Synthesis and antiprotozoal activities of simplified analogs of naphthylisoquinoline alkaloids

Article abstract of DOI:10.1016/j.ejmech.2007.03.003

The naphthylisoquinoline alkaloids (NIQs) represent a class of natural products with manifold activities against various tropical diseases. They are isolated from rare and difficult-to-cultivate tropical plants. In order to find novel, more easily accessi

Full text of DOI:10.1016/j.ejmech.2007.03.003

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 32e42
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antiprotozoal activities of simplified analogs
of naphthylisoquinoline alkaloids
b
b
a
Gerhard Bringmann a, , Reto Brun , Marcel Kaiser , Stefan Neumann
*
a Institute of Organic Chemistry, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
b Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
Received 6 November 2006; received in revised form 27 February 2007; accepted 1 March 2007
Available online 18 March 2007
Dedicated to Prof. Peter Riederer on the occasion of his 65th birthday
Abstract
The naphthylisoquinoline alkaloids (NIQs) represent a class of natural products with manifold activities against various tropical diseases.
They are isolated from rare and difficult-to-cultivate tropical plants. In order to find novel, more easily accessible analogs and to study struc-
tureeactivity relationships, a variety of simplified analogs were produced, which bear the functional groups typical of the NIQs, but avoid the
synthetically difficult elements of chirality, stereogenic centers and rotationally hindered axes. Their syntheses and activities against Plasmodium
falciparum, Trypanosoma cruzi, and Leishmania donovani are described and compared with those of the natural NIQs. Remarkably, quite good
activities were found for naphthalene-devoid halogenated isoquinolinic analogs.
Ó 2007 Elsevier Masson SAS. All rights reserved.
1. Introduction
of the highly active NIQs are only found in traces in their nat-
ural source and because the plants are difficult to cultivate
[11], there is need to either synthesize the authentic natural
products, or to find structural analogs that are easy to prepare
but still bear the functionalities required for bioactivity.
Although elegant pathways have been developed for the
stereoselective total synthesis of NIQs [12e15], there is urgent
demand for the design and synthesis of even more active and
less toxic analogs with simpler structures that permit produc-
tion of the compounds on a larger scale, if required in kilo-
gram quantities. As a first example towards this goal, we
have recently prepared a series of aminomethyl-substituted
phenylnaphthalenes like 4 (see Fig. 1), which are active
against Trypanosoma cruzi, but still bear two stereogenic ele-
ments, viz. a biaryl axis and a stereogenic center [16,17]. In
this paper, we report on a group of new NIQ-related biaryls
of type 5, whose isoquinoline portion is significantly simpli-
fied by the fact that the two methyl groups at C-1 and C-3
are now both located at C-3, thus avoiding the existence of
any of the two stereogenic centers present in the natural alka-
loids 1e3. To the underlying novel 3,3-dimethylisoquinoline
building block, para-substituted aryl substituents with only
one oxygen functionality are coupled instead of naphthyl
Infectious diseases, like malaria, leishmaniasis, and African
sleeping sickness, constitute a major threat to the so-called
Third World countries, causing ca. 1.3 million death cases
per year just to mention malaria [1]. With drug resistance be-
coming a rapidly increasing problem and given the lack of
suitable vaccines, the development of efficient, non-toxic, and
inexpensive new drugs is an urgent task [2e4]. The naph-
thylisoquinoline alkaloids (NIQs) represent a novel class of
natural products that feature manifold promising bioactivities
against these diseases. Among them are the antimalarial com-
pounds dioncophylline C (1) and dioncopeltine A (2) [5], and
ancistrotanzanine B (3), which is active against Leishmania
donovani, the pathogen causing leishmaniasis [6,7]. These
acetogenic isoquinoline alkaloids [8] with their characteristic
structures involving axial chirality and stereogenic centers,
occur exclusively in two families of tropical plants, viz. the Di-
oncophyllaceae and the Ancistrocladaceae [9,10]. Since many
* Corresponding author.
E-mail address: bringman@chemie.uni-wuerzburg.de (G. Bringmann).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.03.003

G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
33
HO OMe
additional methyl group at C-3, compound 11 is also devoid
of stereogenic centers and thus achiral, making it a rewarding,
simple-to-prepare synthetic target molecule. Since 11 (like the
natural precedent 3) is a 3,4-dihydroisoquinoline and thus sp2-
configured at C-1, there was, in this case, no necessity to omit
the methyl group at this C-atom.
The simple and short synthesis of 11 is shown in Scheme 1.
Starting from the known [20] ketone 6, Grignard reaction with
methyl magnesium bromide led to the tertiary alcohol 7,
which was submitted to a Ritter reaction with acetonitrile
with in situ cyclization, directly providing the novel achiral
isoquinoline building block 8. Regioselective 5-bromination
to 9 and Suzuki cross coupling with the known boronic acid
10 gave the desired ancistrotanzanine B analog 11 in good
yields.
Me
R
HO
Me
R
P
H
M
Me
OH
R
Me
MeO
HO
R N
H
HO
Me
dioncopeltine A (2)
dioncophylline C (1)
MeO OMe
Me
R
N
Ph
Me
M
M
Me
MeO
TfO
Me
Me
S
N
2.1.2. The phenyl tetrahydroisoquinoline 18
Me
OMe Me
4
Another possible target molecule, 18, this time related to the
antimalarial alkaloid dioncophylline C (1), was again intended
to bear a phenyl instead of a naphthyl ring, but this time with
a free OH function in the 40-position and a tetrahydroisoquino-
line moiety with a free NH function, as found in 1. Its synthesis,
as shown in Scheme 2, required the preparation of a new, again
achiral, tetrahydroisoquinoline 13, which, due to the sp3 char-
acter of C-1, was planned to have no methyl group at this
C-atom. This building block was again synthesized by a Ritter
reaction of the tertiary alcohol 7, now with sodium cyanide as
the nitrile reagent, again with in situ cyclization to give the 1-
unsubstituted dihydroisoquinoline 12, which was reduced
to provide 13. Bromination to give 14 and subsequent N-
benzylation delivered 15, which underwent a Suzuki cross cou-
pling with the boronic acid 16 to give 17, whose deprotection
completed the synthesis of the achiral 40-hydroxyphenyl tetra-
hydroisoquinoline 18.
ancistrotanzanine B (3)
OMe
OH
( )
OH)
Me
(
Me
(MeO)
MeO
Me
Me
N
N
H
(H)
MeO
5a
(Me)
MeO
5b
Fig. 1. The bioactive naphthylisoquinoline alkaloids dioncophylline C (1),
dioncopeltine A (2), and ancistroealaine A (3), the related simplified biaryl 4,
and the general structures of the new biaryl analogs 5.
groups with three substituents as found in natural NIQs [18].
Furthermore, by using symmetrical and non-bulky, freely ro-
tating phenyl substituents, even NIQ analogs devoid of axial
chirality are produced.
Me
MeMgBr,
Et2O
95%
MeO
MeO
Me
Me
O
OH
7
6
MeO
Br
MeO
2. Results and discussion
MeCN,H2SO4
MeO
78%
Br2,
DMF
Me
Me
Me
Me
2.1. Chemistry
MeO
N
N
70%
2.1.1. A simplified structural analog 11 related to
ancistrotanzanine B (3)
9
8
Me
Me
MeO
MeO
In view of the structures of natural NIQ alkaloids with the
highest activity as yet against L. donovani, ancistrotanzanine B
(3) [6] and its atropisomer, ancistroealaine A [7], a most prom-
ising synthetic analog might be the 5-phenyl dihydroisoquino-
line 11. Although e like the natural precedent e bearing
methoxy groups in the 6- and 8-positions, and also at 40, i.e.,
para to the biaryl axis, it would be simplified in having
a ‘slim’ and symmetric phenyl group at C-5 instead of the
bicyclic naphthyl substituent in 3, which, in addition, would
avoid the phenomenon of axial chirality and the necessity to
synthesize it atropo-selectively (although this has been suc-
cessfully achieved for 3, see [19]). Moreover, due to the
Pd(PPh3)4, Ba(OH)2
OMe
66%
OMe
4'
10
B(OH)2
Me
Me
5
MeO
6
N
8
11
Me
MeO
Scheme 1. Synthesis of the ancistrotanzanine A analog 11.

