Jackson and Kerr
43.8, 37.3, 36.8, 29.9, 21.6, 16.2, 15.5; IR (thin film) νmax 3153,
3062, 2943, 1596, 1457, 1354, 1174, 1091, 976, 955 cm-1; HRMS
calcd for C24H29NO8S2 555.1055, exptl 555.1053.
2.22 (d, J ) 9.6 Hz, 1H), 1.84 (d, J ) 9.6 Hz, 1H), 1.52 (s, 3H),
1.21 (s, 3H), 1.19 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 144.5, 136.3, 131.5, 130.0, 128.8, 128.2, 127.2, 126.7, 124.8,
120.2, 112.8, 106.5, 81.3, 80.7, 47.0, 43.6, 42.7, 25.8, 24.1, 21.5,
20.0, 14.3; IR (thin film) νmax 3447, 2977, 2936, 2873, 1373, 1169,
1139, 1061 cm-1; HRMS calcd for C25H27NO5S 453.1610, exptl
453.1605.
Herbindole A. To a solution of bis-mesylate 23 (80.0 mg, 0.140
mmol) in 5 mL of DME was added NaI (324 mg, 2.16 mmol) and
activated Zn dust (141 mg, 2.16 mmol). The flask was fitted with
a condenser and brought to reflux for 24 h. The mixture was cooled
to room temperature, filtered to remove the Zn, and diluted with
EtOAc. The solution was washed with H2O (3×) and brine (1×),
dried with MgSO4, and concentrated. Purification by preparative
TLC (5% EtOAc/hexanes) afforded 31 mg (60%) of N-tosylherbin-
dole A. To a solution of N-tosylherbindole A (27 mg, 0.073 mmol)
in 10 mL of THF was added TBAF (0.514 mL of a 1.0 M solution
in THF, 0.514 mmol). The flask was purged with argon and brought
to reflux for 24 h. The mixture was cooled to room temperature,
diluted with brine and extracted with EtOAc (3×). The combined
organic fractions were washed with H2O (3×) and brine (1×), dried
with MgSO4, and concentrated in vacuo. Purification by preparative
TLC (5% EtOAc/hexanes, double elution) afforded 11 mg (72%)
Trifluoromethanesulfonic Acid 4-Ethyl-6,10-methano-8,8-
dimethyl-1-(toluene-4-sulfonyl)-6,6a,9a,10-tetrahydro-1H-7,9-di-
oxa-1-azadicyclopenta[a,g]naphthalen-5-yl ester (26). To a chilled
(0 °C) suspension of NaH (261 mg, 6.53 mmol) in 15 mL of THF
was added a solution of 5-hydroxyindole 25 (2.47 g, 5.44 mmol)
in 30 mL of THF via cannula. The mixture was stirred for 30 min
at 0 °C and a solution of PhNTf2 (2.33 g, 6.53 mmol) in 15 mL of
THF was added via cannula. The mixture was warmed to room
temperature and stirred for 18 h. The mixture was diluted with brine
and extracted with EtOAc (3×). The combined organic fractions
were washed with H2O (1×) and brine (1×), dried with MgSO4,
and concentrated in vacuo. Purification by FC (20% EtOAc/
hexanes) afforded 2.50 g (78%) of 5-trifloxyindole 26 as a white
1
of herbindole A. H NMR (600 MHz, CDCl3) δ 7.92 (br s, 1H),
1
7.14-7.13 (m, 1H), 6.57-6.56 (m, 1H), 3.51-3.45 (m, 1H), 3.45-
3.40 (m, 1H), 2.71 (dt, J ) 12.6, 9.0 Hz, 1H), 2.49 (s, 3H), 2.34
(s, 3H), 1.56 (dt, J ) 12.6, 2.4 Hz, 1H), 1.46 (d, 7.2 Hz, 3H), 1.37
(d, J ) 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 142.0, 130.4,
127.7, 126.6, 126.4, 123.2, 122.8, 101.6, 41.8, 39.1, 37.1, 23.8,
22.8, 15.5, 15.3; IR (thin film) νmax 3414, 2958, 2928, 2868, 1448,
1126, 724 cm-1; HRMS calcd for C15H19N 213.1518, exptl
213.1518.
