6
P. B. Chanda et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
4
.5.
Methyl
(Z)-1-benzyl-7-(benzyloxy)-5-((tert-
filtered, concentrated in vacuo and purified by flash chromatogra-
phy (SiO , 30% acetone/hexanes) to afford 13 (28 mg, 0.073 mmol,
82%) as a white solid: H NMR (acetone-d
H), 8.96 (br s, 1H), 7.54 (br s, 1H), 4.25–4.31 (m, 1H), 4.10–4.18
(m, 1H), 4.06 (dd, J = 3.4, 10.7 Hz, 1H), 3.92–3.96 (m, 1H), 3.96 (s,
3H), 3.67 (t, J = 10.1 Hz, 1H), 1.56 (s, 9H); IR (film) max 1745,
20ClN
butyloxycarbonyl)(3-chloroallyl)amino)-4-iodo-benzimidazole-
2
1
2
-carboxylate (11)
6
, 400 MHz) d 12.31 (br s,
1
A solution of 10 (640 mg, 1.04 mmol) in DMF (9.5 mL) was trea-
ted with NaH (60% dispersion in mineral oil, 60 mg, 1.5 mmol) at
°C. After stirring at this temperature for 30 min, cis-1,3-dichloro-
propene (231 mg, 2.1 mmol) was added and the mixture was stir-
red for 5 h at 23 °C. H O (63 mL) was added to the reaction mixture
and the mixture was extracted with EtOAc. The combined organic
extracts were washed with H O, saturated aqueous LiCl and satu-
rated aqueous NaCl, dried (Na SO ) and concentrated in vacuo.
The residue was purified by flash column chromatography (SiO
m
H
ꢁ
1
+
0
1366 cm ; ESI-TOF HRMS m/z 382.1175 (M+H , C17
3 5
O
requires 382.1164).
2
Resolution: Racemic 13 was resolved into its enantiomers by
HPLC on a ChiralPak AD semi-preparative column (2 ꢀ 25 cm,
2
0
2
10% i-PrOH/hexane, 7 mL/min,
0.39, MeOH) for natural enantiomer; Peak 2: [
MeOH) for unnatural enantiomer.
a
= 1.3). Peak 1: [
a]
D
ꢁ52 (c
2
0
2
4
a] = +50 (c 0.42,
D
2
,
2
5
0–35% EtOAc/hexanes, gradient) to afford 11 (398 mg, 0.58 mmol
6%) as a white solid: 1H NMR (CDCl
4.8. 2-(tert-Butyl) 6-methyl 1,2,8,8a-tetrahydrocyclopropa[c]
imidazo[4,5-e]indol-4-one-2,6-dicarboxylate (N-Boc-CImI, 14)
3
, 500 MHz, mixture of rota-
mers) d 7.26–7.31 (m, 3H), 7.22 (s, 3H), 7.11 (d, J = 7.1 Hz, 2H),
6
6
1
.90 (s, 1.4H) & 6.84 (s, 0.6 H), 6.75 (s, 0.3H) & 6.66 (s, 0.7H),
.13 (s, 1.4H) & 6.10 (s, 0.6H), 5.98 (s, 2H), 5.10 (d, J = 11.4 Hz,
H), 5.04 (d, J = 11.7 Hz, 1H), 4.50 (d, J = 13.5 Hz, 1H), 4.29 (d,
A solution of 13 (8 mg, 0.021 mmol) dissolved in THF (0.8 mL)
was treated with aqueous 1 M NaHCO
reaction mixture was stirred at room temperature for 4 h before
it was extracted with EtOAc, dried with anhydrous Na SO , filtered,
and concentrated. The solid product was purified by PTLC (SiO
80% EtOAc/hexane) to yield 14 (4.3 mg, 0.012 mmol, 59%): 1
NMR (CDCl , 400 MHz) d 11.21 (br, 1H), 6.83 (s, 1H), 3.98–4.06
