R
H. Du et al.
Feature
Synthesis
0.042 mmol, 21%, 49% ee) and trans-(10S,11aS)-7ea as a yellow oil
(23.2 mg, 0.058 mmol, 29%; 54% ee).
3.57 (ddd, J = 12.9, 9.7, 3.5 Hz, 1 H), 2.50–2.42 (m, 1 H), 2.36 (s, 3 H),
2.04–1.91 (m, 1 H); δ (minor) = 8.12 (d, J = 8.2 Hz, 1 H), 7.64 (t, J = 7.2
Hz, 1 H), 7.40–7.27 (m, 3 H), 7.18 (d, J = 7.2 Hz, 2 H), 7.11 (d, J = 7.3 Hz,
2 H), 6.62–6.57 (m, 1 H), 6.14 (t, J = 3.1 Hz, 1 H), 5.77 (d, J = 3.3 Hz, 1
H), 4.79 (d, J = 3.9 Hz, 1 H), 4.35–4.26 (m, 2 H), 4.19–4.07 (m, 1 H),
3.71 (dt, J = 12.6, 4.2 Hz, 1 H), 3.65 (dt, J = 7.6, 3.8 Hz, 1 H), 2.56 (td, J =
13.4, 5.6 Hz, 1 H), 2.48 (s, 3 H), 2.12 (dt, J = 13.6, 2.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ (major) = 169.6 (C), 144.7 (C), 136.1 (C),
134.1 (C), 129.3 (C), 128.9 (2 CH), 127.9 (2 CH), 127.0 (2 CH), 125.1
(CH), 124.6 (C), 123.0 (CH), 118.7 (CH), 118.4 (CH), 115.4 (CH), 108.4
(CH), 103.9 (CH), 54.6 (CH), 46.2 (CH2), 45.7 (CH2), 42.3(CH), 39.0
(CH2), 26.8 (CH3); δ (minor) = 169.1 (C), 145.2 (C), 135.9 (C), 131.8 (C),
129.5 (C), 128.8 (2 CH), 126.7 (2 CH), 126.6 (2 CH), 125.0 (CH), 124.2
(C), 123.1 (CH), 118.8 (CH), 118.5 (CH), 116.3 (CH), 108.3 (CH), 103.6
(CH), 50.0 (CH), 46.9 (CH2), 45.6 (CH2), 40.1 (CH), 35.2 (CH2), 27.2
(CH3).
cis-(10S,11aR)-Diastereomer
Rf = 0.29 (PE/EtOAc, 4:1) (UV, vanillin); [α]D20 –11.6 (c 0.2, CHCl3).
HPLC: Lux-Amylose-2, hexane/EtOH (80:20), 25 °C, 1.0 mL/min, λ =
254 nm, tR = 7.15 min (major), tR = 6.20 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.19–7.13 (m, 2 H), 7.13–7.04 (m, 3 H),
6.51–6.42 (m, 1 H), 5.99 (dd, J = 3.5, 2.8 Hz, 1 H), 5.63 (dt, J = 3.5, 1.4
Hz, 1 H), 4.55 (dd, J = 8.6, 3.6 Hz, 1 H), 4.26–4.18 (m, 1 H), 4.07 (dt, J =
13.0, 3.4 Hz, 1 H), 4.03–3.97 (m, 2 H), 3.39 (ddd, J = 13.5, 8.9, 5.2 Hz, 1
H), 2.74–2.57 (m, 3 H), 2.42 (d, J = 1.1 Hz, 3 H), 2.19 (dt, J = 13.6, 8.8
Hz, 1 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 192.4 (C), 149.4 (C), 145.5 (C), 128.9
(C), 128.2 (2 CH), 127.5 (2 CH), 125.9 (CH), 118.5 (CH), 111.4 (C),
108.7 (CH), 103.4 (CH), 53.5 (CH), 45.2 (CH2), 44.4 (CH2), 40.9 (CH),
39.5 (CH2), 23.5 (CH2), 17.4 (CH3), 15.0 (CH3).
HRMS (ESI): m/z calcd for [C25H23N3O + H]+: 382.1914; found:
382.1913.
