Total synthesis of the antitumor active pyrrolo[2,1-a]isoquinoline alkaloid (±)-crispine a

Article abstract of DOI:10.1016/j.tetlet.2004.12.066

Addition of a propargyl Grignard reagent to 3,4-dihydro-6,7- dimethoxyisoquinoline, silver(I)-promoted oxidative cyclization, and chemoselective hydrogenation of the pyrrole ring provide a simple three-step route to the antitumor active pyrrolo[2,1-a]isoquinoline alkaloid (±)-crispine A.

Full text of DOI:10.1016/j.tetlet.2004.12.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1173–1175
Total synthesis of the antitumor active
pyrrolo[2,1-a]isoquinoline alkaloid ( )-crispine A
Hans-Joachim Kno¨lker* and Sameer Agarwal
Institut fu¨r Organische Chemie, Technische Universita¨t Dresden, Bergstrasse 66, 01069 Dresden, Germany
Received 16 November 2004; revised 13 December 2004; accepted 15 December 2004
Available online 11 January 2005
Abstract—Addition of a propargyl Grignard reagent to 3,4-dihydro-6,7-dimethoxyisoquinoline, silver(I)-promoted oxidative cycli-
zation, and chemoselective hydrogenation of the pyrrole ring provide a simple three-step route to the antitumor active pyrrolo-
[2,1-a]isoquinoline alkaloid ( )-crispine A.
Ó 2004 Elsevier Ltd. All rights reserved.
Extracts of the plant Carduus crispus have been applied
in Chinese folk medicine for the treatment of cold, stom-
ach ache, and rheumatism. Moreover, a screening test
revealed that the extracts inhibit the growth of some
human cancer lines in vitro and show a significant cyto-
toxic activity.1 Recent phytochemical studies on C.
crispus by Zhao and co-workers led to the isolation of
the two pyrrolo[2,1-a]isoquinoline alkaloids crispine A
(1) and crispine B (2) along with three bicyclic isoquinoline
alkaloids (Fig. 1).1
product of the alkaloid norsecurinone4 and has
been prepared previously using different synthetic
strategies.4–9 Compound 3 is an a2-adrenoreceptor
antagonist10 and its 5-phenyl derivatives exhibit
antidepressant-like activity.11
We envisaged a short and direct total synthesis of cri-
spine A (1) by using a novel pyrrole synthesis recently
developed in our laboratories.12 Since the simple pyrrole
annulation at 3,4-dihydroisoquinoline (4a)13 has already
been shown,12a we focused initially on the synthesis of
the unsubstituted parent compound 3 (Scheme 1). A clo-
ser inspection of the product resulting from the Lewis
acid promoted addition of 3-trimethylsilylpropargyl-
magnesium bromide to 4a revealed that the allene 6a
was formed as a by-product (11% yield) along with the
propargyl derivative 5a (80% yield). The silver(I)-pro-
moted oxidative cyclization of the homopropargylamine
5a in dichloromethane at room temperature afforded
after 14 h 5,6-dihydropyrrolo[2,1-a]isoquinoline 7a in
72% yield.12a The 5,6-dihydropyrrolo[2,1-a]isoquinoline
ring system has been obtained previously using
alternative procedures.14 Treatment of the allenyl deriv-
ative 6a with silver acetate under the same set of reaction
conditions led only to recovery of starting material.
However, reaction of the allene 6a with silver acetate
in acetone at reflux for 14 h provided the annulated pyr-
role 7a in 56% yield. Chemoselective hydrogenation
of the pyrrole ring15 with 5% rhodium on activated
charcoal in methanol/acetic acid (1:1) afforded
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (3)
in 91% yield. The spectroscopic data of compound 316
are in agreement with those described in the
literature.4–9
Crispine A (1) was already obtained by synthesis prior
to its isolation as a natural product.2,3 1,2,3,5,6,10b-
Hexahydropyrrolo[2,1-a]isoquinoline (3), the parent
framework of crispine A (1), is a known degradation
MeO
MeO
MeO
MeO
Cl−
+
N
N
Crispine A (1)
Crispine B (2)
N
3
Figure 1. Pyrrolo[2,1-a]isoquinoline alkaloids of C. crispus and parent
framework.
Keywords: Total synthesis; Alkaloids; Pyrroles; Hydrogenation.
*
Corresponding author. Fax: +49 351 463 37030; e-mail:
hans-joachim.knoelker@chemie.tu-dresden.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.066

