Synthesis of a novel class of fatty acids-derived isoquinolines

Article abstract of DOI:10.1016/j.chemphyslip.2005.02.008

Two series of novel tetrahydroisoquinoline derivatives bearing at C-1 position a carbon chain derived from fatty acids were prepared employing two complementary synthetic methodologies. The Pictet-Spengler condensation was performed on myristyl, palmityl, stearyl and oleyl aldehydes, whereas the Bischler-Napieralski cyclization used pelargonic, stearic, linolenic and arachidonic acids. The ability to apply both methods allows further labeling of the final 1-substituted-1,2,3,4-tetrahydroisoquinolines for biological studies.

Full text of DOI:10.1016/j.chemphyslip.2005.02.008

Chemistry and Physics of Lipids 135 (2005) 131–145
Synthesis of a novel class of fatty acids-derived isoquinolines
Iwona Matuszewska, Andrzej Leniewski, Piotr Roszkowski, Zbigniew Czarnocki∗
Faculty of Chemistry, Warsaw University, Pasteur St. 1, 02-093 Warsaw, Poland
Received 19 October 2004; received in revised form 31 January 2005; accepted 9 February 2005
Available online 16 March 2005
Abstract
Two series of novel tetrahydroisoquinoline derivatives bearing at C-1 position a carbon chain derived from fatty acids were
prepared employing two complementary synthetic methodologies. The Pictet–Spengler condensation was performed on myristyl,
palmityl, stearyl and oleyl aldehydes, whereas the Bischler–Napieralski cyclization used pelargonic, stearic, linolenic and arachi-
donic acids. The ability to apply both methods allows further labeling of the final 1-substituted-1,2,3,4-tetrahydroisoquinolines
for biological studies.
© 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: N-Acyldopamines; Neurotransmitters; Lipids; Fatty acids; Parkinson disease
1. Introduction
into the brain could be greatly facilitated by linking
them to the lipophilic part of a substance that nor-
mally is able to pass through blood–brain barrier due
to its amphiphilic character (a carrier molecule). Par-
ticularly, the amide derivatives of fatty acids (bioactive
fatty acid amides) were specified as a new class of lipid
bioregulators (Shashoua and Hesse, 1996; Bezuglov
et al., 1997). Even simple long-chain amides like N-
acylethanolamines (anandamides) exhibit a wide range
of biological activity including the role as the endoge-
nous cannabinoids (Hillard et al., 1995).
There are some indications that during the
metabolism of N-acyldopamines they might be trans-
formed into the isoquinoline systems. The presence of
some tetrahydroisoquinoline alkaloids in animal neu-
ral tissues was unambiguously demonstrated (Zhu et
al., 2002). Also, dopamine-derived naturally occurring
The derivatives of biologically important amines
(e.g. catecholamines) and long-chain fatty acids have
gained considerable interest in recent years as a new
family of lipids (Boger et al., 1998). Fatty acids of dif-
ferent chain lengths and a different number of double
bonds were used to construct suitably designed deriva-
tives to study the carrier-mediated transport of cate-
cholamines (e.g. dopamine) to the brain. Due to the
presence of the blood–brain barrier, the central ner-
vous system is prevented from the entry of different
xenobiotics. The uptake of the xenobiotic molecules
∗
Corresponding author. Tel.: +48 22 8220211;
fax: +48 22 8225996.
E-mail address: czarnoz@chem.uw.edu.pl (Z. Czarnocki).
0009-3084/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.chemphyslip.2005.02.008

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I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
endogenous isoquinoline or ␤-carboline alkaloids were
examined in connection with parkinsonism (Nagatsu,
2002; Naoi et al., 1996).
(Zio´łkowski and Czarnocki, 2000; Siwicka et al.,
2002). Also recently we have developed an efficient
and very mild method for amidation of various long-
chain fatty acids (Czarnocki et al., 1998).
The present paper describes the synthesis of tetrahy-
droisoquinoline derivatives that contained a fatty acid-
derived chain that might be regarded as a new class of
lipids.
Bioactive fatty acid amides have been recently sug-
gested to play an important role in the nervous sys-
tem (Bisogno et al., 1998). Amides of polyunsatu-
rated fatty acids and dopamine were demonstrated to
induce cannabinoid-like effects in vivo (Bezuglov et
al., 2001). The possibility that neurotransmitters ex-
ist in N-acylated forms was postulated by Pokorski
and Matysiak already in 1998 (Pokorski and Matysiak,
1998). Pokorski and Czarnocki have recently shown on
the basis of radioactive labeling that N-acyldopamines
can easily move through the brain–blood barrier and
may therefore play role as pro-drugs capable to slow-
release of dopamine within the brain (Pokorski et al.,
2003).
