5,6-Dihydropyrrolo[2,1-b]isoquinolines as scaffolds for synthesis of lamellarin analogues

Article abstract of DOI:10.1016/j.tetlet.2005.01.145

Efficient modular synthetic routes to open chain marine alkaloids such as lamellarins have been developed. 5,6-Dihydropyrrolo[2,1-b]isoquinoline scaffolds were prepared, and protocols enabling regioselective bromination followed by Suzuki cross-coupling were established for the introduction of aryl groups onto the 2- and 3-positions.

Full text of DOI:10.1016/j.tetlet.2005.01.145

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2041–2044
5,6-Dihydropyrrolo[2,1-b]isoquinolines as scaffolds for synthesis
of lamellarin analogues
a,c,
Christian A. Olsen,a, Nu´ria Parera,a,à Fernando Albericioa,b, and Mercedes Alvarez
´
*
*
aBiomedical Research Institute, Barcelona Scientific Park, University of Barcelona, 08028 Barcelona, Spain
bDepartment of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
cLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 22 December 2004; revised 25 January 2005; accepted 26 January 2005
Abstract—Efficient modular synthetic routes to open chain marine alkaloids such as lamellarins have been developed. 5,6-Dihydro-
pyrrolo[2,1-b]isoquinoline scaffolds were prepared, and protocols enabling regioselective bromination followed by Suzuki cross-cou-
pling were established for the introduction of aryl groups onto the 2- and 3-positions.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In the past decade we have witnessed a renaissance in
the research of marine natural products. Several new
compounds derived from natural products of the sea
are now in the clinical pipeline.1 Although, preliminary
and preclinical research is usually carried out with com-
pounds obtained directly by isolation from marine
sources, late clinical phases require an efficient synthetic
route. Accordingly, there is an increased need for the
development of synthetic strategies for preparation of
these kinds of important natural products.
densed to one or two oxazinone rings as observed for
lukianol A and ningalin A, respectively.
The pentacyclic lamellarins can be considered as even
more complex compounds, because the pyrrole is con-
densed to a benzooxazinone and to a substituted dihy-
droisoquinoline or isoquinoline (Lamellarin D, Fig. 1).
More than 30 natural lamellarins have been isolated
from natural marine sources.7 Natural as well as syn-
thetic lamellarins should be excellent candidates for
the development of new drugs due to their unique skele-
tal structure and their important biological activities
especially as antitumor agents.7,8
Pyrrole is the core skeleton of a large number of marine
alkaloids such as ningalins,2 lukianols,3 polycitones,4
purpurone,5 and lamellarins.6 A common feature for
all of these alkaloids is that the pyrrole ring contains
substituted aromatic rings on positions 3 and 4. Among
the more simple compounds are the tetrasubstituted pyr-
roles (e.g., lamellarins O and P) or the symmetrically
pentasubstituted pyrroles (e.g., polycitons A and B).
More complex structures contain a pyrrole ring con-
As part of our synthetic studies concerning lamellarins,9
we here report a concise and efficient route to scaffolds
1a and b, and their roles as synthetic precursors for open
chain analogues of lamellarins (Fig. 1). Scaffolds 1a–b
were obtained by N-alkylation of the pyrrole with a 2
phenylethyl p-toluenesulfonate derivative, followed by
cyclization through a Heck reaction. Regioselective bro-
mination of 1a–b followed by Suzuki cross-coupling ren-
ders the open chain lamellarin analogues.
Keywords: Marine alkaloids; Heterocycles; Cross-coupling reactions;
Palladium.
The initial synthetic target was the model molecule 1a
(R1 = R2 = H), which was obtained in two steps from
methyl pyrrole-2-carboxylate.10 N-Alkylation with the
p-toluenesulfonate11 3a in the presence of K2CO3 and
18-crown-6 ether in DMF at 70 ꢁC afforded 2a (50%
yield).12 The conditions described for N-alkylation of
pyrrole in polycitone B13 were unsuccessful for the
methyl pyrrole-2-carboxylate.
*
Corresponding authors. Tel.: +34 93 403 70 86; fax: + 34 93 403 71
26; e-mail addresses: cao@dfuni.dk; nuriapar@chembio.chalmers.se;
albericio@pcb.ub.es; malvarez@pcb.ub.es
Present address: The Danish University of Pharmaceutical Sciences,
DK-2100 Copenhagen, Denmark.
