Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines

Article abstract of DOI:10.1021/jm020831a

A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC₅₀ < 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.

Full text of DOI:10.1021/jm020831a

5058
J . Med. Chem. 2002, 45, 5058-5068
Syn th eses a n d An titu m or Ta r getin g G1 P h a se of th e Cell Cycle of
Ben zoyld ih yd r oisoqu in olin es a n d Rela ted 1-Su bstitu ted Isoqu in olin es
Almudena Bermejo,† Inmaculada Andreu,† Fernando Suvire,‡ Stephane Le´once,§ Daniel H. Caignard,§
Pierre Renard,§ Alain Pierre´,§ Ricardo D. Enriz,‡ Diego Cortes,*,† and Nuria Cabedo†
Departamento de Farmacologı´a, Laboratorio de Farmacognosia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain,
Departamento de Quı´mica, Facultad de Quı´mica, Bioquı´mica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis,
Argentina, and Laboratoire Servier, 92415 Courbevoie, France
Received J anuary 23, 2002
A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against
the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting
cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized.
The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were
obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective
oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile.
SAR studies let us to identify the essential structural features for cytotoxic activity. The most
bioactive compounds (with IC50 < 5µM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19),
and they are characterized by the following: (i) An R-ketoimine moiety is necessary for potent
antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are
less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems
to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the
unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds
were more potent than compounds with other substitutions.
In tr od u ction
the cytotoxic activity of 1-substituted isoquinoline de-
rivatives, a series of this type of compound were
synthesized and tested in vitro against the leukemia
L 1210 cell line. Their ability to perturb the cell cycle
by accumulating cells in the G1 phase was also evalu-
ated.
Therefore, we describe herein the syntheses of (i)
1-benzoylimines, i.e., 1-benzoyl-3,4-dihydro-isoquino-
lines, 1-benzoylisoquinolines, and N-methyl-1-benzoyl-
3,4-dihydroisoquinolines; (ii) 1-phenylimines, i.e., 1-phen-
yl-3,4-dihydroisoquinolines; and (iii) 1-alkylimines, i.e.,
1-alkyl-3,4-dihydroisoquinolines. The 1-benzoylimine
derivatives were prepared directly by selective oxidation
with Pd/C in acetonitrile from corresponding benzylic
imines previously obtained by standard methods.2,3,9
Cell cycle inhibitors or modulators are highly promis-
ing new therapeutic agents against human cancers. The
G1 phase of the cell cycle is an important period where
several complex signals interact to decide the cell fate:
proliferation, quiescence, differentiation. Malfunction of
cell cycle control in the G1 phase is a critical event for
tumorigenesis and tumor progression.10 Therefore, agents
with the ability to arrest cells in the G1 phase can be
considered as a new type of efficient drug against
tumors, and they might be exploited for biomedical
research and antitumor therapy.
Isoquinoline alkaloids have a variety of powerful
biological activities, including inhibition of cellular
proliferation and development changes. Herein, we are
describing the synthesis of a large number of isoquino-
line compounds in order to establish a structure-
activity relationship for novel agents against malignant
tumors.
Our previous studies on isoquinoline alkaloids have
been directed toward the synthesis and characterization
of dopaminergic 1-benzyltetrahydroisoquinolines (BT-
HIQs). Some natural and synthetic BTHIQs recently
reported by our group have shown affinity for dopamine
receptors from striatal membranes, and in some cases,
they showed inhibition of dopamine uptake by striatal
synaptosomes.1-4 In this way, we described the synthe-
sis of (R)-nor-roefractine, a monophenolic unmethylated
BTHIQ,2 and also the syntheses of racemic monophen-
olic N-alkyl-BTHIQs,3 as well as the enantioselective
syntheses of pairs of dopaminergic (1S)- and (1R)-
BTHIQs using (R)- and (S)-phenylglycinol as the chiral
source.4
As a part of our search for new antitumor agents as
inhibitors of the mitochondrial electron-transport
chain,5-7 we reported for the first time, the cytotoxic
mechanism of a synthetic N-protected isoquinoline, the
N-diisopropyl phosphoryl-BTHIQ, which was found to
be a new class of inhibitor of mitochondrial respiratory
chain targeting complexes I and III.8 To further explore
This paper describes the discovery of novel antitumor
isoquinolines targeting the G1 phase of the cell cycle,
including the design, synthesis, and the structure-
activity relationship.
* To whom correspondence should be addressed. Phone: (34)
96.386.49.75. Fax: (34) 96.386.49.43. E-mail: dcortes@uv.es.
† Universidad de Valencia.
Resu lts a n d Discu ssion
Ch em istr y. We have planned our synthetic routes
by considering the preparation of the isoquinoline or 3,4-
‡
Universidad Nacional de San Luis.
§
Laboratoire Servier.
10.1021/jm020831a CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/15/2002

Isoquinolines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5059
Sch em e 1. Preparation of
Sch em e 2. Preparation of 1-Benzoyl-3,4-dihydro-
â-(3-Benzyloxy-4-methoxyphenyl)ethylaminea
isoquinoline and 1-Benzoylisoquinoline Derivativesa
a
Reagents and conditions: (i) benzyl chloride, K2CO3/EtOH,
reflux, 5 h; (ii) H3CNO2, NH4OAc/AcOH, reflux, 4 h; (iii) LiH4Al,
ether/THF (1:1), reflux, 2 h.
dihydroisoquinoline moiety as a basic structural motive
to carry out the synthesis of three series of isoquinoline
compounds only differentiated at the 1-substitution
level: (i) 1-benzoylimines, i.e., 1-benzoyl-3,4-dihydroiso-
quinolines (BzDHIQ), 1-benzoylisoquinolines (BzIQ),
and N-methyl-1-benzoyl-3,4-dihydroisoquinolines (NMe-
BzDHIQ); (ii) 1-phenylimines, i.e., 1-phenyl-3,4-dihydro-
isoquinolines (PhDHIQ); (iii) 1-alkylimines, i.e., 1-alkyl-
3,4-dihydroisoquinolines (alkyl-DHIQ).
The general synthetic plan for these compounds was
centered on the preparation of the appropriate amide
(I, II, and III) by standard methods starting from
3-hydroxy-4-methoxybenzaldehyde (isovanillin, a ) or
3-methoxy-4-hydroxybenzaldehyde (vanillin, b) or 3-hy-
droxybenzaldehyde (c).11,12 The corresponding â-phen-
ylethylamine intermediates were prepared from these
starting compounds (a , b, or c), and then they were
condensed with the appropriate acid chlorides under
Schotten-Bauman conditions to obtain the expected
N-phenylethylamides (I, II, and III). After a Bischler-
Napieralski cyclodehydration experiment (refluxing with
POCl3 in CH2Cl2), each N-phenylethylamide was con-
verted into the convenient imine 3,4-dihydroisoquinoline
a
Reagents and conditions: (i) CH2Cl2, 5% aqueous NaOH, 0
°C, room temp, 2 h; (ii) POCl3, dry CH2Cl2, refluxed 1.5 h; (iii)
CH3CN, 10% Pd/C, 1-3 h; (iv) MeOH, 20% aqueous KOH, room
temp, 4 h; (v) CH3CN, IMe, refluxed, 30 min.
KOH. Under these conditions, compounds 27-33 (and
27a , 30a derivatives) were obtained in a good yield.
Starting from amides II and III, the 1-phenyl-3,4-
dihydroisoquinolines (34-36 and 34a derivative) and
the 1-alkyl-3,4-dihydroisoquinolines (37-40) were pre-
pared under the previously described Bischler-
Napieralski cyclodehydration conditions.
All synthetic compounds are summarized in Schemes
2 and 3 and in Tables 1 and 2. The R-ketoimines
obtained were stored as their salts.
The structures of all 1-benzoyl derivatives (1-33)
were determined on the basis of their NMR spectral
data and mass spectroscopic analysis. NMR data were
compared between, for example, one of the BzDHIQs
(1) and its BzIQ homologue (27), consisting of an A2B2
system [δ 3.90 (t, CH2-3) and δ 2.75 (t, CH2-4), J 3-4
11,12
(see Schemes 1-3 and Tables 1 and 2).
The syntheses of the 1-benzoyl-3,4-dihydroisoquino-
lines (BzDHIQ) (1-26 and 1a , 8a , 16a , 19a , and 23a
derivatives) from amides I via 1-benzyl-3,4-dihydroiso-
quinoline was performed in a good yield by direct
selective oxidation of the benzylic carbon of the corre-
sponding imines through 10% Pd/C in CH3CN at room
temperature for 1 h.9,13 Under these conditions, the total
oxidation of the pyridine ring of the BzDHIQ was not
observed. So, oxidation at the exo benzylic carbon (C-R)
is faster than at the endo position of the heterocycle.
This method for the preparation of R-ketoimines was
applied to a series of BDHIQs with several substitution
patterns, both in the dihydroisoquinoline and the ben-
zylic rings (see Scheme 2). The R-ketoimines obtained
from an unsubstituted benzylic ring were furnished in
typical 90% yields (1-15). However, when the BDHIQs
mono- or disubstituted on the benzene ring of the
benzylic moiety were treated by the same reagents for
3 h, the corresponding R-ketoimines (16-26) were
obtained in a smaller yield.
3
)
1
7.8 Hz for H NMR for 1; δ 42.2 (CH2-3) and δ 25.3 (CH2-
4) for 13C NMR for 1] or an aromatic AB system [δ 8.44
(d, H-3) and δ 7.63 (d, H-4), 3J 3-4 ) 5.5 Hz for H NMR
1
for 27; δ 139.3 (C-3) and δ 121.7 (C-4) for 13C NMR for
27], assigned to the dihydropyridine or pyridine rings,
respectively.
To determine the relevance for cytotoxic activity of
the total oxidation of the pyridine ring on this series of
compounds, the aromatization of some of the R-ke-
toimines BzDHIQs was performed using 20% aqueous
The remaining resonance signals in both related
BzDHIQ- and BzIQ-type compounds were very close.
Thus, a small downfield carbon signal about δ 195 (δ

5060 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Bermejo et al.
Ta ble 1. 1-Benzoyl-3,4-dihydroisoquinoline and
1-Benzoylisoquinoline Derivatives
Sch em e 3. Preparation of
1-Phenyl-3,4-dihydroisoquinoline and
1-Alkyl-3,4-dihydroisoquinoline Derivativesa
compd
R1
R2
OCH3
OCH3
OCH3
OCH3
R3
R4
R5
1
1a
2
3
4
5
6
7
8
OBn
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH2CH3
OCH2CH(CH3) 2
OCH2CHdC(CH3) 2 OCH3
OCH2Ph-p-OCH3 OCH3
O(CH2)4CH3
OCH3
OCH2CHdCHCH3 OCH3
OCH3
OCH3
OCH3
OBn
OBn
OH
O(CH2)4CH3
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
H
OCH3
OCH3
H
OCH3
OCH3
H
8a
9
10
10a (NCH3) OBn
11
12
13
14
15
16
16a
17
18
19
19a
20
21
22
23
23a
24
25
OCH2CHdC(CH3) 2
OCH2CH(CH3) 2
O(CH2)4CH3
OCH2CHdCHCH3
O(CH2)4COOCH3
OBn
OTs
OH
OCH3
OCH3
H
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
a
Reagents and conditions: (i) CH2Cl2, 5% aqueous NaOH, 0
°C, room temp, 2 h; (ii) POCl3, dry CH2Cl2, refluxed 2 h.
OAc
OH
OTs
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
193.9 for 1 and δ 194.9 for 27) in the 13C NMR spectrum
indicated the existence of a quaternary carbon placed
at the R-keto position, whereas a carbon signal about δ
165 (δ 164.3 for 1 and δ 164.0 for 27) was in accordance
with the presence of a quaternary carbon at the C-1
position in both types of compounds.
OTs
OH
OCH3
H
H
OCH3 OCH3
OCH3 OCH3
OCH3 OCH3
25a (NCH3) OBn
On the other hand, the aromatic isoquinoline signals
26
27
27a
28
29
30
30a
31
32
33
OBn
OBn
OH
1
in the H NMR appeared as two singlet resonances due
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
to protons H-5 and H-8 for the compounds derived from
isovanillin (a ) and vanillin (b), whereas compounds
derived from 3-hydroxybenzaldehyde (c) showed an
ABC system. Compound 1 showed two proton reso-
nances at δ 6.97 (s, H-8) and δ 6.77 (s, H-5), compound
27 showed these methyne signals at δ 7.60 (s, H-8) and
at δ 7.19 (s, H-5), whereas compound 10 (with a
monosubstituted isoquinoline ring) showed three proton
resonances at δ 6.84 (d, H-5, J ) 2.2 Hz), δ 6.80 (dd,
H-7, J ) 2.2 and 8.4 Hz), and δ 7.31 (d, H-8, J ) 8.4
Hz). Finally, it is interesting to note that two of the
benzylic protons are affected by the anisotropic effect
of the carbonyl group. So, all synthesized R-ketoimines
can be easily identified in 1H NMR spectra by the
presence of a characteristic deshielded dd signal at
about δ 8.0 (H-2′ and H-6′).
OCH2Ph-p-OCH3 OCH3
O(CH2)4CH3
OCH3
OCH3
OBn
OCH3
OBn
OH
OCH3
OCH3
OCH3
OH
H
OBn
OBn
OH
H
H
OH
Ta ble 2. 1-Phenyl-3,4-dihydroisoquinoline and
1-Alkyl-3,4-dihydroisoquinoline Derivatives
compd
R1
R2
R3
According to the general route described in Scheme
2, 1-phenylimines (34-36 and 34a derivative) and
1-alkylimines (37-40) were prepared from amides II
and III, respectively. The presence of a 3,4-dihydroiso-
quinoline moiety in all prepared derivatives was indi-
cated by NMR as described above for 1-benzoyl deriva-
tives. Indeed, careful examination of the spectroscopic
data lets us establish the placement of several substitu-
tions introduced at the C-1 level (see Experimental
Section).
34
34a
35
36
37
38
39
40
OBn
OH
OBn
OBn
OBn
O(CH2)4CH3
OBn
OBn
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
H
H
H
H
OH
CH3
CH3
(CH2)3CH3
(CH2)3CH3
vitro for the ability to disturb the cell cycle and to inhibit
L 1210 leukemia cell proliferation. Many of these
compounds were found to possess significant activity at
Str u ctu r e-Activity Rela tion sh ip . All isoquino-
lines synthesized (compounds 1-40) were assayed in

Isoquinolines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5061
Ta ble 3. Inhibition of L 1210 Cell Proliferation by
in the N atom. This fact could explain the different
activities obtained for some pairs of compounds, e.g.,
1/27, 6/29, and 8/30. It is interesting to note that
N-methyl-BzDHIQs (10a and 25a ) were inactive. Thus,
it seems to be reasonable to assume that the lack of
cytotoxic activity of these compounds is a consequence
of the nature of the interaction of the amine moiety.
