A simple and effective approach to the synthesis of pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of arnoamines A and B, pentacyclic marine alkaloids from the ascidian Cystodytes sp.

Article abstract of DOI:10.1016/j.tetlet.2006.08.080

Starting from ethyl 5-hydroxy-2-methyl-1-phenylindole-3-carboxylate, a simple and effective approach to the synthesis of pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of arnoamines A and B, unique pentacyclic alkaloids from the ascidian Cystodytes sp

Full text of DOI:10.1016/j.tetlet.2006.08.080

Tetrahedron Letters 47 (2006) 7819–7822
A simple and effective approach to the synthesis
of pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton
of arnoamines A and B, pentacyclic marine alkaloids
from the ascidian Cystodytes sp.
Oleg S. Radchenko,* Nadezhda N. Balaneva, Vladimir A. Denisenko
and Vyacheslav L. Novikov
Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences, 690022, Vladivostok-22, Russia
Received 15 June 2006; revised 7 July 2006; accepted 17 August 2006
Available online 18 September 2006
Dedicated to the memory of Professor George B. Elyakov, who has been an inspiration to us over the years
Abstract—Starting from ethyl 5-hydroxy-2-methyl-1-phenylindole-3-carboxylate, a simple and effective approach to the synthesis of
pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of arnoamines A and B, unique pentacyclic alkaloids from the ascidian Cysto-
dytes sp., has been developed. Synthesis of this ring system involves seven steps and produces ethyl 4-methoxy-1-methyl-
pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine-2-carboxylate in 41.5% overall yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Arnoamines A 1 and B 2 are the first members of a new
family of marine cytotoxic alkaloids possessing a pyrido-
[4,3,2-mn]pyrrolo[3,2,1-de]acridine ring system which
has not been previously observed in nature.1 In 2000,
Delfourne and co-workers accomplished the first synthe-
sis of these alkaloids.2
product,
ethyl
4-methoxypyrido[4,3,2-mn]pyrrolo-
[3,2,1-de]acridine-1-carboxylate, having the ring system
of arnoamines A and B, was formed in 10 steps with
a 5.5% overall yield, using many expensive chemicals.
Now, we report a simple and effective approach to the
synthesis of pyridopyrroloacridine ring system of arno-
amines A and B.
10
11
9
8
The starting material in our sequence (Scheme 1) was
the known indole 3 readily available by the condensa-
tion of p-benzoquinone with commercially available
ethyl 3-anilinocrotonate.3,4
11a
7b
11b
1
N
1 R=H arnoamine A
2 R=Me arnoamine B
7a
2b
2
7
6
2a
4b
3
4a
N
4
The treatment of 3 with dimethyl sulfate in the presence
of base gave methyl ether 4 in 95% yield. Nitration of 4
with 75% nitric acid in acetic anhydride at ꢀ10 °C affor-
ded a mixture of nitro derivatives 5 and 6 which was sep-
arated by flash chromatography5 to give the desired
nitro compound 5 with 63% yield.6 The conversion of
5 to amine 7 was then achieved in almost quantitative
yield using reduction on Raney nickel.7
5
OR
Starting from commercially available 2-methoxy-5-
nitroaniline, arnoamine B 2 was obtained in 12 steps
with a 5% overall yield. In this synthesis, a pentacyclic
Keywords: Synthesis; Marine alkaloids; Arnoamines A and B; Pyrido-
[4,3,2-mn]pyrrolo[3,2,1-de]acridines; Ascidians; Cytotoxines.