Also, a long-chain N-acylethanolamines exhibit a
wide range of neurochemical activity thus pointing out
the role of fatty acid part of the molecule. The en-
dogenous cannabinoids: N-arachidonoylethanolamide
(anandamide) and oleoylamide may serve as represen-
tative examples. Anandamide has been recently identi-
fied as a ligand for cannabinoid receptors. These recep-
tors, whose activation is responsible for a good mood
and inhibition of adenoyl cyclase, are found in neu-
roblastoma cells and in the brain (Hillard et al., 1995).
Among other simple fatty acids amides, oleamide (cis-
9-octadecenoamide) is known as the sleep-inducting
factor and suppressor for proliferation of human breast
cancer cell. The same kind of anti-cancer activity was
postulated for arachidonoylethanolamide (Bisogno et
al., 1998). The anti-tumor and anti-inflammatory activ-
ity of the endocannabinoidal anandamide and bioactive
amides: N-palmitoylethanolamide and oleamide have
also been described (De Petrocellis et al., 2000).
As it was mentioned above, dopamine derivatives
may serve as endogenous isoquinoline precursors in
the mammalian brain (Naoi et al., 1996). On the
other hand, tetrahydroisoquinolines are very impor-
tant and interesting group of compounds because of
their biological activity, particularly in relation to
their endogenous neurotoxicity (Nagatsu, 1997). They
are among the most often synthesized natural prod-
ucts (Rozwadowska, 1994; Chrzanowska and Rozwad-
owska, 2004).
2. Experimental procedures
2.1. Instrumentation
Melting points were determined using a Boetius ap-
paratus and were uncorrected. Both 1H and 13C NMR
spectra were recorded in CDCl3 solutions (unless oth-
erwise stated) on a Varian Unity plus-500 spectrome-
ter (500 and 125 MHz, respectively) with (CH3)4Si as
the internal standard. Chemical shifts are reported in
ppm (δ) and coupling constants (J) in Hz. The sym-
bols: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) and br (broadened) are used to describe
the multiplicity and shape of signals. Numbering of
structures for the presentation of NMR data is shown
in Fig. 1. The liquid secondary ion mass spectrom-
etry (LSIMS-positive ion mode) and a high resolu-
tion MS spectra were recorded using an AMD-604
spectrometer or Micromass LCT (ESI-TOF) instru-
ment. ESI/MS/MS analyses were carried out in pos-
itive and negative modes. Samples were dissolved in
THF/MeOH/H2O (85:10:5, v/v/v) and recorded us-
ing an Esquire-LC 1.6g instrument. Dopamine hy-
drochloride (3-hydroxytyramine hydrochloride) was
purchased from Sigma–Aldrich. All reactions were
carried out under argon atmosphere. Combining ex-
tracts containing products were dried over anhydrous
In our group we have gained some experience
in the synthesis of isoquinolines and ␤-carbolines
Fig. 1. Numbering convention for presentation of NMR data in the
experimental part.

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
133
MgSO4. Solvents were removed on a vacuum rotary
evaporator at a maximum temperature of about 35 ◦C.
Chromatographic purification was performed on silica
gel MN Kieselgel 60 (70–230 mesh or 100–200 mesh,
Merck). Solvents for column chromatography were re-
distilled. TLC analyses were done on silica gel (Kiesel-
gel 60 F254, Merck) plates using iodine vapors to visu-
alize the spots.
• Starting from stearyl alcohol (1.89 g) aldehyde 2c
(1.65 g, yield 88%) was prepared. m.p. 41–43 ◦C.
Literature m.p. 43–44 ◦C; NMR and IR data (Easton
et al., 2001).
• Starting from oleyl alcohol (1.88 g) aldehyde 2d
(1.70 g, yield 91%) was prepared as a pale yellow
oil. Literature NMR and IR data (Tsay et al., 1990).
2.3. General procedure for the preparation of
1-alk(en)yl-6,7-dihydroxy-1,2,3,4-tetrahydroisoqu-
inolines (3a–3d)
2.2. General procedure for the preparation of
aldehydes (2a–2d)
To a suspension of dopamine hydrochloride 1
(0.70 g, 3.7 mmol) in 1-propanol (25 ml), an equimolar
amount of aldehyde 2a–2d (myristic, palmitic, stearic
or oleic) was added and the mixture was boiled to re-
flux with stirring under argon atmosphere for 5 h. After
cooling to room temperature, the mixture was concen-
trated under reduced pressure and the residue was chro-
matographed using chloroform–methanol-aq. ammo-
nia (9:1:0.05, v/v/v) mixture as eluent to give products
3a–3d.
Into a 100-ml round-bottomed flask provided with
a magnetic stirrer and under argon atmosphere was
placed dry dichloromethane (15 ml). The flask was im-
mersed in dry ice-acetone bath and cooled to −70 ◦C.