à Present address: Chalmers University of Technology, SE-41296
Gothenburg, Sweden.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.145

2042
C. A. Olsen et al. / Tetrahedron Letters 46 (2005) 2041–2044
R2
R1
MeO
HO
MeO
MeO
HO
R1
OH
Heck
R2
CO2Me
N
H
R2
R1
R2
R1
Br
X
CO2Me
N
O
R2
R1
Alkylation
CO2Me
N
N
O
1a (R1 = R2 = H)
1b (R1 = Oi-Pr, R2 = OMe)
Lamellarin D
Open chain lamellarin analogues
Figure 1. Structure of lamellarin D and retrosynthetic overview of the preparation of open chain lamellarin analogues.
An intramolecular Heck reaction14 of 2a using
Pd(PPh3)4 and NaOAc in DMF at 125 ꢁC afforded the
pyrroloisoquinoline 1a in 95% yield.15 Bromination of
1a with NBS in dry THF occurred exclusively on the
more reactive pyrrole part. By modulating the excess
of NBS, the monobromoderivative 4a or the dibromo-
compound 5a could be obtained. The methoxycarbonyl
group in the 3-position of 1a induces the regioselective
bromination at position 1 giving 4a in excellent yield
(94%) when 2 equiv of NBS is used. Increase of the reac-
tion time (from 3 to 8 h) and the amount of NBS
(2.5 equiv) afforded the dibromoderivative 5a in high
yield (92%). The bromide 4a gives access to novel deriv-
atives of lamellarins, containing just one aryl group situ-
ated in the 1-position of the tricyclic system. Such
compounds 8a–b and 10 are related with the structure
of natural compounds with important biological activi-
ties (e.g., variolins).16
R1
TsO
R2
R1
Br
R2
3a/3b
Br
CO2Me
2a/2b
N
CO2Me
N
H
K2CO3,
18-crown-6
or
For all compounds
a: R1= R2= H
NaH, DMF
Pd(PPh3)4, NaOAc
or
PdCl2(PPh3)2, PPh3,
and K2CO3
b: R1= Oi-Pr, R2= OMe
1
10
3
R2
R1
CO2Me
10b
N
5
6a
1a/1b
NBS, THF
Br
Br
Br
R2
R2
CO2Me
CO2Me
N
N
The bromides 4a and 5a were subjected to Suzuki cross-
coupling with the p-isopropoxyphenyl boronic acid (6)
using Pd(PPh3)4 as catalyst in aqueous Na2CO3 and
DMF,17 to give the mono- and diaryl compounds 8a18
and 9a,19 respectively, in good yields.
R1
R1
4a/4b
5a/5b
6, Pd(PPh3)4, Na2CO3, DMF
or
7, Pd(PPh3)4, Na2CO3, DMF
R3O
R2
R3O
OR3
R2
Subsequent removal of the isopropyl protecting groups
with AlCl3 in CH2Cl2 afforded compounds 10a21 and
20
R2
11a22 (Scheme 1).
R2
R2
Scaffold 1b was synthesized in order to target open chain
compounds with a substitution pattern resembling lam-
ellarin D, which is a highly potent cytotoxic agent in
numerous multi drug resistant (MDR) cell lines.8 Prepa-
ration of 1b was achieved from methyl pyrrole-2-car-
boxylate by N-alkylation to give 2b followed by
intramolecular Heck cyclization as also described above
for 1a. The N-alkylation using 2-(2-bromo-5-isoprop-
oxy-4-methoxyphenyl)ethyl p-toluenesulfonate (3b)23
was performed in dry DMF with NaH as base (77%
yield). The presence of two alkoxy groups in the phenyl
ring of 3b presumably causes lower acidity of the ben-
zylic protons as compared to 3a, thus decreasing the
competitive elimination process in favor of the N-
alkylation.
CO2Me
CO2Me
N
N
R1
R1
8a: R3= i-Pr
8b: R3= H
9a: R3= i-Pr
9b: R3= H
AlCl3, CH2Cl2
AlCl3, CH2Cl2
10a: R3= H
11a: R3= H
iPrO
HO
MeO
O
B
B(OH)2
6
7
O
Scheme 1. Synthetic sequences.
