Synthesis of Functionalized Diketopiperazines as Cyclotryprostatin and Tryprostatin Analogues

Article abstract of DOI:10.1055/s-0032-1316911

Various ketopiperazines were synthesized as (cyclo)tryprostatin analogues. Construction of the skeleton started with a Pictet-Spengler reaction followed by acylation or alkylation of the piperidine nitrogen and condensation with a primary amine. 2-Chloroacetyl tetrahydro-β-carbolines rearranged towards the corresponding 2-chloro-N-[2-(1H-indol-3-yl)ethyl]acetamide deriv-atives upon treatment with NBS. These compounds were cyclized with primary amines towards the corresponding functionalized diketopiperazines. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1316911

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0032-1316911
© Georg Thieme Verlag KG Stuttgart · New York 2013
Thieme

Supporting information: synthesis of functionalized diketopiperazines as
cyclotryprostatin and tryprostatin analogues
1
General methods. H NMR spectra (270 MHz) and 13C NMR spectra (68 MHz) were run with a Jeol JNM-EX 270
NMR spectrometer. Peak assignments were performed with the aid of the DEPT technique, 2D-COSY spectra and
HETCOR spectra. IR assignments were obtained from a Perkin Elmer Spectrum One spectrophotometer. Mass
spectra were measured with an Agilent 1100 Series mass spectrometer (detector VL, 70 eV, ES 4000 V). Melting
points were measured with a Buchi B-540 apparatus. Flash chromatography was carried out on a glass column with
ACROS silica gel (particle size 0.035-0.07 mm, pore diameter ca. 6 nm). All solvents and reagents were obtained
from commercial suppliers and were used without further purification.
1. General procedure for the synthesis of compounds 6a-c and 7a-c
A solution of L-trytophan ethyl ester 4 (2.9 g, 11.74 mmol) and benzaldehyde 5a (1.25 g, 11.74 mmol) in benzene (50
ml) was refluxed for 48 h. Then, the solvent was evaporated to give a crude product, which was extracted three times
with EtOAc. The combined organic phases were washed with saturated NaHCO3, dried (MgSO4) and evaporated in
vacuo. Purification by means of column chromatography on silicagel (hexane/EtOAc, 4/6) gave trans- isomers 6a
(1.1 g, 30%) and cis-isomer 7a (2.3 g, 61%).
trans-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 6a
15
1
Yield (30%), white powder, mp: 151-151.5oC, [D]D = -3.4° (c = 0.59, CH2Cl2). H
NMR-270 MHz (CDCl3): G 1.33 (3H, t, J = 7.3 Hz, Me), 3.02 (1H, ddd, J = 2.0, 11.2,
15.2 Hz, H-4a), 3.2 (1H, ddd, J = 1.7, 15.2, 4.3 Hz, H-4b), 3.9 (1H, dd, J = 11.2, 4.3 Hz,
H-3), 4.22-4.31 (2H, m, OCH2), 5.23 (1H, dd J = 1,7, 2.0 Hz, H-1), 7.10-7.25 (3H, m,
3x =CH), 7.34-7.39 (5H, m, 5x =CH), 7.43 (1H, br. s, H-9), 7.55 (1H, dd, J = 7.9, 2.0
5
8
4
1
COOEt
NH
N
H
Hz, H-5). 13C NMR-68 MHz (CDCl3): G 14.23 (Me), 25.68 (C-4), 56.94 (C-3), 58.69 (C-1), 61.20 (OCH2), 108.97
(Cquat), 110.89 (C-8), 118.22 (C-5), 119.59 (C-6), 121.90 (C-7), 127.13 (Cquat), 128.57 (=CH), 128.62 (2x =CH),
128.95 (2x =CH), 134.73 (Cquat), 136.14 (Cquat), 140.77 (Cquat), 172.76 (C=O). IR (KBr) Q 3387 (NH), 1720 (C=O),
1625, 1490, 1470, 1455, 1368, 1324, 1267, 1226, 1144, 1034, cm-1. MS m/z (%). 221 (M+H+, 100), 221 (30), 220
(50).
cis-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 7a
o
15
1
5
8
4
1
Yield (61%), white powder, mp: 167.5-168 C, [D]D = -4.1° (c = 0.48, CH2Cl2). H
NMR-270 MHz (CDCl3): G 1.26 (3H, t, J = 6.9 Hz, Me), 3.10 (1H, ddd, J = 1.8, 7.0,
15.5 Hz, H-4a), 3.28 (1H, ddd, J = 1.0, 15.5, 5.3 Hz, H-4b), 3.94 (1H, dd, J = 7.0, 5.3
Hz, H-3), 4.11-4.23 (2H, m, OCH2), 5.40 (1H, br. s ,H-1), 7.10-7.16 (2H, m, H-6, H-7),
7.18-7.36 (6H, m, 5x =CH, H-8), 7.57 (1H, d, J = 8.9 Hz, H-5), 7.63 (1H, br. s, H-9). 13C
COOEt
NH
N
H
NMR-68 MHz (CDCl3): G 14.19 (Me), 24.69 (C-4), 52.49 (C-3), 54.97 (C-1), 61.04 (OCH2), 108.53 (Cquat), 110.87
(C-8), 118.25 (C-5), 119.48 (C-6), 121.92 (C-7), 127.02 (Cquat), 128.08 (=CH), 128.41 (2x =CH), 128.75 (2x =CH),
1

133.20 (Cquat), 136.15 (Cquat), 142.04 (Cquat), 173.67 (C=O). IR (KBr) Q 3400 (NH), 1737 (C=O), 1625, 1455, 1335,
1214, 1124 cm-1. MS m/z (%). 221 (M+H+, 100), 221 (20), 220 (50).
trans-Ethyl-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 6b
15
1
Yield (28%), white powder, mp : 140.5-141oC, [D]D = -1.9° (c = 0.52, CH2Cl2). H
NMR-300 MHz (CDCl3): G 1.32 (3H, t, J = 7.2 Hz, Me), 2.03 (1H, br. s, NH), 2.97 (1H,
ddd, J = 2.5, 11.3, 15.1 Hz, H-4a), 3.20 (1H, ddd, J = 1.9, 15.1, 4.4 Hz, H-4b), 3.79 (3H,
s, OMe), 3.92 (1H, dd, J = 11.3, 4.4, H-3), 4.20-4.30 (2H, m, OCH2), 5.17 (1H, dd, J =
1,9, 2.5 Hz, H-1), 6.87 (2H, d, J = 8.8 Hz, H-3´, H-5´), 7.07-7.21 (3H, m, 3x =CH), 6.27
5
8
4
CO2Et
NH
1
N
H
(2H, d, J = 8.8 Hz, H-2´, H-6´), 7.52 (1H, br. s, H-9), 7.54 (1H, d, J = 8.8 Hz, H-5). 13
C
OMe
NMR-75 MHz (CDCl3): G 14.19 (Me), 25.66 (C-4), 55.30 (OMe), 56.93 (C-3), 57.97 (C-1), 61.19 (OCH2), 108.81
(Cquat), 110.87 (C-8), 114.22 (C-3´, C-5´), 118.16 (C-5), 119.50 (C-6), 121.80 (C-7), 127.12 (Cquat), 129.77 (C-2´, C-
6´), 132.77 (Cquat), 135.01 (Cquat), 136.06 (Cquat), 159.72 (Cquat), 172.80 (C=O). IR (KBr) Q 3305 (NH), 1721 (C=O),
1609, 1511, 1454, 1303, 1263, 1248, 1210, 1121, 1037, cm-1. MS m/z (%). 351 (M+H+, 100), 349 (30), 250 (30),
236(10).
cis-Ethyl-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 7b
Yield (56%), white powder, mp: 194.5-196 oC, [D]D15 = -6.4° (c = 0.465, CH2Cl2). H
NMR-300 MHz (CDCl3): G 1.25 (3H, t, J = 7.2 Hz, Me), 2.47 (1H, br. s, NH), 3.09 (1H,
ddd, J = 1.7, 7.2, 15.3 Hz, H-4a), 3.24 (1H, ddd, J = 1.1, 15.3, 5.5 Hz, H-4b), 3.78 (3H,
s, OMe), 3.91 (1H, dd, J = 7.2, 5.5 Hz, H-3), 4.10-4.24 (2H, m, OCH2), 5.34 (1H, br. s,
H-1), 6.83 (2H, d, J = 8.8 Hz, H-3´, H-5´), 7.08-7.23 (5H, m, overlap, 3x =CH, H-2´, H-
6´), 7.54 (1H, db, J = 8.8 Hz, H-5), 7.67 (1H, br. s, H-9). 13C NMR-68 MHz (CDCl3): G
1
5
8
4
CO2Et
NH
1
N
H
OMe
14.16 (Me), 24.67 (C-4), 52.36 (C-3), 54.27 (C-1), 55.27 (OMe), 60.97 (OCH2), 108.37 (Cquat), 110.83 (C-8), 113.98
(C-3´, C-5´), 118.17 (C-5), 119.39 (C-6), 121.80 (C-7), 127.00 (Cquat), 129.51 (C-2´, C-6´), 133.57 (Cquat), 134.16
(Cquat), 136.10 (Cquat), 159.35 (Cquat), 173.67 (C=O). IR (KBr) Q 3312 (NH), 1730 (C=O), 1606, 1509, 1453, 1332,
1302, 1248, 1223, 1178, 1126, 1033 cm-1. MS m/z (%). 351 (M+H+, 100), 250 (30), 236 (10).
2. Synthesis of compounds 8a-c and 9a-c.
To a solution of the cis-isomer 6a (800 mg, 2.5 mmol) in a saturated solution of NaHCO3 (20ml) and EtOAc (20ml)
was added chloroacetyl chloride (333mg, 3 mmol). The reaction mixture was stirred at 0oC for 30 min. Afterwards,
the solvent was evaporated and the residue extracted with CH2Cl2. The combined organic phases were washed with
saturated NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on
silicagel (hexane/EtOAc, 6/4) gave compound 9a in 91% (900 mg). Compounds 8a and 8b gave significant peak-
broadening so that no reliable 1H and 13C-NMR spectra could be collected.
cis-Ethyl-2-(2-chloroacetyl)-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 9a
2