solid. Mp 168-170 °C; H NMR (600 MHz, CDCl3) δ 7.81 (d,
J ) 4.2 Hz, 1H), 7.66 (d, J ) 8.4 Hz, 2H), 7.32 (d, J ) 8.4 Hz,
2H), 6.75 (d, J ) 4.2 Hz, 1H), 4.18 (d, J ) 4.8 Hz, 1H), 4.15 (s,
1H), 3.55 (s, 1H), 3.51 (d, J ) 4.8 Hz, 1H), 2.96-2.85 (m, 2H),
2.40 (s, 3H), 2.25 (d, J ) 9.6 Hz, 1H), 1.90 (d, J ) 9.6 Hz, 1H),
1.51 (s, 3H), 1.24 (t, J ) 7.8 Hz, 3H), 1.21 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 145.1, 137.8, 135.9, 135.4, 132.1, 130.3, 129.5,
129.3, 129.0, 128.0, 126.9, 118.6 (q, JCF ) 319.7 Hz, 1C), 112.9,
106.5, 80.6, 80.6, 47.6, 45.8, 43.4, 25.8, 24.2, 21.6, 20.9, 14.4; IR
(thin film) νmax 3152, 2984, 2938, 2881, 2360, 1617, 1494, 1455,
1406, 1374 cm-1; HRMS calcd for C26H26F3NO7S2 585.1103, exptl
585.1239.
4-Iodo-8,8-dimethyl-6,10-methano-1-(toluene-4-sulfonyl)-6,-
6a,9a,10-tetrahydro-1H-7,9-dioxa-1-azadicyclopenta[a,g]naph-
thalen-5-ol (24). To a solution of diol 20 (6.70 g, 13.1 mmol) in
70 mL of DMF was added 2-methoxypropene (1.50 mL, 15.7
mmol) and p-TsOH (498 mg, 2.62 mmol). When complete by TLC
analysis, the mixture was diluted with H2O and extracted with
EtOAc (3×). The combined organic extracts were washed with H2O
(3×), saturated NaHCO3 (aq) (1×), and brine (1×). The solution
was dried with MgSO4 and concentrated in vacuo. Purification by
FC (gradient elution, 15-30% EtOAc/hexanes) afforded 6.36 g
4-Ethyl-8,8-dimethyl-6,10-methano-1-(toluene-4-sulfonyl)-6,-
6a,9a,10-tetrahydro-1H-7,9-dioxa-1-azadicyclopenta[a,g]naph-
thalene (27). 5-Trifloxyindole 26 (2.41 g, 4.11 mmol) was dissolved
in 15 mL of dry DMF sparged with argon in a tube. To the solution
was added LiCl (871 mg, 20.6 mmol), ammonium formate (5.19
g, 82.3 mmol), and Pd(PPh3)2Cl2 (288 mg, 0.410 mmol). The tube
was purged with argon, sealed, immersed in an oil bath at 140 °C,
and stirred for 18 h. The tube was cooled to 0 °C and cautiously
opened. The mixture was diluted with H2O and extracted with
EtOAc (3×). The combined organic fractions were washed with
H2O (3×) and brine (1×), dried with MgSO4, and concentrated in
vacuo. Purification by FC (gradient elution, 5-20% EtOAc/
hexanes) afforded 1.71 g (95%) of the title compound as a white
1
(88%) of acetonide 24 as a white solid. Mp 194-196 °C (d); H
NMR (400 MHz, CDCl3) δ 7.74 (d, J ) 3.8 Hz, 1H), 7.61 (d, J )
8.4 Hz, 2H), 7.27 (d, J ) 8.4 Hz, 2H), 6.56 (d, J ) 3.8 Hz, 1H),
5.35 (s, 1H), 4.15 (br s, 1H), 4.08 (d, J ) 5.4 Hz, 1H), 3.57 (br s,
1H), 3.47 (d, J ) 5.4 Hz, 1H), 2.36 (s, 3H), 2.21 (d, J ) 9.6, 1H),
1.86 (d, J ) 9.6, 1H), 1.52 (s, 3H), 1.19 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 147.0, 144.9, 135.9, 135.5, 131.4, 130.1, 129.2,
128.9, 126.7, 124.2, 112.9, 111.4, 80.9, 80.5, 75.5, 47.1, 44.6, 42.9,
25.9, 24.1, 21.5; IR (thin film) νmax 3482, 3148, 2987, 2935, 1374,
1206, 1172, 1161 cm-1; HRMS calcd for C23H22INO5S 551.0263,
exptl 551.0271.