34
G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
KCN,
I
Me
Me
Me
Me
Me
Me
H2SO4,
HOAc
Me
Me
I2,
MeO
MeO
MeO
MeO
MeO
Ag2SO4
N
N
OH
N
78%
H
H
70%
OBn
7
12
19
MeO
Br
MeO
MeO
13
MeO
NaBH4
MeOH
,
92%
BnBr,
Cs2CO3,
acetone
80%
Br2,
Me
Me
Me
Me
OBn
MeO
DMF
21
B(OH2)
Pd(PPh3)4,
Na2CO3
I
N
N
78%
OBn
H
H
Me
MeO
Me
14
MeO
MeO
13
Me
Me
MeO
N
68%
Bn
BnBr,
N
20
MeO
90%
Cs2CO3,
acetone
Bn
OBn
4'
16
MeO
22
B(OH)2
NH4HCO2, Pd/C
OH
Br
85%
Me
Pd(PPh3)4,
MeO
Me
Ba(OH)2
Me
N
MeO
92%
Me
Bn
N
1
MeO
NH4HCO2,
15
Bn
Pd/C
Me
Me
90%
17
MeO
MeO
OH
4'
N
H
23
MeO
Scheme 3. Synthesis of the naphthylisoquinoline 23.
Me
MeO
Me
1 N
H
2.1.4. Synthesis of 33 as a simplified analog of
dioncopeltine A (2)
18
MeO
One of the most active antiplasmodial NIQ alkaloids, both
in vitro and in vivo, is dioncopeltine A (2) [5]. Its most char-
acteristic structural feature is the presence of a hydroxymethyl
group on the naphthalene portion. Reductive deoxygenation of
the benzylic OH group is known to decrease the antimalarial
activity substantially [21], making the introduction of a
CH2OH group into the phenyl portion of a respective model
analog rewarding. Furthermore, due to results from recent
QSAR studies [22] and following the structures of the highly
antimalarial Dioncophyllaceae alkaloids 2 and 3, the 6-OMe
group was omitted, leading to 33 as a promising structure
with an expected high antimalarial activity. The synthesis of
the required N-protected and halogen-activated new building
block 29 is shown in Scheme 4. Removal of the 6-methoxy
group of 24 was achieved by regioselective O-demethylation
at C-6 to give the phenol 25, followed by O-triflation to give
26 and hydrogenolytic elimination of the OTf group, unfortu-
nately with simultaneous N-debenzylation, leading to the tet-
rahydroisoquinoline 27, which had already been synthesized
earlier [23], but via a different route (yields not specified).
Its iodination under various conditions proved difficult,
accompanied by an undesired oxidation to the respective dihy-
droisoquinoline. The reaction mixture was therefore cautiously
reduced and submitted to a renewed iodinationereduction
sequence, finally giving 28 in an acceptable yield. A renewed
introduction of the N-benzyl group completed the synthesis
of the 6-deoxygenated and thus Dioncophyllaceae-like [9]
isoquinoline 29.
Scheme 2. Synthesis of the phenyl tetrahydroisoquinoline 18 as a simplified
analog of dioncophylline C (1).
2.1.3. The naphthyl tetrahydroisoquinoline 23
For an investigation of the influence of the naphthyl ring
in the natural products, e.g. in 1, vs. a phenyl ring as in 18,
the slightly less simplified analog 23 was synthesized (Scheme
3). Due to the higher steric hindrance of the naphthylboronic
acid 21 as compared to the phenyl analog 16, the brominated
tetrahydroisoquinoline 15 initially failed to undergo the re-
quired Suzuki cross coupling. For this reason, the tetrahydroi-
soquinoline 13 was activated by iodination, leading to 19,
which, after N-protection to 20, did permit the desired cou-
pling with the naphthylboronic acid 21 to give the biaryl 22.
Hydrogenolytic N- and O-deprotection provided the naphthyl
tetrahydroisoquinoline 23. Different from the other simplified
analogs prepared above, 11 and 18, compound 23 is axially
chiral. As already for its precursor 22, its chirality is evident
from the diastereotopic character of the two methyl groups
at C-3 (two singlets at 1.17 and 1.24 ppm) and of the protons
at C-4 (two doublets at 2.15 and 2.51 ppm, J ¼ 16.7 Hz), while
the protons at C-1, being more distant from the chiral axis,
appear as a (slightly broadened) singlet. For the model analogs
11 and 18 and all other compounds prepared above, by con-
trast, the respective resonances had been isochronous. For
reasons of economy, 23 was prepared and tested in a racemic
form.

G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
35
Me
Me
OBn
Me
HO
MeO
Me
Bn
HBr,75°C
Pd(PPh3)4,
Na2CO3
I
N
N
Me
Me
40% (ca. 30%
of educt
recovered)
Bn
90%
CHO
Me
MeO
MeO
24
MeO 25
N
OBn
Me
Bn
N
MeO 29
Tf2O,DABCO 91%
Bn
MeO
31
CHO
30
Me
Me
Me
NH4CO2,
Pd/C
95%
TfO
B(OH)2
LiAlH4 80%
Me
N
N
H
OH
OBn
Bn
MeO
I
26
27
NH4CO2,
Pd/C
OH
Me
OH
N
1. Ag2SO4,I2 NaBH4
2. repeat
58%
I
Me
70%
Me
Me
BnBr,
N
Me
Me
Cs2CO3,
acetone
H
Me
Bn
Me
MeO
MeO
33
32
N
N
80%
H
Bn
Scheme 5. Final steps to the dioncopeltine A analog 24.
MeO
28
29
MeO
Scheme 4. Synthesis of the achiral 6-deoxygenated tetrahydroisoquinoline
building block 29.
therapeutic indices, four examples being the bromo- or iodo-
tetrahydroisoquinolines 14, 15 and 28 and the dihydro analog
9, with indices of 150 and more.
Remarkably, the naphthylisoquinoline 23 displayed better
activities than the phenylisoquinoline 18, by one order of mag-
nitude in the case of T. cruzi. Moreover, 23 was also active in
the antimalarial testing, while 18 was not active at all. This
suggests a larger influence of the aromatic portion than
anticipated.
A likewise remarkable substance is the noncytotoxic and
quite active tetrahydroisoquinoline 25, whose N-benzyl pro-
tection group on the isoquinoline nitrogen might mimic an
aryl substituent similar to those otherwise linked via a biaryl
axis at C-5 or C-7 in 1e3. In this respect, its molecular frame-
work is reminiscent of the recently discovered N,C- instead
of C,C-coupled natural NIQs from Ancistrocladaceae plants
[27e30].
A similar influence of the N-benzyl group is observed with
the results of the antileishmanial testing, where the best activ-
ities were obtained with the naphthalene-free compounds 15
and 20, with IC50 values of 4.2 and 2.4 mg/ml, respectively,
i.e., only ca. a factor of 10 weaker than the standard,
miltefosin.
This valuable new building block 29 was coupled to the com-
mercially available boronic acid aldehyde 30, to give the 5-
(20-formylphenyl)-tetrahydroisoquinoline 31 (see Scheme 5).
Reduction of its aldehyde function to give 32 introduced the de-
sired hydroxymethyl group. Cautious hydrogenolysis of both,
the O- and N-benzyl groups, but with conservation of the
CH2OH function, generated the dioncopeltine A analog 33 as
a relatively unstable compound. It appears chiral on the NMR
time scale, as seen from the diastereotopic nature of the methyl
groups at C-3 and the protons at C-4 and C-1 as already for 23
and, in addition, from the splitting of the two benzylic protons in
the CH2OH side chain (4.16 and 4.23 ppm, J ¼ 17 Hz). Still, as
expected from previous experience [24,25], it should certainly
be configurationally unstable at the biaryl axis, thus not neces-
sitating to develop an atropo-selective synthesis as previously
achieved for dioncopeltine A [26].
2.2. Biology
With the target compounds, 11, 18, 23, and 33 synthetically
available, these four NIQ analogs and also 14 of their isoqui-
nolinic precursors were tested for their bioactivities.
Among the compounds assayed against T. cruzi, the phe-
nylisoquinoline 11 displayed a quite good activity, just some-
what more than an order of magnitude less than the standard,
benznidazole, with a therapeutical index of ca. 12.
Although not yet reaching the excellent antiprotozoal activ-
ities of natural NIQs, the simplified compounds prepared here
and their activities provide further valuable data for our ongoing
QSAR studies [22,31].
