A R T I C L E S
Kinsman and Kerr
pulped at RT for 1 h and then filtered. The cake was washed with
EtOH/water (1:1, 200 mL) and then with EtOH (2 × 100 mL) and
dried on the filter overnight to afford the crude acid 8 (72.90 g, 86%).
A slurry of the crude acid in EtOH (500 mL, anhydrous) and H2SO4
(4.5 mL) was refluxed with a Dean-Stark trap attached for 24 h. The
mixture was allowed to cool to RT over 24 h, then cooled to 5-10 °C,
and filtered, and the product was washed with EtOH (5-10 °C, 2 ×
70 mL) to afford 9 (75.65 g, 96%) as an off-white solid: mp 144-146
exo by HPLC) as a yellow gum: mp (racemate) 192-194 °C (CH2-
Cl2/hexanes). 1H NMR: δ 9.38 (d, J ) 4.3, 1H), 7.94 (d, J ) 8.2, 1H),
7.71 (d, J ) 8.4, 2H), 7.47 (d, J ) 7.8, 1H), 7.43 (s, 1H), 7.29 (t, J )
8.2, 7.2, 1H), 7.22 (obscured t, 1H), 7.19 (d, J ) 8.4, 2H), 5.61 (s,
1H), 3.18 (br d, J ) 6.1, 1H), 2.52 (br s, 1H), 2.49 (dd, J ) 6.1, 4.3,
1H), 2.31 (s, 3H), 1.93 (d, J ) 1.4, 3H), 1.53 (m, 2H), 1.27 (s, 3H),
1.21-1.07 (m, 2H). 13C NMR: δ 203.4, 144.7, 144.2, 135.4, 134.8,
130.4, 129.7, 127.9, 126.6, 124.8, 123.2, 123.0, 122.8, 119.2, 113.8,
61.2, 40.2, 37.5, 35.8, 35.5, 23.4, 21.7, 20.3, 20.1. IR: 1718, 1448,
1369, 1175, 1135 cm-1; MS m/z (relative intensity): 433 (M+, 22),
326 (29), 170 (29), 108 (100). HRMS calcd for C26H27NO3S: 433.1712;
found: 433.1706.
1
°C (CH2Cl2/hexanes). H NMR (300 MHz): δ 7.98 (d, J ) 7.6, 1H),
7.82-7.74 (m, 7H), 7.38-7.21 (m, 4H), 6.50 (d, J ) 16.1, 1H), 4.26
(q, J ) 7.1, 2H), 2.33 (s, 3H), 1.33 (t, J ) 7.1, 3H). 13C NMR (75
MHz): δ 167.0, 145.4, 135.5, 134.7, 130.0, 128.3, 128.0, 126.9, 125.4,
124.0, 120.6, 118.3, 118.1, 113.7, 60.4, 21.5, 14.3. IR: 1707, 1636,
1447, 1370, 1176 cm-1; MS m/z (relative intensity): 369 (M+, 100),
324 (15), 214 (48), 186 (63), 158 (62), 91 (91). HRMS calcd for C20H19-
NO4S: 325.0773; found: 325.0780.
Methyl (1S,2R,3R)-1,5-Dimethyl-3-(1-tosyl-1H-indol-3-yl)bicyclo-
[2.2.2]oct-5-en-2-ylcarbamate (13). To a solution of 6 (2.39 g, 5.51
mmol) in t-BuOH (85 mL) and 2-methyl-2-butene (12 mL) was slowly
added (over 30 min) a solution of NaClO2 (5.50 g, 48.7 mmol) and
NaH2PO4‚H2O (5.31 g, 38.5 mmol) in water (80 mL). After the addition
was complete, the mixture was stirred at RT for 1 h and then
concentrated. The aqueous residue was diluted with CH2Cl2 and water
and separated. Following further extraction (CH2Cl2 × 2), the combined
organic portions were washed with water and brine, dried over MgSO4,
filtered, and concentrated. Purification of the crude residue by FC
(EtOAc/hexanes, 3:7) gave the corresponding acid (2.11 g, 85%, 73%
3-(3-(N-Tosyl)indolyl)acrolein (2). To a cooled (ice-methanol bath)
slurry of ethyl 2-(3-(N-tosylindolyl)acrylate 9 (20.00 g, 54.14 mmol)
in CH2Cl2 (100 mL), DIBAL (74.23 g, 130.5 mmol, 25% w/w in
toluene) was slowly added via an addition funnel. Once the reaction
was complete, the mixture was slowly quenched with Rochelle’s Salt,
which gave a thick gel. This gel was broken down with slow addition
of 5% HCl (aq) (exothermic!), and then the mixture was diluted with
EtOAc and water and then separated. Following two additional
extractions with EtOAc, the combined organics were washed with water
and brine, dried with MgSO4, filtered, and concentrated to afford the
crude allylic alcohol 10 as an off-white solid (18.49 g, >95%), which
was used directly in the next step. To a solution of 10 in CH2Cl2 (200
mL, reagent grade) at 0 °C was added Dess-Martin periodinane22
(25.05 g, 59.08 mmol) portionwise over 10 min. The reaction mixture
was stirred at 0 °C for 30 min and another 30 min at RT, then re-
cooled to 0 °C, and 100 mL of 15% Na2S2O3 (aq) was slowly added.