In conclusion, a series of novel BzDHIQ, BzIQ, Ph-
DHIQ, and alkyl-DHIQ compounds have been synthe-
sized. Among them, compounds 13, 22, 21, 8, 9, 11, 1,
20, 6, and 19 and some of their congeners exhibited
remarkable ability to perturb the cell cycle by an
accumulation of cells in the G1 phase. All these R-ke-
toimine derivatives were prepared by a simple and
efficient method, through a direct selective oxidation of
the benzylic carbon of the 1-benzyl-3,4-dihydroisoquino-
line imine precursors.
1-Substituted Isoquinoline Derivativesa
compd
IC50 (µM)
cells in G1 phaseb
13
22
21
8
1.0
1.4
2.5
63% (5 µM)
3.6
9
11
1
20
6
3.7
3.8
4.1
4.1
63% (5 µM)
85% (10 µM)
70% (25 µM)
4.5
19
19a
3
10
38
4
10a
5
33
32
2
4.7
5.3
6.1
6.5
7.7
9.4
9.8
11.1
11.5
11.6
11.9
11.9
12.3
13.0
13.1
67% (5 µM)
63% (25 µM)
54% (10 µM)
72%
65% (25 µM)
Exp er im en ta l Section
Gen er a l In str u m en ta tion . Melting points were taken on
a Cambridge microscope instrument coupled to a Reichert-
J ung instrument. EIMS, HREIMS, MAB (Ar and N2), and
LSIMS were recorded on a VG Auto Spec Fisons spectrometer
instrument. Liquid chromatography with mass spectrometry
detection (LC-MSD) with an API (atmospheric pressure
ionization) source configured as APCI (atmospheric pressure
chemical ionization) or APIES (electrospray ionization) in
positive or negative mode was conducted on a Hewlett-Packard
(HP-1100). 1H NMR and 13C NMR spectra were recorded with
CDCl3 as solvent on a Bruker AC-250, Bruker AC-300, Varian-
Unity-300, or Varian-Unity-400 spectrometer. Multiplicities
of 13C NMR resonances were assigned by distortionless en-
hancement by polarization transfer (DEPT) experiments.
NOESY, COSY 45, HMQC, HSQC, and HMBC data were
recorded at 400 MHz (Varian-Unity 400). All reactions were
monitored by analytical TLC with silica gel 60 F254 (Merck
5554). The residues were purified with a 60H silica gel column
(5-40 µm, Merck 7736) and by flash chromatography (230-
400 µm, Merck 9385). Solvents and reagents were used as
purchased from commercial sources. Quoted yields are for
purified material. The HCl salts of the synthesized compounds
were prepared from the corresponding base with 5% HCl in
MeOH.
Bioa ssa ys. In h ibition of Cellu la r P r olifer a tion a n d
Cell Cycle Effects. L 1210 cells were cultivated in RPMI 1640
medium supplemented with 10% fetal calf serum, 2 mM
L-glutamine, 50 units/mL penicilin, 50 µg/mL streptomycin,
and 10 mM of Hepes buffer (pH 7.4). Cells were exposed to
graded concentrations of drug for 48 h. Cytotoxicity was
measured by microculture tetrazolium assay.14 Results are
expressed as IC50, the concentration needed to reduce the
optical density of treated cells by 50% with respect to the
optical density of untreated controls.
For the cell cycle analysis, L 1210 cells were incubated for
21 h at 37 °C with various drug concentrations. Cells were
then fixed by 70% EtOH (v/v), washed, and incubated with
PBS containing 100 µM RNAse and 25 µg/mL propidium iodide
for 30 min at 20 °C. For each sample, 104 cells were analyzed
on an Epics XL flow cytometer (Beckman Coulter, France).
Results are expressed as a percentage of cells accumulated in
the G1 phase of the cell cycle.
Gen er a l P r oced u r e for Syn t h esis of â-P h en ylet h yl-
a m in e Der iva tives. These â-phenylethylamines were pre-
pared in three steps by standard methods starting from
3-hydroxy-4-methoxybenzaldehyde (isovanillin, a ), 3-methoxy-
4-hydroxybenzaldehyde (vanillin, b), or 3-hydroxybenzalde-
hyde (c). Herein, we describe, as an example, the preparation
of the appropriate phenylethylamine (Scheme 1) used in the
synthesis of compound 1.15-17 Similar yields were obtained on
the preparation of the phenylethylamines used in the synthesis
of all isoquinoline derivatives (2-40).
12
18
25
7
a
b
IC50 of remaining compound was >10 µM. 44% of untreated
control cells were in G1 phase.
micromolar concentration. The results obtained for the
most active compounds are summarized in Table 3. Ten
of the listed compounds showed potent activity against
L 1210 cell proliferation with IC50 values between 1.0
and 4.7 µM, and six more isoquinoline derivatives
showed IC50 values between 5.3 and 9.8 µM. The
remaining derivatives were less active with IC50 values
greater than 10 µM. The ability to selectively disturb
the G1 phase of the cell cycle, i.e., their capacity to
arrest cells in the G1 phase (e.g., compound 1 induced
the accumulation of 85% of cells at the G1 phase),
suggests that these compounds would possess a thera-
peutic advantage.
These results have illustrated some general trends
of the structure-activity relationship. Our observations
allowed us to establish that the most active compounds
(with IC50 < 5µM) were BzDHIQ (13, 22, 21, 8, 9, 11,
1, 20, 6, and 19), and they showed the following: (i) The
R-ketoimine moiety present in all these compounds is
essential for the potent antiproliferative effect (1-phenyl-
and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40,
are less active). (ii) A hydrophobic, benzyloxy, alkyloxy,
or allyloxy group at the C-6 position seems to be relevant
for cytotoxicity. However, the weak activity obtained for
several compounds possessing a similar side chain (e.g.,
compounds 12 and 14) clearly indicates that the pres-
ence of this hydrophobic side chain would be a structural
requirement but not by itself sufficient for perturbating
the cell cycle. (iii) Regarding the influence of the
benzoylic moiety, both the unsubstituted (13, 8, 9, 11,
1, and 6) and the 3′-monosubstituted (22, 21, 20, and
19) compounds were more potent than compounds with
other substitutions (e.g., 22 f 18 and 20 f 16).
On the other hand, the compounds devoid of cytotoxic
activity have a phenolic hydroxyl group (compounds 1
f 1a and 8 f 8a ). Particularly remarkable was the lack
of activity obtained for 1-benzoylisoquinoline compounds
(27-33). The presence of a double bond at C-3/C-4,
aromatizing ring B, produces profound electronic effects

5062 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Bermejo et al.
O-Ben zylisova n illin . A mixture of isovanillin (a , 1.0 g, 6.6
mmol), benzyl chloride (1.6 mL, 13.9 mmol), and anhydrous
K2CO3 (0.65 g, 4.7 mmol) in EtOH (15 mL) was refluxed for 5
h. After being stirred, the reaction mixture was concentrated
to dryness and redissolved in 10 mL of CH2Cl2, and then 5%
aqueous NaOH (3 × 10 mL) was added. The organic layer was
washed with brine (2 × 10 mL) and H2O (2 × 10 mL), dried
with anhydrous Na2SO4, and evaporated to dryness. Needles
were obtained after crystallization from MeOH/CH2Cl2 corre-
sponding to O-benzylisovanillin (3-benzyloxy-4-methoxyben-
zaldehyde, 1.5 g, 94%); mp 61-63 °C (lit. 61-64 °C).18
3-Ben zyloxy-4-m eth oxy-â-n itr ostyr en e. A mixture of
O-benzylisovanillin (1.0 g, 4.1 mmol), nitromethane (0.7 mL,
12.9 mmol), and NH4OAc (0.8 g, 10.4 mmol) in AcOH (12.5
mL) was refluxed for 4 h. After cooling, the mixture was
diluted with H2O (10 mL) and extracted with CH2Cl2 (3 × 10
mL). The organic solution was washed with brine (2 × 10 mL)
and H2O (2 × 10 mL), dried with anhydrous Na2SO4, and
evaporated to dryness. Yellow needles were obtained from
EtOH corresponding to 3-benzyloxy-4-methoxy-â-nitrostyrene
(1.02 g, 88%); mp 126-128 °C (lit. 126-128 °C).2
â-(3-Ben zyloxy-4-m eth oxyp h en yl)eth yla m in e. A solu-
tion of 3-benzyloxy-4-methoxy-â-nitrostyrene (1.0 g, 3.5 mmol)
in 14 mL of anhydrous THF was added dropwise to a well-
stirred suspension of LiAlH4 (0.5 g, 13.2 mmol) in 20 mL of
anhydrous Et2O under nitrogen atmosphere and was refluxed
for 2 h. After the solution was cooled, the excess reagent was
destroyed by dropwise addition of H2O and 15% aqueous
NaOH. After partial evaporation of the filtered portion, the
aqueous solution was extracted with CH2Cl2 (3 × 10 mL) and
the organic layers were treated with 5% aqueous HCl. The
resulting aqueous acid layer was made basic (5% aqueous NH4-
OH, pH ∼9) and extracted with CH2Cl2. The organic solution
was washed with brine (2 × 10 mL) and H2O (2 × 10 mL),
dried with anhydrous Na2SO4, and evaporated to dryness, and
then â-(3-benzyloxy-4-methoxyphenyl)ethylamine (570 mg,
63%) was obtained as an oil.2
Gen er a l P r oced u r e for Syn t h esis of Am id es I-III.
Formation of the amides I was carried out under Schotten-
Baumann conditions using the appropriate acid chloride:
phenylacetyl chloride or 2-OTs-, 3-OTs-, 3-OAc-, or 4-OTs-
phenylacetyl chloride (previously prepared in two steps from
the corresponding phenylacetic acid or o-, m-, or p-hydroxy-
phenylacetic acid) or o-, m-, p-methoxyphenylacetyl chloride
or dimethoxyphenylacetyl chloride. Amides II and III were
prepared by condensation of the corresponding O-benzylated
â-phenylethylamines with benzoyl chloride or O-acetylsalicyl-
oyl chloride or with acetyl chloride or pentanoyl chloride.
methoxyphenylethyl)phenylacetamide (500 mg, 1.33 mmol),
was refluxed for 4 h with a mixture of equal volumes of EtOH
and concentrated HCl (100 mL). The reaction mixture was
concentrated to dryness and redissolved in 10 mL of CH2Cl2
and was made basic (15% aqueous NH4OH). The organic
solution was washed with brine (2 × 10 mL) and H2O (2 × 10
mL), dried with anhydrous Na2SO4, and evaporated to dryness,
and then the O-debenzylated amide I was obtained, N-(3-
hydroxy-4-methoxyphenylethyl)phenylacetamide (370 mg, 97%).
Then, a solution of N-(3-hydroxy-4-methoxyphenylethyl)phen-
ylacetamide (370 mg, 1.29 mmol) was refluxed for 10 h with
iodoethane (0.2 mL, 2.5 mmol) and anhydrous K2CO3 (400 mg,
2.9 mmol) in dry Me2CO (10 mL). The reaction mixture was
concentrated to dryness and redissolved in 10 mL of CH2Cl2,
and then 5% aqueous NaOH (3 × 10 mL) was added. The
organic layer was washed with brine (2 × 10 mL) and H2O (2
× 10 mL), dried with anhydrous Na2SO4, and evaporated to
dryness, and then, N-(3-ethoxy-4-methoxyphenylethyl)phenyl-
acetamide was obtained (246 mg, 60%),3 which is the amide I
used for the preparation of compound 2.
Gen er a l P r oced u r e for Syn th esis of 1-Ben zoyl-3,4-
d ih yd r oisoqu in olin es (Com p ou n d s 1-26). Herein, we
describe, as an example, the preparation of the appropriate
1-benzyl-3,4-dihydroisoquinolines3 used in the synthesis of the
corresponding 1-benzoyl-3,4-dihydroisoquinolines (compound
1, Scheme 2).
A solution of the appropriate amide, e.g., N-(3-benzyloxy-
4-methoxyphenylethyl)phenylacetamide (500 mg, 1.33 mmol)
in dry CH2Cl2 (10 mL) was treated with POCl3 (0.5 mL, 5.4
mmol) and refluxed for 3 h. The reaction mixture was diluted
with H2O, made basic (5% aqueous NH4OH), and extracted
with CH2Cl2. The organic solution was washed with H2O, dried
with anhydrous Na2SO4, and concentrated to give a brown oil.
This residue was purified with a 60 H silica gel column (CH2-
Cl2-MeOH, 96:4) to afford the corresponding 1-benzyl-6-
benzyloxy-7-methoxy-3,4-dihydroisoquinoline (415 mg, 87%).
Yellow crystals were obtained when the HCl salt was prepared
from 5% HCl in MeOH; mp 178-181 °C.3 This BDHIQ (150
mg, 0.42 mmol) was treated with CH3CN (70 mL) and 10%
Pd/C (150 mg), with stirring at room temperature for 1 h. The
reaction mixture was filtered over Celite and concentrated. The
residue obtained was purified with a 60 H silica gel column
(hexane-EtOAc, 60:40) to yield 1-benzoyl-6-benzyloxy-7-meth-
oxy-3,4-dihydroisoquinoline, 1 (141 mg, 90%). The R-ke-
toimines obtained from an unsubstituted benzylic ring were
furnished in typical 90% yields (1-15). However, when the
BDHIQs mono- or disubstituted on the benzene ring of the
benzylic moiety were treated by the same reagents for 3 h,
the corresponding R-ketoimines (16-26) were obtained in
lesser yield.
Gen er a l P r oced u r e for Syn th esis of 1-Ben zoyliso-
qu in olin es (Com p ou n d s 27-33). A solution of 1-benzoyl-
3,4-dihydroisoquinoline, e.g., 1-benzoyl-6-benzyloxy-7-methoxy-
3,4-dihydroisoquinoline (1, 98 mg, 0.26 mmol) was dissolved
in MeOH (5 mL) and treated with 20% aqueous KOH (5 mL).
The mixture was stirred at room temperature for 4 h. The
reaction mixture was concentrated to dryness and redissolved
in 10 mL of CH2Cl2. The organic solution was washed with
brine (2 × 10 mL) and H2O (2 × 10 mL), dried with anhydrous
Na2SO4, and evaporated to dryness. The residue was subjected
to a 60 H silica gel column (hexane-EtOAc, 60:40) to afford
1-benzoyl-6-benzyloxy-7-methoxyisoquinoline, 27 (39 mg, 41%)
(Scheme 2).
Herein, we describe, as an example, the preparation of the
appropriate phenylacetamide (Scheme 2) used in the synthesis
of compound 1.3 Similar yields were obtained on the prepara-
tion of the phenylacetamides used in the synthesis of all
isoquinoline derivatives (2-40).
