D.A. Goff / Tetrahedron 69 (2013) 242e256
255
2.80e2.89 (dd, J¼16.5, 10.6 Hz, H-1b), 2.63e2.69 (m, 1H, H-13a),
2.45e2.58 (m, 2H, H-1a, H-12), 2.17e2.23 (dd, J¼12.5, 6.2 Hz, H-11b),
1.95e2.04 (t, J¼12.6, 1H, H-11a), 1.74 (br s, 2H, NH2, exchanges with
D2O), 1.61 (m, 1H, H-13), 1.09 (d, J¼6.4 Hz, 3H, 12-CH3); 13C NMR
4.3.1. Compound 16a. White solid, 39.9 mg, 75%. HPLC (method A)
tR¼1.52 min; 1H NMR (300 MHz, CDCl3):
7.36 (d, J¼8.5 Hz,1H, H-10),
d
6.80 (br s,1H, NH), 6.72 (dd, J¼8.5, 2.3 Hz, 1H, H-9), 6.56 (d, J¼2.2 Hz,
1H, H-7), 4.22e4.27 (m, 1H, H-4b), 3.76 (s, 3H, OMe), 3.27e3.31 (m,
1H), 3.10e3.14 (m,1H), 2.82 (d, J¼4.7 Hz, NHCH3), 2.70e2.80 (m, 3H),
2.45 (dd, J¼17.0, 7.7 Hz, 1H), 2.12e2.29 (m, 2H), 1.92e2.02 (m, 3H),
1.75e1.85 (m, 1H), 1.04 (d, J¼6.0 Hz, 3H, 12-CH3); 13C NMR (75 MHz,
(75 MHz, CDCl3):
d 173.0 (CO), 171.7 (CO), 138.5 (C), 136.4 (C), 126.4
(C), 121.6 (CH), 119.4 (CH), 118.4 (CH), 111.3 (CH), 103.4 (C), 68.6 (C-
10b), 55.5 (CH), 52.4 (CO2Me), 49.0 (CH), 48.6 (CH2), 46.0 (CH), 40.4
(CH2), 40.0 (CH2), 35.4 (CH), 21.6 (CH2), 18.6 (12-CH3); MS (ES):
C21H25N3O3 calcd: 368.1974 [MþH]þ; found: 368.1958 [MþH]þ.
CDCl3):
d 173.5 (2 CO), 158.2, 141.7, 136.3, 128.0, 116.6, 111.7, 76.3 (C-
10b), 60.0, 55.4, 51.9, 47.4, 39.6, 38.9, 34.4, 33.7, 26.6,18.5 (12-CH3); MS
(ES): C20H26N2O3 calcd:343.2022[MþH]þ; found: 343.2032 [MþH]þ.
4.2.40. Cyclopenta[20,30]pyrrolo[10,20:1,2]azepino[3,4-b]indole-14-
nitromethyl,1,2,5,10,11,12,13,13a-octahydro-13-methyl-2-oxo-,
(10bR,12S,13R,13aS)-15a. Compound 1 (4.00 g, 18.5 mmol) and 3-
(3-aminopropyl)indole (3.22 g, 18.5 mmol)26 were coupled
according to general procedure 1. The crude product was cyclized
according to general procedure 2 (4 h). Purification by flash chro-
matography on silica gel, eluting with 2e5% MeOH in CH2Cl2 gave
15a as a white foam, 3.06 g (47%). An analytical sample was pre-
pared by HPLC; tR¼1.99 min (method A), tR¼6.06 min (method B);
4.3.2. Compound 16b. White solid, 44.6 mg, 74%. HPLC (method A)
tR¼2.00 min; 1H NMR (300 MHz, CDCl3):
7.43 (d, J¼8.5 Hz, 1H, H-
d
10), 6.71 (dd, J¼8.7, 2.6 Hz, 1H, H-9), 6.56 (d, J¼2.6 Hz, 1H, H-7),
4.22e4.40 (m, 1H, H-4b), 3.76 (s, 3H, OMe), 3.35e3.52 (m, 5H, 2
NCH2CH3 and 1H), 3.05e3.15 (m, 1H), 2.70e2.80 (m, 3H), 2.45e2.57
(m, 2H), 2.24e2.31 (dd, J¼13.5, 7.7 Hz, 1H), 1.96e2.13 (m, 3H),
1.75e1.85 (m, 1H), 1.15e1.21 (m, 6H, 2 NCH2CH3), 1.03 (d, J¼6.6 Hz,
3H, 12-CH3); 13C NMR (75 MHz, CDCl3):
d 173.4 (CO), 172.6 (CO),
1H NMR (300 MHz, CDCl3):
d
8.05 (s, 1H, NH), 7.45e7.48 (m, 1H),
158.1, 141.7, 136.5, 128.2, 116.4, 111.7, 76.2 (C-10b), 55.4, 53.7, 52.9,
47.6, 42.2, 41.1, 38.9, 34.4, 33.7, 26.7, 18.5, 15.6, 13.4; MS (ES):
C23H32N2O3 calcd: 385.2491 [MþH]þ; found: 385.2493 [MþH]þ.