The 2-(2-bromo-5-isopropoxy-4-methoxyphenyl)etha-
nol needed for the preparation of 3b was obtained from
the previously described 2-bromo-5-isopropoxy-4-meth-
oxybenzaldehyde.24 This aldehyde was converted into
the substituted styrene by Wittig reaction,25 and subse-
Scaffold 1b was obtained in excellent yield (81%) from
2b using Pd(PPh3)2Cl2 and Ph3P as catalyst in dry
DMF with K2CO3 added as base. The two-step assem-
bly of this dihydroisoquinoline moiety (62% yield) is rela-
tively similar to that of an intermediate of lamellarin
G trimethylether very recently published.27 However,
26
quent addition of borane–dimethylsulfide and H2O2
afforded the corresponding 2-phenethylalcohol.

C. A. Olsen et al. / Tetrahedron Letters 46 (2005) 2041–2044
2043
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Venkateswarlu, Y. J. Nat. Prod. 2004, 67, 1168.
the latter mentioned required Suzuki cross-coupling,
tosylation, and finally intramolecular alkylation, which
proceded less efficiently with an overall yield of 33%.
Mono- and dibromination of 1b to give 4b and 5b,
respectively, proceeded in good yields as described for
4a/5a above. The subsequent Suzuki cross-coupling
reactions with the commercially available 3-hydroxy-4-
methoxyphenyl boronic ester (7) furnished the mono-
and diaryl lamellarin D-type open chain compounds
8b28(78%) and 9b29 (80%), respectively.
´
7. Cironi, P.; Albericio, F.; Alvarez, M. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.;
Pergamon: Oxford (UK), 2004; Vol. 16, pp 1–26.
8. (a) Shibashi, F.; Tanabe, S.; Oda, T.; Iwao, M. J. Nat.
Preliminary testing of 8b, 9b, 10a, and 11a in various
tumor cell lines showed cytotoxic effects in the low
micromolar area, 9b being the most potent of the four.
´
Prod. 2002, 65, 500; (b) Facompre, M.; Tardy, C.; Bal-
Mahieu, C.; Colson, P.; Perez, C.; Manzanares, I.; Cuevas,
C.; Bailly, C. Cancer Res. 2003, 63, 7392; (c) Tardy, C.;
´
Facompre, M.; Laine, W.; Baldeyrou, B.; Garcıa-Grava-
los, D.; Francesch, A.; Mateo, C.; Pastor, A.; Jimenez, J.
A.; Manzanares, I.; Cuevas, C.; Bailly, C. Bioorg. Med.
Chem. 2004, 12, 1697.
´
´
In summary, efficient preparation of scaffolds suitable
for the synthesis of open chain lamellarin analogues
has been established. A key aspect of these reactions is
the regioselective bromination of the pyrrole scaffold,
which can be modulated to give mono- and dibromo
derivatives, this in turn affords the mono- and the diaryl
lamellarin derivatives. The methodologies presented
herein constitute a concise route to open chain lamella-
rin-type compounds with attractive biological activities.
The positive pharmacological results encourage the
preparation of libraries based on these open structures
for SAR studies. This work is in progress and will be
communicated in due course.
´
´
9. (a) Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M.
Org. Lett. 2003, 5, 2959; (b) Marfil, M.; Albericio, F.;
´
Alvarez, M. Tetrahedron 2004, 60, 8659; (c) Cironi, P.;
´
Cuevas, C.; Fernando Albericio, F.; Alvarez, M. Tetrahe-
dron 2004, 60, 8669.
10. Methyl pyrrole-2-carboxylate was obtained from pyrrole
by acylation with trichloroacetyl chloride as described by
Harbuck, J. W.; Rapoport, H. J. Org. Chem. 1972, 37,
3618. The 2-trichloroacetylpyrrole was treated with a
solution of NaOMe in MeOH at 0 ꢁC to furnish the
methyl ester.
11. The p-toluenesulfonate was obtained by reaction of the 2-
(2-bromophenyl)ethanol with tosyl chloride in Et2O with
KOH as base.
Acknowledgements
12. Stronger base such as NaH in THF resulted in elimina-
tion, which led to isolation of 2-bromostyrene as the major
product.
13. Kreipl, A. P.; Reid, C.; Steglich, W. Org. Lett. 2002, 4,
3287.
14. Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R.;
Longmore, R. W.; Rae, A. D. Aust. J. Chem. 1999, 52,
755.
This work was partially supported by CICYT (BQU
2003-00089) and Pharma Mar S. L., which is also grate-
fully acknowledged for performing the preliminary bio-
logical tests. Authors thank Dr. Carmen Cuevas for her
encouragement to perform the present work.