N-(3-Ben zyloxy-4-m et h oxyp h en ylet h yl)p h en yla cet -
a m id e. An amount of 0.2 mL of phenylacetyl chloride (1.8
mmol) was added dropwise at 0 °C to a solution of â-(3-
benzyloxy-4-methoxyphenyl)ethylamine (550 mg, 2.14 mmol)
in CH2Cl2 (6 mL) and 5% aqueous NaOH (3 mL), with stirring
at room temperature for 2 h. After the mixture was stirred,
2.5% aqueous HCl was added and the organic solution was
washed with brine (2 × 10 mL) and H2O (2 × 10 mL), dried
with anhydrous Na2SO4, and evaporated to dryness. The
residue obtained was purified with a silica gel flash column
(hexane-CH2Cl2-EtOAc, 20:70:10) to afford N-(3-benzyloxy-
4-methoxyphenylethyl)phenylacetamide (552 mg, 68%) as
white crystals obtained from EtOH; mp 111-113 °C.3
Gen er a l P r oced u r e for Syn th esis of 1-P h en yl-3,4-
d ih yd r oisoqu in olin es (Com p ou n d s 34-36) a n d 1-Alk yl-
3,4-d ih yd r oisoqu in olin es (Com p ou n d s 37-40). A solution
of the appropriate amide, e.g., N-(3-benzyloxy-4-methoxyphen-
ylethyl)phenylformamide (300 mg, 0.9 mmol, the amide II used
for the preparation of compound 34), in dry CH2Cl2 (7 mL)
was treated with POCl3 (0.4 mL, 3.6 mmol) and refluxed for 2
h. The reaction mixture was diluted with H2O, made basic,
and extracted with CH2Cl2. The organic solution was washed
with H2O, dried, and concentrated to give a brown oil. This
residue was purified with a 60 H silica gel column (CH2Cl2-
Gen er a l P r oced u r e for P r ep a r a tion of O-Alk yla ted
Am id es I-III. In the case of the preparation of O-alkyl- or
O-allylamides I-III derivatives, the selective hydrolysis of the
O-benzyl protecting group, placed at the C-3 or C-4 position
on amides (see Schemes 2 and 3),17 was carried out, and
subsequent O-alkylation or O-allylation was made by the
appropriate alkyl or allyl bromide, chloride, or iodide.19
solution of the appropriate amide, e.g., N-(3-benzyloxy-4-
A

Isoquinolines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5063
EtOAc-MeOH, 80:14:20) to afford 1-phenyl-6-benzyloxy-7-
methoxy-3,4-dihydroisoquinoline, 34 (40 mg, 13%) (Scheme 3).
281.10617 [M]+ (281.10519 calcd for C17H15NO3), 250.08927
(250.08680 calcd for C16H12NO2), 105.03565 (105.03404 calcd
for C7H5O), 91.05542 (91.05477 calcd for C7H7), 77.03676
(77.03912 calcd for C6H5).
Gen er a l P r oced u r e for N-Meth yla tion of BzDHIQ.
Syn th esis of 10a a n d 25a . A solution of the appropriate
1-benzoyl-3,4-dihydroisoquinoline, e.g., 1-benzoyl-6-benzyloxy-
7,3′,4′-trimethoxy-3,4-dihydroisoquinoline (25, 40 mg, 0.09
mmol) was dissolved in CH3CN (1 mL) and treated with
iodomethane (50 µL).20 The mixture was refluxed for 30 min.
The reaction mixture was concentrated to dryness and redis-
solved in 10 mL of CH2Cl2. The organic solution was washed
with brine (2 × 10 mL) and H2O (2 × 10 mL), dried with
anhydrous Na2SO4, and evaporated to dryness. This residue
was subjected to a silica gel flash column (CH2Cl2-MeOH, 95:
5) to afford N-methyl-1-benzoyl-6-benzyloxy-7,3′,4′-trimethoxy-
3,4-dihydroisoquinoline, 25a (39 mg, 94%).
Gen er a l P r oced u r e for O-Dea cetyla tion . Syn th esis of
19a . A solution of 1-benzoyl-6-benzyloxy-7-methoxy-3′-acetoxy-
3,4-dihydroisoquinoline (19, 94 mg, 0.22 mmol) was dissolved
in a mixture of EtOH-H2O 3:2 (5 mL) and 15% aqueous
NaHCO3 (1.6 mL), and the solution was refluxed for 3 h. The
reaction mixture was concentrated to dryness and redissolved
in 10 mL of CH2Cl2, and 2.5% aqueous HCl was added. The
organic solution was washed with brine (2 × 10 mL) and H2O
(2 × 10 mL), dried with anhydrous Na2SO4, and evaporated
to dryness. The residue was subjected to a 60 H silica gel
column (hexane-EtOAc, 60:40) to afford 1-benzoyl-6-benzyl-
oxy-7-methoxy-3′-hydroxy-3,4-dihydroisoquinoline, 19a (38 mg,
45%).
Gen er a l P r oced u r e for O-Detosyla tion . Syn th esis of
16a a n d 23a . A solution of 1-benzoyl-6-benzyloxy-7-methoxy-
2′-tosyloxy-3,4-dihydroisoquinoline (16, 97 mg, 0.18 mmol) was
refluxed in EtOH (10 mL) and 15% aqueous KOH (10 mL) for
2 h. The reaction mixture was concentrated to dryness and
redissolved in 10 mL of CH2Cl2, and 2.5% aqueous HCl was
added. The organic solution was washed with brine (2 × 10
mL) and H2O (2 × 10 mL), dried with anhydrous Na2SO4, and
evaporated to dryness. The residue was subjected to a 60 H
silica gel column (CH2Cl2-EtOAc, 96:4) to afford 1-benzoyl-
6-benzyloxy-7-methoxy-2′-hydroxy-3,4-dihydroisoquinoline, 16a
(28 mg, 40%).
Gen er a l P r oced u r e for O-Deben zyla tion . Syn th esis of
1a , 8a (BzDHIQ), 27a , 30a (BzIQ), a n d 34a (P h DHIQ).
Selective hydrolysis of the benzyloxy protective groups of 1,
8, 27, 30, and 34, using the same procedure as above for
O-debenzoylated amides I-III, led to 1a , 8a , 27a , 30a and
34a , respectively.
1-Ben zoyl-6-et h oxy-7-m et h oxy-3,4-d ih yd r oisoq u in o-
lin e, 2. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (250 MHz, CDCl3) δ
8.01 (dd, J ) 7.7, 1.5 Hz, 2H, H-2′,6′), 7.57 (td, J ) 7.7, 1.5
Hz, 1H, H-4′), 7.46 (t, J ) 7.7 Hz, 2H, H-3′,5′), 6.92 (s, 1H,
H-8), 6.73 (s, 1H, H-5), 4.13 (q, J ) 6.9 Hz, 2H, OCH2CH3-6),
3.90 (t, J ) 7.0 Hz, 2H, CH2-3), 3.76 (s, 3H, OCH3-7), 2.78 (t,
J ) 7.0 Hz, 2H, CH2-4), 1.47 (t, J ) 6.9 Hz, 3H, OCH2CH3-6);
13C NMR* (62.5 MHz, CDCl3) δ 194.0 (C-R), 164.4 (C-1), 151.0
(C-6), 147.7 (C-7), 135.5 (C-1′), 133.8 (CH-4′), 130.9 (C-4a),
130.4 (2C, CH-2′,6′), 128.5 (2C, CH-3′,5′), 119.1 (C-8a), 111.4
(CH-5), 109.7 (CH-8), 64.3 (OCH2CH3-6), 56.0 (OCH3-7), 47.3
(CH2-3), 25.3 (CH2-4), 14.6 (OCH2CH3-6); EIMS m/z (%) 309
[M]+ (55), 281 (100), 252 (27), 204 (3), 105 (30), 77 (27); C19H19
NO3.
-
1-Ben zoyl-6-isobu tyloxy-7-m eth oxy-3,4-dih ydr oisoqu in -
olin e, 3. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
8.03 (dd, J ) 8.0, 1.5 Hz, 2H, H-2′,6′), 7.59 (tt, J ) 8.0, 1.5 Hz,
1H, H-4′), 7.47 (t, J ) 8.0 Hz, 2H, H-3′,5′), 6.93 (s, 1H, H-8),
6.73 (s, 1H, H-5), 3.91 (t, J ) 7.7 Hz, 2H, CH2-3), 3.83 (d, J )
6.6 Hz, 2H, OCH2CH(CH3)2-6), 3.75 (s, 3H, OCH3-7), 2.80 (t,
J ) 7.7 Hz, 2H, CH2-4), 2.18 (m, 1H, OCH2CH(CH3)2-6), 1.04
(d, J ) 6.6 Hz, 6H, OCH2CH(CH3)2-6); 13C NMR* (75 MHz,
CDCl3) δ 194.0 (C-R), 164.5 (C-1), 151.6 (C-6), 148.0 (C-7), 135.5
(C-1′), 133.8 (CH-4′), 131.1 (C-4a), 130.4 (2C, CH-2′,6′), 128.5
(2C, CH-3′,5′), 119.1 (C-8a), 111.9 (CH-5), 110.4 (CH-8), 75.4
(OCH2CH(CH3)2-6), 56.3 (OCH3-7), 47.3 (CH2-3), 28.0 (1C,
OCH2CH(CH3)2-6), 25.4 (CH2-4), 19.2 (2C, OCH2CH(CH3)2-6);
EIMS m/z (%) 337 [M]+ (57), 309 (50), 264 (22), 253 (100), 236
(23), 105 (52), 77 (44); C21H23NO3.
1-Ben zoyl-6-isop en ten yloxy-7-m eth oxy-3,4-d ih yd r oiso-
qu in olin e, 4. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (300 MHz,
CDCl3) δ 8.03 (dd, J ) 8.0, 1.0 Hz, 2H, H-2′,6′), 7.60 (tt, J )
8.0, 1.0 Hz, 1H, H-4′), 7.47 (t, J ) 8.0 Hz, 2H, H-3′,5′), 6.95 (s,
1H, H-8), 6.74 (s, 1H, H-5), 5.52 (t, J ) 6.3 Hz, 1H, OCH2CH)C-
(CH3)2-6), 4.63 (d, J ) 6.3 Hz, 2H, OCH2CHdC(CH3)2-6), 3.92
(t, J ) 7.7 Hz, 2H, CH2-3), 3.76 (s, 3H, OCH3-7), 2.80 (t, J )
7.7 Hz, 2H, CH2-4), 1.79 and 1.76 (2s, 6H, OCH2CHdC(CH3)2-
6); 13C NMR* (75 MHz, CDCl3) δ 194.0 (C-R), 164.5 (C-1), 151.1
(C-6), 148.0 (C-7), 138.4 (OCH2CHdC(CH3)2-6), 135.6 (C-1′),
133.8 (CH-4′), 130.9 (C-4a), 130.2 (2C, CH-2′,6′), 128.5 (2C,
CH-3′,5′), 119.3 (2C, OCH2CHdC(CH3)2-6 and C-8a), 111.9
(CH-5), 109.8 (CH-8), 65.8 (OCH2CHdC(CH3)2-6), 56.1 (OCH3-
7), 47.4 (CH2-3), 25.8 and 18.3 (2C, OCH2CHdC(CH3)2-6), 25.5
(CH2-4); LC-MS (APIES negative mode) m/z 348 [M - 1]+;
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-3,4-d ih yd r oisoqu in -
olin e, 1. The asterisk (/) indicates that the assignments were
1
made by COSY 45, DEPT, and HMQC. H NMR* (300 MHz,
CDCl3) δ 8.03 (dd, J ) 7.0, 1.7 Hz, 2H, H-2′,6′), 7.59 (tt, J )
7.0, 1.7 Hz, 1H, H-4′), 7.45 (t, J ) 7.0 Hz, 2H, H-3′,5′), 7.50-
7.30 (m, 5H, OCH2Ph-6), 6.97 (s, 1H, H-8), 6.77 (s, 1H, H-5),
5.21 (s, 2H, OCH2Ph-6), 3.90 (t, J ) 7.8 Hz, 2H, CH2-3), 3.78
(s, 3H, OCH3-7), 2.75 (t, J ) 7.8 Hz, 2H, CH2-4); 13C NMR*
(100 MHz, CDCl3) δ 193.9 (C-R), 164.3 (C-1), 150.9 (C-6), 148.2
(C-7), 136.4 and 135.5 (2C, C-1′′ and C-1′), 133.8 (CH-4′), 130.9
(C-4a), 130.4 (2C, CH-2′,6′), 128.7 (2C, CH-3′,5′), 128.6-127.2
(5C, OCH2Ph-6), 119.6 (C-8a), 112.7 (CH-5), 110.2 (CH-8), 70.8
(OCH2Ph-6), 56.2 (OCH3-7), 42.2 (CH2-3), 25.3 (CH2-4); EIMS
m/z (%) 371 [M]+ (36), 280 (61), 266 (4), 105 (25), 91 (100), 77
(27); C24H21NO3.
C
22H23NO3.
1-Ben zoyl-6-(p -m et h oxy)b en zyloxy-7-m et h oxy-3,4-d i-
h yd r oisoqu in olin e, 5. The asterisk (/) indicates that the
assignments were made by COSY 45 and DEPT. 1H NMR*
(250 MHz, CDCl3) δ 8.01 (d, J ) 8.0 Hz, 2H, H-2′,6′), 7.60 (m,
1H, H-4′), 7.50-7.38 (m, 4H, H-3′,5′ and H-3′′,5′′), 6.94 (s, 1H,
H-8), 6.90 (m, 2H, H-2′′,6′′), 6.78 (s, 1H, H-5), 5.13 (s, 2H,
OCH2Ph-p-OCH3-6), 3.90 (t, J ) 7.5 Hz, 2H, CH2-3), 3.81 and
3.70 (2s, 6H, OCH2Ph-p-OCH3-6 and OCH3-7), 2.77 (t, J ) 7.5
Hz, 2H, CH2-4); 13C NMR* (62.5 MHz, CDCl3) δ 194.0 (C-R),
163.0 (C-1), 151.0 (C-6), 149.0 (C-7), 137.0 and 136.0 (2C, C-1′′
and C-1′), 130.4 (CH-4′), 129.0 (C-4a), 128.9-128.5 (8C, CH-
2′,3′,5′,6′ and OCH2Ph-p-OCH3-6), 119.0 (C-8a), 114.0 (CH-5),
110.2 (CH-8), 70.6 (OCH2Ph-p-OCH3-6), 56.2 and 56.1 (OCH3-7
and OCH2Ph-p-OCH3-6), 45.0 (CH2-3), 23.5 (CH2-4); LC-MS
(APIES positive mode) m/z 402 [MH]+; C25H23NO4.