Yield (91%), white powder, mp: 156.5-158 C, [D]D15 = -2.12° (c = 0.47, CH2Cl2). H
NMR-300 MHz (CDCl3): G 0.62-0.90 (3H, m, CH3CH2), 2.98-3.12 (1H, m, CHAHBO),
3.17 (1H, dd and m, J = 6.9 Hz, 15.7 Hz, CHAHB-4 and CHAHBO), 3.67-3.75 (1H, m,
CHAHB-4), 4.21 (1H, d, J = 12.4 Hz, CHAHBCl), 4.35 (1H, d, J = 12.4 Hz, CHAHBCl),
4.91 (1H, d, J = 4.4 Hz, CH-3), 6.95 (1H, s, CH-1), 7.13-7.36 (6H, m, 6xCHAr), 7.60
o
1
5
8
4
CO2Et
1
N
N
Cl
H
O
(1H, d, J = 9.9 Hz, CHAr), 7.80 (1H, br. s, NH). 13C NMR-68 MHz (CDCl3): G 13.55 (CH3CH2), 21.58 (CH2-4), 42.24
(CH2Cl), 52.32 (CH-1), 53.74 (CH-3), 61.77 (CH2O), 107.83 (Cquat), 111.13 (2xCHAr), 118.70 (2xCHAr), 119.92
(CHAr), 122.64 (CHAr), 126.46 (Cquat), 128.35 (CHAr), 128.35 (CHAr), 129.65 (CHAr), 136.52 (Cquat), 139.06 (Cquat),
167.15 (C=O), 169.64 (C=O). IR (KBr) Q 3367, 3315 (NH), 1741, 1728 (C=O), 1658 (C=O), 1626, 1492, 1455, 1425,
1319, 1262, 1238, 1206. cm-1. MS m/z (%). 397/399 (M+H+, 100), 351 (30).
trans-Ethyl-2-(2-chloroacetyl)-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 8a
Yield (96%), white powder, mp: 216.5-218 oC, [D]D15 = -38.4° (c = 0.65, CH2Cl2). 13C
NMR-68 MHz (CDCl3): G 13.54 (Me), 21.60 (C-4), 42.21 (C-2’), 52.35 (C-3), 53.77
(C-1), 61.75 (OCH2), 107.88 (Cquat), 111.12 (C-8), 118.70 (C-5), 119.94 (C-6), 122.66
(C-7), 126.47 (Cquat), 128.44 (C-2´, C-6´), 129.64 (C-3´, C-5´, Cquat), 136.52 (Cquat),
139.06 (Cquat), 167.16 (C=O), 169.62 (C=O). IR (KBr) Q 3391 (NH), 1714, 1667
5
4
CO2Et
1
N
N
Cl
8
H
O
(C=O), 1609, 1511, 1452, 1387, 1367, 1242, 1029. cm-1. MS m/z (%). 397/399 (M+H+, 100), 351 (25).
cis-Ethyl-2-(2-chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 9b
Yield (88%), white powder, mp: 205.5-206 oC, [D]D15 = -2.7° (c = 0.37, CH2Cl2). H
1
5
8
4
1
CO2Et
NMR-300 MHz (CDCl3): G 0.79 (3H, t, J = 6.4 Hz, CH3CH2), 3.14 (2H, dd, J = 7,0 Hz,
15.6 Hz), 3.63-3.77 (6H, s+m, CH2O and OCH3), 4.19 (1H, d, J = 12.1 Hz, CHAHBCl),
4.34 (1H, d, J = 12.1 Hz, CHAHBCl), 4.86 (1H, d, J = 5.0 Hz, CH-3), 6.70 (2H, d, J =
8.3 Hz, 2xCHAr), 6.84 (1H, s, CH-1), 7.11-7.27 (5H, m, 5xCHAr), 7.58 (1H, d, J = 7.2
Hz, CHAr), 8.07 (1H, br. s, NH). 13C NMR-68 MHz (CDCl3): G 13.60 (CH3CH2), 21.57
N
N
Cl
H
O
OMe
(CH2-4), 42.35 (CH2Cl), 51.86 (CH-1), 53.65 (CH-3), 61.83 (CH2O), 107.51 (Cquat), 111.19 (2xCHAr), 113.50 (CHAr),
118.64 (2xCHAr), 119.79 (CHAr), 122.52 (CHAr), 126.47 (Cquat), 130.00 (Cquat), 130.98 (Cquat), 131.39 (Cquat), 136.54
(Cquat), 159.45 (Cquat-OMe), 167.12 (C=O), 169.76 (C=O). IR (KBr) Q 3369 (NH), 1736, 1656 (C=O), 1609, 1510,
1453, 1422, 1304, 1249, 1176 cm-1. MS m/z (%). 427/429 (M+H+, 80), 348 (30), 347 (100), 319 (32).
trans-Ethyl-2-(2-chloroacetyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 8b
3