Amine 7 was treated with 5-(methoxymethylene)-2,2-di-
methyl-1,3-dioxane-4,6-dione8 to produce Meldrum’s
acid derivative 8 in 95% yield.9 The thermal cyclization
*
Corresponding author. Tel.: +7 4232 319 932; fax: +7 4232 314
050; e-mail: radchenko@piboc.dvo.ru
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.080

7820
O. S. Radchenko et al. / Tetrahedron Letters 47 (2006) 7819–7822
R2
18
4
9,10
8
COOEt
Me
COOEt
COOEt
3a
RO
MeO
R1
5
MeO
3
b
c
2
11
98%
N
N
6
7a
N1
12
Me
H2N
Me
7
Ph
Ph
13
14
17
3 R=H
95%
4 R=Me
5 R1=NO2, R2=H (63%)
6 R1=H, R2=NO2 (30%)
7
a
16
15
COOEt
MeO
9,10
8
18
4
COOEt
5
MeO
3a
3
19
d
e
HN
N1 Me
Ph
2
6
19
11
80%
95%
20 CH
7a
HN
N1
Me
7
O
26
O
22
Ph
21
20
O
22
12-17
21
24
O
O
8
9
Me
28
Me
27
3
COOEt
Me
4
MeO
2a
COOEt
Me
MeO
N
2
4a
2b
g
f
5 N
11bN
1
4b
7a
96%
N
11a
97%
7b
6
11
10
Ph
7
Cl
8
11
9
10
Scheme 1. Reagents and conditions: (a) Me2SO4, 2 N NaOH, H2O, dioxane, rt, 30 min; (b) HNO3 (75%), Ac2O, ꢀ10 °C, 3 h; (c) Ni(Ra), H2, i-PrOH,
60 °C, 2 h; (d) Meldrum’s acid, CH(OMe)3, reflux, 1 h; (e) Ph2O, N2, 220 °C, 30 min; (f) POCl3, reflux, 30 min; (g) Bu3SnH, AIBN, PhH, reflux, 24 h.
Table 1. 13C and 1H NMR data for 11 in CDCl3 at 75 and 300 MHz, respectively
Atom
dC (mult)a
dH (mult, J, Hz)
HSQC, HMBC (1H ! 13C)
1
2
2a
2b
3
138.4 s
109.9 s
120.8 s
137.9 s
102.6 d
7.69 s
H(3) ! C(3) H(3) ! C(2a)
H(3) ! C(2b) H(3) ! C(2)
H(3) ! C(4) H(3) ! C(4a)
H(3) ! C(4b)
4
150.8 s
113.3 s
116.2 s
147.4 d
4a
4b
6
8.98 d, J = 5.2
7.80 d, J = 5.2
H(6) ! C(6) H(6) ! C(7)
H(6) ! C(7a) H(6) ! C(4a)
H(6) ! C(7b) H(6) ! C(2b)
H(7) ! C(7) H(7) ! C(6)
H(7) ! C(4a) H(7) ! C(7b)
H(7) ! C(2b) H(7) ! C(2a)
7
110.6 d
7a
7b
8
132.1 s
122.0 s
125.5 d
8.34 dd, J1 = 8.0, J2 = 1.6
H(8) ! C(8) H(8) ! C(10)
H(8) ! C(7a) H(8) ! C(7b)
H(8) ! C(11a) H(8) ! C(11)
H(9) ! C(9) H(9) ! C(11)
H(9) ! C(7b) H(9) ! C(8)
H(9) ! C(11a)
9
124.7 d
130.5 d
117.5 d
7.46 ddd, J1 = 8.0, J2 = 7.2, J3 = 0.6
7.61 ddd, J1 = 8.6, J2 = 7.2, J3 = 1.6
8.23 dd, J1 = 8.6, J2 = 0.6
10
11
H(10) ! C(10) H(10) ! C(11)
H(10) ! C(8) H(10) ! C(7b)
H(10) ! C(11a)
H(11) ! C(11) H(11) ! C(9)
H(11) ! C(11a) H(11) ! C(7b)
H(11) ! C(7a)

O. S. Radchenko et al. / Tetrahedron Letters 47 (2006) 7819–7822
7821
Table 1 (continued)
Atom
dC (mult)a
dH (mult, J, Hz)
HSQC, HMBC (1H ! 13C)
H(OMe) ! C(4)
11a
OCH3
CO
136.2 s
55.9 q
166.0 s
60.1 t
4.14 s
OCH2CH3
4.50 q, J = 7.1
H(OCH2CH3) ! C(CO)
H(OCH2CH3) ! C(OCH2 CH3)
H(OCH2 CH3) ! C(OCH2CH3)
OCH2CH3
CH3
14.5 q
15.9 q
1.57 t, J = 7.1
3.26 s
H(CH3) ! C(CH3) H(CH3) ! C(1)
H(CH3) ! C(2) H(CH3) ! C(11)
H(CH3) ! C(CO)
a Carbon multiplicities were assigned on the basis of the results of DEPT-135, DEPT-90, HSQC, and HMBC experiments.