1174
H.-J. Kno¨lker, S. Agarwal / Tetrahedron Letters 46 (2005) 1173–1175
R
R
R
R
R
R
1. Et2O−BF3, THF, −23 °C, 30 min
2. Me3Si CH2MgBr
Et2O, −23 °C, 15 h
+
N
NH
NH
Me3Si
4a R = H
4b R = OMe
SiMe3
5a R = H
(80%)
5b R = OMe (61%)
6a R = H
6b R = OMe (2%)
(11%)
AgOAc
AgOAc
Me2CO, 56 °C, 6-14 h
CH2Cl2, r.t., 14 h
R = H
(72%)
R = H (56%)
R = OMe (43%)
R = OMe (58%)
R
R
R
5% Rh/C, H2
N
N
HOAc/MeOH (1:1), r.t., 8 d
R
3 R = H
(91%)
7a R = H
7b R = OMe
1 R = OMe (66%)
Scheme 1. Synthesis of ( )-crispine A (1) and the parent compound, 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (3).
3,4-Dihydro-6,7-dimethoxyisoquinoline (4b) is readily
available by Bischler–Napieralski cyclization of N-form-
yl-3,4-dimethoxyphenylethylamine (80–90% yield on a
25 g scale).17 The boron trifluoride promoted addition
of 3-trimethylsilylpropargylmagnesium bromide to 4b
afforded the propargyl compound 5b (61% yield)
and the allene 6b (2% yield). The silver(I)-promoted
oxidative cyclization of 5b using our standard condi-
tions provided 5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]-
isoquinoline (7b) in 58% yield.18 As found previously for
compound 6a, the oxidative cyclization of the allenyl
derivative 6b did not proceed at room temperature.
The conversion of 6b to the pyrrolo[2,1-a]isoquinoline
7b with silver acetate in acetone at reflux for 6 h afforded
the desired product in 43% yield. Finally, chemoselective
hydrogenation of the pyrrole ring provided ( )-crispine
A (1,2,3,5,6,10b-hexahydro-8,9-dimethoxypyrrolo[2,1-a]
isoquinoline) (1). All spectroscopic data of our synthetic
crispine A (1)19 are in full agreement with those reported
for the natural product.1 The catalytic dehydrogenation
of ( )-crispine A (1) (10% Pd/C, C6H6, 80 °C, 12 h) leads
back to compound 7b (88% yield).
References and notes
1. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002,
58, 6795.
2. Schell, F. M.; Smith, A. M. Tetrahedron Lett. 1983, 24,
1883.
3. Orito, K.; Matsuzaki, T.; Suginome, H. Heterocycles 1988,
27, 2403.
4. Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.; Sugimoto,
N.; Hori, Z.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull.
1965, 13, 786.
5. Morlacchi, F.; Losacco, V. J. Heterocycl. Chem. 1976, 13,
165.
6. Lee, Y. S.; Kang, D. W.; Lee, S. J.; Park, H. J. Org. Chem.
1995, 60, 7149.
7. Pearson, W. H.; Fang, W. J. Org. Chem. 2000, 65, 7158.
8. Okamoto, S.; Teng, X.; Fujii, S.; Takayama, Y.; Sato, F.
J. Am. Chem. Soc. 2001, 123, 3462.
9. (a) Itoh, T.; Miyazaki, M.; Nagata, K.; Yokoya, M.;
Nakamura, S.; Ohsawa, A. Heterocycles 2002, 58, 115; (b)
Itoh, T.; Nagata, K.; Yokoya, M.; Miyazaki, M.; Kam-
eoka, K.; Nakamura, S.; Ohsawa, A. Chem. Pharm. Bull.
2003, 51, 951.
10. Chung, S.-H.; Yook, J.; Min, B. J.; Lee, J. Y.; Lee, Y. S.;
Jin, C. Arch. Pharm. Res. 2000, 23, 353.
11. Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.;
Shank, R. P.; Costanzo, M. J.; Nortey, S. O.; Schneider,
C. R.; Setler, P. E. J. Med. Chem. 1987, 30, 1433.
12. (a) Agarwal, S.; Kno¨lker, H.-J. Org. Biomol. Chem. 2004,
2, 3060; (b) Kno¨lker, H.-J.; Agarwal, S. Synlett 2004,
1767.
13. Pelletier, J. C.; Cava, M. P. J. Org. Chem. 1987, 52, 616.
14. See for example: (a) Anderson, W. K.; Heider, A. R.;
Raju, N.; Yucht, J. A. J. Med. Chem. 1988, 31, 2097; (b)
Wasserman, H. H.; Frechette, R.; Oida, T.; van Duzer, J.
In conclusion, the present three-step route provides the
antitumor active pyrrolo[2,1-a]isoquinoline alkaloid
( )-crispine A (1) in 24% overall yield and the biologi-
cally active 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinoline (3) in 58% overall yield. Our approach can
be easily applied to the preparation of a wide range of
synthetic analogues for structure–activity studies. Inves-
tigations in this direction are currently ongoing.
´
H. J. Org. Chem. 1989, 54, 6012; (c) Nemes, P.; Kajtar-
Peredy, M.; Scheiber, P. Synlett 1996, 623; (d) Amombo,
M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999, 1871; (e)
Barun, O.; Chakrabarti, S.; Ila, H.; Junjappa, H. J. Org.
Chem. 2001, 66, 4457.
Acknowledgements
We are grateful to the Deutsche Forschungsgemeins-
chaft (Graduiertenkolleg ÔStruktur-Eigenschafts-Bezieh-
ungen bei HeterocyclenÕ) and the Fonds der Chemischen
Industrie for financial support of our project.
15. (a) Weinstein, B.; Craig, A. R. J. Org. Chem. 1976, 41,
875; (b) Kaiser, H.-P.; Muchowski, J. M. J. Org. Chem.
1984, 49, 4203.