Yield (98%), white powder, mp: 174-176 oC, [D]D15 = -25.4° (c = 0.59, CH2Cl2). IR
(KBr) Q 3369 (NH), 1732, 1639 (C=O), 1609, 1509, 1440, 1342, 1253, 1174, 1045 cm-
1. MS m/z (%). 427/429 (M+H+, 100), 321 (10), 319 (30).
5
8
4
CO2Et
1
N
N
H
Cl
O
OMe
3. General procedure for the synthesis of compounds 10 and 11
A mixture of 9a (100 mg, 0.25 mmol) and propylamine (64 mg, 1.25 mmol) in dry EtOH (10 ml) was stirred for 24 h
at room temperature. Then, the mixture was poured in water and extracted with EtOAc for three times. The combined
organic phases were washed, dried (MgSO4) and evaporated in vacuo. Purification by means of column
chromatography on silicagel (hexane/EtOAc, 1/1) gave pure compound 11a (88 mg, 94%).
cis-6-Phenyl-2-propyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 11a
Yield 94%. White powder, mp : 254-255.5 oC, [D]D15 = -35° (c = 0.4, CH2Cl2). 1H
O
1
H
N
12
6
11
8
N
NMR-270 MHz (CDCl3): G 0.92 (3H, t, J = 7.3 Hz, Me), 1.53-1.67 (2H, m, H-2´),
3.19-3.34 (2H, m, overlap, H-12a, H-1a´), 3.48-3.61 (1H, m, H-1´b), 3.75 (1H, dd,
J = 17.2, 4.6 Hz, H-12b), 3.89 (1H, d, J = 17.5 Hz, H-3a), 4.06 (1H, d, J = 17.5
Hz, H-3b), 4.31 (1H, dd, J = 10.2, 3.3 Hz, H-13), 6.26 (1H, br. s, H-6), 7.13-7.32
3
N
H
7
O
(8H, m, 5x =CH, H-8, H-9, H-10), 7.59 (1H, dd, J = 8.9, 3.0 Hz, H-11), 8.01 (1H, br. s, H-7). 13C NMR-68 MHz
(CDCl3): G 11.14 (Me), 20.20 (C-2´), 23.55 (C-12), 47.89 (C-1´), 50.26 (C-3), 56.17 (C-13), 56.73 (C-6), 108.54
(Cquat), 111.21 (C-8), 118.59 (C-11), 120.03 (C-10), 122.41 (C-9), 126.18 (Cquat), 126.93 (2x =CH), 127.80 (=CH),
128.71 (2x =CH), 132.81 (Cquat), 136.51 (Cquat), 141.38 (Cquat), 166.39 (C=O), 167.17 (C=O). IR (KBr) Q 3317 (NH),
2955, 1671 (C=O), 1656 (C=O), 1623, 1426, 1310, 1271, 1226, 1209, 1155 cm-1. MS m/z (%). 374 (M+H+, 100).
trans-6-Phenyl-2-propyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 10b
Yield 90%. White powder, mp : 192-193.5 oC, [D]D15 = -240° (c = 0.5, CH2Cl2). 1H
O
1
H
N
12
6
11
8
N
NMR-270 MHz (CDCl3): G 0.91 (3H, t, J = 7.3 Hz, Me), 1.49-1.63 (2H, m, H-2´),
2.90 (1H, ddd, dd, J = 1.1, 11.6, 15.2 Hz, H-12a), 3.02-3.12 (1H, m, H-1´a), 3.47-
3.54 (2H, m, overlap, H-1´b, H-12b), 3.84 (1H, d, J = 17.8 Hz, H-3a), 4.40 (1H, d,
J = 17.8 Hz, H-3b), 4.24 (1H, dd, J = 11.6, 4.0 Hz, H-13), 7.02 (1H, br. s, H-6),
3
N
H
7
O
7.08-7.28 (8H, m, 5x =CH, H-8, H-9, H-10), 7.51 (1H, dd, J = 8.9, 2.9 Hz, H-11), 8.58 (1H, br. s, H-7). 13C NMR-68
MHz (CDCl3): G 11.02 (Me), 19.59 (C-2´), 27.60 (C-12), 47.48 (C-1´), 49.24 (C-3), 51.99 (C-6), 52.13 (C-13),
108.68 (Cquat), 111.09 (C-8), 118.26 (C-11), 119.80 (C-10), 122.43 (C-9), 126.15 (Cquat), 128.61 (2x =CH), 128.72 (3x
=CH), 129.62 (Cquat), 136.30 (Cquat), 138.22 (Cquat), 161.59 (C=O), 165.14 (C=O). IR (KBr) Q 3219 (NH), 2929, 1662
(C=O), 1653 (C=O), 1620, 1495, 1455, 1335, 1262, 1164 cm-1. MS m/z (%). 374 (M+H+, 100), 149 (20), 102 (20).
4

cis-2-(4-Chlorobenzyl)-6-phenyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 11d
o
15
O
Yield 91%. White powder, mp: 190-192 C, [D]D = -14.7° (c = 0.475,
CH2Cl2). 1H NMR-270 MHz (CDCl3, acetone-d6): G 3.27 (1H, dd, J = 11.2,
15.9 Hz, H-12a), 3.78 (1H, dd, J = 15.9, 3.6 Hz, H-12b), 3.79 (1H, d, J =
15.8 Hz, H-1a´), 3.89 (1H, d, J = 15.8 Hz, H-1´b), 4.29 (1H, dd, J = 11.2,
3.6 Hz, H-13), 4.37 (1H, d, J = 14.9 Hz, H-3a), 4.81 (1H, d, J = 14.9 Hz,
1
H
N
12
6
11
8
N
3
N
H
Cl
O
7
H-3b), 6.24 (1H, br. s, H-6), 7.11-7.30 (12H, m, 12x =CH), 7.60 (1H, dd, J = 8.9, 3.0 Hz, H-11), 8.09 (1H, br. s, H-7),
13C NMR-68 MHz (CDCl3, acetone-d6 ): G 23.63 (C-12), 49.07 (C-1´), 49.92 (C-3), 56.26 (C-13), 56.57 (C-6), 105.96
(Cquat), 111.43 (C-8), 118.38 (C-11), 119.76 (C-10), 122.14 (C-9), 126.18 (Cquat), 126.97 (2x =CH), 127.63 (=CH),
128.59 (2x =CH), 129.13(2x =CH), 129.77 (2x =CH, Cquat), 133.28 (Cquat), 134.14 (Cquat), 136.74 (Cquat), 141.79
(Cquat), 166.77 (C=O), 167.02 (C=O). IR (KBr) Q 3233 (NH), 2911, 1691 (C=O), 1670 (C=O), 1643, 1597, 1492,
1451, 1411, 1322, 1309, 1217, 1091, 1013 cm-1. MS m/z (%). 456/458 (M+H+, 100), 304 (10), 149 (10), 102 (70).
trans-2-(4-Chlorobenzyl)-6-phenyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
10c
15
Yield 81%. White powder, mp: 268-270 oC, [D]D = -131.6° (c = 0.575,
O
1
H
N
12
6
11
8
1
N
CH2Cl2). H NMR-270 MHz (CDCl3): G 2.93 (1H, ddd, J = 1.0, 12.0, 15.5
3
Hz, H-12a), 3.56 (1H, dd, J = 15.5, 4.3 Hz, H-12b), 3.83 (1H, d, J = 16.5
Hz, H-1a´), 3.93 (1H, d, J = 16.5 Hz, H-1´b), 4.27 (1H, d, J = 14.5 Hz, H-
3a), 4.36 (1H, dd, J = 11.9, 4.3 Hz, H-13), 4.76 (1H, d, J = 14.5 Hz, H-3b),
N
H
7
Cl
O
7.00 (1H, br. s, H-6), 7.11-7.33 (11H, m, 11x =CH), 7.53 (1H, db, J = 8.2, 3.0 Hz, H-11), 8.16 (1H, br. s, H-7). 13C
NMR-68 MHz (CDCl3): G 27.73 (C-12), 48.70 (C-1´), 48.79 (C-3), 52.02 (C-13), 52.54 (C-6), 108.62 (Cquat), 111.14
(C-8), 118.33 (C-11), 119.96 (C-10), 122.59 (C-9), 126.18 (Cquat), 128.68 (2x =CH), 128.80 (2x =CH), 129.14 (2x
=CH), 129.60 (=CH), 129.81 (2x =CH, Cquat), 133.39 (Cquat), 134.16 (Cquat), 136.31 (Cquat), 138.17 (Cquat), 161.59
(C=O), 165.42 (C=O). IR (KBr) Q 3376 (NH), 2926, 1675 (C=O), 1648 (C=O), 1583, 1491, 1461, 1328, 1154, 1091,
1014, 907 cm-1. MS m/z (%). 456/458 (M+H+, 100), 304 (10), 149 (10), 102 (70).
cis-6-(4-Methoxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
11e
Yield 95%. White powder, mp: 250-250.5 oC, [D]D15 = -4.9° (c = 0.41, CH2Cl2). H
1
O
1
H
N
12
6
11
8
Me
N
NMR-270 MHz (CDCl3): G 3.00 (3H, s, Me), 3.22 (1H, ddd, J = 1.1, 11.6, 16.1 Hz, H-
12a), 3.69 (3H, s, OMe), 3.77 (1H, dd, J = 16.1, 4.7 Hz, H-12b), 3.87 (1H, d, J = 17.6
Hz, H-3a), 4.05 (1H, d, J = 17.6 Hz, H-3b), 4.26 (1H, dd, J = 11.6, 4.7 Hz, H-13),
6.20 (1H, br. s, H-6), 6.74 (2H, dd, J = 8.8, 3.0 Hz, H-3´, H-5´), 7.20-7.28 (5H, m,
overlap, H-2´, H-6´, H-8, H-9, H-10), 7.61 (1H, db, J = 9.1 Hz, H-11), 8.15 (1H, br. s,
3
N
H
O
7
OMe
H-7). 13C NMR-68 MHz (CDCl3): G 23.17 (C-12), 33.60 (Me), 52.09 (C-3), 55.22 (OMe), 56.20 (C-13, C-6), 106.48
5