135.4 (s, C-12), 136.2 (s, C-7a), 149.8 (s, C-5), 150.1 (s, C-
of 8 in diphenyl ether at 220 °C gave the cyclized prod-
uct 9 in 80% yield.10 When 9 was treated with phospho-
rus oxychloride at reflux, the chloro derivative 10 was
obtained.11 The thermal cyclization of 10 in benzene at
reflux under the action of tri-n-butyltin hydride in the
presence of a,a0-azoisobutyronitrile furnished ethyl 4-
methoxy-1-methylpyrido[4,3,2-mn]pyrrolo[3,2,1-de]acri-
dine-2-carboxylate 11 in 97% yield.12 Thus, compound
11, possessing the unique pentacyclic ring system of
arnoamines A and B, was synthesized from ethyl 5-hy-
droxy-2-methyl-1-phenylindole-3-carboxylate 3 in seven
steps in 41.5% overall yield. The structure of 11 was con-
2), 165.2 (s, C-8); EIMS (15 eV): m/z (%) = 354 (M+, 22),
353 (M+ꢀ1, 100), 352 (M+ꢀ2, 87), 323 (14), 322 (68), 321
(53), 205 (10). Anal. Calcd for C19H18N2O5: C, 64.38; H,
5.12; N, 7.91. Found: C, 64.52; H, 5.16; N, 8.07.
Numeration of atoms is given in structural formulae of
compounds 7–9, and 11.
7. Compound 7: pale yellow prisms; mp 72–75 °C; IR (CCl4)
m
max: 3481, 3391, 1696, 1634, 1598, 1544, 1503, 1491, 1475,
1
1396, 1301, 1197, 1151, 1076 cmꢀ1; H NMR (300 MHz,
CDCl3) d: 1.45 (t, J = 7.1 Hz, 3H), 2.51 (s, 3H), 3.94 (s,
3H), 4.41 (q, J = 7.1 Hz, 2H), 6.35 (s, 1H, H-7), 7.28 (m,
2Harom), 7.58 (m, 3Harom), 7.60 (s, 1H, H-4); 13C NMR
(75 MHz, CDCl3) d: 13.0 (q, C-11), 14.6 (q, C-10), 55.9 (q,
C-18), 59.3 (t, C-9), 96.3 (d, C-7), 102.3 (d, C-4), 104.9 (s,
C-3), 118.7 (s, C-3a), 128.2 (d, C-13, C-17), 128.5 (d, C-
15), 129.6 (d, C-14, C-16), 132.7 (s, C-6), 133.4 (s, C-7a),
137.0 (s, C-12), 142.3 (s, C-2), 145.4 (s, C-5), 166.3 (s, C-8);
EIMS (15 eV): m/z (%) = 324 (M+, 21), 323 (M+ꢀ1, 100),
322 (M+ꢀ2, 93), 309 (7), 308 (33), 307 (28). Anal. Calcd
for C19H20N2O3: C, 70.34; H, 6.22; N, 8.64. Found: C,
70.50; H, 6.19; N, 8.74.
1
firmed by H and 13C NMR measurements (Table 1).
In conclusion, our approach to the pyrido[4,3,2-mn]pyr-
rolo[3,2,1-de]acridine ring system could be used to syn-
thesize various structural analogues of arnoamines A
and B, that, in turn, has opened up fresh opportunities
for detailed study of the structure-activity relationships
among these potentially cytotoxic compounds.
8. Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun.
1985, 15, 125–133.
9. Compound 8: yellow prisms; mp 223–224 °C; IR (CHCl3)
Acknowledgement
m
max: 3252, 3176, 1717, 1692, 1678, 1625, 1614, 1579, 1540,
1
1502, 1479, 1449, 1323, 1279, 1203, 1156, 1081 cmꢀ1; H
NMR (300 MHz, CDCl3) d: 1.47 (t, J = 7.1 Hz, 3H), 1.72
(s, 6H), 2.55 (s, 3H), 4.04 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H),
6.89 (s, 1H, H-7), 7.31 (m, 2Harom), 7.62 (m, 3Harom), 7. 79
(s, 1H, H-4), 8.45 (d, J = 14.8 Hz, 1H, H-20), 11.71 (d,
J = 14.8 Hz, 1H, H-19); 13C NMR (75 MHz, CDCl3) d:
13.2 (q, C-11), 14.6 (q, C-10), 26.9 (q, C-27, C-28), 56.4 (q,
C-18), 59.7 (t, C-9), 86.7 (s, C-21), 97.4 (d, C-7), 103.1 (d,
C-4), 104.8 (s, C-24), 105.1 (s, C-3), 123.8 (s, C-6), 125.3 (s,
C-3a), 128.1 (d, C-13, C-17), 129.6 (d, C-15), 130.3 (d, C-
14, C-16), 132.1 (s, C-7a), 135.9 (s, C-12), 146.3 (s, C-2),
146.4 (s, C-5), 150.2 (d, C-20), 164.1 (s, C-26), 165.3 (s, C-
22), 165.6 (s, C-8); EIMS (15 eV): m/z (%) = 479 (M++1,
10), 478 (M+, 22), 477 (M+ꢀ1, 52), 476 (M+ꢀ2, 100), 375
(29), 374 (23), 205 (36), 185 (38). Anal. Calcd for
C26H26N2O7: C, 65.25; H, 5.48; N, 5.86. Found: C,
65.32; H, 5.50; N, 5.80.