A sample of oxalyl chloride (0.6 ml, 7.08 mmol) was
then introduced via syringe. To the resulted mixture, a
solution of DMSO (1.0 ml) in dichloromethane (15 ml)
was slowly introduced dropwise, maintaining the tem-
perature below −50 ◦C with a continuous stirring. The
resulted mixture was again cooled down to −70 ◦C and
stirred for 15 min followed by a very slow addition of
the appropriate alcohol (7.0 mmol) in dichloromethane
(5 ml). After 15 min of the additional stirring, a solution
of triethylamine (4.7 ml) in dichloromethane (10 ml)
was added dropwise, maintaining the temperature be-
low −50 ◦C. The mixture was then stirred at −70 ◦C
for 1 h and it was left stand overnight without an exter-
nal cooling. The volatile components were then evap-
orated (caution! evolution of Me2S), taken up into a
fresh portion of dichloromethane (20 ml) and washed
successively with solutions of citric acid (5%), satu-
rated sodium bicarbonate and brine. The organic layer
was dried, evaporated and the residue was taken im-
mediately to the next step. The analytical samples of
aldehydes 2a–2d were prepared by crystallization from
hexane. The NMR data were in accordance with those
reported in the literature.
2.3.1. Data for 1-tridecyl-6,7-dihydroxy-1,2,3,4-
tetrahydroisoquinoline (3a)
Starting from myristic aldehyde 2a (0.79 g) the
product 3a (0.68 g, yield 52.6%) was obtained as a
yellowish amorphous solid following the above pro-
cedure. 1H NMR (DMSO-d6) δ 9.07 (br s, 3H-2,
two OH, NH), 6.61 and 6.55 (two s, 1H-8, 1H-5),
4.19 (t, 1H-1, J = 6.0 Hz), 3.29 and 3.10 (two m,
2H-3), 2.87 (dt, 1H-4, J1 = 16.5, J2 = 6.5 Hz), 2.73
(dt, 1H-4, J1 = 16.5, J2 = 5.5 Hz), 1.84 (m, 2H-1ꢀ),
1.44 (m, 2H-2ꢀ), 1.18–1.36 (m, 20H, 2H-3ꢀ, 2H-
4ꢀ, 2H-5ꢀ, 2H-6ꢀ, 2H-7ꢀ, 2H-8ꢀ, 2H-9ꢀ, 2H-10ꢀ, 2H-
11ꢀ, 2H-12ꢀ), 0.86 (t, 3H-13ꢀ, J = 6.8 Hz); 13C NMR
(DMSO-d6) δ 144.75, 144.12, 123.54, 122.54, 115.27,
113.17, 53.90, 39.11, 33.55, 31.28, 29.07, 29.02,
28.94, 28.87, 28.71, 24.86, 22.07, 13.89; LSIMS(+)
m/z 609, 585, 403, 348 [M + H]+, 258; HR MS
calcd. for C22H38NO2 [M + H]+: 348.2903. Found:
348.2912.
• Starting from myristyl alcohol (1.50 g) aldehyde 2a
(1.40 g, yield 94%) was prepared; m.p. 21–23.5 ◦C.
Literature m.p. 25 ◦C (Syper and Młochowski,
1984). 1H NMR (Aurell et al., 1997).
• Starting from palmityl alcohol (1.70 g) aldehyde 2b
(1.62 g, yield 96%) was prepared. m.p. 35 ◦C. Liter-
ature m.p. 35–36 ◦C (Kornblum et al., 1982), NMR
and IR spectra (Taber et al., 1987).
2.3.2. Data for 1-pentadecyl-6,7-dihydroxy-1,2,
3,4-tetrahydroisoquinoline (3b)
Starting from palmitic aldehyde 2b (0.79 g) the
product 3b (0.83 g, yield 60.0%) was obtained as a col-
1
orless oil following the above procedure. H NMR δ

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I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
8.70 (br s, 3H, two OH, NH), 6.63 (s, 2H, H-5, H-
8), 4.17 (t, 1H-1, J = 6.0 Hz), 3.33 (m, 1H-3), 3.23
(m, 1H-3), 2.89 (m, 1H-4), 2.80 (m, 1H-4), 1.81–1.98
(m, 2H-1ꢀ), 1.48 (m, 2H-2ꢀ), 1.18–1.34 (m, 24H, 2H-
2ꢀ, 2H-3ꢀ, 2H-4ꢀ, 2H-5ꢀ, 2H-6ꢀ, 2H-7ꢀ, 2H-8ꢀ, 2H-9ꢀ,
2H-10ꢀ, 2H-11ꢀ, 2H-12ꢀ, 2H-13ꢀ, 2H-14ꢀ), 0.88 (t, 3H-
15ꢀ, J = 6.8 Hz); 13C NMR δ 144.53, 143.84, 123.63,
122.96, 115.76, 113.66, 55.18, 39.74, 34.36, 31.96,
29.85, 29.80, 29.77, 29.76, 29.71, 29.67, 29.49. 29.40,
24.01, 22.71, 14.14; LSIMS(+) m/z 81, 95, 149, 164,
376 [M + H]+; HR MS calcd. for C24H42NO2 [M + H]+:
376.3216. Found: 376.3202.
2.4. General procedure for the preparation of
methyl 6,7-bis[(methoxycarbonyl)oxy]-1-alk(en)yl-
3,4-dihydro-2(1H)-isoquinolinecarboxylates
(4a–4d)
To a stirred solution of amine 3a–3d (1.50 mmol) in
dry dichloromethane (10 ml) a sample of dry pyridine
(10 ml) was added. The mixture was cooled to 0 ◦C in
an ice bath. Methyl chloroformate (1.16 ml, 15 mmol)
was added dropwise to the solution with stirring. After
removal of the cooling bath, the mixture was stirred
at room temperature for 10 h. The solvents were then
evaporated and water (20 ml) was added to the residue.
The mixture was extracted with toluene (2 × 10 ml) and
the combined toluene extracts were washed with 1%
acetic acid (6 × 5 ml) and sodium hydrogen carbonate
solution and dried. The residue, which was obtained
after evaporation was purified by column chromatog-
raphy using chloroform as eluent. Solid products were
recrystallized from hexane.
2.3.3. Data for 1-heptadecyl-6,7-dihydroxy-
1,2,3,4-tetrahydroisoquinoline (3c)
Starting from stearic aldehyde 2c (0.99 g) the prod-
uct 3c (0.79 g, yield53.1%)wasobtainedasayellowoil
following the above procedure. 1H NMR (DMSO-d6)
δ 9.08 and 8.94 (two br s, 3H, two OH, NH), 6.59 and
6.54(two s, 1H-8, 1H-5), 4.21 (t, 1H-1, J = 6.0 Hz), 3.32
(m, 1H-3), 3.14 (m, 1H-3), 2.84 (dt, 1H-4, J1 = 17.0,
J2 = 6.5 Hz), 2.74(dt, 1H-4, J1 = 17.0, J2 = 5.5 Hz), 1.82
(m, 2H-1ꢀ), 1.42 (m, 2H-2ꢀ), 1.16–1.36 (m, 28H, 2H-3ꢀ,
2H-4ꢀ, 2H-5ꢀ, 2H-6ꢀ, 2H-7ꢀ, 2H-8ꢀ, 2H-9ꢀ, 2H-10ꢀ, 2H-
11ꢀ, 2H-12ꢀ, 2H-13ꢀ, 2H-14ꢀ, 2H-15ꢀ, 2H-16ꢀ), 0.86 (t,
3H-17ꢀ, J = 6.8 Hz); 13C NMR (DMSO-d6) δ 144.73,
144.03, 123.40, 122.32, 115.12, 113.06, 53.86, 39.10,
33.42, 31.19, 28.95, 28.90, 28.81, 28.79, 28.60, 24.76,
22.00, 13.86; LSIMS(+): m/z 81, 136, 154, 164, 404
[M + H]+; HR MS calcd. for C26H46NO2 [M + H]+:
404.3529. Found: 404.3511.
2.4.1. Data for methyl 6,7-bis[(methoxycarbonyl)
oxy]-1-tridecyl-3,4-dihydro-2(1H)-isoquinolin-
ecarboxylate (4a)
Starting from 3a (0.52 g) the product 4a (0.36 g,
yield 46.6%) was obtained as a colorless solid ap-
1
plying the above procedure m.p. 56–57 ◦C. H NMR
(two stable conformers present, ratio ca. 6:5). Major
conformer: δ 7.02 and 7.00 (two broadened s, inten-
sity ratio ca. 3:1, H-8, H-5), 5.05 (dd, H-1, J1 = 7.4,
J2 = 1.8 Hz), 4.25 (dd, H-3, J1 = 13.3, J2 = 4.5 Hz), 3.90
and 3.89 (two broadened s, intensity ratio 3:4, OCOO-
CH3), 3.71 (s, NCOO-CH3), 3.18 (m, H-3), 2.93 (m,
H-4), 2.70 (m, H-4), 1.78 (m, H-1ꢀ), 1.68 (m, H-1ꢀ),
1.20–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ,
H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ), 0.88 (t, H-13ꢀ, J = 6.8 Hz);
minor conformer: δ 7.02 and 7.00 (two broadened
s, intensity ratio ca. 3:1, H-8, H-5), 5.17 (dd, H-1,
J1 = 5.6, J2 = 2.2 Hz), 4.03 (m, H-3), 3.90 and 3.89 (two
