Synthetic Studies on Dragmacidin D
H), 6.51 (d, J = 8.0 Hz, 1 H), 5.89 (ddd, J = 6.5, 1.0, 1.0 Hz, 1 H),
4.58 (dd, J = 8.3, 6.5 Hz, 1 H), 3.83 (dd, J = 8.3, 6.5 Hz, 1 H), 3.62
0.017 mmol) in THF (0.5 mL) at 0 °C. After 30 min, the mixture
was poured into saturated aqueous NaHCO3 (10 mL) and ex-
(s, 3 H), 2.38 (s, 3 H), 1.61 (s, 3 H), 1.50 (s, 3 H) ppm. 13C NMR tracted with EtOAc (15 mL). The combined organic layers were
(125 MHz, CDCl3): δ = 146.8, 144.3, 137.0, 129.6, 129.3 (ϫ2),
128.1, 127.7, 127.0 (ϫ2), 126.8, 120.2, 109.3, 107.7, 103.8, 71.6
(ϫ2), 55.4, 26.5, 25.3, 21.4 ppm. HRMS (FAB): calcd. for
C21H22BrNO5SNa [M + Na]+ 502.0294; found 502.0292.
washed with brine (10 mL), dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (0.5 g, hexane/EtOAc = 8:2) to give
vinyl bromide 36 (6.2 mg, 65%) as a colorless oil. IR (film): ν =
˜
1748, 1507, 1362, 1218, 1037, 814, 669, 578 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.69 (d, J = 7.5 Hz, 2 H),
7.28 (d, J = 7.5 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.70 (d, J =
4.5 Hz, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.99 (s, 1 H), 5.89 (s, 1 H),
4.50 (dd, J = 12.0, 2.5 Hz, 1 H), 4.35 (dd, J = 12.0, 4.5 Hz, 1 H),
3.63 (s, 3 H), 2.40 (s, 3 H), 2.14 (s, 3 H), 2.09 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 170.6, 169.9, 147.6, 144.5, 137.0,
129.4 (ϫ2), 128.4, 127.5, 127.2 (ϫ2), 126.6, 126.1, 124.7, 122.9,
116.2, 109.7, 106.3, 67.2, 65.7, 55.4, 21.6, 21.1, 20.8 ppm. HRMS
(ESI): calcd. for C24H24BrNO7SNa [M + Na]+ 572.0349; found
572.0350.
(Silylethynyl)indole 32: According to the same procedure as for the
synthesis of 24, indole 32 (120 mg, 94%) was obtained as a color-
less oil by starting from 31 (105 mg, 0.219 mmol), ethynyltriiso-
propylsilane (23; 0.262 mL, 1.11 mmol), CuI (4.2 mg, 0.022 mmol),
and [Pd(PPh ) ] (12.7 mg, 0.011 mmol). IR (film): ν = 3420, 2940,
˜
3 4
1652, 1506, 1456, 1371, 1293, 1174, 1057, 671, 575 cm–1. H NMR
1
(500 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.67 (d, J = 8.5 Hz, 2 H),
7.28 (d, J = 8.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 6.57 (d, J =
8.5 Hz, 1 H), 5.93 (dd, J = 6.5, 6.5 Hz, 1 H), 4.62 (dd, J = 8.5,
6.5 Hz, 1 H), 3.73 (dd, J = 8.5, 8.5 Hz, 1 H), 3.64 (s, 3 H), 2.37 (s,
3 H), 1.60 (s, 3 H), 1.47 (s, 3 H), 1.13 (m, 21 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 147.8, 144.3, 137.2, 131.1, 131.0, 129.3
(ϫ2), 127.1 (ϫ2), 126.2, 125.0, 120.9, 109.4, 107.5, 106.7, 105.6,
93.3, 72.1, 71.9, 55.4, 26.7, 25.8, 21.6, 18.7 (ϫ6), 11.4 (ϫ3) ppm.
HRMS (FAB): calcd. for C32H43NO5SSiNa [M + Na]+ 604.2523;
found 604.2522.
Indolylglycine 37: MgSO4 (1.31 g, 10.9 mmol), p-anisidine (1.34 g,
10.9 mmol), and ethyl glyoxylate (1.02 mL, 10.9 mmol) were added
to a stirred solution of bromoindole 9 (1.23 g, 5.44 mmol) in
CH2Cl2 (1.5 mL) at 0 °C. After stirring at room temp. for 12 h, the
mixture was filtered and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (25 g,
hexane/EtOAc = 7:3) to give indolylglycine 37 (1.94 g, 83%) as a
Ethynylindole 33: According to the same procedure as for the syn-
thesis of 25, indole 33 (82.0 mg, 94%) was obtained as a colorless
oil by starting from 32 (120 mg, 0.207 mmol) and TBAF (1 m solu-
colorless oil. IR (film): ν = 1733, 1508, 1457, 1235, 1034, 792,
˜
1
669 cm–1. H NMR (500 MHz, CDCl3): δ = 8.44 (br. s, 1 H), 7.25
tion in THF, 0.227 mL, 0.227 mmol). IR (film): ν = 3277, 2361,
˜
(s, 1 H), 7.20 (d, J = 8.5 Hz, 1 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.65
(d, J = 9.0 Hz, 2 H), 6.50 (d, J = 8.5 Hz, 1 H), 6.06 (s, 1 H), 4.24
(m, 1 H), 4.35 (br. s, 1 H), 4.13 (m, 1 H), 3.91 (s, 3 H), 3.70 (s, 3
H), 1.24 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 173.5, 152.4, 145.6, 140.7, 128.0, 124.4, 123.8, 122.7, 114.9
(ϫ2), 114.7 (ϫ2), 114.0, 104.6, 103.1, 61.4, 55.6, 55.4, 53.3,
14.0 ppm. HRMS (FAB): calcd. for C20H22BrN2O4 [M + H]+
433.0757; found 433.0760.