1-Ben zoyl-6-p en t a n yloxy-7-m et h oxy-3,4-d ih yd r oiso-
qu in olin e, 6. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 8.03 (d, J ) 8.0 Hz, 2H, H-2′,6′), 7.60 (tt, J ) 8.0, 1.0
Hz, 1H, H-4′), 7.47 (t, J ) 8.0 Hz, 2H, H-3′,5′), 6.94 (s, 1H,
H-8), 6.74 (s, 1H, H-5), 4.06 (t, 2H, J ) 6.8 Hz, OCH2(CH2)3-
CH3-6), 3.92 (t, J ) 7.0 Hz, 2H, CH2-3), 3.76 (s, 3H, OCH3-7),
1-Ben zoyl-6-h yd r oxy-7-m eth oxy-3,4-d ih yd r oisoqu in o-
lin e, 1a . The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
8.03 (dd, J ) 7.4, 1.4 Hz, 2H, H-2′,6′), 7.60 (tt, J ) 7.4, 1.4 Hz,
1H, H-4′), 7.48 (t, J ) 7.4 Hz, 2H, H-3′,5′), 6.94 (s, 1H, H-8),
6.81 (s, 1H, H-5), 3.90 (t, J ) 7.7 Hz, 2H, CH2-3), 3.81 (s, 3H,
OCH3-7), 2.78 (t, J ) 7.7 Hz, 2H, CH2-4); 13C NMR* (62.5 MHz,
CDCl3-CD3OD, 90:10) δ 194.3 (C-R), 165.2 (C-1), 150.0 (C-6),
145.9 (C-7), 135.0 (C-1′), 134.1 (CH-4′), 131.6 (C-4a), 130.2 (2C,
CH-2′,6′), 128.5 (2C, CH-3′,5′), 118.1 (C-8a), 114.5 (CH-5), 109.6
(CH-8), 55.9 (OCH3-7), 42.6 (CH2-3), 24.9 (CH2-4); LSIMS m/z
282 [MH]+. EIMS m/z (%) 281 [M]+ (40), 253 (100), 176 (5),
159 (5), 145 (5), 105 (55), 91 (10), 77 (54); HREIMS m/z

5064 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Bermejo et al.
2.80 (t, J ) 7.0 Hz, 2H, CH2-4), 1.88 (m, 2H, OCH2CH2(CH2)2-
CH3-6), 1.43 (m, 4H, OCH2CH2(CH2)2CH3-6), 0.93 (t, J ) 7.0
Hz, 3H, O(CH2)4CH3-6); 13C NMR* (100 MHz, CDCl3) δ 194.0
(C-R), 164.4 (C-1), 151.4 (C-6), 147.9 (C-7), 135.6 (C-1′), 133.7
(C-4a), 131.0-128.5 (5C, CH-2′ to 6′), 119.1 (C-8a), 111.7 (CH-
5), 110.0 (CH-8), 69.0 (OCH2(CH2)3CH3-6), 56.2 (OCH3-7), 47.3
(CH2-3), 28.7 and 27.9 (2C, OCH2(CH2)2CH2CH3-6), 25.4 (CH2-
4), 22.4 (1C, O(CH2)3CH2CH3-6), 13.9 (1C, O(CH2)4CH3-6);
MAB (Ar) m/z 351 (34) [M]+, 323 (100); MAB (N2) m/z 351 (22)
[M]+, 350 (80), 349 (100); C22H25NO3.
OCH2Ph-6), 7.31 (d, J ) 8.4 Hz, 1H, H-8), 6.84 (d, J ) 2.2 Hz,
1H, H-5), 6.80 (dd, J ) 8.4, 2.2 Hz, 1H, H-7), 5.15 (s, 2H, OCH2-
Ph-6), 3.92 (t, J ) 7.7 Hz, 2H, CH2-3), 2.84 (t, J ) 7.7 Hz, 2H,
CH2-4); 13C NMR* (100 MHz, CDCl3) δ 193.9 (C-R), 164.6 (C-
1), 161.0 (C-6), 139.4 and 136.2 (2C, C-1′′ and C-1′), 135.4 (C-
4a), 133.7 (CH-4′), 130.3 (2C, CH-2′,6′), 128.5 (2C, CH-3′,5′),
128.4-127.3 (5C, OCH2Ph-6), 128.0 (CH-8), 120.2 (C-8a), 114.2
(CH-5), 112.8 (CH-7), 69.9 (OCH2Ph-6), 47.0 (CH2-3), 26.0
(CH2-4); EIMS m/z (%) 341 [M]+ (17), 250 (27), 236 (4), 234
(6), 105 (18), 91 (100), 77 (18); C23H19NO2.
1-Ben zoyl-6-(tr a n s-b u t -2-en oxy)-7-m et h oxy-3,4-d ih y-
d r oisoqu in olin e, 7. The asterisk (/) indicates that the
assignments were made by COSY 45. 1H NMR* (300 MHz,
CDCl3) δ 8.03 (dd, J ) 7.0, 1.5 Hz, 2H, H-2′,6′), 7.61 (td, J )
7.0, 1.5 Hz, 1H, H-4′), 7.48 (td, J ) 7.0, 1.5 Hz, 2H, H-3′,5′),
6.94 (s, 1H, H-8), 6.75 (s, 1H, H-5), 5.92-5.72 (m, 2H,
OCH2CHdCHCH3-6), 4.58 (d, J ) 6.0 Hz, 2H, OCH2CHd
CHCH3-6), 3.93 (t, J ) 7.5 Hz, 2H, CH2-3), 3.78 (s, 3H, OCH3-
7), 2.80 (t, J ) 7.5 Hz, 2H, CH2-4), 1.76 (dd, J ) 6.1, 1.7 Hz,
3H, OCH2CHdCHCH3-6); LC-MS (APIES positive mode) m/z
336 [MH]+, 358 [M + Na]+; C21H21NO3.
N-Meth yl-1-ben zoyl-6-ben zyloxy-3,4-d ih yd r oisoqu in o-
lin e, 10a . The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
8.31 (dd, J ) 7.8, 1.5 Hz, 2H, H-2′,6′), 7.80 (tt, J ) 7.8, 1.5 Hz,
1H, H-4′), 7.69 (tt, J ) 7.8, 1.5 Hz, 2H, H-3′,5′), 7.40 (m, 5H,
OCH2Ph-6), 7.26 (d, J ) 8.8 Hz, 1H, H-8), 7.14 (d, J ) 2.2 Hz,
1H, H-5), 6.87 (dd, J ) 8.8, 2.2 Hz, 1H, H-7), 5.23 (s, 2H, OCH2-
Ph-6), 4.90 (m, 1H, CH2-3a), 4.27 (m, 2H, CH2-3b and CH2-
4a), 3.84 (s, 3H, CH3-N), 3.17 (m, 1H, CH2-4b); 13C NMR* (75
MHz, CDCl3) δ 187.9 (C-R), 169.8 (C-1), 167.1 (C-6), 140.9 and
137.4 (2C, C-1′′ and C-1′), 134.6 (C-4a), 134.3 (CH-4′), 131.0
(2C, CH-2′,6′), 128.6 (2C, CH-3′,5′), 127.5 (5CH, OCH2Ph-6),
127.5 (CH-8), 115.8 (C-8a), 115.5 (2C, CH-5,7), 71.2 (OCH2-
Ph-6), 52.6 (CH2-3), 46.1 (N-CH3), 26.7 (CH2-4); LC-MS
(APIES positive mode) m/z 357 [MH]+, 356 [M]+; HREIMS m/z
356.162 83 [M]+ (356.165 05 calcd for C24H22NO2), 252.137 20
(252.138 84 calcd for C17H18NO), 161.085 67 (161.084 06 calcd
1-Ben zoyl-6-m eth oxy-7-ben zyloxy-3,4-d ih yd r oisoqu in -
olin e, 8. The asterisk (/) indicates that the assignments were
1
made by COSY 45, DEPT, and HMQC. H NMR* (400 MHz,
CDCl3) δ 7.98 (d, J ) 7.5 Hz, 2H, H-2′,6′), 7.59 (t, J ) 7.5 Hz,
1H, H-4′), 7.46 (t, J ) 7.5 Hz, 2H, H-3′,5′), 7.33-7.25 (m, 5H,
OCH2Ph-7), 6.97 (s, 1H, H-8), 6.77 (s, 1H, H-5), 5.00 (s, 2H,
OCH2Ph-7), 3.92 (s, 3H, OCH3-6), 3.90 (t, J ) 7.8 Hz, 2H, CH2-
3), 2.82 (t, J ) 7.8 Hz, 2H, CH2-4); 13C NMR* (100 MHz, CDCl3)
δ 193.7 (C-R), 164.7 (C-1), 152.6 (C-6), 146.6 (C-7), 136.3 and
135.3 (2C, C-1′′ and C-1′), 134.0 (CH-4′), 131.6 (C-4a), 130.3
(2C, CH-2′,6′), 128.5 (2C, CH-3′,5′), 128.4-127.5 (5C, OCH2Ph-
7), 118.9 (C-8a), 112.5 (CH-5), 110.9 (CH-8), 71.2 (OCH2Ph-
7), 56.0 (OCH3-6), 46.9 (CH2-3), 25.3 (CH2-4); EIMS m/z (%)
371 [M]+ (66), 280 (67), 266 (21), 174 (10), 105 (73), 91 (100),
77 (75); C24H21NO3.
for
C10H11NO), 105.035 19 (105.034 04 calcd for C7H5O),
91.054 25 (91.054 77 calcd for C7H7), 77.036 64 (77.039 12 calcd
for C6H5).
1-B e n zo y l-6-is o p e n t e n y lo x y -3,4-d ih y d r o is o q u in o -
lin e, 11. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ
8.03 (dd, J ) 7.7, 1.6 Hz, 2H, H-2′,6′), 7.59 (tt, J ) 7.7, 1.6 Hz,
1H, H-4′), 7.47 (tt, J ) 7.7, 1.6 Hz, 2H, H-3′,5′), 7.30 (d, J )
8.4 Hz, 1H, H-8), 6.77 (d, J ) 2.0 Hz, 1H, H-5), 6.74 (dd, J )
8.4, 2.0 Hz, 1H, H-7), 5.45 (t, J ) 6.8 Hz, 1H, OCH2CHd
C(CH3)2-6), 4.54 (d, J ) 6.8 Hz, 2H, OCH2CHdC(CH3)2-6), 3.93
(t, J ) 7.6 Hz, 2H, CH2-3), 2.85 (t, J ) 7.6 Hz, 2H, CH2-4),
1.79 and 1.74 (2s, 6H, OCH2CHdC(CH3)2-6); 13C NMR* (100
MHz, CDCl3) δ 194.1 (C-R), 164.8 (C-1), 161.3 (C-6), 139.4,
138.8 and 135.5 (3C, C-1′, C-4a and OCH2CHdC(CH3)2-6),
133.8 (CH-4′), 130.3 (2C, CH-2′,6′), 128.5 (3C, CH-3′,5′,8), 120.0
(C-8a), 119.0 (1C, OCH2CHdC(CH3)2-6), 114.1 (CH-5), 112.7
(CH-7), 64.9 (1C, OCH2CHdC(CH3)2-6), 47.1 (CH2-3), 26.2
(CH2-4), 25.8 and 18.2 (2C, OCH2CHdC(CH3)2-6); LC-MS
(APCI negative mode) m/z 318 [M - 1]+; C21H21NO2.
1-Ben zoyl-6-m eth oxy-7-h yd r oxy-3,4-d ih yd r oisoqu in o-
lin e, 8a . The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
8.02 and 8.01 (2dd, J ) 7.5, 1.2 Hz, 2H, H-2′ and H-6′), 7.56
(td, J ) 7.5, 1.2 Hz, 1H, H-4′), 7.43 (td, J ) 7.5, 1.2 Hz, 2H,
H-3′,5′), 6.92 (s, 1H, H-8), 6.72 (s, 1H, H-5), 3.92 (t, J ) 7.6
Hz, 2H, CH2-3), 3.91 (s, 3H, OCH3-6), 2.81 (t, J ) 7.6 Hz, 2H,
CH2-4); 13C NMR* (75 MHz, CDCl3) δ 193.9 (C-R), 165.0 (C-
1), 149.3 (C-6), 144.3 (C-7), 135.3 (C-1′), 133.8 (CH-4′), 132.6
(C-4a), 130.5-130.3 (2C, CH-2′,6′), 130.1-129.9 (2C, CH-3′,5′),
119.8 (C-8a), 113.0 (CH-5), 109.9 (CH-8), 56.0 (OCH3-6), 47.1
(CH2-3), 25.4 (CH2-4); EIMS m/z (%) 281 [M]+ (38), 264 (34),
253 (100), 176 (5), 105 (58), 91 (23), 77 (54); C17H15NO3.
1-Ben zoyl-6-isobu tyloxy-3,4-d ih yd r oisoqu in olin e, 12.
The asterisk (/) indicates that the assignments were made by
1
COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ 8.03 (dd,
1-Ben zoyl-6-m et h oxy-7-p en t a n yloxy-3,4-d ih yd r oiso-
qu in olin e, 9. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 8.02 (dd, J ) 8.4, 1.2 Hz, 2H, H-2′,6′), 7.59 (td, J )
7.5, 1.2 Hz, 1H, H-4′), 7.47 (tt, J ) 8.4, 7.5, 1.2 Hz, 2H, H-3′,5′),
6.93 (s, 1H, H-8), 6.74 (s, 1H, H-5), 3.94-3.80 (m, 4H, CH2-3
and OCH2(CH2)3CH3-7), 3.91 (s, 3H, OCH3-6), 2.81 (t, J ) 8.0
Hz, 2H, CH2-4), 1.76 (quint, J ) 7.2 Hz, 2H, OCH2CH2(CH2)2-
CH3-7), 1.38-1.28 (m, 4H, OCH2CH2(CH2)2CH3-7), 0.88 (t, 3H,
O(CH2)4CH3-7); 13C NMR* (100 MHz, CDCl3) δ 193.9 (C-R),
164.5 (C-1), 152.1 (C-6), 147.1 (C-7), 135.5 (C-1′), 133.7 (CH-
4′), 130.9 (C-4a), 130.3 (2C, CH-2′,6′), 128.4 (2C, CH-3′,5′),
119.2 (C-8a), 111.2 (CH-5), 110.7 (CH-8), 69.1 (1C, OCH2(CH2)3-
CH3-7), 55.9 (OCH3-6), 47.2 (CH2-3), 28.6, 27.8, and 22.3 (3C,
OCH2(CH2)3CH3-7), 25.3 (CH2-4), 13.8 (1C, O(CH2)4CH3-7);
LC-MS (APIES positive mode) m/z 352 [MH]+, 374 [M + Na]+;
J ) 7.8, 1.7 Hz, 2H, H-2′,6′), 7.58 (tt, J ) 7.8, 1.7 Hz, 1H, H-4′),
7.46 (t, J ) 7.8 Hz, 2H, H-3′,5′), 7.30 (d, J ) 8.4 Hz, 1H, H-8),
6.77 (d, J ) 2.4 Hz, 1H, H-5), 6.72 (dd, J ) 8.4, 2.4 Hz, 1H,
H-7), 3.93 (t, J ) 7.6 Hz, 2H, CH2-3), 3.74 (d, J ) 6.5 Hz, 2H,
OCH2CH(CH3)2-6), 2.85 (t, J ) 7.6 Hz, 2H, CH2-4), 2.08 (m,
1H, OCH2CH(CH3)2-6), 1.02 (d, J ) 6,5 Hz, 6H, OCH2-
CH(CH3)2-6); 13C NMR* (100 MHz, CDCl3) δ 194.1 (C-R), 164.8
(C-1), 161.7 (C-6), 139.4 and 135.5 (2C, C-1′ and C-4a), 133.7
(CH-4′), 130.3 (2C, CH-2′,6′), 128.5 (3C, CH-3′,5′,8), 119.9 (C-
8a), 113.9 (CH-5), 112.5 (CH-7), 74.4 (1C, OCH2CH(CH3)2-6),
47.1 (CH2-3), 28.1 (1C, OCH2CH(CH3)2-6), 26.2 (CH2-4), 19.1
(2C, OCH2CH(CH3)2-6); LC-MS (APCI negative mode) m/z 306
[M - 1]+; C20H21NO2.