broadened s, intensity ratio 3:4, OCOO-CH3), 3.72 (s,
NCOO-CH3), 3.28 (m, H-3), 2.93 (m, H-4), 2.70 (m,
H-4), 1.78 (m, H-1ꢀ), 1.68 (m, H-1ꢀ), 1.20–1.44 (m,
H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ,
H-11ꢀ, H-12ꢀ), 0.88 (t, H-13ꢀ, J = 6.8 Hz); 13C NMR
δ 156.18, 153.43, 140.53, 140.36, 137.09, 136.93,
133.11, 132.80, 123.19, 122.91, 121.52, 121.22, 55.78,
54.34, 54.29, 52.70, 52.66, 37.46, 36.71, 36.59, 31.94,
29.70, 29.68, 29.66, 29.64, 29.56, 29.37, 28.12, 27.77,
2.3.4. 1-[(Z)-8-heptadecenyl]-6,7-dihydroxy-
1,2,3,4-tetrahydroisoquinoline (3d)
Starting from oleic aldehyde 2d (0.99 g) the prod-
uct 3d (0.90 g, yield 60.3%) was obtained as a yel-
low oil following the above procedure. 1H NMR δ
6.66 and 6.64 (two s, 2H, H-5, H-8), 5.31 (m, 2H,
H-8ꢀ, H-9ꢀ), 4.14 (m, 1H-1), 3.20–3.30 (m, 2H-3),
2.80–2.92 (m, 2H-4), 1.98 (m, 4H, 2H-7ꢀ, 2H-10ꢀ),
1.10–1.36 (m, 24H, H-1ꢀ, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ,
H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.87 (t, 3H-
17ꢀ, J = 6.8 Hz); 13C NMR δ 144.37, 143.61, 130.02,
129.64, 123.77, 122.99, 115.72, 113.68, 55.25, 39.40,
34.12, 31.94, 29.85, 29.82, 29.71, 29.59, 29.51, 29.39,
29.34, 27.30, 25.89, 25.63, 22.70, 14.12; LSIMS(+):
m/z 81, 137, 164, 178, 402 [M + H]+.

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
135
26.25, 26.24, 22.70, 14.13; LSIMS(+) m/z 280, 338,
522 [M + H]+, 1043 [2M + H]+; positive electrospray
MS m/z 446, 490, 522 [M + H]+, 544 [M + Na]+; HR
MS calcd. for C28H44NO8 [M + H]+: 522.3067. Found:
522.3053.
H-8, H-5), 5.04 (dd, H-1, J1 = 10.0, J2 = 3.3 Hz), 4.26
(dd, H-3, J1 = 12.6, J2 = 4.5 Hz), 3.90 and 3.89 (two
broadened s, intensity ratio 2:3, OCOO-CH3), 3.71 (s,
NCOO-CH3), 3.18 (m, H-3), 2.92 (m, H-4), 2.70 (m,
H-4), 1.79 (m, H-1ꢀ), 1.66 (m, H-1ꢀ), 1.22–1.44 (m,
H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ,
H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, H-
17ꢀ, J = 6.8 Hz); minor conformer: δ 7.02 and 7.00 (two
broadened s, intensity ratio ca. 5:2, H-8, H-5), 5.18
(dd, H-1, J1 = 8.8, J2 = 3.8 Hz), 4.03 (m, H-3), 3.90
and 3.89 (two broadened s, intensity ratio 2:3, OCOO-
CH3), 3.72 (s, NCOO-CH3), 3.27 (m, H-3), 2.92 (m,
H-4), 2.70 (m, H-4), 1.79 (m, H-1ꢀ), 1.66 (m, H-1ꢀ),
1.22–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-
8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ, H-
16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz); 13C NMR δ 156.17,
153.42, 140.50, 140.33, 137.20, 136.94, 133.09,
132.81, 123.17, 122.93, 121.52, 121.24, 55.78, 54.32,
52.69, 37.42, 36.68, 31.94, 29.72, 29.70, 29.57, 29.38,
28.09, 27.78, 26.27, 22.71, 14.14; LSIMS(+): m/z 107,
154, 338, 522, 578 [M + H]+, 1155 [2M + H]+; HR
MS calcd. for C32H52NO8 [M + H]+: 578.3693. Found:
578.3672.