7.25e7.28 (m, 1H), 7.09e7.14 (m, 2H), 4.58e4.62 (m, 2H, CH2NO2),
4.34e4.40 (m,1H, H-4b), 3.13e3.18 (m,1H, H-4a), 2.98e3.05 (m,1H,
H-14a), 2.80e2.88 (m, 2H, H-6a and H-6b), 2.60e2.70 (dd, J¼17.6,
8.8 Hz, 1H, H-1b), 2.38e2.46 (dd, 1H, J¼17.6, 7.6 Hz, H-12b),
2.25e2.29 (m, 2H, H-13, H-1a), 2.08e2.11 (m, 1H, H-5b), 1.91e2.08
(m, 3H, H-5a, H-12a, and H-14), 1.11 (d, J¼6.0 Hz, 3H, 13-CH3). As-
signments are tentative, based on the COSY spectrum; 13C NMR
4.3.3. Compound 16c. White solid, 42.7 mg, 74%. HPLC (method A)
tR¼1.72 min; 1H NMR (300 MHz, CDCl3):
d
7.36 (d, J¼8.8 Hz, 1H, H-
10), 6.92 (d, J¼3.0 Hz, 1H, NH), 6.72 (dd, J¼8.5, 2.7 Hz, 1H, H-9), 6.56
(d, J¼2.7 Hz, 1H, H-7), 4.18e4.25 (m, 1H, H-4b), 3.76 (s, 3H, OMe),
3.27e3.33 (m, 1H), 3.05e3.10 (m, 1H), 2.72e2.82 (m, 4H), 2.41e2.50
(dd, J¼17.0, 7.7 Hz, 1H), 2.21e2.29 (dd, J¼13.6, 8.1 Hz, 1H), 2.13 (d,
J¼17.0 Hz, 1H), 1.88e1.98 (m, 3H), 1.75e1.85 (m, 1H), 1.03 (d,
J¼6.6 Hz, 3H, 12-CH3), 0.74e0.78 (m, 2H, CH2ecyclopropyl),
0.47e0.50 (m, 2H, CH2ecyclopropyl); 13C NMR (75 MHz, CDCl3):
(75 MHz, CDCl3):
d 173.1 (CO), 137.9 (C), 135.7 (C), 128.4 (C), 122.4
(CH),119.8 (CH),118.5 (CH),113.3 (C),111.0 (CH), 76.7 (CH2NO2), 72.5
(C-11b), 51.4 (CH), 47.5 (CH), 47.0 (CH2), 40.5 (CH2), 37.9 (CH), 35.0
(CH2), 27.6 (CH2), 22.0 (CH2), 17.9 (13-CH3); MS (ES): C20H23N3O4
calcd: 354.1818 [MþH]þ; found: 354.1810 [MþH]þ.
d
173.9 (CO),173.0 (CO),157.8,141.3,135.9, 127.7, 116.3,111.5, 76.1 (C-
4.2.41. Cyclopenta[20,30]pyrrolo[10,20: 1,2]azepino[3,4-b]indole-14-
aminomethyl,1,2,5,10,11,12,13,13a-octahydro-13-methyl-2-oxo-,
(10bR,12S,13R,13aS) 15b. Compound 15a (2.04 g, 5.78 mmol) was
reduced using general method 3. The crude amine was purified by
flash chromatography on silica gel, eluting with 5% MeOH in
CH2Cl2, then 10% 2 M NH3 in MeOH/90% CH2Cl2 to give 15b as
10b), 59.4, 55.3, 51.8, 47.3, 42.8, 39.4, 38.7, 34.2, 33.5, 26.5, 22.9, 18.4
(12-CH3), 6.7 (2-cyclopropyl CH2); MS (ES): C22H28N2O3 calcd:
369.2178 [MþH]þ; found: 369.2187 [MþH]þ.