1-Ben zoyl-6-p en ta n yloxy-3,4-d ih yd r oisoqu in olin e, 13.
The asterisk (/) indicates that the assignments were made by
HREIMS m/z 351.183 18 [M]+ (351.183 44 calcd for C22H25
-
1
COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ 8.02 (dd,
NO3), 280.095 12 (280.097 37 calcd for C17H14NO3), 264.100 16
(264.102 45 calcd for C17H14NO2), 105.043 97 (105.034 04 calcd
for C7H5O), 77.029 63 (77.039 12 calcd for C6H5).
J ) 8.1, 1.2 Hz, 2H, H-2′,6′), 7.59 (t, J ) 8.1 Hz, 1H, H-4′),
7.46 (t, J ) 8.1 Hz, 2H, H-3′,5′), 7.30 (d, J ) 8.5 Hz, 1H, H-8),
6.76 (d, J ) 2.5 Hz, 1H, H-5), 6.72 (dd, J ) 8.5, 2.5 Hz, 1H,
H-7), 3.98 (t, 2H, J ) 6.0 Hz, OCH2(CH2)3CH3-6), 3.93 (t, J )
7.0 Hz, 2H, CH2-3), 2.86 (t, J ) 7.0 Hz, 2H, CH2-4), 1.79 (sex.,
J ) 6.0 Hz, 2H, OCH2CH2(CH2)2CH3-6), 1.45 (m, 4H, OCH2-
1-Ben zoyl-6-ben zyloxy-3,4-dih ydr oisoqu in olin e, 10. The
asterisk (/) indicates that the assignments were made by
1
COSY 45, DEPT, and HMQC. H NMR* (400 MHz, CDCl3) δ
8.03 (dd, J ) 7.4, 1.0 Hz, 2H, H-2′,6′), 7.57 (t, J ) 7.4 Hz, 1H,
H-4′), 7.45 (tt, J ) 7.4, 1.0 Hz, 2H, H-3′,5′), 7.41-7.30 (m, 5H,
CH2(CH2)2CH3-6), 0.93 (t, J ) 6.0 Hz, 3H, O(CH2)4CH3-6); 13
C
NMR* (100 MHz, CDCl3) δ 185.0 (C-R), 165.3 (C-1), 160.0 (C-

Isoquinolines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5065
6), 138.7 and 135.8 (2C, C-1′ and C-4a), 133.1 (CH-4′), 130.6
(2C, CH-2′,6′), 128.9 (3C, CH-3′,5′,8), 118.8 (C-8a), 114.2 (CH-
5), 111.8 (CH-7), 68.5 (OCH2(CH2)3CH3-6), 47.3 (CH2-3), 29.1,
28.4, and 22.7 (3 C, OCH2(CH2)3CH3-6), 26.5 (CH2-4), 14.3 (1C,
O(CH2)4CH3-6); MAB (Ar) m/z 321 (35) [M]+, 293 (100), 250
(10), 234 (30); MAB (N2) m/z 321 (53) [M]+, 319 (100), 293 (17),
234 (6); HREIMS m/z 321.172 16 [M]+ (321.172 88 calcd for
1-Ben zoyl-6-ben zyloxy-7,2′-d im eth oxy-3,4-d ih yd r oiso-
qu in olin e, 17. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 7.81 (dd, J ) 7.6, 2.0 Hz, 1H, H-6′), 7.51 (td, J ) 8.0,
1.5 Hz, 1H, H-4′), 7.48-7.33 (m, 5H, OCH2Ph-6), 7.06 (td, J )
8.0, 1.5 Hz, 1H, H-3′), 7.03 (s, 1H, H-8), 6.92 (t, 1H, J ) 8.0
Hz, H-5′), 6.75 (s, 1H, H-5), 5.21 (s, 2H, OCH2Ph-6), 3.80 (s,
3H, OCH3-7), 3.76 (t, J ) 7.6 Hz, 2H, CH2-3), 3.65 (s, 3H,
OCH3-2′), 2.68 (t, J ) 7.6 Hz, 2H, CH2-4); 13C NMR (100 MHz,
CDCl3) δ 195.3 (C-R), 165.8 (C-1), 159.3 (C-2′), 150.4 (C-6),
147.9 (C-7), 136.6 (2C, C-1′,1′′), 134.5 and 130.9 (2C, CH-4′
and 6′), 128.6-127.0 (5CH, OCH2Ph-6), 127.9 (C-4a), 120.9
(CH-5′), 119.6 (C-8a), 112.5 (CH-3′), 111.9 (CH-5), 110.2 (CH-
8), 70.8 (OCH2Ph-6), 56.1 and 55.5 (2C, OCH3-7 and OCH3-
2′), 47.2 (CH2-3), 25.3 (CH2-4); LC-MS (APIES positive mode)
m/z 402 [MH]+, 424 [M + Na]+; C25H23NO4.
C
21H23NO2), 293.176 55 (293.177 96 calcd for C20H23NO),
250.087 11 (250.086 80 calcd for 16H12NO2), 234.0918
C
(234.091 89 calcd for C16H12NO), 105.032 00 (105.034 04 calcd
for C7H5O), 77.037 71 (77.039 12 calcd for C6H5).
1-Ben zoyl-6-(tr a n s-bu t-2-en oxy)-3,4-d ih yd r oisoqu in o-
lin e, 14. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
8.03 (dd, J ) 8.0, 1.4 Hz, 2H, H-2′,6′), 7.58 (td, J ) 8.0, 1.4
Hz, 1H, H-4′), 7.46 (t, J ) 8.0 Hz, 2H, H-3′,5′), 7.29 (dd, J )
8.0, 2.0 Hz, 1H, H-7), 6.77 (d, J ) 2.0 Hz, 1H, H-5), 6.70 (d, J
) 8.0 Hz, 1H, H-8), 5.87-5.60 (m, 2H, OCH2CHdCHCH3-6),
4.49 (dd, J ) 4.0, 1.0 Hz, 2H, OCH2CHdCHCH3-6), 3.93 (t, J
) 7.6 Hz, 2H, CH2-3), 2.85 (t, J ) 7.6 Hz, 2H, CH2-4), 1.76
(dd, J ) 6.2, 1.2 Hz, 3H, OCH2CHdCHCH3-6); 13C NMR* (75
MHz, CDCl3) δ 194.0 (C-R), 164.8 (C-1), 161.1 (C-6), 139.4 and
135.5 (2C, C-1′ and C-4a), 133.7 (CH-4′), 131.1 and 125.4 (2C,
OCH2CHdCHCH3-6), 130.3-128.4 (5C, CH-2′,3′,5′,6′, and 8),
124.9 (C-8a), 114.1 (CH-5), 112.3 (CH-7), 68.7 (1C, OCH2CHd
CHCH3-6), 47.1 (CH2-3), 26.1 (CH2-4), 17.8 (1C, OCH2CHd
CHCH3-6); LC-MS (APIES positive mode) m/z 306 [MH]+, 305
[M]+, 328 [M + Na]+; HREIMS m/z 305.142 50 [M]+ (305.141 58
1-Ben zoyl-6-ben zyloxy-2′-m eth oxy-3,4-d ih yd r oisoqu in -
olin e, 18. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ
7.83 (dd, J ) 7.8, 1.8 Hz, 1H, H-6′), 7.50 (ddd, J ) 7.8, 1.8, 0.9
Hz, 1H, H-4′), 7.45-7.36 (m, 6H, OCH2Ph-6 and H-8), 7.05
(td, J ) 7.8, 0.9 Hz, 1H, H-3′), 6.92 (d, J ) 7.8 Hz, 1H, H-5′),
6.85 (m, 2H, H-7 and H-5), 5.10 (s, 2H, OCH2Ph-6), 3.79 (t, J
) 7.6 Hz, 2H, CH2-3), 3.65 (s, 3H, OCH3-2′), 2.78 (t, J ) 7.6
Hz, 2H, CH2-4); 13C NMR* (100 MHz, CDCl3) δ 194.0 (C-R),
166.1 (C-1), 160.6 (C-2′), 159.3 (C-6), 139.7 and 136.9 (2C, C-1′
and C-1′′), 134.5 and 130.9 (2C, CH-4′ and CH-6′), 128.6-127.1
(6C, OCH2Ph-6 and CH-8), 127.0 (C-4a), 120.8 (CH-5′), 120.1
(C-8a), 113.9 (CH-3′), 112.6 (CH-5), 111.8 (CH-7), 69.9 (OCH2-
Ph-6), 55.5 (OCH3-2′), 47.0 (CH2-3), 26.2 (CH2-4); LC-MS
(APIES positive mode) m/z 372 [MH]+, 394 [M + Na]+;
calcd for C20H19NO2), 234.092 40 (234.091 89 calcd for C16H12
-
NO), 105.031 11 (105.034 04 calcd for C7H5O), 77.037 17
(77.039 12 calcd for C6H5).
HREIMS m/z 371.151 76 [M]+ (371.152 14 calcd for C24H21
-
1-Ben zoyl-6-O-m eth yl-p en ta n oa te-3,4-d ih yd r oisoqu in -
olin e, 15. The asterisk (/) indicates that the assignments were
NO3), 341.132 22 (341.141 58 calcd for C23H19NO2), 280.096 35
(280.097 37 calcd for C17H14NO3), 105.032 63 (105.034 04 calcd
for C7H5O), 91.056 10 (91.054 77 calcd for C7H7), 77.037 02
(77.039 12 calcd for C6H5).
1
made by COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ
8.01 (dd, J ) 7.6, 1.4 Hz, 2H, H-2′,6′), 7.59 (tt, J ) 7.6, 1.4 Hz,
1H, H-4′), 7.47 (td, J ) 7.6, 1.4 Hz, 2H, H-3′,5′), 7.29 (d, J )
8.5 Hz, 1H, H-8), 6.76 (d, J ) 2.5 Hz, 1H, H-5), 6.72 (dd, J )
8.5, 2.5 Hz, 1H, H-7), 4.01 (m, 2H, OCH2(CH2)3COOCH3-6),
3.93 (t, J ) 7.5 Hz, 2H, CH2-3), 3.67 (s, 3H, O(CH2)4COOCH3-
6), 2.85 (t, J ) 7.5 Hz, 2H, CH2-4), 2.40 (m, 2H, O(CH2)3CH2-
COOCH3-6), 1.83 (m, 4H, OCH2(CH2)2CH2COOCH3-6); 13C
NMR* (100 MHz, CDCl3) δ 194.0 (C-R), 173.7 (1C, O(CH2)4CO-
OCH3-6), 164.8 (C-1), 161.3 (C-6), 139.5 (C-1′), 135.5 (C-4a),
133.7 (CH-4′), 130.3 (2C, CH-2′,6′), 128.5 (CH-8), 128.4 (2C,
CH-3′,5′), 120.1 (C-8a), 113.9 (CH-5), 112.5 (CH-7), 67.5 (1 C,
OCH2(CH2)3COOCH3-6), 51.5 (1C, O(CH2)4COOCH3-6), 47.1
(CH2-3), 33.5, 28.5, and 21.5 (3C, OCH2(CH2)3COOCH3-6), 26.1
(CH2-4); LC-MS (APIES positive mode) m/z 366 [MH]+;
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-3′-a cetoxy-3,4-d ih y-
d r oisoqu in olin e, 19. The asterisk (/) indicates that the
assignments were made by COSY 45 and DEPT. 1H NMR*
(250 MHz, CDCl3) δ 7.90 (dt, J ) 7.7, 1.0 Hz, 1H, H-6′), 7.78
(t, J ) 1.0 Hz, 1H, H-2′), 7.52-7.31 (m, 7H, H-5′,4′ and
OCH2Ph-6), 6.96 (s, 1H, H-8), 6.75 (s, 1H, H-5), 5.21 (s, 2H,
OCH2Ph-6), 3.93 (t, J ) 7.7 Hz, 2H, CH2-3), 3.80 (s, 3H, OCH3-
7), 2.74 (t, J ) 7.7 Hz, 2H, CH2-4), 2.30 (s, 3H, OCOCH3-3′);
13C NMR* (62.5 MHz, CDCl3) δ 192.5 (C-R), 169.1 (OCOCH3-
3′), 163.9 (C-1), 150.8 (C-6), 150.6 (C-3′), 148.1 (C-7), 136.9 and
136.3 (2C, C-1′ and C-1′′), 130.9 (C-4a), 129.5-127.1 (7 C, CH-
5′,6′ and OCH2Ph-6), 123.2 (2C, CH-2′,4′), 119.4 (C-8a), 112.6
(CH-5), 110.0 (CH-8), 70.7 (OCH2Ph-6), 56.2 (OCH3-7), 47.3
(CH2-3), 25.2 (CH2-4), 21.0 (CH3OCO-3′); EIMS m/z (%) 429
[M]+ (20), 386 (9), 370 (20), 338 (37), 296 (23), 280 (9), 268
(14), 266 (9), 121 (15), 91 (100), 77 (4); HREIMS m/z 429.158 01
[M]+ (429.157 62 calcd for C26H23NO5), 91.054 75 (91.054 77
calcd for C7H7), 77.040 22 (77.039 12 calcd for C6H5).
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-3′-h yd r oxy-3,4-d ih y-
d r oisoqu in olin e, 19a . The asterisk (/) indicates that the
assignments were made by COSY 45 and DEPT. 1H NMR*
(300 MHz, CDCl3) δ 7.46-7.21 (m, 9H, H-2′,4′-6′ and OCH2Ph-
6), 6.91 (s, 1H, H-8), 6.71 (s, 1H, H-5), 5.22 (s, 2H, OCH2Ph-
6), 3.80 (t, J ) 7.7 Hz, 2H, CH2-3), 3.78 (s, 3H, OCH3-7), 2.68
(t, J ) 7.7 Hz, 2H, CH2-4); 13C NMR* (75 MHz, CDCl3) δ 193.7
(C-R), 165.9 (C-1), 157.0 (C-3′), 151.5 (C-6), 148.4 (C-7), 136.2
and 135.9 (2C, C-1′ and C-1′′), 130.8 (C-4a), 129.7-117.2 (9C,
C-2′,4′-6′ and OCH2Ph-6), 119.2 (C-8a), 112.6 (CH-5), 110.4
(CH-8), 70.8 (OCH2Ph-6), 56.2 (OCH3-7), 46.2 (CH2-3), 25.1
(CH2-4); EIMS m/z (%) 387 [M]+ (14), 370 (7), 296 (17), 268
(12), 266 (7), 121 (10), 105 (3), 91 (100), 77 (4); C24H21NO4.
C
22H23NO4.