This work was supported by a Grant from the Program
of Presidium of RAS ‘Molecular and Cell Biology’.
References and notes
1. Plubrukarn, A.; Davidson, B. S. J. Org. Chem. 1998, 63,
1657–1659.
2. Delfourne, E.; Roubin, C.; Bastide, J. J. Org. Chem. 2000,
65, 5476–5479.
3. Grinyov, A. N.; Ermakova, V. N.; Vrotek, E.; Terent’ev,
A. P. Zh. Obsch. Chim. 1959, 29, 2777–2782 (In Russian).
4. This condensation was performed in 1,2-dichloroethane at
reflux with removal of water by azeotropic distillation to
produce 3 in 61% yield.
5. Flash chromatography was performed on flash silica gel
60 (Merck 0.015–0.040 mm), using n-hexane–acetone, 5:1.
6. Compound 5: light yellow needles; mp 153–155 °C
(EtOH); IR (CCl4) mmax: 1704, 1625, 1598, 1582, 1524,
10. Compound 9: a white solid; mp 267–268 °C; IR (CHCl3)
mmax: 3423, 1695, 1685, 1631, 1600, 1584, 1549, 1509, 1475,
1426, 1404, 1387, 1375, 1348, 1290, 1218, 1176, 1142, 1096,
1
1076, 1064 cmꢀ1; H NMR (300 MHz, CDCl3) d: 1.47 (t,
1471, 1457, 1428, 1409, 1331, 1205, 1187, 1174, 1079 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d: 1.48 (t, J = 7.0 Hz, 3H),
2.60 (s, 3H), 4.04 (s, 3H), 4.44 (q, J = 7.0 Hz, 2H), 7.28 (m,
2Harom), 7.60 (m, 3Harom), 7.62 (s, 1H, H-4), 7.87 (s, 1H,
H-7); 13C NMR (75 MHz, CDCl3) d: 13.5 (q, C-11), 14.6
(q, C-10), 56.9 (q, C-18), 59.9 (t, C-9), 104.6 (d, C-4), 105.5
(s, C-3), 108.9 (d, C-7), 128.0 (d, C-13, C-17), 129.7 (d, C-
15), 130.2 (d, C-14, C-16), 130.7 (s, C-6), 131.3 (s, C-3a),
J = 7.1 Hz, 3H), 2.49 (s, 3H), 4.09 (s, 3H), 4.44 (q,
J = 7.1 Hz, 2H), 6.10 (d, J = 7.4 Hz, 1H, H-21), 7.18 (m,
2Harom), 7.38 (m, 1Harom), 7.43 (m, 2Harom), 7.47 (m, 1H,
H-20), 8.13 (s, 1H, H-4), 9.04 (br s, 1H, H-19); 13C NMR
(75 MHz, CDCl3) d: 14.1 (q, C-11), 14.6 (q, C-10), 56.2 (q,
C-18), 59.7 (t, C-9), 104.3 (d, C-4), 104.3 (s, C-3), 111.9 (d,
C-21), 123.1 (s, C-3a), 127.1 (d, C-13, C-17), 127.4 (s, C-6),

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O. S. Radchenko et al. / Tetrahedron Letters 47 (2006) 7819–7822
127.5 (d, C-15), 128.2 (d, C-14, C-16), 129.8 (s, C-7a), C, 66.99; H, 4.86; N, 7.11. Found: C, 67.10; H, 4.91; N,
134.3 (d, C-20), 142.2 (s, C-12), 143.7 (s, C-5), 146.1 (s, C-
2), 166.0 (s, C-8), 176.5 (s, C-22); EIMS (15 eV): m/z
(%) = 376 (M+, 7), 375 (M+ꢀ1, 35), 361 (4), 345 (6), 331
(18), 170 (98), 169 (99), 168 (98), 142 (98), 141 (98), 140
(100). Anal. Calcd for C22H20N2O4: C, 70.19; H, 5.36; N,
7.45. Found: C, 70.23; H, 5.37; N, 7.50.
7.05.
