D. Yang et al. / Bioorg. Med. Chem. 22 (2014) 366–373
371
3.5.3.7. tert-Butyl ((2S,3S)-1-hydroxy-3-methylpentan-2-yl)car-
bamate (5g).
Colorless oil, yield 64%, 1H NMR (600 MHz,
DMSO-d6): d 6.42 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.4 Hz, 1H), 3.36–
3.39 (m, 1H), 3.25–3.34 (m, 3H), 1.47–1.98 (m, 1H), 1.38 (s, 9H),
0.99–1.07 (m, 1H), 0.80–0.83 (m, 6H). MS (ESI): m/z = 218.4 [M+H]+.
3.5.4.5. Methyl 4-(((2S,3S)-2-amino-3-methylpentyl)oxy)-7-
methoxy-1-methyl-1H-indole-2-carboxylate
(6e).
White
solid, yield 88%, mp 187.0–189.1 °C, ½a D25
ꢂ
+20.0° (c 1, MeOH), 1H
NMR (600 MHz, DMSO-d6): d 8.31 (s, 3H), 7.56 (s, 1H), 6.71 (d,
J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.27 (s, 3H), 4.22 (dd,
J = 2.4 Hz and 10.2 Hz, 1H), 4.11–4.14 (m, 1H), 3.86 (s, 3H), 3.84
(s, 3H), 3.45 (br, s, 1H), 1.91–1.95 (m, 1H), 1.57–1.61 (m, 1H),
1.25–1.30 (m, 1H), 0.98 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz,
3.5.4. General method for preparation of compounds (6)
To diisopropyl azodiformate (DIAD) (0.41 g, 2 mmol), triphenyl-
phosphine (0.41 g, 2 mmol) and dried tetrahydrofuran (5 mL) were
slowly added. After 30 min, 5 (3 mmol) in tetrahydrofuran (5 mL)
was slowly added to the solution, and then, the tetrahydrofuran
(10 mL) solution of 3 (0.24 g, 1 mmol) was added to the solution
over the course of 30 min under a nitrogen atmosphere at 0 °C
and allowed to proceed for 12 h. After completion of the reaction,
the solvent was evaporated to obtain an oil, which was extracted
with ethyl acetate/petroleum ether (1:3, 4 ꢁ 10 mL). The organic
phase was evaporated under reduced pressure to yield an oil,
which was purified by column chromatography with petroleum
ether/ethyl acetate (15:1) to obtain a solid. To the solid (0.5 mmol),
ethyl acetate with saturated hydrochloric acid (15 mL) was added
and reacted for 1 h. The solvent was evaporated under reduced
pressure to obtain the crude product, which was recrystallized
with methanol/ether to obtain 6a–6s.
3H).HRMS (ESI): m/z for
C
18H27N2O4 [M+H]+: calculated
335.1965, found 335.1970.
3.5.4.6. (S)-Methyl 4-(2-amino-3-phenylpropoxy)-7-bromo-1-
methyl-1H-indole-2-carboxylate hydrochloride (6f).
White
solid, yield 85.6%, mp 230.3–232.5 °C, ½a D25
ꢂ
+25.0° (c 1, MeOH), 1H
NMR (600 MHz, DMSO-d6): d 8.58 (s, 3H), 7.74 (s, 1H), 7.42 (d,
J = 7.8 Hz, 1H), 7.31–7.34 (m, 2H), 7.25–7.27 (m, 3H), 6.45 (d,
J = 7.8 Hz, 1H), 4.36 (s, 3H), 4.18 (d, J = 10.2 Hz, 1H), 3.97–3.99
(m, 1H), 3.88 (s, 3H), 3.85–3.87 (m, 1H), 3.18–3.20 (m, 1H), 3.04–
3.08 (m, 1H). HRMS (ESI): m/z for C20H22BrN2O3 [M+H]+: calculated
417.0808, found 417.0816.
3.5.4.7. (R)-Methyl 4-(2-amino-3-phenylpropoxy)-7-bromo-1-
methyl-1H-indole-2-carboxylate hydrochloride (6g).