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-2′-tosyloxy-3,4-d ih y-
d r oisoqu in olin e, 16. The asterisk (/) indicates that the
assignments were made by COSY 45 and DEPT. 1H NMR*
(300 MHz, CDCl3) δ 7.82 (dd, J ) 7.6, 1.9 Hz, 1H, H-6′), 7.48-
7.30 (m, 9H, OS(O)2PhCH3-2′ and OCH2Ph-6), 7.12-7.04 (m,
4H, H-3′,4′,5′, and H-8), 6.73 (s, 1H, H-5), 5.24 (s, 2H, OCH2-
Ph-6), 3.88 (s, 3H, OCH3-7), 3.72 (t, J ) 7.8 Hz, 2H, CH2-3),
2.61 (t, J ) 7.8 Hz, 2H, CH2-4), 2.38 (s, 3H, OS(O)2PhCH3-2′);
13C NMR* (75 MHz, CDCl3) δ 192.8 (C-R), 163.7 (C-1), 150.6
(C-6), 147.9 (C-7), 147.1 and 145.4 (3C, C-2′,1′′′ and 4′′′), 136.6
and 135.1 (2C, C-1′ and C-1′′), 131.8 (C-4a), 131.5-122.8
(13CH, OS(O)2PhCH3-2′, OCH2Ph-6, and H-3′ to H-6′), 119.3
(C-8a), 112.2 (CH-5), 111.3 (CH-8), 70.7 (OCH2Ph-6), 56.1
(OCH3-7), 47.6 (CH2-3), 24.9 (CH2-4), 21.6 (OS(O)2PhCH3-2′);
EIMS m/z (%) 541 [M]+ (15), 450 (6), 386 (11), 368 (67), 278
(11), 91 (100), 77 (3); C31H27NSO6.
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-2′-h yd r oxy-3,4-d ih y-
d r oisoqu in olin e, 16a . The asterisk (/) indicates that the
assignments were made by COSY 45. 1H NMR* (300 MHz,
CDCl3) δ 7.71 (dd, J ) 7.8, 1.5 Hz, 1H, H-6′), 7.53 (td, J ) 7.8,
1.5 Hz, 1H, H-4′), 7.44-7.30 (m, 5H, OCH2Ph-6), 7.04 (dd, J
) 7.8, 1.5 Hz, 1H, H-3′), 6.88 (td, J ) 7.8, 1.5 Hz, 1H, H-5′),
6.83 (s, 1H, H-8), 6.76 (s, 1H, H-5), 5.20 (s, 2H, OCH2Ph-6),
3.87 (t, J ) 7.5 Hz, 2H, CH2-3), 3.78 (s, 3H, OCH3-7), 2.77 (t,
J ) 7.5 Hz, 2H, CH2-4); LSIMS m/z 388 [MH]+; C24H21NO4.
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-3′-tosyloxy-3,4-d ih y-
d r oisoqu in olin e, 20. The asterisk (/) indicates that the
assignments were made by COSY 45. 1H NMR* (300 MHz,
CDCl3) δ 7.92 and 7.70 (2 d, J ) 8.0 Hz, 4H, OS(O)2PhCH3-
3′), 7.6-7.27 (m, 9H, OCH2Ph-6 and H-2′,4′-6′), 6.93 (s, 1H,
H-8), 6.75 (s, 1H, H-5), 5.22 (s, 2H, OCH2Ph-6), 3.85 (t, J )
7.6 Hz, 2H, CH2-3), 3.81 (s, 3H, OCH3-7), 2.70 (t, J ) 7.6 Hz,

5066 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Bermejo et al.
2H, CH2-4), 2.41 (s, 3H, OS(O)2PhCH3-3′); EIMS m/z (%) 541
[M]+ (14), 387 (7), 384 (45), 370 (21), 294 (20), 121 (5), 91 (100),
77 (4); C31H27NSO6.
135.043 51 (135.044 61 calcd for C8H7O2), 91.053 88 (91.054 77
calcd for C7H7).
1-Ben zoyl-6-ben zyloxy-7,3′,4′-tr im eth oxy-3,4-dih ydr oiso-
qu in olin e, 25. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 7.65 (d, J ) 2.0 Hz, 1H, H-2′), 7.58 (dd, J ) 8.4, 2.0
Hz, 1H, H-6′), 7.41 (dd, J ) 7.6, 1.2 Hz, 2H, H-2′′,6′′), 7.34 (td,
J ) 7.6, 1.2 Hz, 2H, H-3′′,5′′), 7.28 (dd, J ) 7.6, 1.2 Hz, 1H,
H-4′′), 6.92 (s, 1H, H-8), 6.84 (d, J ) 8.4 Hz, 1H, H-5′), 6.75 (s,
1H, H-5), 5.17 (s, 2H, OCH2Ph-6), 3.92 and 3.90 (2s, 6H, OCH3-
3′ and OCH3-4′), 3.86 (t, J ) 7.6 Hz, 2H, CH2-3), 3.75 (s, 3H,
OCH3-7), 2.72 (t, J ) 7.6 Hz, 2H, CH2-4); 13C NMR* (100 MHz,
CDCl3) δ 192.7 (C-R), 164.5 (C-1), 154.1 and 149.1 (2C, C-3′
and C-4′), 150.8 (C-6), 148.2 (C-7), 136.4 (C-1′′), 130.8 (C-4a),
128.7-127.1 (5C, OCH2Ph-6), 128.6 (C-1′), 126.5 (CH-6′), 119.8
(C-8a), 112.6 (CH-5), 111.2, 110.2 and 110.1 (3C, CH-5′,2′,8),
70.7 (OCH2Ph-6), 56.2, 56.1, and 55.9 (3C, OCH3-7, OCH3-3′,
and OCH3-4′), 47.2 (CH2-3), 25.3 (CH2-4); EIMS m/z (%) 431
[M]+ (82), 400 (75), 340 (63), 312 (64), 268 (39), 165 (71), 91
(100); HREIMS m/z 431.174 49 [M]+ (431.173 27 calcd for
1-Ben zoyl-6-ben zyloxy-7,3′-d im eth oxy-3,4-d ih yd r oiso-
qu in olin e, 21. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 7.55 (dd, J ) 8.0, 2.4 Hz, 1H, H-6′), 7.48-7.31 (m,
7H, H-2′,4′ and OCH2Ph-6), 7.17 (dd, J ) 8.0, 2.4 Hz, 1H, H-5′),
6.96 (s, 1H, H-8), 6.78 (s, 1H, H-5), 5.29 (s, 2H, OCH2Ph-6),
3.90 (t, J ) 7.6 Hz, 2H, CH2-3), 3.90 and 3.74 (2 s, 6H, OCH3-7
and OCH3-3′), 2.77 (t, J ) 7.6 Hz, 2H, CH2-4); 13C NMR* (100
MHz, CDCl3) δ 193.8 (C-R), 164.4 (C-1), 159.7 (C-3′), 150.8 (C-
6), 148.1 (C-7), 136.8 and 136.4 (2C, C-1′ and C-1′′), 130.9 (C-
4a), 129.5-127.1 (6C, CH-5′ and OCH2Ph-6), 123.6 (CH-6′),
120.6 and 113.9 (2C, CH-2′,4′), 119.6 (C-8a), 112.6 (CH-5),
110.1 (CH-8), 70.8 (OCH2Ph-6), 56.2 and 55.4 (2C, OCH3-7 and
OCH3-3′), 47.2 (CH2-3), 25.3 (CH2-4); LC-MS (APIES positive
mode) m/z 402 [MH]+, 424 [M + Na]+; C25H23NO4.
1-Ben zoyl-6-ben zyloxy-3′-m eth oxy-3,4-d ih yd r oisoqu in -
olin e, 22. The asterisk (/) indicates that the assignments were
C
26H25NO5), 340.121 34 (340.118 50 calcd for C19H18NO5),
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
265.106 10 (265.110 28 calcd for 17H15NO2), 165.056 10
C
7.59-7.28 (m, 9H, OCH2Ph-6 and H-8,2′,4′,6′), 7.13 (dd, J )
8.2, 2.6 Hz, 1H, H-5′), 6.85 (d, J ) 2.2 Hz, 1H, H-5), 6.80 (dd,
J ) 8.0, 2.2 Hz, 1H, H-7), 5.09 (s, 2H, OCH2Ph-6), 3.93 (t, J )
7.4 Hz, 2H, CH2-3), 3.84 (s, 3H, OCH3-3′), 2.85 (t, J ) 7.4 Hz,
2H, CH2-4); 13C NMR* (75 MHz, CDCl3) δ 193.8 (C-R), 164.8
(C-1), 161.1 (C-6), 159.7 (C-3′), 139.5, 136.7, and 136.2 (3C,
C-1′, C-1′′, and C-4a), 129.5-127.4 (7C, OCH2Ph-6 and CH-
5′,8), 123.5 (C-6′), 120.5 and 114.3 (2C, CH-2′,4′), 120.3 (C-
8a), 113.7 (CH-5), 112.9 (CH-7), 69.9 (OCH2Ph-6), 55.5 (OCH3-
3′), 47.0 (CH2-3), 26.1 (CH2-4); LC-MS (APIES positive mode)
m/z 372 [MH]+, 394 [M + Na]+; HREIMS m/z 371.150 53 [M]+
(371.152 14 calcd for C24H21NO3), 280.096 85 (280.097 37 calcd
for C17H14NO3), 135.044 88 (135.044 61 calcd for C8H7O2),
91.049 83 (91.054 77 calcd for C7H7).
(165.055 17 calcd for C9H9O3), 91.054 61 (91.054 77 calcd for
C7H7).
N-Meth yl-1-ben zoyl-6-ben zyloxy-7,3′,4′-tr im eth oxy-3,4-
d ih yd r oisoqu in olin e, 25a . The asterisk (/) indicates that the
assignments were made by COSY 45, NOESY, and DEPT. 1H
NMR* (400 MHz, CDCl3) δ 8.12 (dd, J ) 8.6, 2.2 Hz, 1H, H-6′),
7.57 (brd, J ) 2.2 Hz, 1H, H-2′), 7.42-7.34 (m, 5H, OCH2Ph-
6), 7.13 (d, J ) 8.6 Hz, 1H, H-5′), 7.01 (s, 1H, H-5), 6.67 (s,
1H, H-8), 5.28 (s, 2H, OCH2Ph-6), 4.88 (m, 1H, CH2-3a), 4.27
(m, 1H, CH2-4a), 4.07 (m, 1H, CH2-3b), 4.01 and 3.98 (2s, 6H,
OCH3-3′ and OCH3-4′), 3.78 (s, 3H, OCH3-7), 3.67 (s, 3H, CH3-
N), 3.17 (m, 1H, CH2-4b); 13C NMR* (100 MHz, CDCl3) δ 185.7
(C-R), 169.9 (C-1), 157.4 (C-4′), 150.3 (C-6), 149.1 (C-7), 142.0
(C-3′), 134.7 and 134.1 (2C, C-1′′and C-4a), 128.8-112.2 (10C,
OCH2Ph-6 and CH-5,8,2′,5′,6′), 124.4 (C-1′), 115.5 (C-8a), 71.6
(OCH2Ph-6), 56.7 and 56.3 (3C, OCH3-3′, OCH3-4′ and OCH3-
7), 52.5 (CH2-3), 46.1 (CH3-N), 26.4 (CH2-4); LC-MS (APIES
positive mode) m/z 446 [M]+, 447 [MH]+; HREIMS m/z
446.196 19 [M]+ (446.196 75 calcd for C27H28NO5), 282.148 61
(282.149 40 calcd for C18H20NO2), 91.054 01 (91.054 77 calcd
for C7H7).
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-4′-tosyloxy-3,4-d ih y-
d r oisoqu in olin e, 23. The asterisk (/) indicates that the
assignments were made by COSY 45. 1H NMR* (400 MHz,
CDCl3) δ 7.75 (d, J ) 8.5 Hz, 2H, H-2′,6′), 7.48-7.30 (m, 9H,
OS(O)2PhCH3-4′ and OCH2Ph-6), 6.93 (s, 1H, H-8), 6.77 (s, 1H,
H-5), 6.62 (d, J ) 8.5 Hz, 2H, H-3′,5′), 5.23 (s, 2H, OCH2Ph-
6), 3.88 (t, J ) 7.7 Hz, 2H, CH2-3), 3.80 (s, 3H, OCH3-7), 2.80
(t, J ) 7.7 Hz, 2H, CH2-4), 2.38 (s, 3H, OS(O)2PhCH3-4′); LC-
MS (APIES positive mode) m/z 542 [MH]+; C31H27NSO6.
1-Ben zoyl-6-ben zyloxy-3′,4′-d im eth oxy-3,4-d ih yd r oiso-
qu in olin e, 26. The asterisk (/) indicates that the assignments
were made by COSY 45 and DEPT. 1H NMR* (400 MHz,
CDCl3) δ 7.66 (d, J ) 2.0 Hz, 1H, H-2′), 7.58 (dd, J ) 8.4, 2.0
Hz, 1H, H-6′), 7.42-7.33 (m, 5H, OCH2Ph-6), 7.28 (d, J ) 8.4
Hz, 1H, H-8), 6.87 (brs, 1H, H-5), 6.85 (d, J ) 8.4 Hz, 1H, H-5′),
6.80 (dd, J ) 8.4, 2.4 Hz, 1H, H-7), 5.10 (s, 2H, OCH2Ph-6),
3.94 and 3.93 (2s, 6H, OCH3-3′ and 4′), 3.90 (t, J ) 7.6 Hz,
2H, CH2-3), 2.83 (t, J ) 7.6 Hz, 2H, CH2-4); 13C NMR* (100
MHz, CDCl3) δ 192.8 (C-R), 164.9 (C-1), 161.0 (C-6), 154.1 and
149.1 (2C, C-3′ and C-4′), 139.4 and 136.2 (2C, C-1′′ and C-1′),
128.6-126.4 (7C, OCH2Ph-6 and CH-6′,8), 128.1 (C-4a), 120.5
(C-8a), 114.3, 112.9, 111.1, and 109.9 (4C, CH-5,7,2′,5′), 69.9
(OCH2Ph-6), 56.1 and 55.4 (2C, OCH3-3′ and OCH3-4′), 46.9
(CH2-3), 26.1 (CH2-4); LC-MS (APCI negative mode) m/z 400
[M - 1]+; HREIMS m/z 401.161 98 [M]+ (401.162 71 calcd for
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-4′-h yd r oxy-3,4-d ih y-
d r oisoqu in olin e, 23a . The asterisk (/) indicates that the
assignments were made by COSY 45. 1H NMR* (400 MHz,
CDCl3) δ 7.75 (d, J ) 8.5 Hz, 2H, H-2′,6′), 7.43 (d, J ) 6.8 Hz,
2H, H-2′′,6′′), 7.38 (t, J ) 6.8 Hz, 2H, H-3′′,5′′), 7.33 (d, J )
6.8 Hz, 1H, H-4′′), 6.93 (s, 1H, H-8), 6.77 (s, 1H, H-5), 6.62 (d,
J ) 8.5 Hz, 2H, H-3′,5′), 5.30 (s, 2H, OCH2Ph-6), 3.88 (t, J )
7.7 Hz, 2H, CH2-3), 3.87 (s, 3H, OCH3-7), 2.80 (t, J ) 7.7 Hz,
2H, CH2-4); EIMS m/z (%) 387 [M]+ (70), 371 (100), 357 (50),
294 (45), 280 (42), 268 (47), 172 (37), 121 (44), 91 (57), 77 (12);
C
24H21NO4.
