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M. S. Morales-Rıos et al. / Tetrahedron: Asymmetry 16 (2005) 2493–2499
2496
4.2. Synthesis of racemic debromoflustramine B, 1
116.5 (C15), 108.7 (C7), 49.5 (C3), 40.0 (C8), 38.2
(C9), 36.2 (C14), 25.9 (Me17), 25.7 (Me12), 18.2
(Me13), 18.0 (Me18). EIMS m/z (relative intensity) 327
(M+, 18), 259 (93), 213 (15), 203 (100), 158 (26). HRMS
m/e 327.1842 (M+, C20H25NO3 requires 327.1834).
4.2.1. Methyl 2-[1,3-bis(3-methylbut-2-enyl)-2-oxo-2,3-
dihydro-1H-indol-3-yl]acetate, ( )-3. To a precooled
(ꢀ5 ꢁC) solution of ( )-25 (500 mg, 2.44 mmol) in CH2Cl2
(10 mL) were added 15% aq NaOH (5 mL, 18.7 mmol),
tetrabutylammonium hydrogensulfate (TBAHS, 28 mg,
0.08 mmol), and 4-bromo-2-methyl-2-butene (0.61 mL,
5.1 mmol). The resulting mixture was stirred for 5 h, the
organic layer separated and the aqueous phase extracted
with CH2Cl2 (3 · 25 mL). The combined organic phases
were washed with brine (3 · 30 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash chromatography
on silica gel (4:1 hexane–EtOAc) to afford ( )-3 (632 mg,
76%) as a colorless oil. Rf 0.48 (7:3 hexane–EtOAc). IR
4.2.3. 2-[1,3-Bis(3-methylbut-2-enyl)-2-oxo-2,3-dihydro-
1H-indol-3-yl]acetamide, ( )-5. To a precooled (0 ꢁC)
stirred solution of ( )-4 (700 mg, 2.14 mmol) and Et3N
(203 mg, 2.1 mmol) in dry THF (50 mL) was added drop-
wise ClCOOEt (238 mg, 2.2 mmol) and the resulting
reaction mixture stirred for an additional 1 h while cool-
ing was continued. After cooling at ꢀ60 ꢁC, 40% aq
MeNH2 (1.54 mL, 6.1 mmol) was added dropwise and
stirring continued at the same temperature for 1 h. The
mixture was allowed to warm to room temperature,
extracted with EtOAc (3 · 30 mL), and the combined
organic phases washed with brine (2 · 15 mL), dried over
anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash chro-
matography on silica gel (1:9 hexane–EtOAc) to afford
( )-5 (714 mg, 98%) as a colorless solid: mp 92–93 ꢁC.
Rf 0.12 (1:1 hexane–EtOAc). IR (CHCl3, cmꢀ1): 3462,
1
(CHCl3, cmꢀ1): 3014, 2916, 1736, 1708, 1612. H NMR
(CDCl3): d 7.22 (1H, td, J = 7.7, 1.2 Hz, H6), 7.16 (1H,
br d, J = 7.7 Hz, H4), 6.99 (1H, td, J = 7.5, 1.2 Hz, H5),
6.78 (1H, br d, J = 7.5 Hz, H7), 5.14 (1H, t hept.,
J = 6.5, 1.4 Hz, H10), 4.83 (1H, t hept., J = 8.3, 1.5 Hz,
H15), 4.44 (1H, dd, J = 15.6, 6.6 Hz, H9), 4.25 (1H, dd,
J = 15.6, 6.6 Hz, H90), 3.41 (3H, s, CO2Me), 3.02 (1H,
d, J = 16.2 Hz, H8), 2.89 (1H, d, J = 16.2 Hz, H80), 2.47
(1H, dd, J = 13.9, 7.8 Hz, H14), 2.40 (1H, dd, J = 13.9,
7.8 Hz, H140), 1.81 (3H, s, Me13), 1.71 (3H, s, Me12),
1.57 (3H, s, Me17), 1.46 (3H, s, Me18). 13C NMR
(CDCl3): d 178.5 (C2), 170.2 (CO2Me), 143.3 (C7a),
135.9 (C16), 135.8 (C11), 131.0 (3a), 127.8 (C6), 122.7
(C4), 121.7 (C5), 118.7 (C10), 116.9 (C15), 108.3 (C7),
51.5 (CO2Me), 49.7 (C3), 39.9 (C8), 38.1 (C9), 36.5
(C14), 25.9 (Me17), 25.7 (Me12), 18.2 (Me13), 18.0
(Me18). EIMS m/z (relative intensity) 341 (M+, 34), 273
(100), 217 (93), 145 (37). HRMS m/e 341.1975 (M+,
C21H27NO3 requires 341.1990).