(m, 5H), 3.04 (q, J = 5.1, 7.5, 4.8 Hz, 1H), 2.10 (dd, J = 3.9, 7.8 Hz,
3
(0.8 mL, 0.8 mmol). The
J = 12.8 Hz, 0.7H) & 4.16 (d, J = 12.8 Hz, 0.3H), 3.97 (s, 3H), 1.56
1
3
(
s, 3H) & 1.33 (s, 6H); C NMR (CDCl
3
, 125 MHz) d 160.0, 154.1,
2
4
1
1
1
&
1
47.2 & 146.7, 145.3 & 145.1, 141.5, 141.3 & 141.0, 137.7, 135.4,
28.8, 128.6, 128.5, 128.0 & 127.7, 127.5, 127.4, 126.2, 124.5 &
24.3, 120.7 & 120.2, 109.4 & 109.2, 84.5, 81.3 & 80.8, 71.0, 53.6
2
,
H
3
53.1, 50.8, 47.5 & 46.3, 28.6 & 28.3; IR (film)
m
max 2976, 1725,
ꢁ1
13
699, 1579, 1482, 1451, 1367 cm ; ESI-TOF HRMS m/z 688.1070
1H), 1.54 (s, 9H), 1.43 (t, J = 4.6 Hz, 1H);
125 MHz) d 178.0, 161.2, 158.9, 151.6, 148.6, 139.4, 129.3, 109.5,
3.7, 54.0, 53.4, 33.4, 28.3, 25.9, 23.6; IR (film) max 2923, 2852,
3
C NMR (CDCl ,
+
(
M+H , C31
H31IClN
3
O
5
requires 688.1070).
8
m
ꢁ
1
4
.6.
3-(tert-Butyl)
7-methyl 6-benzyl-5-(benzyloxy)-1-
1721, 1603, 1393, 1370, 1345, 1277, 1206 cm ; ESI-TOF HRMS
+
(
chloromethyl)-1,2-dihydro-3H-imidazo[4,5-e]indole-3,7-
m/z 346.1401 (M+H ,
C
17
H
19
N
3
O
5
requires 346.1397).
+ 115 (c 0.27, MeOH) for natural enantiomer;
= ꢁ115 (c 0.27, MeOH) for unnatural enantiomer.
2
2
0
0
dicarboxylate (12)
[a
]
]
D
[a
D
Method A: Benzene (10 mL) degassed by the freeze–pump-thaw
method three times was added to a sealed flask charged with 11
4.9.
Methyl
1-(chloromethyl)-5-hydroxy-3-(5,6,7-
(
200 mg, 0.29 mmol) and AIBN (20 mg, 0.12 mmol). (Me
Si)
3 3
SiH
trimethoxyindole-2-carbonyl)-1,2-dihydro-3H-imidazo[4,5-e]
(
145 mg, 0.58 mmol) was added and the flask was sealed and
indole-2-carboxylate (15)
heated at 80 °C for 4 h. After cooling, the solvent was removed
under a stream of N gas. The reaction mixture was purified by col-
umn chromatography (SiO , 20% EtOAc/hexanes) to afford 12
2
An oven dried vial containing 13 (5.0 mg, 0.013 mmol) was
treated with 4 N HCl in EtOAc (1.6 mL). The reaction mixture was
stirred at room temperature for 2 h. The solvent was evaporated
2
1
(
3
113 mg, 0.20 mmol, 69%) as a pale yellow solid: H NMR (CDCl ,
5
3
5
1
1
1
4
1
00 MHz) d 7.85 (br s, 1H), 7.26–7.33 (m, 3H), 7.20 (t, J = 2.9 Hz,
H), 7.14 (d, J = 7.1 Hz, 2H), 6.90 (d, J = 3.7 Hz, 2H), 6.11 (s, 2H),
.10 (s, 2H), 4.28 (d, J = 11.0 Hz, 1H), 4.17–4.23 (m, 2H), 4.12 (br,
2
under a stream of N . Additional EtOAc was added and the solvent
was evaporated again. The residue was placed under vacuum over-
night. EDCIꢂHCl (7.4 mg, 0.039 mmol), 5,6,7-trimethoxyindole-2-
H), 3.98 (s, 3H), 3.70 (br, 1H), 1.58 (s, 9H); 13C NMR (CDCl