White
solid, yield 93%, mp 228.2–230.9 °C, ½a D25
ꢂ
ꢀ62.5° (c 1, MeOH), 1H
NMR (600 MHz, DMSO-d6): d 8.68 (br, s, 3H), 7.74 (s, 1H), 7.41
(d, J = 7.8 Hz, 1H), 7.31–7.32 (m, 2H), 7.25–7.27 (m, 3H), 6.45 (d,
J = 7.8 Hz, 1H), 4.36 (s, 3H), 4.19 (dd, J = 3.0 Hz and 10.8 Hz, 1H),
3.97–3.99 (m, 1H), 3.88 (s, 3H), 3.82–3.83 (m, 1H), 3.20–3.23 (m,
3.5.4.1. (S)-Methyl 4-(2-amino-3-phenylpropoxy)-7-methoxy-1-
methyl-1H-indole-2-carboxylate hydrochloride (6a).
White
solid, yield 84%, mp 196.2–201.8 °C, ½a D25
ꢂ
+50.0° (c 1, MeOH), 1H
1H), 3.04–3.08 (m, 1H). HRMS (ESI): m/z for
C20H22BrN2O3
NMR (600 MHz, DMSO-d6): d 8.38 (s, 3H), 7.61 (s, 1H), 7.32–7.34
(m, 2H), 7.26–7.28 (m, 3H), 6.66 (d, J = 8.4 Hz, 1H), 6.34 (d,
J = 8.4 Hz, 1H), 4.27 (s, 3H), 4.09 (dd, J = 2.4 Hz and 10.2 Hz, 1H),
3.90 (dd, J = 5.4 Hz and 10.2 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
3.82–3.85 (m, 1H), 3.13 (dd, J = 5.4 Hz and 13.2 Hz, 1H), 3.04–
3.08 (m, 1H). HRMS (ESI): m/z for C21H25N2O4 [M+H]+: calculated
369.1809, found 369.1815.
[M+H]+: calculated 417.0808, found 417.0816.
3.5.4.8. (S)-Methyl 4-(2-amino-3-(1H-indol-3-yl)propoxy)-7-
bromo-1-methyl-1H-indole-2-carboxylate
(6h).
hydrochloride
White solid, yield 85%, mp 223.9–224.8 °C, ½a D25
ꢂ
+50.0°
(c 1, MeOH), 1H NMR (600 MHz, DMSO-d6): d 11.02 (s, 1H), 8.36
(br, s, 3H), 7.51 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.4 Hz,
1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.08 (t,
J = 7.8 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.36
(s, 3H), 4.21–4.24 (m, 1H), 4.05–4.07 (m, 1H), 3.88 (s, 3H), 3.85–
3.87 (m, 1H), 3.20–3.22 (m, 1H). HRMS (ESI): m/z for C22H23BrN3O3
[M+H]+: calculated 456.0917, found 456.0924.
3.5.4.2. (R)-Methyl 4-(2-amino-3-phenylpropoxy)-7-methoxy-1-
methyl-1H-indole-2-carboxylate hydrochloride (6b).
White
solid, yield 89%, mp 188.3–189.9 °C, ½a D25
ꢂ
ꢀ75.0° (c 1, MeOH): 1H
NMR (600 MHz, DMSO-d6): d 8.44 (br, s, 3H), 7.61 (s, 1H), 7.25–
7.34 (m, 5H), 6.67 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 4.27
(s, 3H), 4.10 (dd, J = 3.0 Hz and 10.2 Hz, 1H), 3.91 (dd, J = 4.8 Hz
and 10.8 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82–3.85 (m, 1H),
3.13–3.16 (m, 1H), 3.06–3.08 (m, 1H). HRMS (ESI): m/z for
3.5.4.9. (R)-Methyl 4-(2-amino-3-(1H-indol-3-yl)propoxy)-7-
bromo-1-methyl-1H-indole-2-carboxylate
(6i).