(Cquat), 111.24 (C-8), 113.93 (C-3´, C-5´), 118.55 (C-11), 120.08 (C-10), 122.39 (C-9), 126.16 (Cquat), 128.69 (C-2´,
C-6´), 133.12 (Cquat), 133.34 (Cquat), 136.53 (Cquat), 159.03 (Cquat), 166.53 (C=O), 166.79 (C=O). IR (KBr) Q 3233
(NH), 2930, 1672 (C=O), 1651 (C=O), 1604, 1509, 1324, 1247, 1170, 1031 cm-1. MS m/z (%). 376 (M+H+, 50), 269
(50), 268 (100).
trans-6-(4-Methoxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
10d
o
15
1
O
Yield 86%. White powder, mp: 258-259 C, [D]D = -9.2° (c = 0.435, CH2Cl2). H
NMR-270 MHz (CDCl3): G 2.93 (1H, dd, J = 11.9, 15.2 Hz, H-12a), 2.94 (3H, s, Me),
3.53 (1H, dd, J = 15.2, 4.3 Hz, H-12b), 3.73 (3H, s, OMe), 3.91 (1H, d, J = 17.5 Hz,
H-3a), 4.08 (1H, d, J = 17.5 Hz, H-3b), 4.30 (1H, dd, J = 11.9, 4.3 Hz, H-13), 6.77
(2H, d, J = 8.9 Hz, H-3´, H-5´), 6.98 (1H, br. s, H-6), 7.16 (2H, d, J = 8.9 Hz, H-2´, H-
6´), 7.12-7.19 (2H, m, H-9, H-10), 7.30 (1H, dd, J = 8.2, 1.3 Hz, H-8), 7.52 (1H, db, J
1
H
N
12
6
11
8
Me
N
3
N
H
O
7
OMe
= 8.2 Hz, H-11), 8.32 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G 27.60 (C-12), 33.30 (Me), 51.39 (C-3), 51.59
(C-6), 52.36 C-13), 55.29 (OMe), 108.82 (Cquat), 111.12 (C-8), 114.14 (C-3´, C-5´), 118.31 (C-11), 119.93 (C-10),
122.55 (C-9), 126.27 (Cquat), 129.99 (C-2´, C-6´, Cquat), 130.49 (Cquat), 136.37 (Cquat), 159.89 (Cquat), 161.49 (C=O),
165.48 (C=O). IR (KBr) Q 3300 (NH), 2955, 1676 (C=O), 1650 (C=O), 1608, 1509, 1452, 1408,1320, 1170, 1032
cm-1. MS m/z (%). 376 (M+H+, 100), 269 (15), 268 (98), 240 (10), 203 (15), 189 (10).
cis-6-(4-Methoxyphenyl)-2-propyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
11f
1
O
Yield 89%. White powder, mp: 182.0 °C decomp. H NMR-270 MHz (CDCl3): G
1
H
N
12
6
11
8
0.91 (3H, t, J = 7.3 Hz, Me), 1.51-1.65 (2H, m, H-2´), 3.16-3.30 (2H, m, overlap,
H-1´a, H-12a), 3.48-3.59 (1H, m, H-1´b), 3.67 (3H, s, OMe), 3.73 (1H, dd, J =
16.2, 5.0 Hz, H-12b), 3.86 (1H, d, J = 17.2 Hz, H-3a), 4.04 (1H, d, J = 17.2 Hz, H-
3b), 4.25 (1H, dd, J = 11.6, 5.0 Hz, H-13), 6.20 (1H, br. s, H-6), 6.72 (2H, dd, J =
8.6, 3.0 Hz, H-3´, H-5´), 7.10-7.25 (5H, m, overlap, H-2´, H-6´, H-8, H-9, H-10),
N
3
N
H
7
O
OMe
7.58 (1H, db, J = 8.9, H-11), 8.28 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G 11.09 (Me), 20.16 (C-2´), 23.39 (C-
12), 47.82 (C-1´), 50.26 (C-3), 55.13 (OMe), 55.92 (C-13), 56.15 (C-6), 106.34 (Cquat), 111.19 (C-8), 113.89 (C-3´,
C-5´), 118.45 (C-11), 119.89 (C-10), 122.23 (C-9), 126.13 (Cquat), 128.45 (C-2´, C-6´), 133.14 (Cquat), 133.35 (Cquat),
136.44 (Cquat), 158.94 (Cquat), 166.39 (C=O), 167.17 (C=O). MS m/z (%). 376 (M+H+, 52), 269 (54), 268 (100).
trans-6-(4-Methoxyphenyl)-2-propyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
10e
1
O
Yield 93%. White powder, mp: 174.5°C decomp. H NMR-270 MHz (CDCl3): G
1
H
N
12
6
11
8
0.92 (3H, t, J = 7.3 Hz, Me), 1.50-1.64 (2H, m, H-2´), 2.89 (1H, ddd, J = 2.3, 11.9,
N
3
15.5 Hz, H-12a), 3.09-3.16 (1H, m, H-1´a), 3.44-3.66 (2H, m, overlap, H-12b, H-
N
H
7
O
6
OMe