1
3306, 3016, 1694, 1612. H NMR (CDCl3): d 7.22 (1H,
br d, J = 7.7 Hz, H4), 7.21 (1H, td, J = 7.7, 1.1 Hz,
H6), 7.02 (1H, td, J = 7.9, 1.1 Hz, H5), 6.76 (1H, br d,
J = 7.7 Hz, H7), 6.45 (1H, br, NH), 5.06 (1H, t hept.,
J = 6.6, 1.4 Hz, H10), 4.74 (1H, t hept., J = 7.7, 1.4 Hz,
H15), 4.39 (1H, dd, J = 15.4, 6.3 Hz, H9), 4.21 (1H, dd,
J = 15.6, 6.8 Hz, H90), 2.79 (1H, d, J = 14.6 Hz, H8),
2.66 (1H, d, J = 14.6 Hz, H80), 2.64 (3H, d, J = 4.7 Hz,
NMe), 2.50 (2H, d, J = 7.7 Hz, H14, H140), 1.81 (3H, s,
Me13), 1.70 (3H, s, Me12), 1.53 (3H, s, Me17), 1.43
(3H, s, Me18). 13C NMR (CDCl3): d 179.6 (C2), 169.8
(CONH), 142.7 (C7a), 136.5 (C11), 136.1 (C16), 131.7
(3a), 128.2 (C6), 123.5 (C4), 122.6 (C5), 118.7 (C10),
117.2 (C15), 108.8 (C7), 51.0 (C3), 42.8 (C8), 38.4 (C9),
36.3 (C14), 26.5 (NMe), 26.2 (Me17), 26.0 (Me12), 18.5
(Me13), 18.3 (Me18). EIMS m/z (relative intensity) 340
(M+, 18), 268 (100), 212 (76), 158 (65). HRMS m/e
340.2157 (M+, C21H27NO3 requires 340.2151).
4.2.2. 2-[1,3-Bis(3-methylbut-2-enyl)-2-oxo-2,3-dihydro-
1H-indol-3-yl]acetic acid, ( )-4. A precooled (0 ꢁC)
solution of ( )-3 (700 mg, 2.04 mmol) in MeOH
(8 mL) was treated with 15% aq NaOH (2.1 mL) and
the resulting solution stirred for 1.5 h at 40–50 ꢁC. The
reaction mixture was cooled in an ice/water bath prior
to quenching by the addition of 1 M HCl until pH ca.
1, followed by extraction with EtOAc (2 · 30 mL). The
combined organic phases were washed with brine
(2 · 20 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (19:1
CH2Cl2–MeOH) to afford ( )-4 (583 mg, 87%) as a col-
orless oil. Rf 0.47 (19:1 CH2Cl2–MeOH). IR (CHCl3,
4.2.4. 1-Methyl-3a,8-bis(3-methyl-2-buten-1-yl)-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole, ( )-1. To a precooled
(0 ꢁC) stirred suspension of LiAlH4 (0.88 mmol) in dry
THF (10 mL) was added ( )-5 (100 mg, 0.29 mmol) in
dry THF (10 mL), and the mixture was heated at reflux
for 5 h. After cooling the solution in an ice/water bath,
the reaction was quenched by adding, in sequence,
EtOAc (10 mL) and water (10 mL). The solids were
removed by filtration and washed with EtOAc
(2 · 15 mL). The combined organic phases were washed
with brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc)
1
cmꢀ1): 3508, 3014, 2730, 1712, 1648, 1612. H NMR
(CDCl3): d 9.40 (1H, very br, CO2H), 7.22 (1H, td,
J = 7.7 Hz, 1.2 Hz, H6), 7.14 (1H, br d, J = 7.7 Hz,
H4), 7.00 (1H, td, J = 7.5, 1.2 Hz, H5), 6.76 (1H, br d,
J = 7.5 Hz, H7), 5.05 (1H, tm, J = 6.5 Hz, H10), 4.75
(1H, tm, J = 8.3 Hz, H15), 4.38 (1H, dd, J = 15.6,
6.6 Hz, H9), 4.20 (1H, dd, J = 15.6, 6.6 Hz, H90), 2.98
(1H, d, J = 16.5 Hz, H8), 2.81 (1H, d, J = 16.5 Hz,
H80), 2.44 (2H, d, J = 7.7 Hz, H14, H140), 1.80 (3H, s,
Me13), 1.69 (3H, s, Me12), 1.54 (3H, s, Me17), 1.43
(3H, s, Me18). 13C NMR (CDCl3): d 179.0 (C2), 174.0
(CO2H), 142.8 (C7a), 136.2 (C16), 136.1 (C11), 130.8
(3a), 128.0 (C6), 122.7 (C4), 122.2 (C5), 118.3 (C10),
1
to afford ( )-1 (57 mg, 59%) as a colorless oil. The H
and 13C NMR, IR, and MS data are identical to those
described.1,2e
4.2.5. 3a,8-Bis(3-methyl-2-buten-1-yl)-2-oxo-2,3,3a,8a-
tetrahydro-8H-furo[2,3-b]indole, ( )-6. To a precooled
(0 ꢁC) solution of ( )-4 (1.7 g, 5.19 mmol) in dry THF
(20 mL) was added NaH (0.15 g, 6.25 mmol), and the