0, 5.0 Hz, 1H), 2.50 (ddd, J=16.0, 9.0, 7.0 Hz, 1H), 2.46 (ddd, J=16.0,
9.0, 7.5 Hz, 1H), 2.26 (ddd, J=16.0, 9.0, 7.5 Hz, 1H), 2.23 (ddd, J=15.0,
9.0, 7.0 Hz, 1H), 2.06 (ddd, J=13.5, 11.0, 5.0 Hz, 1H), 1.94 ppm (ddd, J=
13.5, 5.0, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=172.9, 168.7,
141.6, 140.9, 135.7, 135.2, 129.2, 128.6, 128.31, 128.28, 124.6, 124.0, 120.1,
116.7, 116.5, 106.3, 66.5, 42.0, 33.7, 30.8, 30.2, 29.5 ppm; IR (neat): n˜ =
1732, 1705, 1456, 1350, 1180, 754 cmÀ1; MS (EI): m/z 373 [M+]; HRMS
(EI): m/z calcd for C24H23NO3: 373.1678 [M+]; found: 373.1675.
ACHUTNGRENUN(G 3aR)-(+)-1,2,3,3a,4,5-Hexahydro-3a-ethyl-6H-pyridoACHTUNGTRNE[NUGN 3,2,1-jk]-carbazol-
1,6-dione (29): A 50 mL round-bottomed flask equipped with a magnetic
stirring bar was charged with indole 30 (206.3 mg, 0.814 mmol), triethyla-
mine (1.1 mL, 7.9 mmol), acetonitrile (6.4 mL) and water (1.6 mL). The
solution was cooled to 08C and ceric ammonium nitrate (2.11 g,
3.85 mmol) at 08C, and the resulting mixture was stirred at 08C for
15 min. Cerium(IV) ammonium nitrate (1.04 g, 1.90 mmol) was added to
the mixture at 08C, and the resulting mixture was stirred at 08C for
45 min, after which time TLC (hexanes/EtOAc=1:1) indicated complete
consumption of 30. The reaction was quenched with water. The resulting
mixture was extracted with EtOAc three times. The combined organic
extracts were washed with water and brine, dried over anhydrous sodium
sulfate, and filtered. The filtrate was concentrated under reduced pres-
sure. The residue was purified by using silica gel column chromatography
(hexanes/EtOAc=1:1 to 1:3) to afford ketone 29 (143.0 mg, 0.535 mmol,
(S)-(À)-Benzyl
2-(6-oxo-9-vinyl-6,7,8,9-tetrahydropyridoACTHNGUTERNNU[G 1,2-a]indol-9-
yl)propionate (27): (see Table 1, entry 5): A two-necked 30 mL round-
bottomed flask equipped with a magnetic stirring bar was charged with
[PdACHTUNGTRENNUNG(OAc)2] (4.5 mg, 20 mmol), (S)-BINAP (25.0 mg, 40.1 mmol), and de-
gassed DMF (2.0 mL). The solution was stirred at room temperature for
0.5 h. To the solution were added N-acyl-2-iodoindole 26 (102 mg,
0.203 mmol) in DMF (2.0 mL) and Ag3PO4 (167 mg, 0.400 mmol) at
room temperature. The solution was heated at 1008C for 84 h, after
which time TLC (hexanes/EtOAc=3:1) indicated complete consumption
of 26. The reaction mixture was diluted with EtOAc, washed with water
and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexanes/EtOAc=17:3) to afford
lactam 27 (14.8 mg, 0.0396 mmol, 19%, 19% ee) as a pale-yellow oil. The
enantiomeric excess of 27 was determined by HPLC (DAICEL-CHIR-
66%) as
a
colorless oil. [a]D26 = +86.8 (c=1.00, CDCl3); 1H NMR
(600 MHz, CDCl3): d=8.41–8.38 (m, 1H), 8.20–8.16 (m, 1H), 7.40–7.35
(m, 2H), 2.98 (ddd, J=19.2, 13.8, 5.4 Hz, 1H), 2.87 (ddd, J=19.2, 4.8,
2.4 Hz, 1H), 2.80 (ddd, J=18.0, 13.8, 4.8 Hz, 1H), 2.61 (ddd, J=18.0, 4.8,
2.4 Hz, 1H), 2.34 (ddd, J=13.8, 4.8, 2.4 Hz, 1H), 2.26 (ddd, J=13.8, 5.4,
2.4 Hz, 1H), 1.95 (dddd, J=13.8, 13.8, 4.8, 1.2 Hz, 1H), 1.93–1.81 (m,
3H), 1.06 ppm (t, J=7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
193.4, 168.1, 157.5, 134.8, 125.5, 125.4, 125.3, 121.3, 115.9, 113.8, 34.7,
34.1, 32.5, 30.5, 29.6, 25.2, 8.6 ppm; IR (neat-ATR): n˜ =2945, 1714, 1659,
1572, 1479, 1451, 1363, 1305, 1165, 1134, 1098, 770, 757 cmÀ1; HRMS
(EI): m/z calcd for C17H17NO2: 267.1259 [M+]; found: 267.1266.
ALCEL-OJ-H, hexane/iPrOH=80:20, flow rate=0.5 mLminÀ1
65.8 min, tÀ =76.4 min). [a]2D9 =À6.8 (c=0.34, CHCl3).
, t+ =
(3aS)-(À)-1,2,3,3a,4,5-Hexahydro-3a-ethyl-6H-pyrido
ACHTUNGERTN[NUNG 3,2,1-jk]-carbazol-
1,6-dione (29): A 10 mL Schlenk tube equipped with a magnetic stirring
bar was charged with benzyl ester 27 (12.4 mg, 0.0332 mmol, 19% ee)
prepared in the enantioselective Mizoroki–Heck reaction (Table 1,
entry 5), 10% Pd/C (3.5 mg, 3.3 mmol), EtOAc (0.17 mL), and EtOH
(0.17 mL). To the flask was charged with hydrogen gas (1 atm). The re-
9332
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 9325 – 9334