Job/Unit: O40064
/KAP1
Date: 17-03-14 11:56:02
Pages: 8
S.-W. Hsu, H.-Y. Cheng, A.-C. Huang, T.-L. Ho, D.-R. Hou
FULL PAPER
5.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.8, 147.8,
137.1, 131.9, 129.3, 126.1, 121.5, 119.9, 117.7, 116.5, 112.0, 111.0,
60.5, 46.4, 45.1, 35.9, 27.7, 26.7, 24.7, 15.0, 11.2, 5.1 ppm. HRMS
(ESI): calcd. for C22H29N2O4 [M]+ 385.2127; found 385.2129.
1133, 1028, 735, 701, 542 cm–1. HRMS (ESI): calcd. for C19H27N2
[M + H]+ 283.2174; found 283.2180.
[7-Ethyl-4,5,6,7,8,9-hexahydro-1H-3,7-methano[1]azacycloundec-
ino[5,4-b]indol-10(2H)-yl]methanol (21): Compound 16 (80 mg,
0.217 mmol) in THF (10 mL) was added at 0 °C to a solution of
lithium aluminiumhydride (42 mg, 1.08 mmol) in THF (5 mL). Af-
ter the addition, the reaction mixture was heated to reflux for
30 min and quenched with satd. NH4Cl(aq.) (1 mL). The organic
layer was decanted and concentrated to give 21 (52.7 mg,
0.169 mmol, 77%) as a light yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H),
7.15–7.09 (dt, J = 8.4, J = 7.8 Hz, 2 H), 5.63–5.57 (m, 2 H), 3.38–
3.33 (m, 1 H), 2.89–2.78 (m, 3 H), 2.68–2.66 (m, 1 H), 2.46–2.30
(m, 2 H), 2.29–2.23 (m, 2 H), 2.20 (br., 1 H), 1.89–1.81 (m, 1 H),
1.66–1.47 (m, 3 H), 1.30–1.19 (m, 3 H), 1.17–1.10 (m, 2 H), 0.86
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.1,
135.4, 128.7, 120.7, 119.5, 117.6, 110.4, 108.4, 66.4, 56.5, 55.2, 53.0,
37.6, 34.7, 32.6, 31.9, 22.6, 22.3, 18.6, 7.8 ppm. HRMS (FAB):
calcd. for C20H29N2O [M + H]+ 313.2280; found 313.2275.
Ethyl (Z)-7-Ethyl-2-oxo-4,5,6,7-tetrahydro-1H-3,7-methano[1]aza-
cycloundecino[5,4-b]indole-10(2H)-carboxylate (20): N,N-Diiso-
propylethylamine (91 μL, 0.522 mmol) was added to a mixture of
17 (67 mg, 0.174 mmol), O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-tetra-
methyluroniumhexafluorophosphate (131 mg, 0.348 mmol), molec-
ular sieves (3 Å, 40 mg) and DMF (17 mL). The reaction mixture
was stirred at 25 °C for 48 h and treated with citric acid(aq.) (1 n,
5 mL) and ethyl acetate (10 mL). The organic layer was separated,
washed with satd. NaHCO3(aq.) (5 mL) and sat, NaCl(aq.) (5 mL),
dried with Na2SO4, filtered and concentrated. The crude product
was purified by column chromatography (SiO2, MeOH/CHCl3 1:1;
Rf 0.5) to give 20 (44.6 mg, 0.12 mmol, 70%) as a light yellow solid,
1
m.p. 145.5–150.0 °C. H NMR (300 MHz, CDCl3): δ = 8.10 (d, J
= 8.0 Hz, 1 H), 7.37–7.21 (m, 3 H), 6.57 (d, J = 12.9 Hz, 1 H), 5.44
(d, J = 12.9 Hz, 1 H), 4.61 (d, J = 12.8 Hz, 1 H), 4.45 (q, J =
7.2 Hz, 2 H), 4.26 (d, J = 13.5 Hz, 1 H), 3.93–3.76 (m, 2 H), 2.75
(d, J = 13.5 Hz, 1 H), 2.57–2.48 (dd, J = 12.8, J = 3.5 Hz, 1 H),
1.87–1.82 (m, 2 H), 1.59–1.54 (m, 1 H), 1.43 (t, J = 7.2 Hz, 3 H),
1.30–1.20 (m, 3 H), 0.78 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.6, 151.5, 137.6, 135.3, 130.7, 128.9,
