Journal of Natural Products
Note
h). The mixture was cooled to rt and quenched with H2O (22 mL).
The product was extracted with EtOAc (3 × 20 mL), and the
combined organic extracts were dried over anhydrous K2CO3. After
filtration and evaporation of the solvent, crude 15 was purified by flash
chromatography (eluent: n-hexane−EtOAc, 2:1, + 1% Et3N; Rf = 0.40)
to afford intermediate 15, which was immediately used in the
acetylation step: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.63
(s, 1H), 7.52−7.47 (m, 3H), 7.42−7.38 (m, 2H), 7.35−7.33 (m, 1H),
7.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.14 (s, 2H), 4.03 (s, 3H), 1.66 (s, 6H).
A solution of enynyl alcohol 15 (1.62 mmol) in anhydrous
dichloromethane (DCM) (16.2 mL) was cooled to 0 °C (ice bath),
and 4-(dimethylamino)pyridine (DMAP) (30 mg, 0.24 mmol), Et3N
(1.13 mL, 8.1 mmol), and Ac2O (605 μL, 4.9 mmol) were added. After
10 min, the ice bath was removed and the reaction mixture was stirred
at 25 °C for 15 h, quenched by addition of a saturated solution of
NaHCO3 (15 mL). After separation of the phases, the aqueous layer
was extracted with DCM (2 × 15 mL) and the combined organic
extracts were dried over anhydrous K2CO3. After filtration and
evaporation of the solvent, crude 16 was obtained and purified by flash
column chromatography (eluent: n-hexane−EtOAc, 7:1, + 1% Et3N;
Rf = 0.24), affording pure acetate 16 (591 mg, 90% over two steps) as
a colorless oil. This was stored at 4 °C as a 0.1 M solution in the eluent
until use: 1H NMR (400 MHz, CDCl3) δ 7.81 (br s, 1H), 7.66 (s, 1H),
7.54 (d, J = 8.4 Hz, 1H), 7.49−7.46 (m, 2H), 7.42−7.37 (m, 2H),
7.36−7.31 (m, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.13 (s, 2H), 4.02
(s, 3H), 2.07 (s, 3H), 1.79 (s, 6H); 13C NMR (100.4 MHz, CDCl3) δ
169.3 (s), 157.7 (s), 150.9 (s), 136.9 (s), 135.5 (s), 128.5 (d, 2 C),
128.0 (d), 127.6 (d, 2 C), 127.3 (d), 124.5 (s), 120.7 (d), 113.3 (d),
103.6 (d), 100.6 (s), 94.0 (s), 75.8 (s), 72.5 (s), 70.5 (t), 54.0 (q), 29.2
(q, 2 C), 22.0 (q); MS (ESI) m/z 428 [M + Na]+ (8), 346 [M −
CO2Me]+ (100).
Methyl 6-Benzyloxy-3,3-dimethyl-1-oxo-2,3-dihydro-1H-
cyclopenta[b]indole-4-carboxylate (17). The solution of 16 in
the eluent was concentrated and dried under vacuum (no heating) for
30 min. Gold(I) complex (4-CF3C6H4)3PAuCl (31 mg, 44 μmol) was
dissolved in DCM (8.8 mL, 0.005 M), and AgSbF6 (15 mg, 44 μmol)
was added. The suspension was left to stir at 25 °C under a nitrogen
atmosphere. After 15 min a solution of enynyl acetate 16 (591 mg,
1.46 mmol) in DCM (20.2 mL; final concentration 0.05 M) was
added, and the reaction mixture was stirred at 25 °C for 50 min. Water
(50 mL) was added, the phases were separated, and the product was
extracted with DCM (2 × 25 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered, and concentrated. The
oily residue was purified by flash chromatography (eluent: n-hexane−
EtOAc, 4:1; Rf = 0.22), affording pure compound 17 (435 mg, 82%) as
an orange solid: mp = 115.3−116.5 °C; 1H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.49−7.45 (m,
2H), 7.42−7.38 (m, 2H), 7.36−7.31 (m, 1H), 7.03 (dd, J = 8.4, 2.4
Hz, 1H), 5.14 (s, 2H), 4.10 (s, 3H), 2.90 (s, 2H), 1.60 (s, 6H); 13C
NMR (100.4 MHz, CDCl3) δ 196.0 (s), 171.5 (s), 157.6 (s), 150.8
(s), 141.9 (s), 136.8 (s), 128.6 (d, 2 C), 128.0 (d), 127.5 (d, 2 C),
124.8 (s), 121.2 (d), 115.7 (s), 113.2 (d), 103.0 (d), 70.6 (t), 59.2 (s),
54.1 (q), 39.8 (t), 26.8 (q, 2 C); MS (ESI) m/z 749 [2M + Na]+
(100), 364 [M + H]+ (52); anal. C 72.67, H 5.72, N 3.54%, calcd for
C22H21NO4, C 72.71, H 5.82, N 3.85%.