1´b), 3.71 (3H, s, OMe), 3.83 (1H, d, J = 17.5 Hz, H-3a), 4.05 (1H, d, J = 17.48 Hz, H-3b), 4.27 (1H, dd, J = 11.9, 4.0
Hz, H-13), 6.73 (2H, d, J = 8.6 Hz, H-3´, H-5´), 6.94 (1H, br. s, H-6), 7.09-7.20 (4H, m, overlap, H-2´, H-6´, H-9, H-
10), 7.28 (1H, db, J = 7.9 Hz, H-8), 7.52 (1H, db, J = 8.6 Hz, H-11), 8.53 (1H, br. s, H-7). 13C NMR-68 MHz
(CDCl3): G 11.03 (Me), 19.61 (C-2´), 27.60 (C-12), 47.48 (C-1´), 49.29 (C-3), 51.50 (C-6), 52.38 (C-13), 55.20
(OMe), 108.61 (Cquat), 111.09 (C-8), 114.00 (C-3´, C-5´), 118.24 (C-11), 119.77 (C-10), 122.39 (C-9), 126.20 (Cquat),
129.94 (C-2´, C-6´), 130.04 (Cquat), 130.44 (Cquat), 136.28 (Cquat), 159.69 (Cquat), 161.78 (C=O), 165.19 (C=O). MS
m/z (%) 390 (M+H+, 30), 387 (30), 386 (100), 250 (25), 222 (10).
cis-6-(4-Methoxyphenyl)-2-butyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione 11g
Yield 90. White powder, mp: 176-177 oC, [D]D15 = -39.5° (c = 0.405, CH2Cl2).
O
1
H
N
12
6
11
8
1H NMR-270 MHz (CDCl3): G 0.93 (3H, t, J = 7.3 Hz, Me), 1.28-1.38 (2H, m,
H-3´), 1.48-1.59 (2H, m, H-2´), 3.16-3.34 (2H, m, overlap, H-1´a, H-12a),
3.52-3.63 (1H, m, H-1´b), 3.68 (3H, s, OMe), 3.70 (1H, dd, overlap, H-12b),
3.87 (1H, d, J = 17.5 Hz, H-3a), 4.00 (1H, d, J = 17.5 Hz, H-3b), 4.26 (1H, dd,
J = 11.2, 4.0 Hz, H-13), 6.21 (1H, br. s, H-6), 6.73 (2H, d, J = 8.6 Hz, H-3´´, H-
N
3
N
H
7
O
OMe
5´´), 7.13-7.25 (5H, m, overlap, H-2´´, H-6´´, H-8, H-9, H-10), 7.58 (1H, db, J = 7.9 Hz, H-11), 8.14 (1H, br. s, H-7).
13C NMR-68 MHz (CDCl3): G 13.00 (Me), 19.93 (C-3´), 23.45 (C-12), 28.95 (C-2´), 46.07 (C-1´), 50.28 (C-3), 55.17
(OMe), 55.99 (C-13), 56.21 (C-6), 106.47 (Cquat), 111.21 (C-8), 113.94 (C-3´, C-5´), 118.49 (C-11), 119.96 (C-10),
122.30 (C-9), 126.16 (Cquat), 128.50 (C-2´, C-6´), 133.14 (Cquat), 133.37 (Cquat), 136.48 (Cquat), 159.01 (Cquat), 166.34
(C=O), 167.19 (C=O). IR (KBr) Q 3247 (NH), 2955, 1671 (C=O), 1656 (C=O), 1623, 1511, 1425, 1320, 1249, 1174,
1029 cm-1. MS m/z (%). 418 (M+H+, 50), 311 (20), 310 (100).
trans-6-(4-Methoxyphenyl)-2-butpyl-2,3,6,7,12,12a-hexahydro-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
10f
o
15
O
Yield 93%. White powder, mp: 209-209.5 C, [D]D = -94.7° (c = 0.54,
CH2Cl2). 1H NMR-270 MHz (CDCl3): G 0.94 (3H, t, J = 7.3 Hz, Me), 1.25-1.36
(2H, m, H-3´), 1.39-1.58 (2H, m, H-2´), 2.90 (1H, dd, J = 15.2, 11.9 Hz, H-
12a), 3.11-3.21 (1H, m, H-1´a), 3.48-3.59 (2H, m, overlap, H-12b, H-1´b), 3.72
(3H, s, OMe), 3.88 (1H, dd, J = 17.8 Hz, H-3a), 4.06 (1H, d, J = 17.8 Hz, H-
3b), 4.27 (1H, dd, J = 11.9, 4.0 Hz, H-13), 6.74 (2H, d, J = 8.6 Hz, H-3´´, H-
1
H
N
12
6
11
8
N
3
N
H
O
7
OMe
5´´), 6.95 (1H, br. s, H-6), 7.10-7.26 (4H, m, overlap, H-2´´, H-6´´, H-9, H-10), 7.29 (1H, db, J = 8.3 Hz, H-8), 7.51
(1H, db, J = 8.2 Hz, H-11), 8.44 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G 13.69 (Me), 19.87 (C-3´), 27.60 (C-
12), 28.41 (C-2´) , 45.57 (C-1´), 49.31 (C-3), 51.52 (C-6), 52.40 (C-13), 55.24 (OMe), 108.68 (Cquat), 111.09 (C-8),
114.02 (C-3´´, C-5´´), 118.26 (C-11), 119.80 (C-10), 122.43 (C-9), 126.21 (Cquat), 129.97 (C-2´´, C-6´´), 130.04
(Cquat), 130.42 (Cquat), 136.28 (Cquat), 159.73 (Cquat), 161.78 (C=O), 165.10 (C=O). IR (KBr) Q 3316 (NH), 2954, 1666
(C=O), 1660 (C=O), 1622, 1584, 1513, 1452, 1308, 1253, 1175, 1160, 1034 cm-1. MS m/z (%). 418 (M+H+, 100), 391
(10), 347 (30), 311 (10), 310 (30).
7

cis-2-(4-Chlorobenzyl)-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-
1,4-dione 11i
o
15
O
Yield 91%. White powder, mp : 194-196 C. decomp, [D]D = -25° (c =
1
H
N
12
6
11
8
1
N
0.36, CH2Cl2). H NMR-270 MHz (CDCl3): G 3.28 (1H, ddd, d, J = 1.0,
3
11.5, 15.8 Hz, H-12a), 3.73 (3H, s, OMe), 3.80 (1H, dd, J = 5.0, 15.5 Hz,
H-12b), 3.83 (1H, d, J = 17.5 Hz, H-1´a), 3.94 (1H, d, J = 17.5 Hz, H-1´b),
4.36 (1H, dd, J = 5.0, 11.5 Hz, H-13), 4.37 (1H, d, J = 14.9 Hz, H-3a), 4.84
(1H, d, J = 14.9 Hz, H-3b), 6.21 (1H, br. s, H-6), 6.76 (2H, d, J = 8.9 Hz,
N
H
7
Cl
O
OMe
H-3´´, H-5´´), 7.15-7.32 (8H, m, 8x =CH), 7.62 (1H, db, J = 9.2 Hz, H-11), 7.83 (1H, br. s, H-7). 13C NMR-68 MHz
(CDCl3): G 23.59 (C-12), 49.13 (C-1´), 49.85 (C-3), 55.20 (C-13), 56.05 (OMe), 56.24 (C-6), 106.45 (Cquat), 111.23
(C-8), 113.98 (C-3´, C-5´), 118.51 (C-11), 119.57 (Cquat), 120.07 (C-10), 122.44 (C-9), 126.16 (Cquat), 128.55 (C-2´,
C-6´), 129.14 (2x =CH), 129.70 (2x=CH), 133.04 (Cquat), 133.22 (Cquat), 133.78 (Cquat), 136.50 (Cquat), 159.10 (Cquat),
166.67(C=O), 166.73 (C=O). IR (KBr) Q 3333 (NH), 2928, 1686 (C=O), 1642 (C=O), 1623, 1510, 1491, 1438, 1409,
1307, 1251, 1091 cm-1. MS m/z (%). 486 (M+H+, 90), 378 (70), 264 (30), 230 (30), 125 (100).
trans-2-(4-Chlorobenzyl)-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-
1,4-dione 10h
o
15
O
Yield 92%. White powder, mp: 277-279 C, [D]D = -64.8° (c = 0.46,
CH2Cl2). 1H NMR-270 MHz (CDCl3): G 2.94 (1H, dd, d, J = 11.9, 14.2 Hz,
H-12a), 3.60 (1H, dd, J = 4.3, 14.2 Hz, H-12b), 3.75 (3H, s, OMe), 3.84
(1H, d, J = 17.5 Hz, H-1´a), 3.95 (1H, d, J = 17.5 Hz, H-1´b), 4.32 (1H, d,
J = 14.5 Hz, H-3a), 4.37 (1H, dd, J = 4.3, 11.9 Hz, H-13), 4.75 (1H, d, J =
14.5 Hz, H-3b), 6.78 (2H, d, J = 8.6 Hz, H-3´´, H-5´´), 6.95 (1H, br. s, H-
1
H
N
12
6
11
8
N
3
N
H
Cl
O
7
OMe
6), 7.14-7.34 (9H, m, 9x =CH), 7.54 (1H, db, J = 7.9 Hz, H-11), 8.08 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G
27.78 (C-12), 48.72 (C-1´), 48.84 (C-3), 51.55 (C-6), 52.43 (C-13), 55.31 (OMe), 108.73 (Cquat), 111.12 (C-8), 114.14
(C-3´, C-5´), 118.34 (C-11), 120.02 (C-10), 122.64 (C-9), 126.22 (Cquat), 129.18 (C-2´, C-6´), 129.88 (2x=CH),
129.97 (Cquat), 130.06 (2x=CH), 130.26 (Cquat), 133.44 (Cquat), 134.19 (Cquat), 136.26 (Cquat), 159.91 (Cquat), 161.45
(C=O), 165.46 (C=O). IR (KBr) Q 3323 (NH), 2927, 1686 (C=O), 1652 (C=O), 1624, 1611, 1512, 1467, 1330, 1255,
1176, 1185, 1092, 1033 cm-1. MS m/z (%). 486/488 (M+H+, 100), 391 (50), 380 (25), 378 (40), 279 (25), 238 (20),
149 (350).
cis-2-Benzyl-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
11h
Yield 89%. White powder, mp: 190-191 oC, [D]D15 = -32.6° (c = 0.46, CH2Cl2).
1H NMR-270 MHz (CDCl3): G 3.28 (1H, dd, d, J = 10.9, 15.2, H-12a), 3.70
O
1
H
N
12
6
11
8
N
3
N
H
7
8
O
OMe