carboxylic acid (19, 4.2 mg, 0.017 mmol) and DMF (140 lL) were
3
,
25 MHz) d 160.1, 147.3, 141.4, 139.8, 138.2, 135.8, 128.7, 128.6,
28.4, 128.3, 127.3, 126.2, 123.1, 97.5, 81.0, 71.2, 53.2, 50.2, 47.2,
added to the amine salt. The reaction mixture was stirred for 2 d
at room temperature. The solvent was removed under a stream
1.1, 29.9, 28.6; IR (film)
264 cm ; ESI-TOF HRMS m/z 562.2104 (M+H , C31
m
max 1726, 1697, 1455, 1419, 1339,
of N
(SiO
NMR (DMSO-d
2
. The crude product was purified by column chromatography
ꢁ1
+
1
3
H32ClN O
5
2 2 2
, 3% MeOH/CH Cl ) to yield 15 (4.1 mg, 0.0079 mmol, 61%): H
requires 562.2103).
6
, 500 MHz) d 10.33 (s, 1H) 7.65 (br, 1H), 7.00 (s, 1H),
Method B: Benzene (42 mL) degassed by the freeze–pump-thaw
method three times was added to a sealed flask charged with 11
6.96 (s, 1H), 4.70 (t, J = 10.2 Hz, 1H), 4.40 (dd, J = 3.3, 11.2 Hz, 1H),
4.09–4.12 (m, 1H), 3.80–3.96 (m, 2H, embedded within –OMe sin-
(
(
770 mg, 1.1 mmol) and AIBN (18 mg, 0.1 mmol). Bu
460 mg, 1.6 mmol) was added and the flask was sealed and heated
3
SnH
glets), 3.95 (s, 3H), 3.93 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H); ESI-TOF
+
HRMS m/z 515.1327 (M+H , C24
H
23ClN
4
O
7
requires 515.1328).
2
6
26
at 80 °C for 7 h. After cooling, the solvent was removed under a
stream of N gas. The reaction mixture was purified by column
chromatography (SiO , 30% EtOAc/hexanes) to afford 12 (457 mg,
.81 mmol, 73%) as a yellow solid identical to the material
described above.
[a]
D
= ꢁ14 (c 0.08, MeOH) for natural enantiomer; [
D
a] = +15
2
(c 0.06, MeOH) for unnatural enantiomer.
2
0
4.10.
Methyl
2-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-
1,2,8,8a-tetrahydrocyclopropa[c]imidazo[4,5-e]indole-4-one-6-
carboxylate (16)
4
.7. 3-(tert-Butyl) 7-methyl 1-(chloromethyl)-5-hydroxy-1,2-
dihydro-3H-imidazo[4,5-e]indole-2,6-dicarboxylate (13)
A sample of 15 (2.0 mg, 3.88
lmol) was dissolved in THF
(
0.2 mL). Aqueous 1 M NaHCO (0.2 mL) was added and the reac-
3
A solution of 12 (50 mg, 0.089 mmol) in THF (2 mL) under Ar
was charged with 10% Pd/C (18 mg, 0.017 mmol) and placed under
tion mixture was stirred at room temperature for 4 h. The reaction
mixture was extracted with EtOAc and the combined organic phase
5
0 psi pressure of H
2
. The reaction mixture was agitated in a Parr
was dried with anhydrous Na
solid product was purified by PTLC (SiO
2
SO
4
, filtered, and concentrated. The
, 8% MeOH/CH Cl ) to yield
Shaker apparatus for 2 h at 23 °C. The reaction mixture was
2
2
2