2.4.2. Data for methyl 6,7-bis[(methoxycarbonyl)
oxy]-1-pentadecyl-3,4-dihydro-2(1H)-isoquino-
linecarboxylate (4b)
Starting from 3b (0.56 g) the product 4b (0.51 g,
yield 61.3%) was obtained as a colorless solid apply-
ing the above procedure 2.4. m.p. 63–65 ◦C. 1H NMR
(two stable conformers present, ratio ca. 10:9). Major
conformer: δ 7.02 and 7.00 (two broadened s, inten-
sity ratio ca. 5:3, H-8, H-5), 5.04 (dd, H-1, J1 = 7.8,
J2 = 1.8 Hz), 4.25 (dd, H-3, J1 = 12.6, J2 = 4.5 Hz), 3.90
and 3.89 (two broadened s, intensity ratio 3:4, OCOO-
CH3), 3.71 (s, NCOO-CH3), 3.17 (m, H-3), 2.92 (m,
H-4), 2.71 (m, H-4), 1.78 (m, H-1ꢀ), 1.67 (m, H-1ꢀ),
1.20–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-
8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ), 0.88 (t,
H-15ꢀ, J = 6.8 Hz); minor conformer: δ 7.02 and 7.00
(two broadened s, intensity ratio ca. 5:3, H-8, H-5),
5.17 (dd, H-1, J1 = 6.5, J2 = 1.4 Hz), 4.03 (m, H-3), 3.90
and 3.89 (two broadened s, intensity ratio 3:4, OCOO-
CH3), 3.72 (s, NCOO-CH3), 3.27 (m, H-3), 2.92 (m,
H-4), 2.71 (m, H-4), 1.78 (m, H-1ꢀ), 1.67 (m, H-1ꢀ),
1.20–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ,
H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ), 0.88 (t, H-
15ꢀ, J = 6.8 Hz); 13C NMR δ 156.17, 153.42, 153.35,
140.50, 140.34, 137.17, 136.92, 133.11, 132.80,
123.19, 122.90, 121.51, 121.22, 55.79, 55.77, 54.38,
54.28, 52.70, 52.67, 37.43, 36.69, 36.57, 31.94, 29.71,
29.68, 29.67, 29.64, 29.56, 29.38, 28.11, 27.76, 26.29,
26.24, 22.71, 14.13; LSIMS(+) m/z 91, 107, 136, 338,
550 [M + H]+, 572 [M + Na]+; positive electrospray
MS m/z 474, 518, 550 [M + H]+, 572 [M + Na]+; HR
MS calcd. for C30H48NO8 [M + H]+: 550.3380. Found:
550.3355.
2.4.4. Data for methyl 6,7-bis[(methoxycarbonyl)
oxy]-1-[(Z)-8-heptadecenyl]-3,4-dihydro-2(1H)-
isoquinolinecarboxylate (4d)
Starting from 3d (0.60 g) the product 4d (0.64 g,
yield 74.2%) was obtained as a yellow oil apply-
1
ing the above procedure. H NMR (two stable con-
formers present, ratio ca. 10:9). Major conformer: δ
7.02 and 7.00 (two broadened s, intensity ratio ca.
3:1, H-8, H-5), 5.35 (m, H-8ꢀ, H-9ꢀ), 5.04 (dd, H-
1, J1 = 10.0, J2 = 3.9 Hz), 4.25 (dd, H-3, J1 = 13.2,
J2 = 4.5 Hz), 3.90 and 3.89 (two broadened s, inten-
sity ratio 2:3, OCOO-CH3), 3.71 (s, NCOO-CH3), 3.17
(m, H-3), 2.91 (m, H-4), 2.70 (m, H-4), 2.01 (m, H-
7ꢀ, H-10ꢀ), 1.79 (m, H-1ꢀ), 1.65 (m, H-1ꢀ), 1.22–1.44
(m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-11ꢀ, H-12ꢀ, H-
13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz);
minor conformer: δ 7.02 and 7.00 (two broadened
s, intensity ratio ca. 3:1, H-8, H-5), 5.35 (m, H-8ꢀ,
H-9ꢀ), 5.17 (dd, H-1, J1 = 8.8, J2 = 4.2 Hz), 4.02 (m,
H-3), 3.90 and 3.89 (two broadened s, intensity ra-
tio 2:3, OCOO-CH3), 3.72 (s, NCOO-CH3), 3.27 (m,
H-3), 2.91 (m, H-4), 2.70 (m, H-4), 1.79 (m, H-1ꢀ),
2.01 (m, H-7ꢀ, H-10ꢀ), 1.79 (m, H-1ꢀ), 1.65 (m, H-
2.4.3. Data for methyl 6,7-bis[(methoxycarbonyl)
oxy]-1-heptadecyl-3,4-dihydro-2(1H)-isoquinol-
inecarboxylate (4c)
Starting from 3c (0.60 g) the product 4c (0.49 g,
yield 56.6%) was obtained as a colorless solid applying
the procedure 2.4. m.p. 68–70 ◦C. 1H NMR (two stable
conformers present, ratio ca. 6:5). Major conformer: δ
7.02 and 7.00 (two broadened s, intensity ratio ca. 5:2,

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I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
1ꢀ), 1.22–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-
11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, H-
17ꢀ, J = 6.8 Hz); 13C NMR δ 156.17, 153.42, 153.34,
140.50, 140.33, 137.15, 136.90, 133.10, 132.80,
129.99, 129.94, 129.85, 129.78, 129.04, 128.23,
125.30, 123.19, 122.92, 121.51, 121.21, 55.79, 55.78,
54.33, 54.26, 52.71, 52.67, 37.42, 36.68, 36.55, 31.91,
29.78, 29.76, 29.53, 29.46, 29.33, 29.29, 28.10, 27.74,
27.23, 26.28, 26.22, 22.70, 14.13; LSIMS(+) m/z 95,
109, 280, 338, 576 [M + H]+; positive electrospray
MS m/z 500, 544, 576 [M + H]+, 598 [M + Na]+; HR
MS calcd. for C32H50NO8 [M + H]+: 576.3536. Found:
576.3508.