1-Ben zoyl-6-ben zyloxy-4′-m eth oxy-3,4-d ih yd r oisoqu in -
olin e, 24. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (250 MHz, CDCl3) δ
C
25H23NO4), 310.107 41 (310.107 93 calcd for C18H16NO4),
8.01 (d, J ) 6.9 Hz, 2H, H-2′,6′), 7.42-7.36 (m, 5H, OCH2Ph-
6), 7.28 (d, J ) 8.4 Hz, 1H, H-8), 6.92 (d, J ) 6.9 Hz, 2H,
H-3′,5′), 6.83 (d, J ) 2.2 Hz, 1H, H-5), 6.78 (dd, J ) 8.4, 2.2
Hz, 1H, H-7), 5.07 (s, 2H, OCH2Ph-6), 3.90 (t, J ) 7.6 Hz, 2H,
CH2-3), 3.84 (s, 3H, OCH3-4′), 2.83 (t, J ) 7.6 Hz, 2H, CH2-4);
13C NMR* (62.5 MHz, CDCl3) δ 192.6 (C-R), 164.9 (C-1), 164.1
(C-4′), 160.9 (C-6), 139.4 and 136.2 (2C, C-1′′ and C-1′), 130.0
(C-4a), 128.5-128.4 (2C, CH-2′,6′), 128.4-127.3 (5 C, OCH2Ph-
6), 128.0 (CH-8), 120.3 (C-8a), 114.1 (CH-5), 113.7 (2C, CH-
3′,5′), 112.7 (CH-7), 69.9 (OCH2Ph-6), 55.4 (OCH3-4′), 46.9
(CH2-3), 26.0 (CH2-4); EIMS m/z (%) 371 [M]+ (68), 343 (65),
280 (73), 135 (78), 91 (100), 77 (27); LC-MS (APCI negative
mode) m/z 370 [M - 1]+; LC-MS (APCI positive mode) m/z
372 [MH]+; HREIMS m/z 371.153 16 [M]+ (371.152 14 calcd
for C24H21NO3), 280.098 40 (280.097 37 calcd for C17H14NO3),
165.055 62 (165.055 17 calcd for C9H9O3), 91.054 20 (91.054 77
calcd for C7H7).
1-Ben zoyl-6-ben zyloxy-7-m eth oxyisoqu in olin e, 27. The
asterisk (/) indicates that the assignments were made by
COSY 45 and DEPT. 1H NMR* (300 MHz, CDCl3) δ 8.44 (d, J
) 5.5 Hz, 1H, H-3), 7.94 (dd, J ) 8.2, 1.3 Hz, 2H, H-2′,6′),
7.63 (d, J ) 5.5 Hz, 1H, H-4), 7.60 (s, 1H, H-8), 7.49 (m, 1H,
H-4′), 7.47-7.30 (m, 7H, H-3′,5′, and OCH2Ph-6), 7.19 (s, 1H,
H-5), 5.33 (s, 2H, OCH2Ph-6), 3.95 (s, 3H, OCH3-7); 13C NMR*
(75 MHz, CDCl3) δ 194.9 (C-R), 164.0 (C-1), 152.6 (C-6), 151.7
(C-7), 139.3 (CH-3), 137.0 and 135.7 (2C, C-1′′ and C-1′), 134.1
(C-4a), 133.5 (CH-4′), 130.8 (2C, CH-2′,6′), 128.7-127.3 (7C,
CH-3′,5′and OCH2Ph-6), 123.0 (C-8a), 121.7 (CH-4), 106.6 (CH-
5), 104.2 (CH-8), 70.8 (OCH2Ph-6), 56.1 (OCH3-7); EIMS m/z

Isoquinolines
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23 5067
(%) 369 [M]+ (55), 354 (25), 338 (100), 278 (65), 264 (5), 105
(40), 91 (47), 77 (52); C24H19NO3.
7.53 (dd, J ) 8.0, < 1.0, 1H, H-6′), 7.49-7.42 (m, 5H, OCH2Ph-
6), 7.40 (s, 1H, H-8), 7.36 (dd, 1H, J ) 8.0, <1.0 Hz, 1H, H-4′),
7.18 (s, 1H, H-5), 7.09 (d, J ) 8.0 Hz, 1H, H-3′), 6.82 (t, J )
8.0 Hz, 1H, H-5′), 5.33 (s, 2H, OCH2Ph-6), 3.95 (s, 3H, OCH3-
7); 13C NMR* (62.5 MHz, CDCl3) δ 190.0 (C-R), 163.8 (C-1),
152.4-151.5 (3C, C-6,7 and C-2′), 139.9 (CH-3), 137.1 (CH-
4′), 135.7 (C-1′′), 134.1, 118.9, and 118.3 (3C, CH-3′,6′,5′), 132.0
and 130.1 (2C, C-1′ and C-4a), 128.8-128.3 (5C, OCH2Ph-6),
121.4 (CH-4), 119.6 (C-8a), 106.6 (CH-5), 103.7 (CH-8), 70.8
(OCH2Ph-6), 56.1 (OCH3O-7); EIMS m/z (%) 386 [MH]+ (95),
385 [M]+ (30), 368 (43), 356 (72), 294 (17), 277 (7), 266 (100),
105 (7), 91 (38), 77 (61); C24H19NO4.
1-Ben zoyl-6-h yd r oxy-7-m eth oxyisoqu in olin e, 27a . The
asterisk (/) indicates that the assignments were made by
COSY 45 and DEPT. 1H NMR* (250 MHz, CDCl3) δ 8.44 (d, J
) 5.4 Hz, 1H, H-3), δ 7.95 (dd, J ) 8.0, 1.2 Hz, 2H, H-2′,6′), δ
7.64 (s, 1H, H-8), δ 7.63 (d, J ) 5.4 Hz, 1H, H-4), δ 7.60 (tt, J
) 8.0, 1.2 Hz, 1H, H-4′), δ 7.47 (t, J ) 8.0 Hz, 2H, H-3′,5′), δ
7.28 (s, 1H, H-5), 3.94 (s, 3H, OCH3-7); 13C NMR* (62.5 MHz,
CDCl3) δ 195.4 (C-R), 174.0 (C-1), 150.1 (C-6), 149.3 (C-7), 139.7
(CH-3), 136.9 (C-1′), 134.4 (C-4a), 133.4 (CH-4′), 130.8 (2C, CH-
2′,6′), 128.3 (2C, CH-3′,5′), 122.6 (C-8a), 121.6 (CH-4), 108.3
(CH-5), 103.6 (CH-8), 56.0 (OCH3-7); EIMS m/z (%) 279 [M]+
(83), 264 (96), 251 (73), 236 (100), 188 (2), 105 (40), 91 (15), 77
(61); C17H13NO3.
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-3′-h yd r oxyisoqu in o-
lin e, 32. The asterisk (/) indicates that the assignments were
made by COSY 45. 1H NMR* (250 MHz, CDCl3) δ 8.12 (d, J )
5.6 Hz, 1H, H-3), 7.50-7.38 (m, 7H, OCH2Ph-6 and H-2′,6′),
7.35 (d, J ) 5.6 Hz, 1H, H-4), 7.25 (d, J ) 8.0 Hz, 1H, H-5′),
7.10 (s, 1H, H-8), 7.01 (s, 1H, H-5), 6.87 (dd, J ) 8.0, 2.3 Hz,
1H, H-4′), 5.35 (s, 2H, OCH2Ph-6), 3.95 (s, 3H, OCH3-7); LC-
MS (APIES negative mode) m/z 348 [M - 1]+; C24H19NO4.
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-4′-h yd r oxyisoqu in o-
lin e, 33. The asterisk (/) indicates that the assignments were
made by COSY 45. 1H NMR* (400 MHz, CDCl3) δ 8.40 (d, J )
5.6 Hz, 1H, H-3), 7.70 (d, J ) 6.6 Hz, 2H, H-2′,6′), 7.62 (d, J )
5.6 Hz, 1H, H-4), 7.51 (s, 1H, H-8), 7.49 (dd, J ) 7.2, 1.4 Hz,
2H, H-2′′,6′′), 7.41 (td, J ) 7.2, 1.4 Hz, 2H, H-3′′,5′′), 7.35 (m,
1H, H-4′′), 7.17 (s, 1H, H-5), 6.69 (d, J ) 6.6 Hz, 2H, H-3′,5′),
5.33 (s, 2H, OCH2Ph-6), 3.94 (s, 3H, OCH3-7); LC-MS (APIES
negative mode) m/z 384 [M - 1]+; C24H19NO4.
1-Ben zoyl-6-(p-m eth oxy)ben zyloxy-7-m eth oxyisoqu in -
olin e, 28. The asterisk (/) indicates that the assignments were
1
made by COSY 45. H NMR* (300 MHz, CDCl3) 8.44 (d, J )
5.1 Hz, 1H, H-3), 7.95 (dd, J ) 8.2, 1.5 Hz, 2H, H-2′,6′), 7.64
(s, 1H, H-8), 7.61 (d, J ) 5.1 Hz, 1H, H-4), 7.60 (m, 1H, H-4′),
7.50-7.40 (m, 4H, H-3′,5′ and 3′′,5′′), 7.19 (s, 1H, H-5), 6.90
(m, 2H, H-2′′,6′′), 5.25 (s, 2H, OCH2Ph-p-OCH3-6), 3.94 (s, 3H,
OCH2Ph-p-OCH3-6), 3.83 (s, 3H, OCH3-7); LSIMS m/z 400
[MH]; EIMS m/z 399 [M]+, 278 (55), 122 (64), 105 (53), 77 (100);
C
25H21NO4.
1-Ben zoyl-6-p en ta n yloxy-7-m eth oxyisoqu in olin e, 29.
The asterisk (/) indicates that the assignments were made by
COSY 45 and DEPT. 1H NMR* (400 MHz, CDCl3) δ 8.45 (d, J
) 5.6 Hz, 1H, H-3), 7.96 (ddd, J ) 8.0, 2.7, 1.2 Hz, 2H, H-2′,6′),
7.64 (s, 1H, H-8), 7.63 (d, J ) 5.6 Hz, 1H, H-4), 7.60 (dt, J )
7.4, 1.2 Hz, 1H, H-4′), 7.48 (dt, J ) 8.0, 7.4, 1.2 Hz, 2H, H-3′,5′),
7.13 (s, 1H, H-5), 4.18 (t, J ) 6.8 Hz, 2H, OCH2(CH2)3CH3-6),
3.94 (s, 3H, OCH3-7), 1.56 (p, J ) 6.8 Hz, 2H, OCH2CH2(CH2)2-
CH3-6), 1.46 (m, 4H, O(CH2)2(CH2)2CH3-6), 0.96 (t, 3H, J )
6.8 Hz, O(CH2)4CH3-6); 13C NMR* (100 MHz, CDCl3) δ 195.4
(C-R), 162.0 (C-1), 152.9 (C-6), 151.5 (C-7), 139.9 (CH-3), 137.1
and 134.0 (2C, C-4a and C-1′), 133.3-128.3 (5C, CH-2′-6′),
122.9 (C-8a), 121.5 (CH-4), 105.5 (CH-5), 104.0 (CH-8), 69.1
(OCH2(CH2)3CH3-6), 56.0 (OCH3-7), 28.5-22.4 (3C, OCH2(CH2)3-
CH3-6), 13.9 (O(CH2)4CH3-6); LC-MS (APIES positive mode)
m/z 350 [MH]+, 372 [M + Na]+; C22H23NO3.
1-Ben zoyl-6-m eth oxy-7-ben zyloxyisoqu in olin e, 30. The
asterisk (/) indicates that the assignments were made by
COSY 45 and DEPT. 1H NMR* (400 MHz, CDCl3) δ 8.44 (d, J
) 5.3 Hz, 1H, H-3), 7.95 (d, J ) 7.7 Hz, 2H, H-2′,6′), 7.73 (s,
1H, H-8), 7.63 (d, J ) 5.3 Hz, 1H, H-4), 7.59 (t, J ) 7.7 Hz,
1H, H-4′), 7.46 (t, J ) 7.7 Hz, 2H, H-3′,5′), 7.35-7.28 (m, 5H,
OCH2Ph-7), 7.13 (s, 1H, H-5), 5.18 (s, 2H, OCH2Ph-7), 4.01 (s,
3H, OCH3-6); 13C NMR* (100 MHz, CDCl3) δ 195.3 (C-R), 155.0
(C-1), 152.9 (C-6), 150.2 (C-7), 140.0 (CH-3), 136.9 and 135.7
(2C, C-1′′ and C-1′), 133.9 (C-4a), 133.3 (CH-4′), 130.6 (2C, CH-
2′,6′), 128.5-127.6 (7C, CH-3′,5′ and OCH2Ph-7), 122.7 (C-8a),
121.4 (CH-4), 105.5 (CH-5), 104.8 (CH-8), 70.6 (OCH2Ph-7),
55.9 (OCH3-6); EIMS m/z (%) 369 [MH]+ (43), 278 (54), 264
(8), 105 (10), 91 (100), 77 (15); HREIMS m/z 369.135 74 [M]+
(369.136 50 calcd for C24H19NO3), 278.079 19 (278.081 72 calcd
for C17H12NO3), 264.104 05 (264.102 45 calcd for C17H14NO2),
91.053 20 (91.054 77 calcd for C7H7).
1-P h en yl-6-ben zyloxy-7-m eth oxy-3,4-d ih yd r oisoqu in o-
lin e, 34. The asterisk (/) indicates that the assignments were
1
made by COSY 45. H NMR* (400 MHz, CDCl3) δ 7.61-7.30
(m, 10H, OCH2Ph-6 and H-2′ to H-6′), 6.82 and 6.80 (2s, 2H,
H-8 and H-5), 5.22 (s, 2H, OCH2Ph-6), 3.79 (t, J ) 7.4 Hz, 2H,
CH2-3), 3.73 (s, 3H, OCH3-7), 2.67 (t, J ) 7.4 Hz, 2H, CH2-4);
13C NMR* (100 MHz, CDCl3) δ 167.1 (C-1), 150.6 (C-6), 148.1
(C-7), 139.5 and 137.1 (2C, C-1′′ and C-1′), 132.9 (C-4a), 129.7-
127.0 (10C, OCH2Ph-6 and CH-2′-6′), 122.4 (C-8a), 112.9 and
112.7 (2C, CH-5 and CH-8), 71.3 (OCH2Ph-6), 56.7 (OCH3-7),
48.0 (CH2-3), 26.3 (CH2-4); LC-MS (APIES positive mode) m/z
344 [MH]+; HREIMS m/z 343.156 90 [M]+ (343.157 23 calcd
for C23H21NO2), 252.104 78 (252.102 45 calcd for C16H14NO2),
91.054 26 (91.054 77 calcd for C7H7).