15. 1a was totally characterized with the aid of NOE and
1
References and notes
HMBC experiments. H NMR (CDCl3, 400 MHz) d 7.56
(d, J = 7.4 Hz, 1H, H10); 7.24 (m, 3H, H7, H8, H9); 7.01
(d, J = 4.2 Hz, 1H, H2); 6.53 (d, J = 4.2 Hz, 1H, H1); 4.63
(t, J = 6.6 Hz, 2H, H5); 3.83 (s, 3H, OMe); 3.07 (t,
J = 6.6 Hz, 2H, H6). 13C NMR (CDCl3, 100 MHz) d 162.0
(s, CO); 136.4 (s, C3); 131.9 (s, C10b); 128.6 (s, C10a);
128.6 (d, C10); 128.1 (d, C8); 127.7 (d, C9); 123.9 (d, C7);
122.0 (s, C6a); 118.6 (d, C2); 104.7 (d, C1); 51.3 (q, OMe);
42.4 (t, C5); 29.1 (t, C6).
1. For recent reviews, see: (a) Kijjoa, A.; Sawangwong, P.
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Kashman, Y. J. Nat. Prod. 2000, 63, 832.
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6. (a) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van
Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1985, 107,
5492; (b) Lindquist, N.; Fenical, W.; Van Duyne, G. D.;
Clardy, J. J. Org. Chem. 1988, 53, 4570; (c) Carroll, A. R.;
Bowden, B. F.; Coll, J. C. Aust. J. Chem. 1993, 46, 489; (d)
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1994, 47, 1919; (e) Urban, S.; Hobbs, L.; Hooper, J. N. A.;
Capon, R. J. Aust. J. Chem. 1995, 48, 1491; (f) Urban, S.;
Capon, R. J. Aust. J. Chem. 1996, 49, 711; (g) Reddy, M.
V. R.; Faulkner, D. J.; Venkateswarlu, Y.; Rao, M. R.
16. (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.;
Munro, M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994,
50, 3987; (b) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.;
Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H.
G.; Jameson, G. B. Tetrahedron 1994, 50, 3993.
17. General procedure: To a solution of 4 (1 equiv) in dry
DMF (25 mL) was added 4-isopropoxy phenyl boronic
acid 6 (1.5 equiv), Pd(PPh3)4 (25%), and 2 M aqueous
Na2CO3 (1.63 mL). The reaction mixture was stirred at
125 ꢁC for 24 h. After this time the solvent was evaporated
and the residue was dissolved in CH2Cl2. The organic
solution was washed with brine and water, dried and
concentrated to give a crude material which was purified
by column chromatography on silica gel.
18. The position of the introduced aryl group as well as the
regioselectivity in the formation of monobromoderivative

2044
C. A. Olsen et al. / Tetrahedron Letters 46 (2005) 2041–2044
3a was confirmed with NOE experiments. Irradiation on
H600, H7); 6.70 (dd, J = 8.6 Hz, 2H, H30, H50); 6.65 (d,
J = 8.6 Hz, 2H, H300, H500); 4.57 (t, J = 6.6 Hz, 2H, H5);
3.54 (s, 3H, OMe); 3.11 (t, J = 6.6 Hz, 2H, H6).
the H2 (d 6.96 ppm) enhances the intensity of the methyl
singlet at 3.83 ppm. 8a: 1H NMR (CDCl3, 400 MHz) d
7.32 (m, 3H, H10, H20, H60); 7.22 (m, 1H, H8); 7.12 (td,
J = 7.4 and 1.2 Hz, 1H, H9); 7.00 (td, J = 7.8 and 1.2 Hz,
1H, H7); 6.96 (s, 1H, H2); 6.88 (d, J = 8.5 Hz, 2H, H30,
H50); 4.61 (t, J = 6.6 Hz, 2H, H5); 4.57 (m, 1H, OCH);
3.83 (s, 3H, OMe); 3.10 (t, J = 6.6 Hz, 2H, H6); 1.37 (d,
J = 5.8 Hz, 6H, Me).
23. The tosyl derivative was obtained by standard procedure
from 2-(2-bromo-5-isopropoxy-4-methoxyphenyl)ethanol
[tosyl chloride in CH2Cl2 using KOH as base].
24. Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377.