Surprisingly, the biaryl compounds did not show the best
antimalarial activities. Thus, compound 33 only showed
a very weak antiplasmodial activity, despite bearing the as-
sumed key functionalities of dioncopeltine A, but, at least,
proved to be not cytotoxic. The most active candidates were,
by contrast, the halogenated isoquinoline precursors, some
of them with virtually no cytotoxicity, resulting in excellent
3. Conclusions
New, simplified synthetic di- and tetrahydroisoquinoline
building blocks have been designed and prepared, mimicking
the difficult-to-access, authentic tetrahydroisoquinoline por-
tions of the anti-infectious naphthylisoquinoline alkaloids.
The replacement of a 1,3- by a 3,3-dimethyl substitution

36
G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
pattern makes these compounds achiral and thus easy to pre-
pare. The attachment of symmetric phenyl instead of naphthyl
substituents at C-5 furthermore avoids the e stereochemically
intriguing, but difficult-to-control e phenomenon of axial
chirality. Several representatives of this class of compounds
possess promising activities against T. cruzi, L. donovani,
and Plasmodium falciparum. Surprisingly, the best antiplasmo-
dial activities were found for the simple, non-coupled, i.e.,
naphthalene- or phenyl-devoid tetrahydroisoquinolines. The
results give further valuable information on structureeactivity
relationships, involving new, more efficient QSAR methods
[31], which will hopefully lead to the directed prediction
of simplified, even more active and less toxic substances for
further development.
4.2.2. General procedure for the Ritter reaction of 7 leading
to dihydroisoquinolines
This reaction was carried out following a literature protocol
[36]. To a solution of the alcohol 7 in glacial acetic acid
(1.5 mol/l), the nitrile (1.00 eq) was added. Concd. sulfuric
acid (1.4 ml/mmol) was added dropwise to the mixture with
ice cooling. Caution! during the reaction HCN gas is formed;
it was quenched in bottles filled with aqueous sodium hypo-
chloride (NaOCl, 2 M) solution. The reaction mixture was al-
lowed to warm to room temperature. The brownish solution
was transferred to a separation funnel equipped with ice and
washed three times with diethyl ether. The aqueous layer was
treated with a saturated sodium carbonate solution and extracted
three times with diethyl ether. Drying with MgSO4 and removal
of the solvent afforded the respective dihydroisoquinoline.
4. Experimental
4.2.2.1. 1,3,3-Trimethyl 6,8-dimethoxy-3,4-dihydroisoquino-
line (8). Brownish oil. Yield: 65%. IR (neat, cmꢁ1) n 2965,
1
1604, 1574, 1464, 1340, 1301, 1205, 1150, 1100. H NMR
4.1. Instrumentation and chemicals
(CDCl3) d 6.37 (d, J ¼ 2.3 Hz, 1H, AreH), 6.33 (d,
J ¼ 2.3 Hz, 1H, AreH), 3.88 (s, 3H, OeCH3), 3.87 (s, 3H,
OeCH3), 2.71 (s, 2H, CeCH2), 2.68 (s, 3H, CeCH3), 1.35
(s, 6H, CeCH3). 13C NMR (CDCl3) d 161.8, 160.8, 158.3,
141.1, 112.3, 105.1, 97.05, 55.28, 55.26, 52.59, 40.43,
28.01, 27.45. EI-MS (70 eV) m/z (%): 234 (15) [Mþ þ 1],
233 (100) [Mþ], 219 (9), 218 (71), 204 (6), 203 (25), 192
(7), 191 (55), 190 (10), 177 (12), 176 (28), 161 (8), 91 (9),
77 (10), 40 (19). Anal. calcd for C14H19NO2 (233.31): C,
72.07; H, 8.21; N, 6.00; found: C, 72.10; H, 8.38; N, 5.99.
Melting points were determined with a Kofler melting
point apparatus and are uncorrected. IR spectra were scanned
from KBr pellets or neat using a Jasco FT-410 spectrometer.
1H and 13C NMR spectra were recorded with a Bruker
Avance 400 (400 MHz) instrument using the deuterated sol-
vent as an internal reference; J values are given in Hertz.
Elemental analyses were performed at the Institute of Inor-
ganic Chemistry of the University of Wurzburg. Mass spectra
¨
were measured on a Finnigan MAT 2000 mass spectrometer
at 70 eV. All reactions with moisture and/or air sensitive
materials were carried out with flame-dried glassware using
the Schlenk tube technique under inert argon atmosphere.
The ketone 6 [33] and the boronic acids 10, 16, and 21
were synthesized according to literature procedures [34,35].
The commercially available boronic acid 30 was purchased
from Frontier Scientific, Inc.
4.2.2.2. 3,3-Dimethyl 6,8-dimethoxy-3,4-dihydroisoquinoline
(12). Brownish oil. Yield: 78%. IR (neat, cmꢁ1) n 2965,
1
1604, 1574, 1464, 1340, 1301, 1205, 1150, 1100. H NMR
(CDCl3) d 8.54 (s, 1H, CeH), 6.35 (d, J ¼ 2.3 Hz, 1H, Are
H), 6.26 (d, J ¼ 2.3 Hz, 1H, AreH), 3.86 (s, 3H, OeCH3),
3.85 (s, 3H, OeCH3), 2.66 (s, 2H, CeCH2), 1.27 (s, 6H,
CeCH3). 13C NMR (CDCl3) d 206.7, 201.9, 152.6, 139.3,
105.1, 96.22, 55.43, 55.36, 53.69, 38.87, 30.77, 27.56. EI-
MS (70 eV) m/z (%): 219 (85) [Mþ], 204 (100), 189 (23),
163 (35), 77 (13), 51 (8). MS (EI) exact mass calcd for
C13H17NO2: 219.2859; found: 219.1254.
4.2. Chemistry
4.2.1. 1,1-Dimethyl(30,50-dimethoxyphenyl)ethanol (7)
To a solution of 6 (6.00 g, 30.9 mmol) in diethyl ether
(100 ml), a 1.5 M solution of methyl magnesium bromide in
diethyl ether (21 ml, 31.5 mmol) was added dropwise at
0 ꢀC. After refluxing for 1 h, the solution was acidified with
2 N HCl (40 ml) with ice cooling. Washing of the organic
layer with water (50 ml), drying over MgSO4 and removal
of the solvent yielded 7 (6.17 g, 29.4 mmol, 95%) as a yellow
oil. IR (neat, cmꢁ1) n 3416, 2967, 2837, 1595, 1462, 1430,
4.2.3. 3,3-Dimethyl 6,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (13)
The dihydroisoquinoline 12 (2.00 g, 9.13 mmol) was dis-
solvedin methanol (20 ml) and treated with sodium borohydride
(346 mg, 9.13 mmol). The solvent was removed in vacuo. The
residue was taken up in dichloromethane and filtered through
a plug of celite. Removal of the solvent delivered 13 (1.85 g,
8.34 mmol, 92%) as colorless crystals (diethyl ether); mp
81 ꢀC. IR (KBr, cmꢁ1) n 3253, 2957, 2924, 2852, 1592, 1293,
1
1340, 1205, 1150, 1064. H NMR (CDCl3) d 6.34 (m, 3H,
AreH), 3.79 (s, 6H, OeCH3), 2.71 (s, 2H, CeCH2), 1.25 (s,
6H, CeCH3). 13C NMR (CDCl3) d 161.0, 140.4, 109.0,
98.83, 71.03, 55.69, 50.39, 29.68. EI-MS (70 eV) m/z (%):
210 (10) [Mþ], 195 (14), 192 (21), 177 (28), 152 (100), 91
(26), 77 (20), 59 (53), 51 (11), 43 (23). Anal. calcd for
C12H18O3 (210.28): C, 68.25; H, 8.46; found: C, 68.55;
H, 8.62.
1
1222, 1201, 1147, 1103, 1081, 1051, 953, 802, 734. H NMR
(CDCl3) d 6.28 (d, J ¼ 2.3 Hz, 1H, AreH), 6.19 (d,
J ¼ 2.3 Hz, 1H, AreH), 3.90 (s, 2H, NeCH2), 3.79 (s, 3H,
OeCH3), 3.78 (s, 3H, OeCH3), 2.58 (s, 2H, CeCH2), 1.18 (s,
6H, CeCH3). 13C NMR (CDCl3) d 157.7, 155.8, 136.3, 115.8,
104.7, 95.76, 55.16, 55.06, 48.23, 41.89, 39.57, 27.51. EI-MS

G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
37
(70 eV) m/z (%): 221 (29) [Mþ], 220 (17), 206 (47), 164 (100),
91 (10). Anal. calcd for C13H19NO2 (221.30): C, 70.56; H, 8.65;
N, 6.33; found: C, 69.99; H, 8.38; N, 5.99.