1-P h en yl-6-h yd r oxy-7-m et h oxy-3,4-d ih yd r oisoq u in o-
lin e, 34a . The asterisk (/) indicates that the assignments were
1
made by COSY 45. H NMR* (300 MHz, CDCl3) δ 7.62 (dd, J
) 7.8, 1.6 Hz, 2H, H-2′,6′), 7.53-7.42 (m, 3H, H-3′,4′, and 5′),
6.77 (s, 1H, H-8), 6.72 (s, 1H, H-5), 3.80 (t, J ) 7.5 Hz, 2H,
CH2-3), 3.69 (s, 3H, OCH3-6), 2.76 (t, J ) 7.5 Hz, 2H, CH2-4);
13C NMR* (75 MHz, CDCl3) δ 167.4 (C-1), 145.8 (2C, C-6,7),
137.0 (C-1′), 134.1 (C-4a), 130.2 (CH-4′), 129.2 (2C, CH-2′,6′),
128.3 (2C, CH-3′,5′), 118.9 (C-8a), 114.5 (CH-5), 112.0 (CH-8),
56.1 (OCH3-7), 45.7 (CH2-3), 25.9 (CH2-4); LC-MS (APIES
positive mode) m/z 254 [MH]+, 276 [M + Na]+; HREIMS m/z
253.109 89 [M]+ (253.110 28 calcd for C16H15NO2), 237.079 77
(237.078 98 calcd for C15H11NO2), 77.038 35 (77.039 12 calcd
for C6H5).
1-P h en yl-6-ben zyloxy-3,4-d ih yd r oisoqu in olin e, 35. The
asterisk (/) indicates that the assignments were made by
COSY 45. 1H NMR* (300 MHz, CDCl3) δ 7.70 (dd, J ) 7.5, 1.5
Hz, 2H, H-2′,6′), 7.62 (td, J ) 7.5, 1.5 Hz, 1H, H-4′), 7.54 (d, J
) 7.5 Hz, 2H, H-3′,5′), 7.40 (m, 5H, OCH2Ph-6), 7.36 (d, J )
8.6 Hz, 1H, H-8), 6.97 (d, J ) 2.5 Hz, 1H, H-5), 6.90 (dd, J )
8.6, 2.5 Hz, 1H, H-7), 5.16 (s, 2H, OCH2Ph-6), 4.00 (t, J ) 7.4
Hz, 2H, CH2-3), 3.06 (t, J ) 7.4 Hz, 2H, CH2-4); 13C NMR* (75
MHz, CDCl3) δ 170.0 (C-1), 163.0 (C-6), 141.8 and 136.5 (2C,
C-1′ and C-1′′), 130.9 (C-4a), 129.1 (CH-8), 128.8-127.8 (10C,
OCH2Ph-6 and CH-2′-6′), 121.8 (C-8a), 114.6 (CH-5), 113.3
(CH-7), 70.6 (OCH2Ph-6), 47.0 (CH2-3), 27.1 (CH2-4); LC-MS
(API ES positive mode) m/z 314 [MH]+; HREIMS m/z 313.146 12
[M]+ (313.146 66 calcd for C22H19NO), 222.089 92 (222.091 89
calcd for C15H12NO), 105.034 87 (105.034 04 calcd for C7H5O),
91.056 41 (91.054 77 calcd for C7H7).
1-Ben zoyl-6-m eth oxy-7-h yd r oxyisoqu in olin e, 30a . The
asterisk (/) indicates that the assignments were made by
1
COSY 45. H NMR* (400 MHz, CDCl3) δ 8.36 (d, J ) 5.6 Hz,
1H, H-3), 7.87 (dd, J ) 7.8, 1.2 Hz, 2H, H-2′,6′), 7.63 (d, J )
5.6 Hz, 1H, H-4), 7.57 (td, J ) 7.8, 1.2 Hz, 1H, H-4′), 7.54 (s,
1H, H-8), 7.44 (t, J ) 7.8 Hz, 2H, H-3′,5′), 7.13 (s, 1H, H-5),
4.04 (s, 3H, OCH3-6); EIMS m/z (%) 279 [M]+ (87), 262 (100),
250 (90), 235 (40), 174 (10), 105 (40), 91 (73), 77 (62); HREIMS
m/z 279.089 28 [M]+ (279.089 54 calcd for C17H13NO3),
262.087 79 (262.086 80 calcd for
C17H12NO2), 105.041 08
(105.034 04 calcd for C7H5O), 77.036 57 (77.039 12 calcd for
C6H5).
1-Ben zoyl-6-ben zyloxy-7-m eth oxy-2′-h yd r oxyisoqu in o-
lin e, 31. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (400 MHz, CDCl3) δ
8.44 (d, J ) 5.4 Hz, 1H, H-3), 7.61 (d, J ) 5.4 Hz, 1H, H-4),

5068 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Bermejo et al.
1-P h en yl-6-ben zyloxy-7-m eth oxy-2′-h yd r oxy-3,4-d ih y-
d r oisoqu in olin e, 36. The asterisk (/) indicates that the
assignments were made by COSY 45, HMQC, and HMBC. 1H
NMR* (400 MHz, CDCl3) δ 7.60 (dd, J ) 8.0, 1.6 Hz, 1H, H-6′),
7.48 (dd, J ) 7.6, 1.6 Hz, 2H, H-2′′,6′′), 7.40 (t, J ) 7.6 Hz,
2H, H-3′′,5′′), 7.32 (t, J ) 7.6 Hz, 1H, H-4′′), 7.30 (dd, J ) 8.0,
1.6 Hz, 1H, H-4′), 7.16 (s, 1H, H-8), 7.05 (dd, J ) 8.0, 1.6 Hz,
1H, H-3′), 6.83 (dd, J ) 8.0, 1.6 Hz, 1H, H-5′), 6.82 (s, 1H,
H-5), 5.23 (s, 2H, OCH2Ph-6), 3.85 (s, 3H, OCH3-7), 3.70 (t, J
) 6.8 Hz, 2H, CH2-3), 2.63 (t, J ) 6.8 Hz, 2H, CH2-4); 13C
NMR* (100 MHz, CDCl3) δ 168.4 (C-1), 162.4 (C-2′), 150.4 (C-
6), 147.4 (C-7), 136.4 (C-1′′), 132.9 (C-4a), 131.6 (CH-4′), 130.2
(CH-6′), 128.6 (2C, CH-3′′,5′′), 128.1 (CH-4′′), 127.2 (2C, CH-
2′′,6′′), 120.4 (C-8a), 118.4 (CH-3′), 118.0 (C-1′), 117.1 (CH-5′),
112.8 (CH-8), 112.5 (CH-5), 70.8 (OCH2Ph-6), 56.3 (OCH3-7),
44.9 (CH2-3), 26.1 (CH2-4); EIMS m/z (%) 359 [M]+ (100), 344
(5), 328 (20), 268 (45), 238 (15); HREIMS m/z 359.151 33 [M]+
(359.152 14 calcd for C23H21NO3), 328.134 11 (328.133 75 calcd
for C22H18NO2), 268.097 79 (268.097 37 calcd for C16H14NO3),
91.054 16 (91.054 77 calcd for C7H7).
(1C, CH3(CH2)3-1); LC-MS (APIES negative mode) m/z 292
[M - 1]+, 293 [M]+. HREIMS m/z 293.177 47 [M]+ (293.177 96
calcd for C20H23NO), 251.129 06 (251.131 01 calcd for C17H17
-
NO), 202.119 68 (202.123 19 calcd for C13H16NO), 160.072 34
(160.076 24 calcd for C10H10NO), 91.049 77 (91.054 77 calcd for
C7H7), 77.033 94 (77.0391 25 calcd for C6H5).
Refer en ces
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1-Meth yl-6-ben zyloxy-7-m eth oxy-3,4-d ih yd r oisoqu in o-
lin e, 37. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (250 MHz, CDCl3) δ
7.37-7.29 (m, 5H, OCH2Ph-6), 7.15 (s, 1H, H-8), 6.81 (s, 1H,
H-5), 5.25 (s, 2H, OCH2Ph-6), 3.90 (s, 3H, OCH3-7), 3.80 (m,
2H, CH2-3), 2.95 (m, 2H, CH2-4), 2.86 (s, 3H, CH3-1); 13C NMR*
(62.5 MHz, CDCl3) δ 173.7 (C-1), 155.4 (C-6), 149.1 (C-7), 135.0
(C-1′), 132.7 (C-4a), 128.8-127.2 (5C, OCH2Ph-6), 118.1 (C-
8a), 112.2 (CH-5), 111.6 (CH-8), 71.1 (OCH2Ph-6), 56.4 (OCH3-
7), 40.7 (CH2-3), 25.1 (CH2-4), 19.6 (CH3-1); LC-MS (APIES
positive mode) m/z 282 [MH]+; HREIMS m/z 281.140 19 [M]+
(281.141 58 calcd for C18H19NO2), 190.085 40 (190.086 80 calcd
for C11H12NO2), 91.055 28 (91.054 77 calcd for C7H7).
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Cortes, D. Synthesis of N-Diisopropyl Phosphoryl Benzyltet-
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Sugi, N. H.; Nagasu, T.; Koyanagi, N.; Kitoh, K. Discovery of
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quinolines by Selective Benzylic Oxidation with C/Pd in Aceto-
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Dizier, D.; Regnier, G.; Dhainaut, A.; Bizzari, J . P.; Atassi, G.
In Vitro and in Vivo Circumvention of Multidrug Resistance by
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macology; Academc Press: New York, 1972; pp 45-89.
(16) Ammar, H. A.; Schiff, P. L., J r.; Slatkin, D. J . Synthesis of 7,7-
Dimethylaporphine Alkaloids. Heterocycles 1983, 20, 451-454.
(17) Chen, C. M.; Fu, Y. F.; Yang, T. H. Synthesis of (()-annonel-
liptine and (()-anomoline. J . Nat. Prod. 1995, 58, 1767-1771.
(18) Meyers, A. I.; Guiles, J . The asymmetric total synthesis of (+)-
reticuline. Heterocycles 1998, 28, 295-301.
(19) Dubery, I. A.; Louw, A. E.; Van-Heerden, F. R. Synthesis and
Evaluation of 4-(3-Methyl-2-butenoxy)-isonitrosoacetophenone,
a Radiation-Induced Stress Metabolite in Citrus. Phytochemistry
1999, 50, 983-989.
1-Meth yl-6-pen tan yloxy-7-m eth oxy-3,4-dih ydr oisoqu in -
olin e, 38. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (400 MHz, CDCl3-
CD3OD 90:10) δ 7.12 (s, 1H, H-8), 6.77 (s, 1H, H-5), 4.11 (m,
2H, OCH2(CH2)3CH3-6), 3.92 (s, 3H, OCH3-7), 3.69 (m, 2H,
CH2-3), 3.02 (m, 3H, CH3-1), 2.89 (m, 2H, CH2-4), 1.88-0.93
(m, 6H, OCH2(CH2)3CH3-6), 0.60 (m, 3H, O(CH2)4CH3-6); 13C
NMR* (100 MHz, CDCl3) δ 173.0 (C-1), 156.3 (C-6), 149.0 (C-
7), 133.0 (C-4a), 117.6 (C-8a), 111.6 and 111.5 (2C, CH-5 and
CH-8), 69.6 (OCH2(CH2)3CH3-6), 56.5 (OCH3-7), 40.0 (CH2-3),
28.4-25.3 (4C, OCH2(CH2)3CH3-6 and CH2-4), 22.3 (CH3-1),
13.9 (1C, O(CH2)4CH3-6); LC-MS (APIES positive mode) m/z
262 [MH]+; C16H23NO2.
1-Bu t yl-6-ben zyloxy-7-m et h oxy-3,4-d ih yd r oisoqu in o-
lin e, 39. The asterisk (/) indicates that the assignments were
1
made by COSY 45 and DEPT. H NMR* (300 MHz, CDCl3) δ
7.46-7.33 (m, 5H, OCH2Ph-6), 7.07 (s, 1H, H-8), 6.76 (s, 1H,
H-5), 5.21 (s, 2H, OCH2Ph-6), 3.89 (s, 3H, OCH3-7), 3.67 (t, J
) 7.5 Hz, 2H, CH2-3), 2.86 (t, J ) 7.3 Hz, 2H, CH3CH2CH2CH2-
1), 2.67 (t, J ) 7.5 Hz, 2H, CH2-4), 1.67 (m, 2H, CH3CH2CH2-
CH2-1), 1.45 (q, J ) 7.3 Hz, 2H, CH3CH2CH2CH2-1), 0.95 (t, J
) 7.3 Hz, 3H, CH3CH2CH2CH2-1); 13C NMR* (75 MHz, CDCl3)
δ 170.0 (C-1), 148.7 (2C, C-6,7), 136.6 (C-1′), 132.4 (C-4a), 129.1
(2C, CH-2′,6′), 128.6 (CH-4′), 127.6 (2C, CH-3′,5′), 120.0 (C-
8a), 112.9 (CH-5), 110.6 (CH-8), 71.3 (OCH2Ph-6), 56.9 (OCH3-
7), 35.2 (CH2-3), 30.2-23.0 (4C, CH3(CH2)3-1 and CH2-4), 14.3
(1C, CH3(CH2)3-1); LC-MS (APIES positive mode) m/z 323
[M]+, 322 [M - 1]+; C21H25NO2.
1-Bu tyl-6-ben zyloxy-3,4-d ih yd r oisoqu in olin e, 40. The
asterisk (/) indicates that the assignments were made by
COSY 45 and DEPT. 1H NMR* (400 MHz, CDCl3) δ 7.72 (d, J
) 8.0 Hz, 1H, H-8), 7.39-7.35 (m, 5H, OCH2Ph-6), 7.01 (dd, J
) 8.0, 1.2 Hz, 1H, H-7), 6.92 (d, J ) 1.2 Hz, 1H, H-5), 5.18 (s,
2H, OCH2Ph-6), 3.86 (t, J ) 6.7 Hz, 2H, CH2-3), 3.21 (t, J )
7.3 Hz, 2H, CH3CH2CH2CH2-1), 3.01 (t, J ) 6.7 Hz, 2H, CH2-
4), 1.73 (m, 2H, CH3CH2CH2CH2-1), 1.47 (m, 2H, CH3CH2CH2-
CH2-1), 0.93 (t, J ) 7.3 Hz, 3H, CH3CH2CH2CH2-1); 13C NMR*
(100 MHz, CDCl3) δ 177.1 (C-1), 165.2 (C-6), 140.6 (C-1′), 135.0
(C-4a), 132.1 (CH-8), 128.8-127.4 (5C, OCH2Ph-6), 117.7 (C-
8a), 115.1 (CH-7), 114.7 (CH-5), 70.6 (OCH2Ph-6), 40.4 (CH2-
3), 32.1, 31.0, and 22.5 (3C, CH3(CH2)3-1), 25.9 (CH2-4), 13.6
(20) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.; Suginome,
H. Synthesis of Phthalideisoquinoline and Protoberberine Al-
kaloids and Indolo [2,1-a]isoquinolines in a Divergent Route
Involving Palladium (O)-Catalized Carbonylation. J . Org. Chem.
1999, 64, 6583-6596.
J M020831A