(3H, s, OMe), 3.82 (1H, dd, J = 4.6, 15.2 Hz, H-12b), 3.84 (1H, d, J = 17.5 Hz, H-1´a), 3.93 (1H, d, J = 17.5 Hz, H-
1´b), 4.34 (1H, dd, J = 4.6, 10.9 Hz, H-13), 4.38 (1H, d, J = 14.5 Hz, H-3a), 4.90 (1H, d, J = 14.5 Hz, H-3b), 6.20
(1H, br. s, H-6), 6.74 (2H, d, J = 8.6 Hz, H-3´´, H-5´´), 7.14-7.35 (10H, m, 10x =CH), 7.61 (1H, db, J = 8.9 Hz, H-
11), 7.93 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G 23.65 (C-12), 49.74 (C-1´), 49.79 (C-3), 55.20 (C-13), 56.05
(OMe), 56.28 (C-6), 106.54 (Cquat), 111.21 (C-8), 113.98 (C-3´´, C-5´´), 118.53 (C-11), 120.05 (C-10), 122.41 (C-9),
126.20 (Cquat), 128.12 (=CH), 128.33 (2x =CH), 128.52 (2x=CH), 128.97 (2x=CH), 133.10 (Cquat), 133.33 (Cquat),
135.20 (Cquat), 136.49 (Cquat), 159.06 (Cquat), 166.57 (C=O), 166.95 (C=O). IR (KBr) Q 3323 (NH), 2928, 1686
(C=O), 1641 (C=O), 1609, 1509, 1495, 1438, 1415, 1363, 1322, 1306, 1277, 1218, 1174, 1030 cm-1. MS m/z (%).
452 (M+H+, 100), 445 (15), 320 (15), 319 (15), 212 (9), 196 (45).
trans-2-Benzyl-6-(4-methoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
10g
15
Yield 85%. White powder, mp: 230oC decomp, [D]D = -53.3° (c = 0.45,
O
1
H
N
12
6
11
8
CH2Cl2). 1H NMR-270 MHz (CDCl3): G 2.94 (1H, dd, d, J = 11.6, 15.5 Hz, H-
12a), 3.56 (1H, dd, J = 5.0, 15.5 Hz, H-12b), 3.72 (3H, s, OMe), 3.83 (1H, d, J
= 17.8 Hz, H-1´a), 3.92 (1H, d, J = 17.8 Hz, H-1´b), 4.29 (1H, d, J = 14.5 Hz,
H-3a), 4.36 (1H, dd, J = 4.0, 11.6 Hz, H-13), 4.82 (1H, d, J = 14.5 Hz, H-3b),
6.75 (2H, d, J = 8.6 Hz, H-3´´, H-5´´), 6.92 (1H, br. s, H-6), 7.24-7.30 (4H, m,
N
3
N
H
7
O
OMe
4x =CH), 7.31-7.54 (6H, m, 6x =CH), 7.53 (1H, db, J = 8.2 Hz, H-11), 8.27 (1H, br. s, H-7). 13C NMR-68 MHz
(CDCl3): G 27.87 (C-12), 48.86 (C-1´), 49.34 (C-3), 51.57 (C-6), 52.52 (C-13), 55.34 (OMe), 108.86 (Cquat), 111.14
(C-8), 114.17 (C-3´´, C-5´´), 118.38 (C-11), 120.02 (C-10), 122.62 (C-9), 126.29 (Cquat), 128.24 (=CH), 128.53 (C-
2´´, C-6´´), 129.02 (2x=CH, Cquat), 130.10 (2x=CH), 130.36 (Cquat), 133.91 (Cquat), 136.31 (Cquat), 159.92 (Cquat),
161.68 (C=O), 165.42 (C=O). IR (KBr) Q 3323 (NH), 2927, 1686 (C=O), 1652 (C=O), 1624, 1611, 1512, 1467, 1330,
1255, 1176, 1185, 1092, 1033 cm-1. MS m/z (%). 486 (M+H+, 100), 391 (50), 380 (25), 378 (40), 279 (25), 238 (20),
194 (100).
4. Synthesis of trans-ethyl-2-(2-bromoethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-
carboxylate 12
A mixture of 6a (800 mg, 2.5 mmol), 1,2-dibromoethane (5.52 g, 60.4 mmol) and K2CO3 (380 mg, 2.75 mmol) was
stirred at reflux for 24 h. Then, the mixture was poured in water and extracted with EtOAc for three times. The
combined organic phases were washed with saturated NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification
by means of column chromatography on silicagel (hexane/EtOAc) gave pure 12 in 48% yield.
trans-Ethyl-2-(2-bromoethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-ȕ-carboline-3-carboxylate 12
1
O
Yield 45%. Yellow oil. H NMR-300 MHz (CDCl3): Gꢀ1.19 (3H, t, J = 7.2 Hz, Me),
1
5
4
1
6
3.00 (1H, dd, J = 3.58, 9.1 Hz, H-4a), 3.10-3.22 (3H, m, overlap, H-4b, H-1´), 3.29-
OEt
Br
N
N
8
H
9