The mixture was diluted with water and CH2Cl2 and separated. The
aqueous portion was treated with 1 M NaOH (aq) and extracted again
with CH2Cl2. The combined organic portions were washed with water,
NaHCO3 (sat aq), and brine, dried with MgSO4, filtered, and concen-
trated. Purification by FC followed by trituration in EtOAc/hexanes
(1:1) gave enal 2 (12.76 g, 72% over two steps): mp 150-152 °C
(hexane trit). 1H NMR: δ 9.65 (d, J ) 7.7, 1H), 7.99 (d, J ) 8.0, 1H),
7.92 (s, 1H), 7.80 (d, J ) 8.2, 2H), 7.77 (d, J ) 8.3, 1H), 7.56 (d, J )
16.0, 1H), 7.39 (ddd, J ) 8.3, 7.2, 1.0, 1H), 7.34 (ddd, J ) 8.0, 7.2,
1.2, 1H), 7.25 (d, J ) 8.2, 2H), 6.79 (dd, J ) 16.0, 7.7, 1H), 2.35 (s,
3H). 13C NMR: δ 193.4, 145.6, 143.5, 135.4, 134.3, 130.0, 129.3, 128.4,
127.4, 126.9, 125.6, 124.2, 120.5, 117.8, 113.7, 21.7. IR: 1675, 1628,
1447, 1378, 1176 cm-1. MS m/z (relative intensity): 325 (M+, 47),
170 (100), 115 (20), 91 (33). HRMS calcd for C18H15NO3S: 325.0773;
found: 325.0780.
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1
de by H NMR) as a white solid: mp 122-124 °C dec (hex trit). H
NMR: δ 7.93 (d, J ) 8.4, 1H), 7.70 (d, J ) 8.2, 2H), 7.46 (s, 1H),
7.44 (d, J ) 8.0, 1H), 7.27 (t, J ) 7.4, 1H), 7.18 (t, J ) 7.9, 1H), 7.14
(d, J ) 8.2, 2H), 5.57 (s, 1H), 3.17 (d, J ) 7.5, 1H), 2.61 (d, J ) 7.5,
1H), 2.42 (br s, 1H), 2.32 (br s, 1H), 2.25 (s, 3H), 1.91 (d, J ) 1.0,
3H), 1.52 (d, J ) 10.0, 2H), 1.24 (s, 3H), 1.15 (m, 2H). 13C NMR: δ
180.3, 144.6, 142.6, 135.5, 134.7, 130.5, 129.6, 128.8, 126.9, 124.7,
123.5, 123.0, 122.6, 119.3, 113.8, 53.4, 40.7, 40.4, 37.8, 36.5, 23.3,
21.6, 20.2, 19.6. IR: 1701, 1449, 1174 cm-1; MS m/z (relative
intensity): 449 (M+, 13), 341 (41), 108 (100). HRMS calcd for C26H27-
NO4S: 449.1661; found: 499.1659. To the above acid (2.19 g, 4.87
mmol) dissolved in toluene (20 mL) were added TEA (0.70 mL, 5.51
mmol) and diphenylphosphoryl azide (1.1 mL, 5.10 mmol). The mixture
was heated at reflux for 30 min, and then MeOH (10 mL, dried over
4 Å molecular sieves) was added and heating continued for another 30
min. The reaction was then transferred to a sealed tube (rinsing the
initial reaction flask with 5 mL of MeOH) and heated at 150 °C for 17
h. After cooling to RT, the mixture was diluted with EtOAc and
NaHCO3 (saturated aq). The layers were separated, and the aqueous
portion was extracted again with EtOAc. The combined organic portions
were washed with water and brine, dried over MgSO4, filtered, and
concentrated. Purification of the crude residue by FC (EtOAc/hexanes,
3:7) gave 13 (1.84 g, 79%, 70% de by 1H NMR) as a white solid: mp
1