hydrochloride
White solid, yield 80%, mp 223.9–224.6 °C, ½a D25
ꢀ63.6°
ꢂ
(c 1, MeOH), 1H NMR (600 MHz, DMSO-d6): d 11.3 (s, 1H), 8.46
(br, s, 3H), 7.76 (s, 1H), 7.60 (dd, J = 3.0 Hz and 7.8 Hz, 1H), 7.41
(d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H),
7.08 (t, J = 7.8 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.45 (d, J = 8.4 Hz,
1H), 4.36 (s, 3H), 4.22 (dd, J = 2.4 Hz and 10.2 Hz, 1H), 4.05–4.07
(m, 1H), 3.88 (s, 3H), 3.83–3.85 (m, 1H), 3.19–3.25 (m, 1H). HRMS
(ESI): m/z for C22H23BrN3O3 [M+H]+: calculated 456.0917, found
456.0925.
C
21H25N2O4 [M+H]+: calculated 369.1809, found 369.1814.
3.5.4.3. (S)-Methyl 4-((2-amino-4-methylpentyl)oxy)-7-meth-
oxy-1-methyl-1H-indole-2-carboxylate
(6c).
hydrochloride
White solid, yield 90%, mp 189.1–192.0 °C, ½a D25
ꢂ
+14.3° (c
1, MeOH), 1H NMR (600 MHz, DMSO-d6): d 8.28 (s, 3H), 7.57 (s, 1H),
6.71 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 4.27 (s, 3H), 4.22 (dd,
J = 2.4 Hz and 10.2 Hz, 1H), 4.06 (dd, J = 5.4 Hz and 10.2 Hz, 1H), 3.86
(s, 3H), 3.84 (s, 3H), 3.55–3.57 (m, 1H), 1.76–1.80 (m, 1H), 1.58–1.64
(m, 2H), 0.93 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).HRMS (ESI):
m/z for C18H27N2O4 [M+H]+: calculated 335.1963, found 335.1970.
3.5.4.10. (S)-Methyl 4-(2-amino-3-phenylpropoxy)-7-chloro-1-
methyl-1H-indole-2-carboxylate hydrochloride (6j).
White
solid, yield 88%, mp 235.4–237.1 °C, ½a D25
ꢂ
+33.3° (c 1, MeOH), 1H
NMR (600 MHz, DMSO-d6): d 8.56 (br, s, 3H), 7.74 (s, 1H), 7.31–
7.34 (m, 2H), 7.25–7.27 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 6.50 (d,
J = 8.4 Hz, 1H), 4.35 (s, 3H), 4.18 (dd, J = 3.0 Hz and 10.2 Hz, 1H),
3.97–4.00 (m, 1H), 3.88 (s, 3H), 3.84–3.86 (m, 1H), 3.18 (dd,
J = 4.8 Hz and 13.2 Hz, 1H), 3.04–3.08 (m, 1H). HRMS (ESI): m/z
for C20H22ClN2O3 [M+H]+: calculated 373.1313, found 373.1321.
3.5.4.4. (S)-Methyl 4-(2-amino-4-(methylthio)butoxy)-7-meth-
oxy-1-methyl-1H-indole-2-carboxylate
(6d).
hydrochloride
White solid, yield 80%, mp 219.8–223.0 °C, ½a D25
ꢂ
+13.3°
(c 1, MeOH), 1H NMR (600 MHz, DMSO-d6): d 8.36 (br, s, 3H),
7.56 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 4.27
(s, 3H), 4.25 (m, 1H), 4.10–4.13 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
3.66 (s, 1H), 2.65–2.67 (m, 2H), 2.08 (s, 3H), 2.00–2.05 (m, 2H).
HRMS (ESI): m/z for C17H25N2O4S [M+H]+: calculated 353.1530,
found 353.1534.
3.5.4.11. (R)-Methyl 4-(2-amino-3-phenylpropoxy)-7-chloro-1-
methyl-1H-indole-2-carboxylate hydrochloride (6k).
White
solid, yield 81%, mp 228.8–230.6 °C, ½a D25
ꢂ
ꢀ92.3° (c 1, MeOH), 1H