12. Compound 11: yellow–green needles, mp 236–237.5 °C; IR
(CHCl3) mmax: 1697, 1655, 1617, 1602, 1572, 1561, 1526,
1507, 1496, 1470, 1437, 1425, 1396, 1381, 1358, 1300, 1271,
1256, 1222, 1211, 1196, 1173, 1140, 1106, 1087 cmꢀ1; H
1
NMR (300 MHz, CDCl3/TFA-d, v/v = 20:1) d: 1.63 (t,
J = 7.1 Hz, 3H), 3.64 (s, 3H), 4.28 (s, 3H), 4.64 (q,
J = 7.1 Hz, 2H), 7.89 (br t, J = 8.3 Hz, 1H, H-9), 8.15 (br
t, J = 8.3 Hz, 1H, H-10), 8.50 (s, 1H, H-3), 8.53 (d,
J = 6.4 Hz, 1H, H-7), 8.80 (dd, J1 = 8.3 Hz, J2 = 1.7 Hz,
1H, H-11), 8.82 (br d, J = 8.3 Hz, 1H, H-8), 9.04 (d,
J = 6.4 Hz, H-6); 13C NMR (75 MHz, CDCl3/TFA-d, v/
v = 20:1) d: 14.2 (q, OCH2 CH3), 16.3 (q, C(1)-CH3), 57.0
(q, OMe), 62.4 (t, OCH2CH3), 109.8 (d, C-3), 111.1 (d, C-
7), 112.8 (s, C-2), 113.6 (s, C-4a), 118.6 (d, C-11), 119.0 (s,
C-4b), 119.5 (s, C-2a), 120.0 (s, C-7b), 126.3 (s, C-7a), 127.0
(d, C-9), 128.1 (d, C-8), 135.6 (d, C-10), 137.7 (s, C-11a),
139.2 (d, C-6), 142.4 (s, C-2b), 143.1 (s, C-1), 145.0 (s, C-4),
166.6 (s, CO). EIMS (15 eV) m/z (%) = 358 (M+, 9), 357
(M+ꢀ1, 9), 344 (12), 343 (41), 342 (32), 313 (15), 312 (22),
311 (19), 268 (60), 267 (30), 266 (39), 265 (28), 264 (32), 191
(88), 185 (100). Anal. Calcd for C22H18N2O3: C, 73.73; H,
5.06; N, 7.82. Found: C, 73.55; H, 4.90; N, 7.71.
11. Compound 10: a yellow solid; mp 105–107 °C; IR (CCl4)
m
max: 1703, 1607, 1570, 1561, 1537, 1498, 1467, 1428, 1389,
1
1326, 1285, 1215, 1153, 1123, 1101, 1077 cmꢀ1; H NMR
(300 MHz, CDCl3) d: 1.50 (t, J = 7.1 Hz, 3H), 2.66 (s,
3H), 4.19 (s, 3H), 4.49 (q, J = 7.1 Hz, 2H), 7.11 (m,
2Harom), 7.25 (d, J = 4.5 Hz, 1H, H-21), 7.39 (m, 1Harom),
7.42 (m, 2Harom), 8.14 (s, 1H, H-4), 8.65 (d, J = 4.5 Hz,
1H, H-20); 13C NMR (75 MHz, CDCl3) d: 14.2 (q, C-11),
14.5 (q, C-10), 56.2 (q, C-18), 59.9 (t, C-9), 103.0 (d, C-4),
107.7 (s, C-3), 117.3 (s, C-7), 118.8 (s, C-6), 122.6 (d, C-
21), 123.8 (s, C-3a), 127.0 (d, C-13, C-17), 127.7 (d, C-15),
129.3 (d, C-14, C-16), 137.8 (s, C-22), 140.7 (s, C-7a), 142.0
(s, C-12), 145.5 (d, C-20), 147.1 (s, C-2), 151.6 (s, C-5),
165.6 (s, C-8); EIMS (15 eV): m/z (%) = 396 (M+, 1), 395
(M+ꢀ1, 3), 394 (M+, 7), 393 (M+ꢀ1, 9), 392 (M+ꢀ2, 3),
381 (2), 379 (6), 351 (6), 349 (19), 252 (5), 224 (4), 223 (6),
171 (100), 170 (99). Anal. Calcd for C22H19ClN2O3: