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P. Talukder et al. / Bioorg. Med. Chem. 22 (2014) 5924–5934
[2,3-b]pyridine (5) as a yellow oil: yield 783 mg (52%); silica gel TLC
Rf 0.15 (4:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 400 MHz) d
0.51(d, 3H, J = 6.8 Hz), 0.78 (d, 3H, J = 8 Hz), 1.99–2.03 (m, 1H),
2.22 (s, 3H), 3.07–3.12 (m, 3H), 3.57 (s, 3H), 3.60 (s, 3H), 4.22–4.25
(m, 1H), 7.02–7.05 (m, 1H), 7.13 (d, 1H, J = 8 Hz), 7.36 (s, 1H), 7.74
(dd, 1H, J = 8.0 and 1.6 Hz), 7.87 (d, 2H, J = 8.4 Hz) and 8.29 (dd, 1H,
J = 4.8 and 1.6 Hz); 13C NMR (CDCl3, 400 MHz) d 16.4, 18.8, 21.5,
29.1, 31.3, 52.1, 52.3, 55.5, 60.4, 114.9, 118.3, 123.7, 124.6, 127.5,
128.2, 129.5, 135.5, 144.6, 144.8, 147.1, 161.8 and 164.0; mass spec-
trum (APCI), m/z 469.1921 (M+H)+ (C24H29N4O4S requires m/z
469.1909).
at room temperature for 2 h. The reaction mixture was then poured
slowly into 30 mL of NaHCO3 and then extracted with two 30-mL
portions of EtOAc. The combined organic phase was dried (MgSO4)
and concentrated under diminished pressure. Methyl (S)-2-
amino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate was
obtained as a yellow oil and was used directly in the next step with-
out further purification. To a stirred solution containing 36 mg
(0.15 mmol) of methyl (S)-2-amino-3-(1-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl)propionate (8) in 2 mL of 1:1 dioxane/water was
added 75 mg (0.54 mmol) of K2CO3 followed by 52 mg (0.24 mmol)
of NVOC-Cl. The reaction mixture was stirred at room temperature
for 14 h under argon, then diluted with 50 mL of brine and extracted
with two 50-mL portions of EtOAc. The combined organic phase was
dried (MgSO4) and concentrated under diminished pressure. The
residue was purified by chromatography on a silica gel column
(10 ꢂ 2 cm). Elution with 1:3 hexanes/ethyl acetate gave methyl
(S)-2-((4,5-dimethoxy-2-nitrobenzyloxy)carbonylamino)-3-(1-
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate (9) as a yellow
oil: yield 58 mg (62% for two steps); silica gel TLC Rf 0.3 (1:1 hex-
anes/ethyl acetate); 1H NMR (CDCl3, 400 MHz) d 3.24–3.26 (m,
2H), 3.66 (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.88 (s, 3H), 4.65–4.67
(m, 1H), 5.46 (d, 1H, J = 8 Hz), 5.57 (d, 1H, J = 8.4 Hz), 6.88 (s, 1H),
6.96–6.99 (m, 2H), 7.63 (s, 1H), 7.76 (d, 1H, J = 7.2 Hz), 8.27 (dd,
1H, J = 4.8 and 1.2 Hz) and 8.60 (d, 1H, J = 7.2 Hz); 13C NMR (CDCl3,
400 MHz) d 27.9, 31.1, 52.5, 54.5, 56.4, 56.4, 63.9, 106.8, 108.1,
110.0, 115.3, 120.3, 126.8, 127.7, 127.8, 139.6, 143.1, 147.8, 148.0,
153.6, 155.3 and 172.2; mass spectrum (APCI), m/z 473.1673
(M+H)+ (C22H25N4O8 requires m/z 473.1672).
5.2.5. 3-(((2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropy-
razin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine (6)
To a stirred solution containing 303 mg (0.65 mmol) of 3-
(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)
methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (5) in 5 mL of 2:1 THF/
methanol was added 685 mg (1.94 mmol) of Cs2CO3. The reaction
mixture was stirred at room temperature for 12 h under argon, then
diluted with 20 mL of brine and extracted with two 50-mL portions
of EtOAc. The combined organic phase was dried (MgSO4) and con-
centrated under diminished pressure. The residue was purified by
chromatography on a silica gel column (10 ꢂ 2 cm). Elution with
ethyl acetate gave 3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridine (6) as a
yellow oil: yield 77 mg (39%); silica gel TLC Rf 0.3 (1:1 hexanes/ethyl
acetate); 1H NMR (CDCl3, 400 MHz) d 0.60 (d, 3H, J = 6.8 Hz), 0.91 (d,
3H, J = 6.8 Hz), 2.10–2.13 (m, 1H), 3.26–3.29 (m, 2H), 3.36–3.38 (m,
1H), 3.65 (s, 3H), 3.68 (s, 3H), 4.34–4.35 (m, 1H), 7.02 (dd, 1H, J = 4.4
and 4.4 Hz), 7.08 (s, 1H), 7.95 (d, 1H, J = 6.8 Hz),), 8.26 (d, 1H,
J = 4.8 Hz) and 11.52 (s, 1H); 13C NMR (CDCl3, 400 MHz) d 16.5,
19.0, 29.7, 31.4, 52.3, 52.4, 56.7, 60.5, 109.8, 114.5, 121.3 123.9,
127.8, 142.0, 148.8, 162.8 and 163.9; mass spectrum (APCI), m/z
315.1829 (M+H)+ (C17H23N4O2 requires m/z 315.1821).