HRMS (ESI): m/z calcd for [C21H24N2OS + H]+: 353.1682; found:
353.1681.
tert-Butyl (2S,13bS)-11-Methoxy-4-methyl-2-phenyl-2,6,7,13b-
tetrahydro-1H-pyrido[2′,1′:3,4]pyrazino[1,2-a]indole-3-carboxyl-
ate (9)
trans-(10S,11aS)-Diastereomer
Rf = 0.2 (PE/EtOAc, 4:1) (UV, vanillin); [α]D20 –28.9 (c 0.2, CHCl3).
A reaction tube was charged with the trimethylsilyl ether 4 (12.0 mg,
0.020 mmol, 0.1 equiv), anhydrous PhCF3 (2.5 mL), flushed with ar-
gon, and placed at 0 °C. tert-Butyl acetoacetate (1a; 31.6 mg, 32.9 μL,
0.200 mmol, 1 equiv) and (E)-cinnamaldehyde (2a; 39.7 mg, 37.8 μL,
0.300 mmol, 1.5 equiv) were then added. After full conversion of 1a as
monitored by TLC (48 h), followed by the addition of 2-(5-methoxy-
1H-indol-1-yl)ethanamine (8; 38.0 mg, 0.200 mmol, 1 equiv), the
mixture was stirred at 0 °C for another 24 h. After the reaction, the
solution was filtered through a short pad of silica gel, which was thor-
oughly washed with EtOAc. The solvent was evaporated under re-
duced pressure to obtain the crude compound, which was analyzed
HPLC: Chiralpak AD-H, hexane/EtOH (80:20), 25 °C, 1.0 mL/min, λ =
254 nm, tR = 12.07 min (major), tR = 8.08 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.29 (m, 2 H), 7.24–7.19 (m, 3 H),
6.55 (tt, J = 1.7, 0.6 Hz, 1 H), 6.12 (dd, J = 3.6, 2.7 Hz, 1 H), 5.80 (dt, J =
3.6, 1.4 Hz, 1 H), 4.37 (dd, J = 4.9, 2.7 Hz, 1 H), 4.21–4.10 (m, 2 H),
4.07–3.99 (m, 2 H), 3.43 (ddd, J = 13.8, 9.6, 4.4 Hz, 1 H), 2.86–2.77 (m,
1 H), 2.67 (dt, J = 13.3, 7.4 Hz, 1 H), 2.60 (s, 3 H), 2.46 (ddd, J = 13.1,
4.0, 2.7 Hz, 1 H), 2.17 (ddd, J = 13.1, 12.0, 4.8 Hz, 1 H), 1.15 (t, J = 7.4
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 190.2 (C), 152.5 (C), 145.6 (C), 129.4
(C), 128.5 (2 CH), 127.9 (2 CH), 126.4 (CH), 118.9 (CH), 108.6 (CH),
106.2 (C), 103.0 (CH), 49.6 (CH), 44.9 (CH2), 44.7 (CH2), 38.6 (CH), 36.1
(CH2), 23.5 (CH2), 17.9 (CH3), 15.1 (CH3).
1
by H NMR and identified as the dihydropyridine 10. Purification by
flash column chromatography [PE/EtOAc (80:20) and then PE/EtOAc/
AcOH (80:20:0.5)] on silica gel provided the pure trans-(2S,13bS)-in-
dolopiperazine 9 as a pale yellow solid (28.4 mg, 0.064 mmol, 32%;
85% ee); Rf = 0.53 (PE/EtOAc, 4:1) (UV, vanillin).
HRMS (ESI): m/z calcd for [C21H24N2OS + H]+: 353.1682; found:
353.1685.