4.3.4. Compound 16d. White solid, 44.6 mg, 64%. HPLC (method A)
tR¼1.72 min; 1H NMR (300 MHz, CDCl3):
d 7.37 (s, 1H, NH), 7.33 (d,
a white foam, 0.52 g (28%). HPLC (method A) tR¼1.55 min, (method
J¼8.5 Hz, 1H, H-10), 6.72 (dd, J¼8.6, 2.5 Hz, 1H, H-9), 6.55 (d,
24
B) tR¼3.05 min (92%); [
a
]
þ45.6 (c 0.61, CHCl3); 1H NMR
J¼2.5 Hz,1H, H-7), 4.65e4.69 (dd, J¼9.0, 2.5 Hz,1H, H-
a), 4.24e4.34
D
(300 MHz, CDCl3, 60 ꢀC):
d
10.44 (br s, 1H, NH), 7.46 (m, 1H),
(m, 2H, H- and H-4b), 3.76 (s, 3H, OMe), 3.26e3.31 (m, 1H),
b
7.25e7.30 (m, 1H), 7.02e7.07 (m, 2H), 4.33e4.42 (m, H-4b), 3.22 (br
s, 2H), 3.02e3.23 (m, 3H), 2.80e3.00 (m, 3H), 2.64e2.73 (m, 1H),
2.20e2.36 (m, 3H), 1.97e2.07 (m, 2H), 1.71e1.78 (m, 1H), 1.39e1.45
(m, 1H), 0.99 (d, J¼6.1 Hz, 3H, 13-CH3); 13C NMR (75 MHz, CDCl3,
3.10e3.16 (m, 1H), 2.70e2.75 (m, 3H), 2.47e2.50 (dd, J¼17.4, 7.4 Hz,
1H), 2.30e2.41 (m, 1H), 2.10e2.18 (t, J¼10.8 Hz, 1H), 1.99e2.05 (m,
2H), 1.79e1.90 (m, 1H), 1.21 (d, J¼6.3 Hz, 3H, CH(OH)CH3), 1.11 (d,
J¼6.3 Hz, 12-CH3); 13C NMR (75 MHz, CDCl3):
d 174.1 (CO), 173.5
60 ꢀC):
d
173.1 (CO), 139.8 (C), 135.3 (C), 128.3 (C), 121.4 (CH), 119.0
(CO), 171.6 (CO), 158.2, 141.6, 136.0, 128.0, 116.6, 111.9, 76.8 (C-10b),
68.1, 60.0, 58.1, 55.4, 52.7, 52.3, 47.7, 39.8, 39.0, 34.3, 33.5, 26.5, 20.5,
18.5 (12-CH3); MS (ES): C24H32N2O6 calcd: 445.2339 [MþH]þ;
found: 445.2357 [MþH]þ.
(CH), 118.1 (CH), 111.4 (CH), 110.8 (C), 73.0 (C-11b), 55.6 (CH), 48.2
(CH2), 45.6 (CH), 41.5 (CH2), 40.7 (CH2), 37.2 (CH2). 35.4 (CH), 27.8
(CH2), 22.9 (CH2), 18.1 (13-CH3); MS (ES): C20H25N3O calcd:
324.2076 [MþH]þ; found: 324.2086 [MþH]þ.
4.3.5. Compound 16e. White solid, 31.3 mg, 55%. HPLC (method A)
4.3. Compounds 16aeg. General procedure
tR¼1.73 min; 1H NMR (300 MHz, CDCl3):
d 8.42 (br t,1H, NH), 7.33 (d,
J¼8.8 Hz,1H, H-10), 6.74 (dd, J¼8.7, 2.7 Hz,1H, H-9), 6.59 (d, J¼2.5 Hz,
Compound 8c (800 mg, 2.43 mmol) was dissolved in a mixture
of CH2Cl2 (15 mL) and THF (5 mL) and 1.30 mL (0.156 mmol) of this
stock solution was aliquoted to seven glass vials. The appropriate
amine (0.20 mmol) was added to each vial, followed by 1.0 mL of
1H, H-7), 4.22e4.26 (m,1H, H-4b), 4.15e4.20 (m, 2H, a-CH2), 3.77 (s,
3H, OMe), 3.24e3.28 (m, 1H), 3.15e3.20 (m, 1H), 2.70e2.77 (m, 3H),
2.50e2.54 (dd, J¼17.0, 7.7 Hz,1H), 2.25e2.33 (m, 1H), 2.09e2.20 (m,
1H), 1.97e2.20 (m, 3H), 1.80e1.85 (m, 1H), 1.08 (d, J¼6.3 Hz, 3H, 12-
a
stock solution prepared from 1-hydroxy-7-azabenzotriazole
CH3); 13C NMR (75 MHz, CDCl3):
d 173.6 (CO),173.5 (CO),158.3,141.6,
(1.22 g, 8.97 mmol), EDC (1.72 g, 8.97 mmol) and Et3N (3.8 mL,
27.2 mmol) in dry CH2Cl2 (45 mL). The vials were shaken at rt for
48 h. The mixtures were diluted with CH2Cl2 and washed either
with satd aq NaCl solution or 10% aq HCl solution as appropriate.
After concentration under reduced pressure, the crude residues
were purified by C-18 RP-HPLC to give 16aeg in the yields
indicated.
135.7,127.9,116.7,116.5,111.9, 76.7 (C-10b), 59.0, 55.5, 52.2, 47.4, 39.7,
39.0, 34.4, 33.6, 27.6, 26.6,18.4 (12-CH3); MS (ES): C21H25N3O3 calcd:
368.1974 [MþH]þ; found: 368.1997 [MþH]þ.
4.3.6. Compound 16f. Oil, 54.5 mg, 69%. HPLC (method A)
tR¼2.40 min; 1H NMR (300 MHz, CDCl3):
7.41 (d, J¼8.6 Hz, 1H, H-
d
10), 7.14e7.18 (m, 1H), 6.74 (dd, J¼8.5, 2.8 Hz, 1H, H-9), 6.57 (d,