124.9, 123.7, 123.0, 118.1, 115.5, 113.7, 63.1, 55.9, 43.6, 43.5, 38.1,
Kopsiyunnanine D (2):[3b] Acetyl chloride (50 μL, 0.7 mmol) was
added at 0 °C to a flask containing molecular sieves (3 Å, 100 mg)
and methanol (1.5 mL). Compound 21 (12.1 mg, 0.038 mmol) in
methanol (0.5 mL) was added to the above flask at 25 °C. The reac-
tion mixture was stirred for 16 h, concentrated, diluted with ethyl
acetate (3 mL), washed with satd. NaHCO3(aq.) (3 mL), dried with
Na2SO4, filtered and concentrated. The crude product was purified
by column chromatography (SiO2, ethyl acetate/hexanes 1:9; Rf
0.15) to give 2 (7.8 mg, 0.12 mmol, 68%) as a colourless oil. 1H
NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 6.9 Hz, 1 H), 7.38 (d,
J = 7.5 Hz, 1 H), 7.10 (dt, J = 7.5, J = 6.9 Hz, 2 H), 5.47–5.38 (m,
2 H), 3.36–3.32 (m, 1 H), 3.24 (s, 3 H), 2.89–2.80 (m, 3 H), 2.64–
2.56 (m, 1 H), 2.46–2.30 (m, 2 H), 2.44–2.22 (m, 2 H), 1.83–1.77
(m, 1 H), 1.66–1.47 (m, 3 H), 1.30–1.19 (m, 3 H), 1.17–1.10 (m, 2
H), 0.85 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 141.8, 136.8, 128.4, 120.5, 119.2, 117.4, 110.2, 108.8, 73.8, 56.5,
55.6, 55.2, 53.0, 37.5, 34.7, 32.5, 31.8, 22.6, 22.3, 18.5, 7.8 ppm.
HRMS (FAB): calcd. for C21H31N2O [M + H]+ 327.2436; found
327.2442.
34.9, 32.6, 21.1, 14.3, 7.8 ppm. IR (neat): ν = 2933, 1733, 1646,
˜
1459, 1375, 1326, 1228, 1143, 1027, 750 cm–1. HRMS (FAB): calcd.
for C22H27N2O3 [M + H]+ 367.2022; found 367.2017.
Ethyl 7-Ethyl-2-oxo-4,5,6,7,8,9-hexahydro-1H-3,7-methano[1]aza-
cycloundecino[5,4-b]indole-10(2H)-carboxylate (16): A mixture of 20
(26 mg, 0.07 mmol), ethanol (2 mL) and Raney nickel (50% slurry
in water, 4 mL) was heated to reflux for 12 h under hydrogen, fil-
tered with a plug of celite and concentrated. The crude product
was purified by column chromatography (SiO2, EtOAc/hexanes 1:1;
Rf 0.55) to give 16 (55 mg, 0.15 mmol, 74%) as a light yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.98 (d, J = 6.9 Hz, 1 H), 7.71
(d, J = 5.7 Hz, 1 H), 7.23 (dt, J = 6.9, 5.7 Hz, 2 H), 4.59–4.54 (m,
1 H), 4.46 (q, J = 7.2 Hz, 2 H), 4.43–4.41 (m, 1 H), 3.99 (d, J =
13.8 Hz, 1 H), 3.48 (d, J = 13.8 Hz, 1 H), 3.47–3.44 (m, 1 H), 2.83–
2.78 (m, 1 H), 2.71–2.65 (m, 1 H), 2.47–2.42 (m, 1 H), 1.86–1.83
(m, 1 H), 1.62–1.56 (m, 2 H), 1.48 (t, J = 7.2 Hz, 3 H), 1.45–1.40
(m, 3 H), 1.23–1.21 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.3, 152.0, 140.4, 135.1, 130.2,
123.8, 123.2, 118.6, 115.3, 114.0, 63.0, 54.5, 43.3, 39.8, 34.2, 31.6,
30.1, 27.9, 20.7, 19.8, 14.3, 7.3 ppm. HRMS (FAB): calcd. for
C22H28N2O3Na [M + Na]+ 391.1998; found 391.1997.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for compounds 13, 18 and 19 and
copies of the 1H NMR and 13C NMR spectra for the new and key
compounds.