(dichloromethane/petroleum ether, 5:1) resulting in colorless
crystals (diethyl ether) of 19 (2.20 g, 6.33 mmol, 70%); mp
118 ꢀC. IR (neat, cmꢁ1) n 3418, 2976, 1605, 1458, 1434,
1360, 1311, 1204, 1158, 1102, 1072, 1044, 992, 856, 731.
1H NMR (CDCl3) d 6.35 (s, 1H, AreH), 3.91 (s, 2H, Ne
CH2), 3.88 (s, 3H, OeCH3), 3.84 (s, 3H, OeCH3), 2.56 (s,
2H, CeCH2), 1.24 (s, 6H, CeCH3). 13C NMR (CDCl3)
d 157.3, 157.1, 138.3, 117.5, 93.36, 83.16, 56.95, 55.39,
50.07, 47.24, 39.53, 27.28. EI-MS (70 eV) m/z (%): 347 (1)
[Mþ], 219 (100), 204 (98), 189 (17), 163 (27), 71 (8). Anal.
calcd for C13H18INO2 (347.20): C, 44.97; H, 5.23; N, 4.03;
found: C, 45.29; H, 5.23; N, 3.80.
4.2.4. General procedure for the bromination of
isoquinolines
To a solution of the isoquinoline (0.25 M) in dichlorome-
thane (20 ml), a catalytic amount of DMF and a solution of
bromine (1.05 eq) in dichloromethane (0.25 M) were added
dropwise at 0 ꢀC. After stirring for 1 h, the solution was
washed twice with 50 ml of a saturated aqueous solution of
sodium carbonate. The residue was purified by column chro-
matography on deactivated silica gel.
4.2.5.2. 5-Iodo-3,3-dimethyl-8-methoxy-1,2,3,4-tetrahydroiso-
quinoline (28). According to Section 4.2.5.1, the isoquinoline
27 (47 mg, 0.25 mmol) was iodinated with silver sulfate
(307 mg, 0.98 mmol) and iodine (75 mg, 9.50 mmol). The re-
action mixture contained the desired product 28 along with the
corresponding dihydroisoquinoline and its iodide. The solvent
was removed under reduced pressure, the mixture was taken
up with methanol and treated with sodium borohydride
(0.5 eq) giving a mixture of the iodide 28 and starting material.
Repetition of the iodinationereduction sequence and chroma-
tography on deactivated silica gel (dichloromethane/petroleum
ether/methanol, 100:20:1) yielded 28 as bright yellow crystals
(diethyl ether) (45 mg, 0.14 mmol, 58%); mp 114 ꢀC. IR
(KBr) n 3300, 3094, 2953, 2930, 2831, 1647, 1578, 1457,
1432, 1380, 1364, 1289, 1251, 1088, 1074, 1029, 822, 803.
1H NMR (CDCl3) d 7.64 (d, J ¼ 8.6 Hz, 1H, AreH), 6.48
(d, J ¼ 8.6 Hz, 1H, AreH), 3.93 (s, 2H, NeCH2), 3.79 (s,
3H, OeCH3), 2.50 (s, 2H, CeCH2), 1.21 (s, 6H, CeCH3).
13C NMR (CDCl3) d 156.0, 137.4, 136.8, 126.0, 109.5,
91.90, 55.30, 49.52, 47.03, 40.02, 27.43. EI-MS (70 eV) m/z
(%): 318 (3) [Mþ þ 1], 317 (25) [Mþ], 303 (13), 302 (100),
300 (11), 286 (11), 285 (4), 261 (6), 260 (50), 230 (10), 174
(9), 151 (11), 103 (13), 80 (13). MS (EI) exact mass calcd
for C12H16NOI: 317.0276; found: 317.0270.
4.2.4.1. 5-Bromo-1,3,3-trimethyl 6,8-dimethoxy-3,4-dihydroi-
soquinoline (9). Yellow solid (diethyl ether). Yield: 70%;
mp 143 ꢀC. IR (KBr, cmꢁ1) n 2960, 2924, 2867, 1612, 1585,
1561, 1470, 1437, 1338, 1306, 1259, 1219, 1174, 1089,
1
1066, 1026, 970, 946, 898, 821. H NMR (CDCl3) d 6.42 (s,
1H, AreH), 3.95 (s, 3H, OeCH3), 3.88 (s, 3H, OeCH3),
2.72 (s, 2H, CeCH2), 2.40 (s, 3H, CeCH3), 1.17 (s, 6H,
CeCH3). 13C NMR (CDCl3) d 160.6, 158.1, 157.9, 140.3,
113.9, 104.8, 94.83, 56.21, 55.68, 52.88, 39.64, 27.76,
27.63. EI-MS (70 eV) m/z (%): 314 (Mþ þ 3, 16), 313 (99)
[Mþ þ 2], 312 (39) [Mþ þ 1], 311 (100) [Mþ], 298 (55),
296 (60), 283 (12), 281 (11), 271 (39), 269 (41), 256 (20),
254 (24), 217 (27), 202 (14), 176 (13), 161 (11), 109 (12),
86 (22), 84 (40), 77 (12), 57 (11), 42 (15). Anal. calcd for
C14H18BrNO2 (312.21): C, 53.86; H, 5.81; N, 4.49; found:
C, 53.71; H, 5.90; N, 3.92.
4.2.4.2. 5-Bromo-3,3-dimethyl 6,8-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (14). Colorless crystals (diethyl ether). Yield:
78%; mp 157 ꢀC. IR (KBr, cmꢁ1) n 3299, 3004, 2960, 2938,
2839, 1599, 1571, 1478, 1464, 1450, 1435, 1350, 1330,
1313, 1278, 1208, 1150, 1091, 1071, 1016, 828, 798, 749,
1
700. H NMR (CDCl3) d 6.37 (s, 1H, AreH), 3.94 (s, 2H,
NeCH2), 3.82 (s, 3H, OeCH3), 3.88 (s, 3H, OeCH3), 2.64
(s, 2H, CeCH2), 1.25 (s, 6H, CeCH3). 13C NMR (CDCl3)
d 155.8, 155.1, 135.2, 116.2, 105.1, 93.94, 56.44, 55.41,
49.61, 41.64, 39.12, 27.11. EI-MS (70 eV) m/z (%): 301 (24)
[Mþ þ 2], 300 (16) [Mþ þ 1], 299 (37) [Mþ], 286, 284
(100), 244 (79), 242 (79), 204 (18), 202 (15), 162 (19), 103
(15), 77 (14), 42 (12). Anal. calcd for C13H18BrNO2
(300.20): C, 52.01; H, 6.04; N, 4.67; found: C, 52.05; H,
6.05; N, 4.77.
4.2.6. General procedure for the N-benzylation of
tetrahydroisoquinolines
The reactions were performed as described for similar
substances in the literature [37]. A suspension of the iso-
quinoline, benzyl bromide (1.05 eq), and cesium carbonate
(2.10 eq) in acetone was stirred overnight. The suspension
was filtered from inorganic salts and the residue purified by
column chromatography on deactivated silica gel (petroleum
ether/dichloromethane/methanol, 100:10:1) giving the N-ben-
zylated tetrahydroisoquinolines.