3.35 (2H, m, H-2´), 4.01-4.17 (3H, m, overlap, H-3, OCH2), 5.42 (1H, s, H-6), 7.05-7.16 (3H, m, 3x =CH), 7.24-7.39
(5H, m, 5x =CH), 7.51 (1H, db, J = 8.8, H-5). 13C NMR-68 MHz (CDCl3): G 14.21 (Me), 24.94 (C-2´), 31.42 (C-4),
54.70 (C-1´), 59.51 (C-3), 60.61 (OCH2), 61.62 (C-1), 106.14 (Cquat), 110.81 (C-8), 118.22 (C-5), 119.36 (C-6),
121.70 (C-7), 126.88 (Cquat), 128.37 (=CH), 128.78 (2x =CH), 129.01 (2x =CH), 134.86 (Cquat), 136.48 (Cquat), 141.82
(Cquat), 173.18 (C=O). IR (KBr) Q 3396 (NH), 2927, 2854, 1731 (C=O), 1603, 1493, 1463, 1455, 1268, 1186, 1113,
1028 cm-1. MS m/z (%) 443/445 (M+H+, 10), 426/428 (10), 426/428 (30), 363/365(10), 348 (27), 347 (100), 220 (32).
5. General procedure for the synthesis of compounds 13
A mixture of 12 (100 mg, 0.25 mmol) and the appropriate amine (1.25 mmol) in dry EtOH (10 ml) was stirred for 24
h at room temperature. Then, the solvent was evaporated and the residue extracted with EtOAc. The combined
organic phases were washed with saturated NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means
of column chromatography on silicagel (hexane/EtOAc) gave pure 13.
trans-2-Methyl-6-phenyl-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-1-one 13a
o
1
O
Yield 94%. White powder, mp: 253.4-255.8 C H NMR-300 MHz (CDCl3): Gꢀ2.48
(1H, ddd, J = 3.99, 9.20, 12.11 Hz, H-3a), 2.93 (3H, s, Me), 2.95 (1H, dd, J = 11.01,
15.93 Hz, H-12a), 3.05 (1H, dt, J = 12.11, 3.99 Hz, H-3b), 3.20 (1H, dt, J = 11.55,
3.99 Hz, H-4a), 3.48 (1H, dd, J = 15.93, 4.68 Hz, H-12b), 3.58 (1H, ddd, J = 11.55,
3.99, 9.20 Hz, H-4b), 3.70 (1H, dd J = 11.01, 4.68 Hz, H-13), 5.11 (1H, s, H-6), 7.08-
1
H
N
12
6
11
8
Me
N
3
N
H
4
7
7.20 (4H, m, 4x =CH), 7.22-7.33 (4H, m, 4x =CH), 7.58 (1H, db, J = 8.81, H-11), 7.78 (1H, br. s, H-7). 13C NMR-68
MHz (CDCl3): G 24.87 (C-12), 34.39 (Me), 46.70 (C-3), 48.41 (C-4), 54.66 (C-13), 63.13 (C-6), 109.21 (Cquat),
110.84 (C-8), 118.59 (C-11), 119.58 (C-10), 122.04 (C-9), 126.89 (Cquat), 128.37 (3x =CH), 129.52 (2x =CH), 131.93
(Cquat), 136.39 (Cquat), 137.21 (Cquat), 169.93 (C=O). IR (KBr) Q 3219 (NH), 2924, 2853, 1632 (C=O), 1493, 1454,
1333, 1164, 1074 cm-1. MS m/z (%). 332 (M+H+, 80), 328 (10), 221 (10), 220 (100).
trans-6-Phenyl-2-propyl-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-1-one 13b
o
1
O
Yield 90%. White powder, mp : 215.5-216.5 C. H NMR-300 MHz (CDCl3):
Gꢀꢁꢂꢃꢃꢀꢄꢅ+ꢆꢀm, Me), 1.46-1.60 (2H, m, H-2´), 2.42 (1H, ddd, J = 3.9, 9.9, 11.9 Hz,
H-3a), 2.92 (1H, dd, J = 11.3, 16.0 Hz, H-12a), 3.04 (1H, dt, J = 11.9, 4.0 Hz, H-
3b), 3.13-3.20 (2H, m, overlap, H-1´a, H-4a), 3.42-3.60 (3H, m, overlap, H-1´b,
H-4b, H-12b), 3.70 (1H, dd J = 11.0, 4.7 Hz, H-13), 5.12 (1H, s, H-6), 7.08-7.15
1
H
N
12
6
11
8
N
3
N
H
4
7
(4H, m, 4x =CH), 7.17-7.30 (4H, m, 4x =CH), 7.57 (1H, db, J = 8.8 Hz, H-11), 7.74 (1H, br. s, H-7). 13C NMR-68
MHz (CDCl3): G 11.22 (Me), 20.17 (C-2´), 25.44 (C-12), 46.34 (C-1´), 46.93 (C-3), 48.44 (C-4), 54.76 (C-13), 63.15
(C-6), 109.39 (Cquat), 110.83 (C-8), 118.59 (C-11), 119.55 (C-10), 121.99 (C-9), 126.91 (Cquat), 128.34 (3x =CH),
129.59 (2x =CH), 132.02 (Cquat), 136.39 (Cquat), 136.92 (Cquat), 169.58 (C=O). IR (KBr) Q 3218 (NH), 2937, 2872,
1623 (C=O), 1496, 1455, 1332, 1336, 1265, 1227, 1164 cm-1. MS m/z (%). 360 (M+H+, 100), 356 (30), 357 (30), 221
(10), 220 (98).
10

trans-2-(4-Chlorobenzyl)-6-phenyl-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-1-one
13d
o
1
O
Yield 92%. White powder, mp: 98-99 C. H NMR-300 MHz (CDCl3):
Gꢀ2.41 (1H, ddd, J = 3.9, 9.9, 11.6 Hz, H-3a), 2.95-3.15 (3H, m, overlap, H-
3b, H-4a, H-12a), 3.46 (1H, ddd, J = 11.3, 11.0, 3. 9 Hz, H-4b), 3.57 (1H,
dd, J = 16.0, 5.0 Hz, H-12b), 3.78 (1H, dd, J = 11.0, 5.0, H-13), 4.54 ( 2H,
t, J = 16.8 Hz, H-1´), 5.13 (1H, s, H-6), 7.09-7.33 (12H, m, 12x =CH), 7.61
1
H
N
12
6
11
8
N
3
Cl
N
H
4
7
(1H, db, J = 8.8 Hz, H-11), 7.65 (1H, br. s, H-7). 13C NMR-68 MHz (CDCl3): G 25.37 (C-12), 45.82 (C-4), 46.90 (C-
3), 49.35 (C-1´), 54.95 (C-13), 63.13 (C-6), 109.23 (Cquat), 110.86 (C-8), 118.62 (C-11), 119.68 (C-10), 122.13 (C-9),
126.86 (Cquat), 128.43 (2x =CH), 128.84 (2x =CH), 129.47 (3x =CH), 129.56 (2x =CH), 131.93 (Cquat), 133.40 (Cquat),
135.17 (Cquat), 136.39 (Cquat), 136.91 (Cquat), 169.99 (C=O). IR (KBr) Q 3401 (NH), 2914, 2853, 1658 (C=O), 1597,
1492, 1467, 1452, 1324, 1159 cm-1. MS m/z (%). 442/444 (M+H+, 100), 438/440 (70), 220 (88).
trans-2-Benzyl-6-phenyl-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyrido[3,4-b]indol-1-one 13c
Yield 93%. White powder, mp: 109-110 oC. 1H NMR-300 MHz (CDCl3): Gꢀ2.37
O
1
H
N
12
6
11
8
(1H, ddd, J = 3.9, 9.6, 11.6 Hz, H-3a), 2.97 (1H, dd, J = 4.2, 11.6 Hz, H-3b),
3.01-3.17 (2H, m, overlap, H-12a, H-4a), 3.43 (1H, ddd, J = 15.1, 4.2, 10.0 Hz,
H-4b), 3.58 (1H, dd, J = 16.0, 5.0 Hz, H-12b), 3.76 (1H, dd, J = 11.0, 5.0 Hz,
H-13), 4.51 (1H, d, J = 14.6 Hz, H-1´a), 4.59 (1H, d, J = 14.6 Hz, H-1´d), 5.07
N
3
N
H
7
4
(1H, s, H-6), 7.05-7.38 (13H, m, 13x =CH), 7.58 (1H, db, J = 8.8 Hz, H-11), 7.89 (1H, br. s, H-7). 13C NMR-68 MHz
(CDCl3): G 25.37 (C-12), 45.74 (C-4), 46.87 (C-3), 49.89 (C-1´), 54.93 (C-13), 63.10 (C-6), 109.12 (Cquat), 110.89 (C-
8), 118.56 (C-11), 119.56 (C-10), 122.01 (C-9), 126.89 (Cquat), 127.50 (=CH), 128.05 (2x =CH), 128.36 (3x =CH),
128.66 (2x =CH), 129.55 (2x =CH), 132.05 (Cquat), 136.44 (Cquat), 136.59 (Cquat), 137.09 (Cquat), 169.96 (C=O). IR
(KBr) Q 3400 (NH), 2916, 2853, 1633 (C=O), 1597, 1493, 1467, 1454, 1328, 1258, 1146, 1074cm-1. MS m/z (%) 408
(M+H+, 100), 404 (40), 221 (12), 420 (80), 412 (27), 178 (17).
6. General procedures for the synthesis of compounds 18
9b (500 mg, 0.226 mmol) and NBS (65 mg, 1.13 mmol) in a mixture of THF (10ml), CH3COOH (10ml) and H2O
(10ml) were stirred at 0 oC for 15 min and subsequently at room temperature for 3 h. Then, the mixture was poured in
water and extracted tree times with EtOAc. The combined organic phases were washed with aqueous Na2CO3, dried
(MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silicagel (hexane/EtOAc,
4/6) gave pure 18b (460 mg, 88%).
11