1
solid. Mp 164-166 °C; H NMR (600 MHz, CDCl3) δ 7.68 (d,
J ) 4.2 Hz, 1H), 7.64 (d, J - 8.4 Hz, 2H), 7.25 (d, J ) 4.2 Hz,
1H), 6.96 (s, 1H), 6.71 (d, J ) 4.2 Hz, 1H), 4.10 (br s, 1H), 4.04
(d, J ) 5.4 Hz, 1H), 3.51 (d, J ) 5.4 Hz, 1H), 3.23 (br s, 1H),
2.83-2.77(m, 2H), 2.35 (s, 3H), 2.20 (d, J ) 9.6 Hz, 1H), 1.84 (d,
J ) 9.6 Hz, 1H), 1.51 (s, 3H), 1.26 (t, J ) 7.2 Hz, 3H), 1.18 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 144.5, 143.1, 136.4, 135.4,
130.0 (2C), 129.9, 127.3, 126.9, 126.2, 117.3, 112.5, 106.3, 81.5,
81.2, 47.9, 46.6, 42.9, 25.9 (2C), 24.1, 21.5, 14.8; IR (thin film)
4-Ethyl-8,8-dimethyl-6, 10-methano-1-(toluene-4-sulfonyl)-6,-
6a,9a,10-tetrahydro-1H-7,9-dioxa-1-azadicyclopenta[a,g]naph-
thalen-5-ol (25). To a solution of 4-iodoindole 24 (3.00 g, 5.44
mmol) in 50 mL of dry 1,4-dioxane sparged with argon was added
Et2Zn (19.4 mL of a 1.0 M solution in hexanes, 19.4 mmol) and
Pd(dppf)Cl2‚CH2Cl2 (660 mg, 0.816 mmol). The reaction mixture
was refluxed under argon until TLC analysis showed complete
consumption of the starting material. The reaction mixture was
cooled to 0 °C and quenched by the dropwise addition of MeOH.
The mixture was filtered through a pad of Celite and rinsed with
EtOAc (3×). The layers were separated and the aqueous fraction
was extracted with EtOAc (3×). The combined organic fractions
were washed with 10% aqueous HCl (1×), NaHCO3 (1×), and
brine (1×) and dried with MgSO4. The solution was concentrated
to afford 2.42 g (98%) of the title compound as a white solid
ν
max 3049, 2977, 2936, 2874, 1371, 1266, 1175, 1130 cm-1; HRMS
calcd for C25H27NO4S 437.1661, exptl 437.1653.
Methanesulfonic Acid 4-Ethyl-6-methanesulfonyloxymethyl-
1-(toluene-4-sulfonyl)-1,6,7,8-tetrahydro-1-aza-as-indacen-8-yl
Methyl Ester (29). Acetonide 27 (320 mg, 0.730 mmol) was
suspended in 25 mL of concentrated HCl/MeOH (1:3) and brought
to reflux for 18 h. The solution was cooled to room temperature,
neutralized with 1 N KOH, and extracted with EtOAc (3×). The
combined organic fractions were washed with brine (1×), dried
with MgSO4, and concentrated to afford 261 mg (90%) of glycol
28 requiring no further purification. The glycol (261 mg, 0.660
mmol) was dissolved in 15 mL of THF/H2O (3:2) and NaIO4 (988
mg, 4.62 mmol) was added. When complete by TLC analysis, the
mixture was diluted with 25 mL of THF and cooled to 0 °C. NaBH4
(375 mg, 9.90 mmol) was added and the reaction mixture was stirred
1
requiring no further purification. Mp 218-220 °C (d); H NMR
(600 MHz, CDCl3) δ 7.65 (d, J ) 3.6 Hz, 1H), 7.62 (d, J ) 8.4
Hz, 2H), 7.25 (d, J ) 8.4 Hz, 2H), 6.64 (d, J ) 3.6 Hz, 1H), 4.81
(br s, 1H), 4.13 (br s, 1H), 4.09 (d, J ) 5.4 Hz, 1H), 3.55 (d, J )
5.4 Hz, 1H), 3.41 (br s, 1H), 2.83-2.72 (m, 2H), 2.36 (s, 3H),
1410 J. Org. Chem., Vol. 72, No. 4, 2007