line I in sufficient quantities for its further evaluation in various
biological tests.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
recorded on a Buchi melting point B540 apparatus and are
̈
uncorrected. Optical rotations were determined with a JASCO DIP-
370 instrument. 1H NMR and 13C NMR spectra were recorded at 400
and 100.4 MHz, respectively, in the specified deuterated solvent.
Solvent reference lines were set at 7.26 and 77.00 (CDCl3), 2.05 and
29.84 (acetone-d6), and 3.31 and 49.00 (methanol-d4), in H and 13C
1
NMR spectra, respectively. Mass spectra were carried out by direct
inlet of a 20 ppm solution in CH3OH on an LCQ Fleet Ion Trap LC/
MS system with an ESI interface in the positive mode, unless
otherwise stated. Microanalyses were carried out with a CHN
elemental analyzer. Chromatographic separations were performed
under pressure on silica gel by flash-column techniques; Rf values refer
to thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates (Merck F254), with the same eluent as indicated for the column
chromatography. HPLC analyses were carried out with an HPLC
instrument equipped with a Lux 5 μm cellulose-4 column, 250 × 4.60
mm, and eluting at a 0.3 mL/min flow rate in isocratic 15% isopropyl
alcohol and 85% n-hexane. 6-[(Triisopropylsilyl)oxy]indole14 (10)
and 6-benzyloxyindole13 (11) were prepared as reported. Enynyl
acetate 16 proved to be quite unstable when neat, and elemental
analysis could not be performed.
Methyl 6-Benzyloxy-3-iodo-1H-indole-1-carboxylate (14).
Crushed KOH (205 mg, 3.7 mmol) was added to a solution of 6-
benzyloxyindole (11) (327 mg, 1.46 mmol) in anhydrous DMF (1.7
mL), and the resulting suspension was stirred at room temperature for
20 min. A solution of I2 (372 mg, 1.46 mmol) in anhydrous DMF (1.7
mL) was added dropwise, and after 1 h the reaction mixture was
poured into ice H2O (34 mL) containing NH4OH (0.5%) and K2S2O5
(0.1%). A precipitate immediately formed, and this was collected by
filtration, washed with chilled water (30 mL), and dried under reduced
pressure. The 3-iodo-6-benzyloxy-1H-indole (13) (455 mg, 89%) was
1
immediately used in the next step: H NMR (400 MHz, CDCl3) δ
8.19 (br s, 1H), 7.48−7.42 (m, 2H), 7.42−7.36 (m, 2H), 7.35−7.31
(m, 2H), 7.17 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 6.92
(d, J = 2.0 Hz, 1H), 5.12 (s, 2H).