4.2.5. Iodination of tetrahydroisoquinolines
4.2.5.1. 5-Iodo-3,3-dimethyl 6,8-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (19). Following a procedure for the iodination
of related tetrahydroisoquinolines [37], silver sulfate (8.45 g,
4.2.6.1. N-Benzyl-3,3-dimethyl 6,8-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (24). Yield: 92%; mp 109 ꢀC (petroleum
ether). IR (neat, cmꢁ1) n 2963, 2835, 1604, 1496, 1453,
1426, 1377, 1360, 1328, 1278, 1208, 1149, 1109, 1055, 826,
27.1 mmol) was added to
a solution of 13 (2.00 g,
1
9.04 mmol), and then added dropwise a solution of iodine
(2.41 g, 9.50 mmol) in ethanol (20 ml). After stirring for
30 min, the inorganic salts were removed by filtration, and
the residue was chromatographed on deactivated silica gel
699. H NMR (CDCl3) d 7.41 (d, J ¼ 7.1 Hz, 2H, AreH),
7.31 (t, J ¼ 7.6 Hz, 2H, AreH), 7.23 (t, J ¼ 7.3 Hz, 1H, Are
H), 6.24 (d, J ¼ 2.1 Hz, 1H, AreH), 6.22 (d, J ¼ 2.1 Hz, 1H,
AreH), 3.76 (s, 3H, OeCH3), 3.73 (s, 2H, NeCH2), 3.69 (s,

38
G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
3H, OeCH3), 3.50 (s, 2H, NeCH2), 2.74 (s, 2H, CeCH2),
1.21 (s, 6H, CeCH3). 13C NMR (CDCl3) d 159.2, 157.3,
136.5, 129.0, 128.6, 127.0, 104.4, 96.11, 55.68, 55.46,
54.23, 53.02, 46.37, 44.09, 24.03. EI-MS (70 eV) m/z (%):
311 (20) [Mþ], 310 (15), 297 (20), 296 (100), 205 (7), 204
(24), 165 (9), 164 (76), 146 (8), 91 (74). Anal. calcd for
C20H25NO2 (311.43): C, 77.14; H, 8.09; N, 4.50; found: C,
76.65; H, 8.06; N, 4.40.
65 (8). MS (EI) exact mass calcd for C19H22NOI: 407.0745;
found: 407.0739.
4.2.7. General procedure for the Suzuki coupling of
isoquinolines
The coupling reactions were carried out as described for
similar reactions in the literature [37]. In the case of the bro-
mide 9, dimethoxyethane/water, 3:1 was used as the solvent,
and barium hydroxide as the base; the mixture was kept under
argon overnight at 80 ꢀC. For the iodides 20 and 29, the reac-
tions were performed in toluene:water, 1:1 and heated for 12 h
to 90 ꢀC. Tetrakis(triphenylphosphane)-palladium(0) was used
in a catalytical amount of 0.1 eq.
4.2.6.2.
N-Benzyl-5-bromo-3,3-dimethyl
6,8-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (15). Yield: 90%; mp 198 ꢀC
(petroleum ether). IR (KBr, cmꢁ1) n 2960, 2927, 1596,
1576, 1488, 1449, 1430, 1373, 1342, 1322, 1207, 1164,
1107, 1080, 982, 803, 762, 723, 697. 1H NMR (C3D6O)
d 7.42 (d, J ¼ 7.6 Hz, 2H, AreH), 7.31 (t, J ¼ 7.6 Hz, 2H,
AreH), 7.22 (t, J ¼ 7.6 Hz, 1H, AreH), 6.61 (s, 1H, AreH),
3.88 (s, 3H, OeCH3), 3.76 (s, 5H, OeCH3 and NeCH2),
3.47 (s, 2H, NeCH2), 2.74 (s, 2H, CeCH2), 1.25 (s, 6H,
CeCH3). 13C NMR (C3D6O) d 156.7, 155.8, 136.0, 129.2,
129.0, 127.4, 104.4, 94.99, 56.57, 55.70, 53.31, 54.02,
46.35, 44.87, 23.67. EI-MS (70 eV) m/z (%): 391 (3) [Mþ],
390 (3), 389 (4), 377 (5), 376 (30), 374 (31), 284 (5), 282
(5), 244 (13), 242 (12), 146 (6), 91 (100), 77 (7), 65 (11),
57 (13), 43 (10). Anal. calcd for C20H24BrNO2 (390.32): C,
61.54; H, 6.20; N, 3.59; found: C, 62.06; H, 6.14; N, 3.60.
4.2.7.1. 5-(40-Methoxyphenyl)-1,3,3-trimethyl 6,8-dimethoxy-
3,4-dihydroisoquinoline (11). Yield: 66%; mp 128 ꢀC (diethyl
ether). IR (KBr, cmꢁ1) n 2957, 2926, 2857, 2840, 1609, 1582,
1516, 1482, 1460, 1435, 1367, 1338, 1309, 1287, 1246, 1207,
1
1166, 1103, 1089, 1025, 838, 806. H NMR (C3D6O) d 7.06
(d, J ¼ 8.9 Hz, 2H, AreH), 6.95 (d, J ¼ 8.9 Hz, 2H, AreH),
6.69 (s, 1H, AreH), 3.97 (s, 3H, OeCH3), 3.83 (s, 3H, Oe
CH3), 2.78 (s, 3H, OeCH3), 2.34 (s, 3H, CeCH3), 2.25 (s,
2H, CeCH2), 0.96 (s, 6H, CeCH3). 13C NMR (C3D6O)
d 160.4, 160.2, 159.4, 158.8, 139.4, 132.4, 129.4, 123.0,
114.1, 112.5, 94.95, 55.89, 55.78, 55.34, 53.26, 38.29,
28.27, 27.76. EI-MS (70 eV) m/z (%): 326 (16) [Mþ þ 1],
325 (100) [Mþ], 311 (9), 310 (41), 283 (27), 268 (14), 238
(5), 155 (6), 42 (7). Anal. calcd for C21H23NO3 (339.44): C,
74.31; H, 7.42; N, 4.13; found: C, 74.43; H, 7.11; N, 3.93.
4.2.6.3. N-Benzyl-5-iodo-3,3-dimethyl 6,8-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (20). Yield: 80%; mp 174 ꢀC (petro-
leum ether). IR (neat, cmꢁ1) n 3026, 3006, 2962, 2930,
2886, 2836, 2758, 1583, 1483, 1455, 1431, 1340, 1206,
1
1159, 1080, 1057, 1027, 979, 853, 808, 755, 738. H NMR
4.2.7.2. N-Benzyl-5-(4-benzoxyphenyl)-3,3-dimethyl-6,8-dime-
thoxy-1,2,3,4-tetrahydroiso-quinoline (17). Yield: 92%; mp
194 ꢀC (diethyl ether). IR (KBr, cmꢁ1) n 2924, 2835, 1599,
1517, 1491, 1454, 1376, 1324, 1239, 1197, 1141, 1068,
(CDCl3) d 7.40 (m, 2H, AreH), 7.31 (t, J ¼ 7.2 Hz, 2H,
AreH), 7.23 (t, J ¼ 7.2 Hz, 1H, AreH), 6.30 (s, 1H, Ar-H),
3.87 (s, 3H, OeCH3), 3.73 (br s, 5H, OeCH3 and NeCH2),
3.51 (s, 2H, NeCH2), 2.71 (s, 2H, CeCH2), 1.24 (s, 6H,
CeCH3). 13C NMR (CDCl3) d 157.1, 157.0, 140.7, 138.6,
129.6, 128.5, 128.2, 126.6, 93.07, 82.13, 56.59, 55.23,
53.41, 49.32, 45.82, 23.73. EI-MS (70 eV) m/z (%): 437 (14)
[Mþ], 423 (19), 422 (100), 330 (4), 294 (4), 290 (32), 254
(10), 204 (6), 203 (6), 133 (5), 103 (6), 91 (84), 77 (6).
Anal. calcd for C20H24INO2 (437.32): C, 54.93; H, 5.53; N,
3.20; found: C, 55.08; H, 5.56; N, 3.09.
1
1026, 825, 810, 722, 734, 698. H NMR (CDCl3) d 7.20e
7.52 (m, 10H, AreH), 7.14 (d, J ¼ 8.8 Hz, 2H, AreH), 7.05
(d, J ¼ 8.8 Hz, 2H, AreH), 6.39 (s, 1H, AreH), 5.11 (s, 2H,
OeCH2), 3.78 (s, 3H, OeCH3), 3.72 (s 3H, OeCH3), 3.72
(s, 2H, NeCH2), 3.57 (s, 2H, NeCH2), 2.43 (s, 2H, Ce
CH2), 1.21 (s, 6H, CeCH3). 13C NMR (CDCl3) d 157.5,
155.9, 155.7, 155.1, 137.2, 134.9, 131.6, 129.6, 128.8,
128.6, 128.6, 128.1, 127.9, 127.6, 126.5, 122.0, 114.4,
92.81, 70.00, 56.06, 55.11, 53.88, 52.40, 46.26, 42.35,
29.69, 23.45. EI-MS (70 eV) m/z (%): 493 (12) [Mþ], 492
(12), 479 (34), 478 (100), 387 (13), 346 (13), 255 (77), 91
(74), 57 (15). Anal. calcd for C33H35NO3 (493.65): C,
80.29; H, 7.15; N, 2.84; found: C, 79.93; H, 7.22; N, 2.50.