HPLC: Chiralpak AZ-H, heptane/EtOH (90:10), 25 °C, 1.0 mL/min, λ =
254 nm, tR = 11.47 min (major), tR = 9.83 min (minor).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 2 H), 7.27–7.17 (m, 3 H),
7.15 (d, J = 8.8 Hz, 1 H), 7.00 (d, J = 2.3 Hz, 1 H), 6.82 (dd, J = 8.8, 2.3 Hz,
1 H), 6.09 (s, 1 H), 4.38–4.23 (m, 2 H), 4.21–4.08 (m, 2 H), 4.02 (td, J =
11.3, 4.2 Hz, 1 H), 3.83 (s, 3 H), 3.41 (ddd, J = 13.9, 11.5, 3.7 Hz, 1 H),
2.55 (s, 3 H), 2.40 (dt, J = 13.3, 3.3 Hz, 1 H), 2.25 (ddd, J = 13.2, 11.3, 5.7
Hz, 1 H), 1.18 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 168.5 (C), 154.6 (C), 152.5 (C), 147.5
(C), 137.9 (C), 131.3 (C), 128.7 (C), 128.3 (C), 128.3 (2 CH), 128.1 (2
CH), 126.0 (CH), 111.2 (CH), 109.3 (CH), 102.5 (CH), 96.1 (CH), 78.8
(C), 56.1 (CH3), 50.2 (CH), 44.3 (CH2), 42.6 (CH2), 38.9 (CH), 36.1 (CH2),
28.2 (3 CH3), 17.5 (CH3).
1-[(5S)-5-Phenyl-4,5,12,13-tetrahydropyrrolo[2′′,1′′:3′,4′]pyrazi-
no[1′,2′:1,6]pyrido[3,2-b]indol-6(3bH)-yl)ethanone (7ha)
Prepared according to general procedure A at 0 °C using 1-acetylindo-
lin-3-one (6h; 35.0 mg, 0.200 mmol, 1 equiv), (E)-cinnamaldehyde
(2a; 39.7 mg, 37.8 μL, 0.300 mmol, 1.5 equiv), and N-(2-aminoeth-
yl)pyrrole (3a; 22.0 mg, 21.6 μL, 0.200 mmol, 1 equiv), with CH2Cl2
(2.5 mL) instead of PhCF3 as solvent. Purification by flash chromatog-
raphy (PE/Et2O, 4:1) afforded 7ha as a white solid (52.8 mg, 0.136
mmol, 68%; ~1.5:1 dr, 88% ee and 87% ee); Rf = 0.15 (PE/Et2O, 4:1) (UV,
vanillin).
HPLC: cis-(10S,11aR)-Diastereomer (major): Chiralpak AZ-H, hex-
ane/EtOH (50:50), 25 °C, 1.0 mL/min, λ = 254 nm, tR = 14.25 min (ma-
jor), tR = 10.45 min (minor); trans-(10S,11aS)-Diastereomer (minor):
Chiralpak AZ-H, hexane/EtOH (50:50), 25 °C, 1.0 mL/min, λ = 254 nm
(major), tR = 11.58 min, tR = 7.09 min (minor).
1H NMR (400 MHz, CDCl3): δ (major) = 8.04 (d, J = 8.1 Hz, 1 H), 7.64 (t,
J = 7.2 Hz, 1 H), 7.41–7.27 (m, 3 H), 7.23 (d, J = 7.7 Hz, 2 H), 7.01 (d, J =
7.2 Hz, 2 H), 6.62–6.57 (m, 1 H), 6.17 (t, J = 3.1 Hz, 1 H), 5.98 (d, J = 3.2
Hz, 1 H), 4.70 (dd, J = 10.4, 7.5 Hz, 1 H), 4.62 (d, J = 11.3 Hz, 1 H), 4.38
(d, J = 10.2 Hz, 1 H), 4.19–4.07 (m, 1 H), 3.79 (dt, J = 12.7, 3.9 Hz, 1 H),
HRMS (ESI): m/z calcd for [C28H32N2O3 + H]+: 445.2486; found:
445.2485.
tert-Butyl (S)-1-[2-(5-Methoxy-1H-indol-1-yl)ethyl]-2-methyl-4-
phenyl-1,4-dihydropyridine-3-carboxylate (10)
A reaction tube was charged with the trimethylsilyl ether 4 (12.0 mg,
0.020 mmol, 0.1 equiv), anhydrous PhCF3 (2.5 mL), flushed with ar-
gon, and placed at 0 °C. tert-Butyl acetoacetate (1a; 31.6 mg, 32.9 μL,
0.200 mmol, 1 equiv) and (E)-cinnamaldehyde (2a; 39.7 mg, 37.8 μL,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–Y