Acknowledgments
This research was supported by the National Science Council of
Taiwan (NSC 101-2113-M-008-002). The authors are grateful to
Ms. Ping-Yu Lin at the Institute of Chemistry, Academia Sinica,
Taiwan, and the Valuable Instrument Center at National Central
University, Taiwan, for mass analysis.
Quebrachamine (1):[6g] Compound 16 (31 mg, 0.085 mmol) in THF
(3 mL) was added at 0 °C to a solution of lithium aluminiumhy-
dride (16 mg, 0.425 mmol) in THF (3 mL). After the addition, the
reaction mixture was heated to reflux for 2 h, quenched with satd.
NH4Cl(aq.) (1 mL) and extracted with diethyl ether (3 mL). The or-
ganic layer was separated, dried with Na2SO4 and concentrated to
give quebrachamine (15.0 mg, 0.053 mmol, 66%) as a light yellow
[1] a) J. E. Saxton, in: The Alkaloids, vol. 51 (Ed.: G. A. Cordell),
Academic Press, New York, 1998, Chapt. 1; b) G. A. Cordell,
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rigo), Academic Press, New York, 1979, p. 199.
[2] a) J. A. Joule, in: The Alkaloids, vol. 1 (Ed.: J. E. Saxton), The
Chemical Society, London, 1971, p. 178; b) H. F. Deutsch,
M. A. Evenson, P. Drescher, C. Sparwasser, P. O. Madsen, J.
Pharm. Biomed. Anal. 1994, 12, 1283.
1
oil. H NMR (300 MHz, CDCl3): δ = 7.69 (br., 1 H), 7.47 (d, J =
6.0 Hz, 1 H), 7.26 (d, J = 5.3 Hz, 1 H), 7.09–7.04 (dt, J = 6.0, J =
5.3 Hz, 2 H), 3.25–3.21 (m, 1 H), 2.93–2.83 (m, 2 H), 2.72–2.66 (m,
2 H), 2.46–2.40 (m, 2 H), 2.39–2.34 (m, 1 H), 2.32–2.23 (m, 1 H),
1.95–1.87 (m, 1 H), 1.60–1.50 (m, 2 H), 1.49–1.47 (m, 1 H), 1.26–
1.13 (m, 3 H), 1.11–1.01 (m, 2 H), 0.82 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.9, 134.8, 128.9, 120.2, 118.7,
117.4, 110.0, 108.7, 56.7, 55.1, 53.3, 37.1, 34.8, 33.5, 32.1, 22.7,
[3] a) M. A. Beniddir, M.-T. Martin, M.-E. T. H. Dau, P. Grellier,
P. Rasoanaivo, F. Guéritte, M. Litaudon, Org. Lett. 2012, 14,
4162; b) Y. Wu, M. Suehiro, M. Kitajima, T. Matsuzaki, S.
22.5, 22.0, 7.8 ppm. IR (neat): ν = 3407, 2923, 1645, 1459, 1301,
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