4.2.6.4. N-Benzyl-5-iodo-3,3-dimethyl-8-methoxy-1,2,3,4-tetra-
hydroisoquinoline (29). Yield: 90%; mp 149 ꢀC (petroleum
ether). IR (KBr, cmꢁ1) n 2959, 2935, 2875, 1647, 1576,
1472, 1455, 1436, 1370, 1295, 1261, 1231, 1207, 1093,
1
1054, 1026, 797, 735, 702, 605. H NMR (CDCl3) d 7.64
(d, J ¼ 8.6 Hz, 1H, AreH), 7.41 (d, J ¼ 7.3 Hz, 2H, AreH),
7.33 (t, J ¼ 7.3 Hz, 2H, AreH), 7.26 (t, J ¼ 7.1 Hz, 1H, Are
H), 6.43 (d, J ¼ 8.6 Hz, 1H, AreH), 3.75 (s, 2H, NeCH2),
3.69 (s, 3H, OeCH3), 3.57 (s, 2H, NeCH2), 2.68 (s, 2H,
CeCH2), 1.26 (s, 6H, CeCH3). 13C NMR (CDCl3) d 156.1,
149.3, 136.5, 129.5, 129.4, 128.3, 126.7, 113.1, 109.3,
90.77, 55.19, 53.37, 48.93, 46.11, 29.68, 23.67. EI-MS
(70 eV) m/z (%): 407 (11) [Mþ], 393 (20), 392 (100), 265
(5), 260 (16), 224 (8), 173 (7), 146 (13), 103 (7), 91 (100),
4.2.7.3. N-Benzyl-5-(40-benzoxynaphthyl)-3,3-dimethyl-6,8-di-
methoxy-1,2,3,4-tetrahydroiso-quinoline (22). Yield: 68%;
mp 204 ꢀC (diethyl ether). IR (KBr, cmꢁ1) n 2955, 2836,
1588, 1508, 1452, 1433, 1371, 1318, 1279, 1233, 1200,
1
1110, 1096, 1071, 1020, 811, 767, 696. H NMR (CDCl3)
d 8.36 (d, J ¼ 8.3 Hz, 1H, AreH), 7.67 (d, J ¼ 7.3 Hz, 2H,
AreH), 7.33e7.50 (m, 10H, AreH), 7.24 (t, J ¼ 7.7 Hz, 1H,
AreH), 7.17 (d, J ¼ 7.7 Hz, 1H, AreH), 7.12 (d, J ¼ 7.9 Hz,
1H, AreH), 6.65 (s, 1H, AreH), 5.37 (s, 2H, OeCH2), 3.89

G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
39
(s, 3H, OeCH3), 3.58 (s, 3H, OeCH3), 3.40e3.88 (m, 4H, Ne
CH2), 2.41 (d, J ¼ 16.7 Hz, 1H, CeCH2), 1.20 (d, J ¼ 16.7 Hz,
(70 eV) m/z (%): 298 (4) [Mþ þ 1], 297 (21) [Mþ], 296
(18), 283 (21), 282 (100), 191 (6), 190 (24), 150 (17), 148
(41), 146 (10), 91 (99). Anal. calcd for C19H23NO2 (297.40):
C, 76.64; H, 7.80; N, 4.71; found: C, 76.07; H, 8.01; N, 4.38.
1H, CeCH2), 1.05 (s, 3H, CeCH3), 0.97 (s, 3H, CeCH3). 13
C
NMR (CDCl3) d 157.7, 156.9, 154.4, 141.9, 138.5, 136.3,
134.6, 129.3, 129.1, 128.9, 128.6, 128.6, 128.5, 127.3,
126.7, 126.2, 125.6, 122.9, 120.5, 115.9, 106.0, 93.71,
70.67, 55.92, 55.44, 54.53, 52.62, 47.16, 42.86, 24.70,
22.04. EI-MS (70 eV) m/z (%): 543 (10) [Mþ], 542 (11),
529 (29), 528 (71), 478 (15), 468 (23), 467 (40), 452 (17),
451 (30), 438 (12), 437 (18), 377 (21), 376 (62), 361 (18),
360 (29), 347 (22), 346 (13), 306 (10), 305 (38), 105 (13),
91 (9), 91 (100). Anal. calcd for C37H37NO3 (543.71): C,
81.74; H, 6.86; N, 2.58; found: C, 81.43; H, 7.02; N, 2.51.
4.2.9. N-Benzyl-3,3-dimethyl-6-trifluormethansulfonyloxy-8-
methoxy-1,2,3,4-tetrahydroiso-quinoline (26)
To a suspension of the tetrahydroisoquinoline 25 (400 mg,
1.35 mmol) in absolute dichloromethane, DABCO (332 mg,
2.96 mmol) and trifluoromethanesulfonyl anhydride (0.25 ml,
418 mg, 1.48 mmol) were added at 0 ꢀC. The reaction mixture
was allowed to warm to room temperature. The solvent was
removed under reduced pressure, the residue dissolved in
dichloromethane and washed twice with a saturated aqueous
sodium carbonate solution. Flash chromatography on deacti-
vated silica gel (petroleum ether/dichloromethane/methanol,
100:10:1) resulted in 26 as white crystals (petroleum ether)
(547 mg, 1.27 mmol, 95%); mp 145 ꢀC. IR (KBr, cmꢁ1) n
2923, 2853, 1588, 1514, 1465, 1383, 1351, 1250, 1099,
4.2.7.4. 5-[(20-Carboxy-40-benzoxy)phenyl])-N-benzyl-3,3-di-
methyl-8-methoxy-3,4-dihydroisoquinoline (31). Yellow oil.
Yield: 90%. IR (KBr, cmꢁ1) n 2958, 2927, 2852, 1690,
1646, 1601, 1481, 1383, 1272, 1223, 1166, 1081, 1028, 818,
1
739, 698. H NMR (C3D6O) d 9.70 (s, 1H, C(O)eH), 7.20e
7.57 (m, 13H, AreH), 7.03 (d, J ¼ 8.2 Hz, 1H, AreH), 6.84
(d, J ¼ 8.3 Hz, 1H, AreH), 5.26 (s, 2H, OeCH2), 3.67e3.83
(m, 5H, OeCH3 and NeCH2), 3.62 (d, J ¼ 17.6 Hz, 1H, Ne
CH2), 3.55 (d, J ¼ 17.6 Hz, 1H, NeCH2), 2.50 (d,
J ¼ 16.3 Hz, 1H, CeCH2), 2.32 (d, J ¼ 16.3 Hz, 1H, Ce
CH2), 1.13 (s, 3H, CeCH3), 1.08 (s, 3H, CeCH3). 13C
NMR (C3D6O) d 191.7, 159.0, 156.2, 141.5, 138.7, 137.7,
135.9, 134.7, 133.4, 129.6, 129.5, 129.1, 128.9, 128.7,
128.6, 128.3, 127.2, 124.0, 121.9, 111.3, 107.2, 70.54,
55.26, 54.28, 52.45, 47.19, 43.30, 23.90, 22.48. EI-MS
(70 eV) m/z (%): 491 (6) [Mþ], 490 (4), 478 (6), 477 (29),
476 (94), 385 (6), 344 (5), 327 (8), 253 (21), 225 (11), 146
(16), 91 (100). Anal. calcd for C33H33NO3 (491.64): C,
80.62; H, 6.77; N, 2.85; found: C, 81.41; H, 7.02; N, 2.51.