1.18–1.36 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ,
H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ), 0.88 (t, H-13ꢀ, J = 6.8 Hz);
13C NMR major conformer δ 156.89, 143.30, 142.29,
129.40, 125.35, 114.76, 113.63, 55.08, 53.08, 38.40,
36.74, 31.94, 29.72, 29.69, 29.68, 29.64, 29.59, 29.38,
27.64, 26.34, 22.70, 14.13; minor conformer δ 156.89,
143.30, 142.53, 129.98, 125.83, 115.28, 113.48, 54.59,
52.86, 37.80, 36.88, 31.94, 29.72, 29.69, 29.68, 29.64,
29.59, 29.38, 27.43, 26.31, 22.70, 14.13; LSIMS(+):
m/z 137, 154, 222, 406 [M + H]+, 811 [2M + H]+; pos-
itive electrospray MS m/z 331, 374, 406 [M + H]+,
428 [M + Na]+, 811 [2M + H]+, 833 [2M + Na]+;
negative electrospray MS m/z 329, 372, 404
[M-H]-.
2.5. General procedure for the preparation of
methyl 1-alk(en)yl-6,7-dihydroxy-3,4-dihydro-
2(1H)-isoquinolinecarboxylates (5a–5d)
2.5.2. Data for methyl 1-pentadecyl-6,
7-dihydroxy-3,4-dihydro-2(1H)-isoqui-
nolinecarboxylate (5b)
A solution of isoquinolinecarboxylate 4a–4d
(0.80 mmol) in dry methanol (25 ml), containing 1 ml
of 25% aqueous solution of ammonia, was allowed
to stand overnight at 5 ◦C. The reaction mixture
was then evaporated in vacuo to dryness and the
residue was chromatographed using chloroform and
chloroform–methanol mixture (96:4, v/v) to give col-
orless solids. The crude products were subsequently
recrystallized from hexane-cyclohexane to collect
5a–5d.
Starting from 4b (0.44 g) the product 5b (0.21 g,
yield 61.7%) was obtained applying the above proce-
dure. m.p. 127–128 ◦C; 1H NMR (two stable conform-
ers present, ratio ca. 7:3). Major conformer: δ 7.46 and
5.66 (two br s, two OH), 6.63 and 6.61 (two s, H-8,
H-5), 5.00 (dd, H-1, J1 = 9.4, J2 = 4.5 Hz), 3.94 (m,
H-3), 3.77 (s, NCOO-CH3), 3.33 (m, H-3), 2.78 (m,
H-4), 2.63 (dt, H-4, J1 = 15.8, J2 = 3.8 Hz), 1.72 (m, H-
1ꢀ), 1.63 (m, H-1ꢀ), 1.16–1.40 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-
5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ,
H-14ꢀ), 0.88 (t, H-15ꢀ, J = 6.8 Hz); minor conformer:
δ 6.06 and 5.69 (two br s, two OH), 6.59 and 6.58
(two s, H-8, H-5), 4.91 (dd, H-1, J1 = 9.0, J2 = 4.7 Hz),
4.12 (m, H-3), 3.72 (s, NCOO-CH3), 3.20 (m, H-3),
2.78 (m, H-4), 2.54 (dt, H-4, J1 = 15.4, J2 = 4.0 Hz),
1.72 (m, H-1ꢀ), 1.63 (m, H-1ꢀ), 1.16–1.40 (m, H-2ꢀ,
H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-
11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ), 0.88 (t, H-15ꢀ, J = 6.8 Hz);
13C NMR: major conformer δ 156.85, 143.42, 142.24,
129.45, 125.42, 114.74, 113.62, 55.06, 53.05, 38.39,
36.75, 31.94, 29.73, 29.69, 29.68, 29.64, 29.59, 29.38,
27.65, 26.34, 22.71, 14.13; minor conformer δ 156.74,
143.42, 142.35, 130.20, 126.03, 115.33, 113.53, 54.51,
52.79, 37.72, 36.89, 31.94, 29.73, 29.69, 29.68, 29.64,
29.59, 29.38, 27.42, 26.29, 22.71, 14.13; LSIMS(+)
m/z 222, 434 [M + H]+, 867 [2M + H]+; negative elec-
trospray MS m/z 357, 400, 432 [M − H]; HR MS
calcd. for C26H44NO4 [M + H]+: 434.3270. Found:
434.3258.