Ethyl-3-(2-benzoyl-1H-indol-3-yl)-2-(2-chloroacetylamino)-propionate 18a
1
Cl
Yield 84%. White powder, mp. 158°C. H NMR-300 MHz (CDCl3): Gꢀ1.24 (3H, t, J = 7.2
Hz, CH3CH2), 3.54-3.62 (2H, m, CH2-3), 3.83 (1H, d, JAB = 15.4 Hz, CHAHBCl), 3.96 (1H,
d, JAB = 15.4 Hz, CHAHBCl), 4.05-4.22 (2H, m, CH2CH3), 4.75 (1H, td, J = 6.1, 7.2 Hz, CH-
2), 7.22 (1H, sextet, J = 4.4 Hz, CHAr), 7.39 (2H, d, J = 3.9 Hz, 2xCHAr), 7.53-7.58 (2H, m,
2xCHAr), 7.63-7.67 (1H, m, CHAr), 7.77-7.84 (3H, m, 3xCHAr), 8.15 (1H, br. d, J = 6.6 Hz,
NH), 8.51 (1H, br. s, NH). 13C NMR-75 MHz (CDCl3): G 14.12 (CH3CH2), 26.70 (CH2-3),
42.27 (CH2Cl), 54.76 (CH-2), 61.71 (CH2CH3), 112.55 (CHAr), 119.91 (Cquat), 120.72
O
1
EtO2C
NH
2
3
O
N
H
(CHAr), 121.25 (CHAr), 126.78 (CHAr), 127.73 (Cquat), 128.93 (2xCHAr), 129.39 (2xCHAr), 131.94 (Cquat), 132.84
(CHAr), 136.51 (Cquat), 138.29 (Cquat), 166.66 (HN-C=O), 171.27 (EtO-C=O), 188.68 (Ph-C=O). IR (ATR) Q 3264
(NH), 1752 (C=O), 1649 (C=O), 1632 (C=O), 1535, 1446, 1269, 1179 cm-1. MS m/z (%) 413 (M+H+, 100), 415 (32).
Ethyl-3-(2-(4-methoxybenzoyl)-1H-indol-3-yl)-2-(2-chloroacetylamino)-propionate 18b
1
Cl
Yield 88%. White powder, mp. 175.5°C. H NMR-300 MHz (CDCl3): Gꢀ1.25 (3H, td, J
= 7.4, 1.7 Hz, CH3CH2), 3.51-3.60 (2H, m, CH-3), 3.84 (1H, d, JAB = 14.8 Hz,
CHAHBCl), 3.92 (3H, s, OCH3), 3.97 (1H, d, JAB = 14.8 Hz, CHAHBCl), 4.04-4.21 (2H,
m, CH2CH3), 4.73 (1H, q, J = 6.6 Hz, CH-2), 7.01-7.04 (2H, m, 2xCHAr), 7.19-7.25
(1H, m, CHAr), 7.38-7.40 (2H, m, 2xCHAr), 7.76-7.86 (3H, m, 3xCHAr), 8.38 (1H, br. d,
J = 5.5 Hz, NH), 8.49 (1H, br. s, NH). 13C NMR-75 MHz (CDCl3): G 14.07 (CH3CH2),
26.50 (CH2-3), 42.26 (CH2Cl), 54.91 (CH-2), 55.66 (OCH3), 61.74 (CH2CH3), 112.60
(CHAr), 114.14 (2xCHAr), 119.01 (Cquat), 120.46 (CHAr), 121.07 (CHAr), 126.38 (CHAr),
O
NH
EtO2C
O
N
H
OMe
127.59 (Cquat), 130.67 (Cquat), 132.05 (2xCHAr), 132.40 (Cquat), 136.41 (CHAr), 163.58 (Cquat-OMe), 166.86 (HN-
C=O), 171.39 (EtO-C=O), 187.36 (Ph-C=O). IR (ATR) Q 3253 (NH), 2982, 1732 (C=O), 1650 (C=O), 1626, 1597,
1531, 1509, 1252, 1170, 1024 cm-1. MS m/z (%) 443 (M+H+, 100), 445 (40).
7. General procedure for the synthesis of 3-(2-aroyl-1H-indol-3-ylmethyl)- piperazine-2,5-diones
19
A mixture of 18b (100 mg, 0.226 mmol) and propylamine (65 mg, 1.25 mmol) in dry EtOH (10ml) was stirred for
24h at room temperature. Then, the mixture was poured in water and extracted with EtOAc for three times. The
combined organic phases were washed, dried (MgSO4) and evaporated in vacuo. Purification by means of column
chromatography on silicagel (EtOAc/MeOH, 9/1) gave pure 19b (76 mg, 80%).
3-(2-Benzoyl-1H-indol-3-ylmethyl)-1-propylpiperazine-2,5-dione 19a
12

1
O
O
Yield 80%. Pale white powder, mp. 221°C decomp. H NMR-300 MHz (CDCl3):
Gꢀ0.84 (3H, t, J = 7.3 Hz, CH3CH2), 1.42-1.51 (2H, m, CH2CH3), 3.15-3.37 (4H, m,
NCH2 and CH2-1’), 3.56-3.70 (2H, m, CH2-6), 4.15-4.22 (1H, br. s, CH-3), 7.14
(1H, d, J = 16.0 Hz, NH), 7.21-7.28 (1H, m, CHAr), 7.33-7.39 (2H, m, 2xCHAr),
7.43-7.55 (4H, m, 4xCHAr), 7.61-7.65 (1H, m, CHAr), 7.82 (1H, m, J = 7.7 Hz,
N
HN
O
N
H
CHAr), 10.62 (1H, br. d, J = 28.1 Hz, NH). 13C NMR-75 MHz (CDCl3): G 11.11 (CH3CH2), 19.80 (CH3CH2), 29.68
(CH-1’), 47.91 (NCH2), 49.14 (CH2-6), 56.71 (CH-3), 112.84 (CHAr), 118.50 (Cquat), 121.13 (CHAr), 121.24 (CHAr),
126.90 (CHAr), 127.39 (Cquat), 128.58 (2xCHAr), 129.31 (2xCHAr), 132.26 (CHAr), 132.84 (Cquat), 137.36 (Cquat),
137.41 (Cquat), 138.69 (Cquat), 165.81 (HN-C=O), 166.26 (HN-C=O), 189.06 (Ph-C=O). IR (ATR) Q 3254 (NH), 2932,
1738 (C=O), 1677 (C=O), 1664 (C=O), 1598, 1524, 1434, 1252, 1170 cm-1. MS m/z (%) 390 (M+H+, 100).
3-[2-(4-Methoxybenzoyl)-1H-indol-3-ylmethyl]-1-propylpiperazine-2,5-dione 19b
Yield 80%. Pale white powder, mp. 210.5°C. 1H NMR-300 MHz (CDCl3): Gꢀ0.82-
O
N
0.89 (3H, m, CH3CH2), 1.38-1.48 (2H, m, CH2CH3), 3.03-3.64 (6H, m, NCH2,
CH2-1’ and CH2-6), 4.06-4.18 (1H, br. s, CH-3), 6.745-6.78 (2H, m, CHAr), 6.95
(1H, br. s, NH), 7.18-7.48 (4H, m, 4xCHAr), 7.43-7.55 (4H, m, 4xCHAr), 7.58 (1H,
HN
O
N
H
O
d, J = 7.7 Hz, CHAr), 7.75 (1H, d, J = 8.3 Hz, CHAr), 10.23 (1H, br. s, NH). 13
C
MeO
NMR-75 MHz (CDCl3): G 11.05 (CH3CH2), 19.77 (CH3CH2), 28.82 (CH-1’),
47.68 (NCH2), 49.16 (CH2-6), 55.59 (OCH3), 56.29 (CH-3), 112.90 (CHAr), 113.73 (2xCHAr), 117.65 (Cquat), 120.91
(CHAr), 121.13 (CHAr), 126.28 (CHAr), 127.36 (Cquat), 130.90 (Cquat), 131.90 (2xCHAr), 133.06 (Cquat), 136.99 (Cquat),
163.12 (Cquat-OMe), 166.02 (HN-C=O), 166.29 (HN-C=O), 187.53 (Ph-C=O). IR (ATR) Q 3396 (NH), 3257 (NH),
1683 (C=O), 1651 (C=O), 1627 (C=O), 1606, 1463, 1423, 1316, 1253, 1031 cm-1. MS m/z (%) 420 (M+H+, 100).
13