3-Iodo-6-benzyloxy-1H-indole (13) (450 mg, 1.29 mmol) was
dissolved in anhydrous THF (8.6 mL), and after cooling at −78 °C
LiHMDS 1.0 M in THF (1.35 mL, 1.35 mmol) was slowly added,
keeping the temperature below −70 °C. After 15 min, methyl
chloroformate (105 μL, 1.35 mmol) was slowly added, and after a
further 15 min the cooling bath was removed and the reaction mixture
was stirred at room temperature until complete consumption of the
starting material (2 h). A 0.5 M aqueous solution of NaHCO3 (15
mL) was added under vigorous stirring, and the product extracted with
EtOAc (3 × 15 mL). The combined organic extracts were dried over
anhydrous Na2SO4. After filtration and evaporation of the solvent,
crude 14 was isolated and purified by flash chromatography (eluent: n-
hexane−EtOAc, 12:1; Rf = 0.26), affording pure 14 as a white solid
1
(664 mg, 79%): mp = 94.1−94.8 °C; H NMR (400 MHz, CDCl3) δ
Methyl 6-Benzyloxy-3,3-dimethyl-1,2-dioxo-2,3-dihydro-1H-
cyclopenta[b]indole-4-carboxylate (18). Compound 17 (420 mg,
1.16 mmol) was dissolved in 1,4-dioxane (13 mL), and SeO2 (513 mg,
4.6 mmol) was added in one portion. The mixture was heated at 100
°C for 17 h; after cooling to room temperature, H2O (220 mL) was
added and the product extracted with EtOAc (3 × 75 mL). The
combined organic extracts were dried over anhydrous Na2SO4, filtered,
and concentrated. Purification of the crude by flash chromatography
(n-hexane−EtOAc, 4:1; Rf = 0.17) afforded pure 18 (236 mg, 64%) as
a yellow solid: mp = 173.7−174.7 °C; 1H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.49−7.46 (m, 2H),
7.43−7.38 (m, 2H), 7.37−7.33 (m, 1H), 7.11 (dd, J = 8.4, 2.0 Hz,
1H), 5.17 (s, 2H), 4.17 (s, 3H), 1.59 (s, 6H); 13C NMR (100.4 MHz,
CDCl3) δ 204.7 (s), 177.7 (s), 169.7 (s), 158.9 (s), 150.1 (s), 139.8
(s), 136.4 (s), 128.6 (d, 2 C), 128.2 (d), 127.5 (d, 2 C), 127.4 (s),
7.83 (br s, 1H), 7.62 (s, 1H), 7.51−7.46 (m, 2H), 7.44−7.37 (m, 2H),
7.37−7.31 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.4 Hz,
1H), 5.15 (s, 2H), 4.02 (s, 3H); 13C NMR (100.4 MHz, CDCl3) δ
157.9 (s), 150.5 (s), 136.8 (s), 135.5 (s), 128.6 (d, 2 C), 128.4 (d),
128.0 (d), 127.6 (d, 2 C), 126.0 (s), 122.1 (d), 113.4 (d), 100.2 (d),
70.5 (t), 66.2 (s), 54.0 (q); MS/MS (ESI) m/z 408 [M + H]+ (6), 281
[M + H − I]+ (100); anal. C 50.35, H 3.50, N 3.54%, calcd for
C17H14INO2, C 50.14, H 3.47, N 3.44%.
Methyl 3-(3-Acetoxy-3-methylbut-1-ynyl)-6-benzyloxyin-
dole-1-carboxylate (16). A 5:1 (v/v) solution of Et3N−DMF (7.2
mL) was added to a round-bottom flask containing compound 14
(660 mg, 1.62 mmol), (Ph3P)2PdCl2 (57 mg, 0.081 mmol), and CuI
(9 mg, 0.049 mmol). Neat 2-methyl-3-butyn-2-ol (190 μL, 1.94 mmol)
was added, and the reaction mixture heated at 40 °C under vigorous
stirring until complete consumption of the starting material (TLC; 1
C
J. Nat. Prod. XXXX, XXX, XXX−XXX