1
1068, 1024, 810. H NMR (C3D6O) d 7.40 (d, J ¼ 7.4 Hz,
2H, AreH), 7.31 (t, J ¼ 7.5 Hz, 2H, AreH), 7.23 (t,
J ¼ 7.2 Hz, 1H, AreH), 6.81 (d, J ¼ 2.3 Hz, 1H, AreH),
6.77 (d, J ¼ 2.3 Hz, 1H, AreH), 3.79 (s, 3H, OeCH3), 3.77
(s, 2H, NeCH2), 3.50 (s, 2H, NeCH2), 2.82 (s, 2H, Ce
CH2), 1.22 (s, 6H, CeCH3). 13C NMR (C3D6O) d 157.8,
149.2, 141.5, 138.4, 129.1, 129.0, 127.4, 124.6, 119.6
3
(q, JCeF ¼ 320 Hz), 113.6, 101.9, 56.13, 54.29, 52.61,
46.70, 44.15, 23.36. EI-MS (70 eV) m/z (%): 429 (7) [Mþ],
416 (4), 415 (12), 414 (62), 296 (4), 282 (6), 281 (10),
205 (4), 190 (5), 180 (6), 146 (15), 121 (6), 97 (6), 91
(100), 83 (6), 71 (12), 57 (16), 55 (10), 43 (13), 41 (10).
MS (EI) exact mass calcd for C20H22F3NO4S: 429.1220;
found: 429.1214.
4.2.8. N-Benzyl-3,3-dimethyl 6-hydroxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (25)
4.2.10. General procedure for the removal of benzyl and
triflate protection groups
A suspension of the N-benzylated isoquinoline (500 mg,
1.61 mmol) 24 in 48% HBr (20 ml) was heated for 45 min
to 75 ꢀC until the conversion was approximately 50% accord-
ing to tlc, because further heating was shown to give double
O-demethylation and subsequent decomposition, and thus
loss of material. The reaction mixture was quenched by addi-
tion of an aqueous sodium carbonate solution. The crude prod-
uct was extracted with dichloromethane and separated from the
starting material by column chromatography on deactivated
silica gel (eluent: petroleum ether/dichloromethane/methanol,
100:25:1) (192 mg, 0.64 mmol, 40% 25 and 150 mg,
0.48 mmol, 30% starting material 24); mp 217 ꢀC. IR (KBr,
cmꢁ1) n 3399, 2962, 2839, 1604, 1457, 1381, 1315, 1261,
1148, 1023, 805, 758, 698. 1H NMR (C3D6O) d 7.39 (d,
J ¼ 7.5 Hz, 2H, AreH), 7.29 (t, J ¼ 7.2 Hz, 2H, AreH),
7.21 (t, J ¼ 7.3 Hz, 1H, AreH), 6.22 (d, J ¼ 2.0 Hz, 1H,
AreH), 6.18 (d, J ¼ 2.0 Hz, 1H, AreH), 3.73 (s, 2H, Ne
CH2), 3.64 (s, 3H, OeCH3), 3.40 (s, 2H, NeCH2), 2.65 (s,
2H, CeCH2), 1.18 (s, 6H, CeCH3). 13C NMR (C3D6O)
d 157.7, 157.2, 142.1, 136.9, 129.1, 128.9, 127.3, 114.7,
107.4, 96.81, 55.23, 54.57, 52.75, 46.95, 44.57, 23.60. EI-MS
A solution of the protected compound, ammonium formate
(4 eq) and 10% Pd/C in methanol (0.1 M) was refluxed for
30 min. The solvent was removed in vacuo, the residue dis-
solved in dichloromethane and washed with water. The prod-
uct was gained by column chromatography on deactivated
silica gel.
4.2.10.1. 5-(40-Hydroxyphenyl)-3,3-dimethyl-6,8-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (18). Yield: 90%; mp 235 ꢀC
(dichloromethane). IR (KBr, cmꢁ1) n 3383, 2246, 2961,
2839, 1608, 1518, 1465, 1405, 1328, 1270, 1198, 1138,
1
1092, 1023, 836. H NMR (CDCl3) d 6.95 (d, J ¼ 8.1 Hz,
2H, AreH), 6.84 (d, J ¼ 8.1 Hz, 2H, AreH), 6.42 (s, 1H,
AreH), 4.11 (s, 2H, NeCH2), 3.86 (s, 3H, OeCH3), 3.69 (s,
3H, OeCH3), 2.42 (s, 2H, CeCH2), 1.26 (s, 6H, CeCH3).
13C NMR (CDCl3) d 158.9, 157.5, 157.4, 133.9, 132.5,
128.5, 124.4, 116.1, 115.9, 94.86, 56.39, 56.09, 52.91,
39.30, 39.27, 25.39. EI-MS (70 eV) m/z (%): 314 (7)
[Mþ þ 1], 313 (36) [Mþ], 311 (37), 299 (15), 298 (72), 257
(20), 256 (100), 255 (24), 241 (32), 239 (36), 225 (36), 149

40
G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
(10). Anal. calcd for C19H23NO3 (313.40): C, 72.82; H, 7.40;
N, 4.47; found: C, 72.46; H, 7.22; N, 4.39.
55.00, 54.20, 52.29, 47.14, 42.65, 24.77, 21.47. EI-MS
(70 eV) m/z (%): 493 (3) [Mþ], 492 (3), 480 (6), 479 (32),
478 (100), 476 (5), 387 (6), 315 (6), 255 (11), 91 (47). EI-
MS exact mass calcd for C32H32NO3: 478.2377; found:
478.2376.
4.2.10.2. 5-(40-Hydroxynaphthyl)-3,3-dimethyl-6,8-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (23). Yield: 85%; mp 168 ꢀC
(dichloromethane). IR (KBr, cmꢁ1) n 3436, 2926, 2855,
1738, 1587, 1460, 1382, 1350, 1321, 1261, 1203, 1104,
1084, 1024, 810, 767. 1H NMR (CDCl3) d 8.25 (d,
J ¼ 8.4 Hz, 1H, AreH), 7.36 (m, 1H, AreH), 7.26 (m, 1H,
AreH), 7.19 (d, J ¼ 8.3 Hz, 1H, AreH), 6.99 (d, J ¼ 7.5 Hz,
1H, AreH), 6.88 (d, J ¼ 7.5 Hz, 1H, AreH), 6.73 (s, 1H,
AreH), 4.21 (s, 2H, NeCH2), 3.98 (s, 3H, OeCH3), 3.64 (s,
3H, OeCH3), 2.51 (d, J ¼ 16.7 Hz, 1H, CeCH2), 2.15 (d,
J ¼ 16.7 Hz, 1H, CeCH2), 1.24 (s, 3H, CeCH3), 1.17 (s,
3H, CeCH3). 13C NMR (CDCl3) d 160.4, 158.3, 154.7,
135.3, 134.2, 129.8, 127.6, 127.1, 126.3, 126.3, 125.8,
124.1, 122.6, 109.5, 109.2, 95.36, 56.73, 56.64, 54.17,
39.36, 38.63, 25.67, 24.60. EI-MS (70 eV) m/z (%): 363 (1)
[Mþ], 280 (4), 265 (7), 264 (13), 167 (4), 151 (4), 149 (7),
137 (4), 125 (4), 123 (5), 113 (25), 112 (64), 97 (19), 85
(7), 84 (16), 83 (32), 71 (88), 70 (36), 67 (16), 57 (100), 55
(45), 43 (42), 41 (29). Anal. calcd for C23H25NO3 (363.46):
C, 76.01; H, 6.93; N, 3.85; found: C, 76.52; H, 6.84; N, 3.79.
