N-p-Toluenesulfonyl-2-octadecyl-3-methylene-2,3-dihydroin-
dole (8). To a cooled (-78 °C) solution of 14 (106 mg, 0.30 mmol)
in THF (3.0 mL) was slowly dropped C14H29MgBr (0.5 M, THF
solution, 1.80 mL, 0.90 mmol). The mixture was stirred at 0 °C
for 20 min, and the reaction was quenched by saturated aqueous
NH4Cl. The organic compounds were extracted with AcOEt, and
the combined organic layers were washed with brine and dried over
Na2SO4. After removal of the solvent, the residue was subjected to
column chromatography (n-hexane/AcOEt ) 6:1) to give the
alcohol (153 mg, 93%) as a colorless oil.
To a solution of alcohol (209 mg, 0.38 mmol), DMAP (46.1
mg, 0.38 mmol), and Et3N (0.26 mL, 1.89 mmol) in CH2Cl2 (9.0
mL) was added methanesulfonyl chloride (0.09 mL, 1.13 mmol)
dropwise, and the mixture was stirred for 30 min at room
temperature. After addition of saturated aqueous NH4Cl, the organic
compounds were extracted with CH2Cl2. The combined organic
layers were washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was subjected to column
chromatography (n-hexane/AcOEt ) 5:1) to give the mesylate (204
mg, 86%) as a colorless oil.
to give 16b, which could be purified by recrystallization from
n-hexane/AcOEt. Although the crystals of 16b were not suitable
for X-ray analysis, other spectra including 2D-NMR spectra
(1H-1H COSY, HMBC, and HMQC) unambiguously confirmed
the structure of 16b. Oxindole 17 was synthesized by the
procedures reported by Overman and co-workers.11 However,
the spectral data of both 16b and 17 were also not consistent
with the reported data of fistulosin (Table in Supporting
Information). Further investigations are necessary to elucidate
the structure of fistulosin.
In conclusion, we have achieved the first synthesis of the
reported structure of fistulosin featuring our ruthenium-catalyzed
cycloisomerization of diene. Further applications of our meth-
odology to the syntheses of pharmacologically active products
are currently in progress.
Experimental Section
N-p-Toluenesulfonyl-2-(3-methoxycarbonylpropyl)-3-methyl-
ene-2,3-dihydroindole (13). To a stirred solution of 12 (262 mg,
0.68 mmol) and vinyloxytrimethylsilane 3 (79.0 mg, 0.68 mmol)
in xylene (54.4 mL) was added ruthenium carbene catalyst B (57.7
mg, 0.068 mmol) under an Ar atmosphere, and the mixture was
refluxed for 2 h. After the removal of solvent, the residue was
purified by column chromatography (n-hexane/Et2O ) 5:1) to give
13 (229 mg, 87%) as a colorless prism. Mp 140-141 °C (n-hexane/
AcOEt); 1H NMR δ 7.75 (d, 1H, J ) 8.1 Hz), 7.52 (d, 2H, J ) 8.4
Hz), 7.26-7.31 (m, 2H), 7.14 (d, 2H, J ) 8.6 Hz), 7.05 (dd, 1H,
J ) 7.7, 7.7 Hz), 5.37 (d,1H, J ) 2.6 Hz), 4.88 (d, 1H, J ) 2.0
Hz), 4.60-4.63 (m, 1H), 3.63 (s, 3H), 2.25-2.44 (m, 2H), 2.33 (s,
3H), 2.09-2.17 (m, 1H), 1.71-1.86 (m, 2H), 1.61-1.68 (m, 1H);
13C NMR δ 173.8, 144.6, 144.0, 143.8, 134.1, 130.1, 130.0, 129.5,
127.2, 124.5, 120.9, 117.0, 103.0, 66.1, 51.5, 36.4, 33.8, 21.5, 18.6;
IR (neat) cm-1 2947, 1732, 1460, 1352, 1163, 662; LRMS (EI)
m/z 385 (M+, 41%), 230 (100%, base peak); HRMS (FAB) calcd
for C21H24NO4S (M+ + H) 386.1426, found 386.1420. Anal. Calcd
for C21H23NO4S: C 65.43 H 6.01 N 3.63. Found: C 65.48 H 6.09
N 3.62.
4-(N-p-Toluenesulfonyl-3-methylene-2,3-dihydroindolyl)bu-
tanal (14). To a cooled (-78 °C) solution of 13 (159 mg, 0.41
mmol) in toluene (25.0 mL) under Ar atmosphere was added
DIBAL (1.01 M, toluene solution, 0.49 mL, 0.49 mmol). The
mixture was stirred at -78 °C for 20 min, and the reaction was
quenched by the addition of MeOH and saturated aqueous Roch-
elle’s salt. Then the solution was allowed to stir at room temperature
until separation of organic and water layers. The mixture was
extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. After removal of the
solvent, the residue was subjected to column chromatography (n-
hexane/AcOEt ) 4:1) to give 14 (126 mg, 87%) as a colorless oil.
1H NMR δ 9.72 (t, 1H, J ) 1.5 Hz), 7.75 (d, 1H, J ) 8.1 Hz),
7.52 (d, 2H, J ) 8.3 Hz), 7.26-7.31 (m, 2H), 7.14 (d, 2H, J ) 8.5
Hz), 7.05 (dd, 1H, J ) 7.6, 7.6 Hz), 5.38 (d, 1H, J ) 2.4 Hz), 4.89
(d, 1H, J ) 2.0 Hz), 4.60-4.62 (m, 1H), 2.40-2.48 (m, 2H), 2.33
(s, 3H), 2.10-2.16 (m, 1H), 1.75-1.85 (m, 2H), 1.60-1.70 (m,
1H); 13C NMR δ 202.4, 144.6, 144.1, 143.8, 134.0, 130.13, 130.10,
129.6, 127.2, 124.6, 120.9, 117.1, 103.0, 66.1, 43.6, 36.5, 21.5,
15.8; IR (neat) cm-1 1720, 1460, 1351, 1163, 661; LRMS (EI)
m/z 355 (M+, 36%), 200 (100%, base peak); HRMS (FAB) calcd
for C20H22NO3S (M+ + H) 356.1320, found 356.1309.