5.2.8. Cyanomethyl (S)-2-((4,5-dimethoxy-2-nitrobenzyloxy)
carbonylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)
propionate (10)
To a stirred solution containing 31.0 mg (0.07 mmol) of methyl
(S)-2-((4,5-dimethoxy-2-nitrobenzyloxy)carbonyl)amino-3-(1-
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate (9) in 1 mL of
5.2.6. 3-(((2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropy-
razin-2-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (7)
To a stirred solution containing 76 mg (0.24 mmol) of 3-
(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)
methyl)-1H-pyrrolo[2,3-b]pyridine (6) in 3 mL of anhydrous DMF at
0 °C was added 11.5 mg (0.48 mmol) of NaH followed by 0.03 mL (69
mg, 0.48 mmol) of MeI. The reaction mixture was stirred at 0 °C
under argon for 30 min, then diluted with 100 mL of NaHCO3 and
extracted with two 50-mL portions of EtOAc. The combined organic
phase was dried (MgSO4) and concentrated under diminished
pressure. The residue was purified by chromatography on a silica
gel column (10 ꢂ 2 cm). Elution with ethyl acetate gave 3-
(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)
methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (7) as a yellow oil:
yield 68 mg (83%); silica gel TLC Rf 0.4 (1:1 hexanes/ethyl acetate);
1H NMR (CDCl3, 400 MHz) d 0.59 (d, 3H, J = 6.8 Hz), 0.91 (d, 3H,
J = 7.2 Hz), 2.09–2.13 (m, 1H), 3.22 (d, 2H, J = 4.4 Hz), 3.40–3.41 (m,
1H), 3.62 (s, 3H), 3.66 (s, 3H), 3.79 (s, 3H), 4.28–4.29 (m, 1H), 6.86
(s, 1H), 6.95–6.98 (m, 1H), 7.87 (dd, 1H, J = 8.0 and 1.6 Hz), and
8.25 (dd, 1H, J = 8.4 and 1.6 Hz); 13C NMR (CDCl3, 400 MHz) d 16.6,
19.1, 29.6, 31.1, 31.5, 52.2, 52.3, 56.7, 60.6, 108.9, 114.8, 121.3
127.6, 127.7, 142.6, 147.7, 162.8 and 163.9; mass spectrum (APCI),
m/z 329.1977 (M+H)+ (C18H25N4O2 requires m/z 329.1977).
1:3:1 water/THF/methanol was added 214 lL (0.21 mmol) of 1 N
LiOH. The reaction mixture was stirred at room temperature for
3 h, and then concentrated under diminished pressure. The residue
was dissolved in 1 mL of anhyd DMF and 30.0
0.21 mmol) of Et3N was added followed by 13.0
l
l
L (22.0 mg,
L (16.0 mg,
0.21 mmol) of chloroacetonitrile. The reaction mixture was stirred
at 23 °C for 16 h, then diluted with 20 mL of NaHCO3 and extracted
with two 50-mL portions of EtOAc. The combined organic phase
was dried (MgSO4) and concentrated under diminished pressure.
The residue was purified by chromatography on a silica gel column
(10 ꢂ 2 cm). Elution with ethyl acetate gave cyanomethyl (S)-2-
((4,5-dimethoxy-2-nitrobenzyloxy)carbonylamino)-3-(1-methyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)propionate (10) as a light yellow
solid: yield 22 mg (71%); silica gel TLC Rf 0.4 (1:1 hexanes/ethyl ace-
tate); 1H NMR (CDCl3, 400 MHz) d 3.32 (d, 2H, J = 5.6 Hz), 3.84 (s, 3H),
3.89 (s, 3H), 3.93 (s, 3H), 4.62–4.81 (m, 3H), 5.43–5.55 (m, 2H), 6.90
(s, 1H), 7.04–7.07 (m, 2H), 7.69 (s, 1H), 7.83 (d, 1H, J = 7.6 Hz), 8.33
(dd, 1H, J = 4.8 and 1.6 Hz); 13C NMR (CDCl3, 400 MHz) d 27.9, 31.3,
49.1, 54.6, 56.5, 56.6, 64.3, 105.9, 108.3, 110.3, 113.9, 115.7, 120.2,
126.8, 127.5, 128.1, 139.9, 143.5, 147.9, 148.4, 153.7, 155.4 and
170.7; mass spectrum (APCI), m/z 498.1638 (M+H)+ (C23H24N5O8
requires m/z 498.1625).
5.2.9. (S)-2-((4,5-Dimethoxy-2-nitrobenzyloxy)carbonylamino)-
3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pdCpA (11)
5.2.7. Methyl (S)-2-((4,5-dimethoxy-2-nitrobenzyloxy)carbonyl)
amino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate
(9)
To a stirred solution containing 67.0 mg (0.21 mmol) of 3-
(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)
methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (7) in 4 mL of THF at
0 °C was added 4 mL of 2 N aq HCl. The reaction mixture was stirred
To a stirred solution containing 5.20 mg (4.00
tetrabutylammonium salt in 100 L of 9:1 anhyd DMF/anhy-
drous triethylamine was added 10.4 mg (21.0 mol) of
lmol) of pdCpA
l
l
cyanomethyl (S)-2-((4,5-dimethoxy-2-nitrobenzyloxy)carbonylami-
no)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate (10). The
reaction mixture was sonicated for 2 h. The reaction mixture