25. Hasegawa, T.; Yoshida, K.; Hachiya, K.; Miyazaki, M.;
Tsuruta, H.; Nambu, F.; Ohuchida, S.; Kawamura, M.
Synlett 1997, 511.
26. Fernandes, R. A.; Bodas, M. S.; Kumar, P. Tetrahedron
2002, 58, 1223.
27. Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004,
69, 2362.
19. Compound 9a: 1H NMR (CDCl3, 400 MHz) d 7.21 (d,
J = 7.4 Hz, 1H, H10); 7.12 (td, J = 7.4 and 1.2 Hz, 1H,
H8); 7.01 (td, J = 7.4, 1.2 Hz, H9); 6.96 (d, J = 8.9 Hz, 4H,
H20, H200, H60, H600); 6.94 (td, J = 7.4 and 1.2 Hz, H7);
6.72 (d, J = 8.9 Hz, 4H, H30, H300, H50, H500); 4.61 (t,
J = 6.6 Hz, 2H, H5); 4.50 (q, J = 6.0 Hz, 2H, OCH); 3.59
(s, 3H, OMe); 3.10 (t, J = 6.6 Hz, 2H, H6); 1.31 (d,
J = 6.0 Hz, 6H, Me); 1.30 (d, J = 6.0 Hz, 6H, Me).
20. (a) Mata, E. Tetrahedron Lett. 1997, 38, 6335; (b) Banwell,
M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998, 63,
9139.
28. Compound 8b: 1H NMR (CDCl3, 400 MHz) d 6.97 (s, 1H,
H10); 6.96 (dd, J = 8.0 and 2.0 Hz, 1H, H60); 6.94 (d,
J = 2.0 Hz, 1H, H20); 6.92 (d, J = 8.0 Hz, 1H, H50); 6.89
(s, 1H, H7); 6.74 (s, 1H, H2); 5.62 (br s, 1H, OH); 4.60 (t,
J = 6.4 Hz, 2H, H5); 4.53 (heptet, J = 6.0 Hz, 1H, OCH);
3.84 (s, 6H, 2 · OMe); 3.42 (s, 3H, OMe); 2.99 (t,
J = 6.4 Hz, 2H, H6); 1.37 (d, J = 6.0 Hz, 6H, 2·Me).
29. Compound 9b: 1H NMR (CDCl3, 400 MHz) d6.82 (d,
J = 8.0 Hz, 1H, H50); 6.78 (d, J = 8.0 Hz, 1H, H500); 6.75
(dd, J = 8.0 and 1.6 Hz, 1H, H60); 6.73 (s, 1H, H10); 6.69
(dd, J = 8.0 and 1.6 Hz, 1H, H600); 6.68 (s, 1H, H7); 6.57
(d, J = 1.6 Hz, 1H, H200); 6.56 (d, J = 1.6 Hz, 1H, H20);
5.58 (s, 1H, OH); 5.54 (s, 1H, OH); 4.61 (t, J = 6.2 Hz, 2H,
H5); 4.53 (heptet, J = 6.4 Hz, 1H, OCH); 3.65 (s, 3H,
OMe); 3.62 (s, 6H, 2·OMe); 3.33 (s, 3H, OMe); 3.03 (t,
J = 6.2 Hz, 1H, H6); 1.36 (d, J = 6.4 Hz, 6H, 2·Me).
1
21. Compound 10a: H NMR (CDCl3, 400 MHz) d 7.28 (m,
3H, H10, H20, H60); 7.22 (d, J = 7.4 Hz, 1H, H8); 7.13 (td,
J = 7.4 and 1.2, 1H, H9); 7.00 (td, J = 7.4 and 1.2 Hz, 1H,
H7); 6.98 (s, 1H, H2); 6.85 (d, J = 8.6 Hz, 2H, H30, H50);
4.45 (s, 1H, OH); 4.61 (t, J = 6.6 Hz, 2H, H5); 3.85 (s, 3H,
OMe); 3.07 (t, J = 6.6 Hz, 2H, H6).
1
22. Compound 11a: H NMR (Acetone-d6, 400 MHz) d 8.31
(s, 1H, OH); 8. 15 (s, 1H, OH); 7.28 (d, J = 7.4 and 1.2 Hz,
1H, H10); 7.13 (td, J = 7.4 and 1.2 Hz, 1H, H8); 6.97 (td,
J = 7.4 and 1.2 Hz, 1H, H9); 6.91 (m, 5H, H20, H200, H60,