4.2.12. 5-[(20-Hydroxymethyl-40-hydroxy)phenyl)]-3,3-
dimethyl-8-methoxy-3,4-dihydroiso-quinoline (33)
To a solution of 32 (12 mg) in abs. methanol (4 ml) under
nitrogen, a small amount of 10% Pd/C was added. Hydrogen
was flushed into the Schlenk tube. After 20 min, the solution
was filtered over Celite and the pure 33 was gained after
chromatography (eluent: dichloromethane/methanol, 3:1) (6 mg,
21 mmol, 70%). IR (KBr, cmꢁ1) n 3400, 2926, 2853, 1655,
1633, 1600, 1406, 1370, 1288, 1259, 1156, 1104, 1084,
1018, 831, 704, 669. 1H NMR (CD3OD) d 7.02 (d,
J ¼ 2.5 Hz, 1H, AreH), 6.94 (d, J ¼ 8.4 Hz, 1H, AreH),
6.83 (d, J ¼ 8.2 Hz, 1H, AreH), 6.80 (d, J ¼ 8.3 Hz, 1 H,
AreH), 6.70 (dd, J ¼ 8.2 Hz, J ¼ 2.6 Hz, 1H, AreH), 4.23
(d, J ¼ 13.4 Hz, 1H, CH2eOH), 4.16 (d, J ¼ 13.4 Hz, 1H,
CH2eOH), 3.83 (s, 3H, OeCH3), 3.72 (d, J ¼ 17.1 Hz, 1H,
NeCH2), 3.64 (d, J ¼ 17.1 Hz, 1H, NeCH2), 2.38 (d,
J ¼ 16.9 Hz, 1H, CeCH2), 2.18 (d, J ¼ 16.9 Hz, 1H, Ce
CH2), 1.03 (s, 3H, CeCH3), 0.98 (s, 3H, CeCH3). 13C
NMR (CD3OD) d 157.9, 156.3, 141.9, 134.6, 133.7, 131.9,
131.6, 129.7, 122.9, 114.9, 114.8, 107.9, 62.81, 55.76,
53.41, 50.67, 42.30, 23.37, 20.78. EI-MS (70 eV) m/z (%):
313 (23) [Mþ], 312 (100), 311 (20), 296 (8), 278 (11), 237
(22), 226 (11), 225 (23), 207 (12), 195 (10), 165 (8), 147
(8), 137 (10), 121 (7), 119 (10), 111 (26), 110 (8), 109 (23),
97 (42), 95 (34), 91 (8), 85 (32), 83 (44), 81 (33), 71 (49),
69 (53), 67 (23), 57 (83), 55 (60), 43 (67), 41 (38). Anal. calcd
for C19H23NO3 (313.40): C, 72.82; H, 7.40; N, 4.47; found: C,
73.03; H, 7.50; N, 4.51.
4.2.10.3. 3,3-Dimethyl-8-methoxy-1,2,3,4-tetrahydroisoquino-
line (27). Yield: 95%; mp 55 ꢀC (diethyl ether). IR (KBr,
cmꢁ1) n 3303, 2923, 2853, 1586, 1468, 1434, 1380, 1353,
1
1253, 1084, 1071, 1021, 852, 824, 776. H NMR (C3D6O)
d 7.07 (t, J ¼ 7.7 Hz, 1H, AreH), 6.72 (d, J ¼ 7.9 Hz, 1H,
AreH), 6.63 (d, J ¼ 7.7 Hz, 1H, AreH), 3.85 (s, 2H, Ne
CH2), 3.80 (s, 3H, OeCH3), 2.55 (s, 2H, CeCH2), 1.10 (s,
6H, CeCH3). 13C NMR (C3D6O) d 156.7, 136.9, 127.0,
124.5, 122.3, 107.6, 55.33, 48.40, 42.09, 40.54, 27.69.
4.2.11. 5-[(20-Hydroxymethyl-40-benzoxy)phenyl]-N-benzyl-
3,3-dimethyl-8-methoxy-3,4-dihydroisoquinoline (32)
4.3. Biological tests (Table 1)
To a solution of 31 (20 mg) in absolute diethyl ether at
0 ꢀC, 8 mg of lithium aluminium hydride was added slowly.
After 5 min an aqueous solution of sodium carbonate was
added. Extraction with dichloromethane and chromatography
on deactivated silica gel (eluent: petroleum ether/dichlorome-
thane/methanol, 30:10:1) resulted in 32 (16 mg, 16.2 mmol,
80%); mp 157 ꢀC (diethyl ether). IR (KBr, cmꢁ1) n 3416,
2958, 2927, 2851, 1602, 1477, 1464, 1374, 1293, 1262,
1230, 1159, 1100, 1078, 1026, 813, 737, 696. 1H NMR
(C3D6O) d 7.54 (d, J ¼ 7.3 Hz, 2H, AreH), 7.42 (m, 4H,
AreH), 7.27e7.38 (m, 4H, AreH), 7.22 (t, J ¼ 7.3 Hz, 1H,
AreH), 6.95 (m, 2H, AreH), 6.89 (d, J ¼ 8.3 Hz, 1H, Are
H), 6.76 (d, J ¼ 8.3 Hz, 1H, AreH), 4.35 (d, J ¼ 13.8 Hz,
1H, CH2eOH), 4.26 (d, J ¼ 13.8 Hz, 1H, CH2eOH), 3.85
(d, J ¼ 17.4 Hz, 1H, NeCH2), 3.74 (s, 3H, OeCH3), 3.63
(m, 2H, NeCH2), 3.49 (d, J ¼ 17.4 Hz, 1H, NeCH2), 2.45
(d, J ¼ 16.5 Hz, 1H, CeCH2), 2.25 (d, J ¼ 16.5 Hz, 1H, Ce
CH2), 1.13 (s, 3H, CeCH3), 1.08 (s, 3H, CeCH3). 13C
NMR (C3D6O) d 158.8, 155.5, 142.3, 141.5, 138.2, 134.3,
132.5, 132.1, 131.1, 128.9, 128.8, 128.6, 128.2, 128.2,
128.1, 127.0, 123.5, 113.4, 113.0, 107.0, 70.06, 62.07,
4.3.1. P. falciparum
Antiplasmodial activity was determined using the K1 strain
of P. falciparum (resistant to chloroquine and pyrimethamine).
A modification of the [3H] hypoxanthine incorporation assay
[38] was used [39]. Briefly, infected human red blood cells
were exposed to serial drug dilutions in microtiter plates for
48 h at 37 ꢀC in a gas mixture with reduced oxygen and
elevated CO2. [3H] hypoxanthine was added to each well
and after further incubation for 24 h the wells were harvested
on glass fiber filters and counted in a liquid scintillation
counter. From the sigmoidal inhibition curve the IC50 value
was calculated.
4.3.2. T. cruzi
Rat skeletal myoblasts (L 6 cells) were seeded in 96-well
microtiter plates at 2000 cells/well/100 ml in RPMI 1640
medium with 10% FBS and 2 mM L-glutamine. After 24 h
5000 trypomastigotes of T. cruzi [Tulahuen strain C2C4 con-
taining the galactosidase (Lac Z) gene] were added in 100 ml
per well with 2ꢂ of a serial drug dilution. The plates were

G. Bringmann et al. / European Journal of Medicinal Chemistry 43 (2008) 32e42
41
Table 1
In vitro activities against T. cruzi, L. donovani, P. falciparum and L 6 cells
Compound
T. cruzi
IC50 (mg/ml)
Therapeutic
index
L. donovani
IC50 (mg/ml)
Therapeutic
index
P. falciparum K1
IC50 (mg/ml)
Therapeutic
index
Cytotoxicity (L 6 cells)
IC50 (mg/ml)
8
44.78
19.80
3.60
18.2
18.9
>30
18.3
>30
>10
4.2
4.059
0.377
>5
22.17
152.5
>90
9
11
57.5
43.4
12.06
14.62
12
13
59.10
>90
>5
>90
>90
3.458
0.628
0.424
>5
26.03
>143.3
200
14
15
40.70
5.80
>90
20.19
84.8
28.2
18
19
45.20
37.70
3.70
12.75
>10
2.4
0.463
1.023
0.349
1.396
0.521
4.670
>5
71.6
64.5
33.2
66
20
23
17.84
1.53
27.50
1.62
5.50
5.2
24.1
64.5
8.4
24
25
20.10
22.70
12.05
33.00
10.00
5.20
>10
30
>90
152.8
>19.2
79.6
26
27
n.a.
n.a.
>90
>90
28
29
n.a.
n.a.
0.341
3.866
3.554
0.055 (Chloroquine)
246
7.8
83.9
30.0
5.77
33
Standard drugs
>30
0.25 (Benznidazole)
>30
0.23 (Miltefosin)
25.32
1090
>90
0.006 (Podophyllotoxin)
>360
IC50 values are means of at least two independent assays run in duplicate. n.a.: These compounds were not active in the axenic amastigote assay [32] and therefore
no assay was performed in infected mouse macrophages.
incubated at 37 ꢀC in 5% CO2 for 4 d. For measurement of the
IC50 the substrate CPRG/Nonidet was added to the wells. The
color reaction that developed during the following 2e4 h was
read photometrically at 540 nm. IC50 values were calculated
from the sigmoidal inhibition curve. Cytotoxicity was assessed
in the same assay using non-infected L 6 cells and the same
serial drug dilution. The MIC was determined microscopically
after 4 d.
by the Fonds der Chemischen Industrie. We thank A. Dreher
for her help in preparing the manuscript.
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