To a solution of mesylate (104 mg, 0.17 mmol) in HMPA (2.2
mL) was added NaBH4 (24.9 mg, 0.66 mmol), and the mixture
was stirred at 50 °C for 2 h. After addition of saturated aqueous
NaHCO3, the organic compounds were extracted with AcOEt. The
combined organic layers were washed with brine and dried over
Na2SO4. After removal of the solvent, the residue was subjected to
column chromatography (n-hexane/AcOEt ) 40:1) to give 8 (62.6
mg, 71%) as a colorless oil. 1H NMR δ 7.74 (d, 1H, J ) 8.1 Hz),
7.53 (d, 2H, J ) 8.1 Hz), 7.29 (d, 1H, J ) 7.1 Hz), 7.27 (dd, 1H,
J ) 7.5, 7.5 Hz), 7.13 (d, 2H, J ) 8.2 Hz), 7.04 (dd, 1H, J ) 7.5,
7.5 Hz), 5.34 (d, 1H, J ) 2.4 Hz), 4.85 (d, 1H, J ) 1.8 Hz), 4.60-
4.62 (m, 1H), 2.32 (s, 3H), 2.03-2.09 (m, 1H), 1.73-1.79 (m,
1H), 1.22-1.43 (m, 32H), 0.88 (t, 3H, J ) 6.4 Hz); 13C NMR δ
145.2, 144.0, 143.8, 134.4, 130.3, 129.9, 129.5, 127.1, 124.4, 120.7,
117.0, 102.6, 66.7, 37.2, 31.9, 29.4-29.7 (m), 22.8, 22.7, 21.5,
14.1; IR (neat) cm-1 2920, 2850, 1457, 1353, 1167; LRMS (EI)
m/z 537 (M+, 100%, base peak), 382 (44%); HRMS (FAB) calcd
for C34H52NO2S (M+ + H) 538.3719, found 538.3732.
N-p-Toluenesulfonyl-2-octadecyl-3-indolinone (15). To a cooled
(-78 °C) solution of 8 (137 mg, 0.25 mmol) in CH2Cl2 (25.0 mL)
was bubbled O3 gas until the color of the solution turned to blue.
After the addition of PPh3 (200 mg, 0.76 mmol), the mixture was
stirred at room temperature for 2 h. The solvent was removed under
reduced pressure, and the residue was subjected to column
chromatography (n-hexane/AcOEt ) 30:1 to 8:1) to give 15 (94.0
1
mg, 70%) as a red oil. H NMR δ 8.08 (d, 1H, J ) 8.3 Hz), 7.67
(ddd, 1H, J ) 7.3, 7.3, 1.5 Hz), 7.61 (d, 2H, J ) 8.5 Hz), 7.61 (d,
1H, J ) 8.5 Hz), 7.20 (d, 2H, J ) 8.1 Hz), 7.19 (ddd, 1H, J ) 7.1,
7.1, 0.7 Hz), 3.98 (dd, 1H, J ) 6.1, 3.7 Hz), 2.35 (s, 3H), 2.08-
2.27 (m, 2H), 1.06-1.44 (m, 32H), 0.88 (t, 3H, J ) 6.6 Hz); 13C
NMR δ 198.8, 153.5, 144.9, 137.1, 133.5, 129.9, 127.2, 125.2,
124.5, 124.2, 117.1, 67.4, 32.0, 31.9, 29.3-29.7 (m), 23.0, 22.7,
21.5, 14.1; IR (neat) cm-1 2915, 2848, 1733, 1604, 1355, 1151;
LRMS (EI) m/z 539 (M+, 12%), 433 (42%), 91 (100%, base peak);
HRMS (FAB) calcd for C33H50NO3S (M+ + H) 540.3511, found
540.3535.
2-Octadecyl-3-indolinone (16a). A mixture of 15 (90.0 mg, 0.17
mmol) and concentrated H2SO4 (2.0 mL) was stirred at 0 °C for
1.5 h. To the solution was slowly poured cooled water at 0 °C, and
the aqueous layer was neutralized with saturated aqueous NaHCO3.
The organic compounds were extracted with AcOEt, and the
combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo
to give 16a (66.0 mg, 100%) as an orange solid. Mp 100-102 °C;
1H NMR δ 7.61 (d, 1H, J ) 7.9 Hz), 7.44 (dd, 1H, J ) 8.2, 7.1
Hz), 6.88 (d, 1H, J ) 8.6 Hz), 6.82 (dd, 1H, J ) 7.3, 7.3 Hz), 4.70
(brs, 1H), 3.75 (dd, 1H, J ) 8.4, 4.2 Hz), 1.83-1.96 (m, 1H), 1.55-
1.64 (m, 1H), 1.25-1.40 (m, 32H), 0.88 (t, 3H, J ) 6.8 Hz); 13C
(10) For 3-hydroxyindoles, see: (a) Capon, B.; Kwok, F.-C. J. Am. Chem.
Soc. 1989, 111, 5346-5356. (b) Hickman, Z. L.; Sturino, C. F.; Lachance,
N. Tetrahedron Lett. 2000, 41, 8217-8220. (c) Kirby, G. W.; Shah, S. W.
Chem. Commun. 1965, 381.
(11) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043-14053.
J. Org. Chem, Vol. 71, No. 3, 2006 1271