140-142 °C dec (hex trit). H NMR (600 MHz, major isomer): δ
3-[(2S,3R,4R)-4,6-Dimethyl-3-formylbicyclo[2.2.2]oct-5-en-2-yl]-
1-tosyl-1H-indole (endo-6). To a solution of 2 (5.82 g, 17.9 mmol) in
DMF, MeOH, and water (38, 38, and 4 mL, respectively) was added
organocatalyst 47 (1.808 g, 7.10 mmol). After the solution was stirred
for 20 min at RT, 1,3-dimethyl-1,3-cyclohexadiene 35 (5.6 mL, ∼45%,
25.0 mmol) was added dropwise. The reaction was stirred for 36 h,
then diluted with water and MTBE and separated. The aqueous portion
was extracted again with MTBE, and the organic portions were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was treated with 5% HCl (aq) THF (1:1) for
12 h. The reaction was then diluted with MTBE and water. The aqueous
portion was extracted again with MTBE, and the organics were
combined, washed with NaHSO3 (saturated aq), water, and brine, dried
over MgSO4, filtered, and concentrated. Purification of the residue by
FC (EtOAc/hexanes, 1:9) afforded 6 as an 85:15 mixture (70% de) of
endo:exo isomers (2.39 g, 35%, 70% de, 93% ee for endo, 92% ee for
7.96 (d, J ) 8.2, 1H), 7.76 (d, J ) 7.9, 2H), 7.63 (s, 1H), 7.40 (d, J )
7.6, 1H), 7.27 (t, J ) 7.6, 1H), 7.19 (t, J ) 7.6, 1H), 7.16 (d, J ) 7.9,
2H), 5.50 (s, 1H), 4.40 (d, J ) 10.1, 1H), 3.91 (dd, J ) 10.1, 5.0, 1H),
3.57 (s, 3H), 2.56 (s, 1H), 2.41 (s, 1H), 2.29 (s, 3H), 1.89 (s, 3H), 1.54
(m, 1H), 1.43 (m, 1H), 1.23 (m, 1H), 1.17 (s, 3H), 1.02 (m, 1H). 13C
NMR (150 MHz): δ 156.7, 145.3, 144.5, 135.8, 134.9, 130.9, 129.7,
127.4, 126.9, 124.6, 123.4, 123.3, 123.0, 119.2, 114.0, 59.1, 51.8, 46.5,
40.7, 39.1, 33.2, 21.8, 21.5, 20.1, 20.1. IR: 3395, 1720, 1517, 1448,
1369, 1174 cm-1. MS m/z (relative intensity): 478 (M+, 8), 370 (100),
215 (68), 91 (12). HRMS calcd for C27H30N2O4S: 478.1926; found:
478.1921.
(1S,2S,3R,5R,6R)-1,3-Dimethyl-5-(1-tosyl-1H-indol-3-yl)-6-
[(methoxycarbonyl)amino]bicyclo[2.2.2]octane-2,3-diol (14a) and
(1S,2R,3S,5R,6R)-1,3-dimethyl-5-(1-tosyl-1H-indol-3-yl)-6-nitrobicyclo-
[2.2.2]octane-2,3-diol (14b). To a RT solution of 13 (401 mg, 0.838
mmol) in THF (15 mL) and t-BuOH (15 mL) was added a solution of
a homogenized (mortar and pestle) K3FeCN6 (0.829 g, 2.52 mmol),
K2CO3 (0.360 g, 2.53 mmol), methane sulfonamide (80 mg, 0.845
mmol) in water (25 mL), DABCO (30 mg, 0.26 mmol), and K2OsO2-
(22) Dess-Martin periodinane was prepared according to literature procedure:
Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J.; Minbiole, K. P.; Smith, A.
B. Org. Synth. 1999, 77, 141.
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14124 J. AM. CHEM. SOC. VOL. 125, NO. 46, 2003