1653, 1558, 1506, 1372, 1287, 1173, 1047, 802, 670, 574 cm–1. 1H
NMR (500 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.69 (d, J = 8.5 Hz, 2
H), 7.29 (d, J = 8.5 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 6.59 (d, J
= 8.5 Hz, 1 H), 5.86 (ddd, J = 6.5, 6.5, 1.0 Hz, 1 H), 4.54 (dd, J =
8.5, 6.5 Hz, 1 H), 3.83 (dd, J = 8.5, 6.5 Hz, 1 H), 3.65 (s, 3 H), 3.22
(s, 1 H), 2.38 (s, 3 H), 1.61 (s, 3 H), 1.49 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 148.1, 144.3, 137.2, 130.3, 129.4 (ϫ2),
127.2 (ϫ2), 127.0, 126.5, 121.7, 120.7, 109.5, 106.6, 102.0, 79.4,
78.1, 72.3, 71.8, 55.4, 26.7, 25.8, 25.5 ppm. HRMS (FAB): calcd.
for C23H24NO5S [M + H]+ 426.1370; found 426.1361.
N-Ts-indole 38: TsCl (1.00 g, 5.28 mmol), DMAP (107 mg,
0.879 mmol), and Et3N (1.83 mL, 13.2 mmol) were added to a solu-
tion of indole 37 (1.90 g, 4.40 mmol) in toluene (10 mL) at room
temp. After stirring at 70 °C for 18 h, the mixture was poured into
water (100 mL) and EtOAc (100 mL). The organic layer was sepa-
rated, washed successively with saturated aqueous NaHCO3
(150 mL), saturated aqueous NH4Cl (150 mL), and brine (50 mL),
dried with Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (40 g,
hexane/EtOAc = 8:2) to give N-Ts-indole 38 (1.79 g, 69%) along
with unreacted 37 (427 mg, 23%). N-Ts-indole 38 was obtained as
Diacetate 35: CSA (2.5 mg, 0.011 mmol) was added to a stirred
solution of acetonide 33 (9.1 mg, 0.022 mmol) in MeOH (0.5 mL)
at room temp. After 2 h, Et3N (0.5 mL) was added, and the mixture
was concentrated under reduced pressure to give the crude diol.
The residue was dissolved in pyridine (0.5 mL), and Ac2O
(0.0031 mL, 0.033 mmol) and DMAP (0.26 mg, 0.0022 mmol) were
added successively at room temp. After 12 h, the mixture was
poured into saturated aqueous NH4Cl (10 mL) and extracted with
EtOAc (20 mL). The combined organic layers were washed with
brine (5 mL) and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (1 g, hexane/
EtOAc = 7:3) to give diacetate 35 (8.1 mg, 79% for two steps) as a
a colorless solid. IR (film): ν = 1732, 1652, 1508, 1457, 1374, 1245,
˜
1173, 991, 813, 669, 555 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.92 (s, 1 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 1 H),
7.22 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 9.0 Hz, 2 H), 6.66 (d, J =
9.0 Hz, 2 H), 6.53 (d, J = 8.5 Hz, 1 H), 6.05 (br. s, 1 H), 4.28 (m,
1 H), 4.21 (m, 1 H), 3.72 (s, 3 H), 3.63 (s, 3 H), 2.38 (s, 3 H), 1.23
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2,
152.7, 146.9, 144.5, 140.3, 136.7, 129.6, 129.4 (ϫ2), 128.6, 128.3,
127.6, 127.1 (ϫ2), 117.5, 115.2 (ϫ2), 114.7 (ϫ2), 108.0, 104.8, 61.8,
55.6, 55.6, 53.4, 21.6, 14.1 ppm. HRMS (FAB): calcd. for
C27H28BrN2O6S [M + H]+ 587.0846; found 587.0848.
colorless oil. IR (film): ν = 1748, 1558, 1507, 1364, 1220, 1173,
˜
1035, 813, 668, 578 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.93
(s, 1 H), 7.66 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.26
(d, J = 8.5 Hz, 2 H), 6.93 (dd, J = 6.5, 3.0 Hz, 1 H), 6.56 (d, J =
8.0 Hz, 1 H), 4.63 (dd, J = 12.0, 3.0 Hz, 1 H), 4.42 (dd, J = 12.0,
6.5 Hz, 1 H), 3.63 (s, 3 H), 3.25 (s, 1 H), 2.34 (s, 3 H), 2.15 (s, 3
H), 2.07 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.6,
169.8, 147.9, 144.5, 136.9, 131.1, 130.6, 129.4 (ϫ2), 127.7, 127.1
(ϫ2), 124.7, 116.8, 106.8, 106.2, 81.7, 80.3, 66.9, 65.4, 55.3, 21.6,
21.2, 20.8 ppm. HRMS (ESI): calcd. for C48H46N2O14S2Na [2 M
+ H]+ 961.2283; found 961.2298.
Amine 39: A solution of CAN (216 mg, 0.394 mmol) in water
(1.2 mL) was added to a stirred solution of (p-methoxyphenyl)-
amine 38 (115 mg, 0.197 mmol) in CH3CN (2.0 mL) and water
(0.5 mL) at –15 °C. After 15 min, aqueous Na2S2O3 (5%, 5 mL)
was added, and the mixture was poured into a vigorously stirred
Vinyl Bromide 36: HBr·AcOH (33%, 0.022 mL, 0.081 mmol) was
added to
a stirred solution of ethynylindole 35 (8.1 mg,
Eur. J. Org. Chem. 2011, 4654–4666
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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