H.-J. Kno¨lker, S. Agarwal / Tetrahedron Letters 46 (2005) 1173–1175
16. 1,2,3,5,6,10b-Hexahydropyrrolo[2,1-a]isoquinoline (3):
1175
CDCl3): d = 29.05 (CH2), 44.25 (CH2), 56.00 (CH3), 56.01
(CH3), 102.22 (CH), 105.91 (CH), 108.30 (CH), 111.29
(CH), 120.36 (CH), 122.57 (C), 122.75 (C), 129.91 (C),
147.20 (C), 148.22 (C). MS (EI): m/z (%) = 229 (100) [M+],
214 (46), 186 (19), 185 (6), 171 (7). HRMS: m/z calcd for
C14H15NO2 [M+]: 229.1103; found: 229.1105. Anal. Calcd
for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.37; H, 6.88; N, 6.05.
light yellow oil. IR (ATR): m = 2922, 2872, 2783, 1578,
1493, 1452, 1377, 1351, 1325, 1285, 1255, 1218, 1182, 1162,
1136, 1116, 1082, 1040, 1013, 932, 913, 740 cmÀ1 1H
.
NMR (500 MHz, CDCl3): d 1.71–1.78 (m, 1H), 1.82–1.98
(m, 2H), 2.37 (m, 1H), 2.62 (q, J = 8.1 Hz, 1H), 2.70 (ddd,
J = 14.8, 10.1, 4.7 Hz, 1H), 2.84 (dt, J = 16.6, 4.0 Hz, 1H),
3.04–3.12 (m, 2H), 3.14–3.20 (m, 1H), 3.53 (t, J = 8.3 Hz,
1H), 7.06–7.16 (m, 4H). 13C NMR and DEPT (125 MHz,
CDCl3): d 22.22 (CH2), 28.31 (CH2), 30.40 (CH2), 48.24
(CH2), 53.25 (CH2), 63.04 (CH), 125.69 (CH), 125.84
(CH), 126.05 (CH), 128.41 (CH), 134.01 (C), 138.51 (C).
MS (EI): m/z (%) = 173 (46) [M+], 172 (100), 170 (11), 145
(36), 117 (18). HRMS: m/z calcd for C12H15N [M+]:
173.1204; found: 173.1206.
19. ( )-Crispine A (1): colorless crystals; mp 76–78 °C. IR
(ATR): m = 2921, 2801, 1607, 1517, 1466, 1409, 1376, 1359,
1323, 1312, 1250, 1228, 1211, 1198, 1159, 1135, 1111, 1086,
1012, 850, 811, 762, 721 cmÀ1 1H NMR (500 MHz,
.
CDCl3): d 1.71 (m, 1H), 1.86 (m, 1H), 1.92 (m, 1H), 2.31
(m, 1H), 2.55 (br q, J = 8.5 Hz, 1H), 2.63 (dt, J = 4.6,
10.8 Hz, 1H), 2.72 (br dt, J = 16.4, 3.5 Hz, 1H), 3.01 (m,
1H), 3.07 (dt, J = 3.7, 8.7 Hz, 1H), 3.17 (ddd, J = 11.3, 6.2,
2.9 Hz, 1H), 3.41 (br t, J = 8.0 Hz, 1H), 3.83 (s, 3H), 3.84
(s, 3H), 6.56 (s, 1H), 6.60 (s, 1H). 13C NMR and DEPT
(125 MHz, CDCl3): d 22.21 (CH2), 28.03 (CH2), 30.47
(CH2), 48.35 (CH2), 53.14 (CH2), 55.87 (CH3), 55.98
(CH3), 62.94 (CH), 108.81 (CH), 111.30 (CH), 126.20 (C),
130.94 (C), 147.19 (C), 147.31 (C). MS (EI): m/z (%) = 233
(63) [M+], 232 (100), 218 (6), 216 (7), 205 (49), 190 (28),
177 (5). HRMS: m/z calcd for C14H19NO2 [M+]: 233.1416;
found: 233.1391.
17. Jahangir; MacLean, D. B.; Holland, H. L. Can. J. Chem.
1986, 64, 1031.
18. 5,6-Dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinoline (7b):
light yellow crystals; mp: 110–112 °C. IR (ATR): m =
2935, 1611, 1553, 1506, 1464, 1441, 1333, 1266, 1226, 1210,
1166, 1131, 1073, 1050, 1015, 859, 791, 711 cmÀ1 1H
.
NMR (500 MHz, CDCl3): d = 2.99 (t, J = 6.6 Hz, 2H),
3.88 (s, 3H), 3.91 (s, 3H), 4.05 (t, J = 6.6 Hz, 2H), 6.19 (br
s, 1H), 6.38 (br d, J = 2.3 Hz, 1H), 6.64 (br s, 1H), 6.69 (s,
1H), 7.01 (s, 1H). 13C NMR and DEPT (125 MHz,