2.5.1. Data for methyl 1-tridecyl-6,7-dihydroxy-
3,4-dihydro-2(1H)-isoquinolinecarboxylate (5a)
Starting from 4a (0.42 g) the product 5a (0.20 g,
yield 62.8%) was obtained applying the above pro-
1
cedure m.p. 124–125 ◦C; H NMR (two stable con-
formers present ratio ca. 2:1). Major conformer: δ
7.57 and 5.88 (two br s, two OH), 6.63 and 6.61
(two s, H-8, H-5), 5.00 (dd, H-1, J1 = 9.2, J2 = 5.3 Hz),
3.94 (dt, H-3, J1 = 13.7, J2 = 4.4 Hz), 3.76 (s, NCOO-
CH3), 3.32 (m, H-3), 2.77 (m, H-4), 2.62 (dt, H-4,
J1 = 15.8, J2 = 3.8 Hz), 1.72 (m, H-1ꢀ), 1.63 (m, H-
1ꢀ), 1.18–1.36 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-
7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ), 0.88 (t, H-13ꢀ,
J = 6.8 Hz); minor conformer: δ 6.52 and 6.03 (two br
s, two OH), 6.59 and 6.56 (two br s, H-8, H-5), 4.89
(dd, H-1, J1 = 9.0, J2 = 4.0 Hz), 4.10 (m, H-3), 3.73
(s, NCOO-CH3), 3.20 (m, H-3), 2.77 (m, H-4), 2.54
(dt, H-4, J1 = 5.5 Hz), 1.72 (m, H-1ꢀ), 1.63 (m, H-1ꢀ),

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
137
2.5.3. Data for methyl 1-heptadecyl-6,
7-dihydroxy-3,4-dihydro-2(1H)-isoquino-
linecarboxylate (5c)
5), 6.36 and 5.90 (two br s, two OH), 5.33 (m, H-
8ꢀ, H-9ꢀ), 4.90 (dd, H-1, J1 = 9.3 J2 = 2.2 Hz), 4.10
(m, H-3), 3.73 (s, NCOO-CH3), 3.21 (m, H-3), 2.78
(m, H-4), 2.54 (m, H-4), 2.00 (m, H-7ꢀ, H-10ꢀ), 1.72
(m, H-1ꢀ), 1.63 (m, H-1ꢀ), 1.18–1.42 (m, H-2ꢀ, H-3ꢀ,
H-4ꢀ, H-5ꢀ, H-6ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ,
H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz); 13C NMR major
conformer δ 156.88, 143.43, 142.33, 130.01,129.84,
129.46, 129.45, 125.40, 114.80, 113.65, 55.06, 53.04,
38.43, 36.75, 31.92, 29.78, 29.59, 29.54, 29.48, 29.34,
29.33, 27.67, 27.24, 27.22, 26.30, 22.69, 14.11; minor
conformer δ 156.88, 142.50, 130.01,129.84, 129.46,
129.45, 125.84, 115.31, 113.52, 54.60, 5.82, 37.85,
36.91, 31.92, 29.78, 29.59, 29.54, 29.48, 29.34, 29.33,
27.43, 27.24, 27.22, 26.30, 22.69, 14.11;LSIMS(+)m/z
107, 137, 472, 482 [M + Na]+, 504 [M + H+2Na]+; neg-
ative electrospray MS m/z 458 [M-H]-; positive elec-
trospray MS m/z 460 [M + H]+, 482 [M + Na]+; HR
MS calcd. for C28H46NO4 [M + H]+: 460.3427. Found:
460.3406.
Staring from 4c (0.46 g) the product 5c (0.26 g,
yield 69.5%) was obtained applying the above pro-
1
cedure. m.p. 116–119 ◦C; H NMR (two stable con-
formers present ratio ca. 2:1). Major conformer: δ
7.33 and 5.63 (two br s, two OH), 6.63 and 6.61
(two s, H-8, H-5), 5.01 (dd, H-1, J1 = 9.7, J2 = 5.5 Hz),
3.93 (m, H-3), 3.76 (s, NCOO-CH3), 3.32 (m, H-
3), 2.79 (m, H-4), 2.03 (m, H-4), 1.57–1.80 (m,
H-1ꢀ), 1.16–1.40 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ,
H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-
14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz); mi-
nor conformer: δ 6.59 (s, H-5 and H-8), 5.94 and
5.63 (two br s, two OH), 4.91 (dd, H-1, J1 = 9.0,
J2 = 4.7 Hz), 4.12 (dt, H-3, J1 = 10.8, J2 = 2.7 Hz), 3.72
(s, NCOO-CH3), 3.20 (m, H-3), 2.79 (m, H-4), 2.55
(dt, H-4, J1 = 15.4, J2 = 1.8 Hz), 1.57–1.80 (m, H-
1ꢀ), 1.16–1.40 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-
7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ,
H-15ꢀ, H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz); 13C NMR
major conformer δ 156.80, 142.21, 129.54, 125.47,
114.75, 113.69, 55.02, 53.00, 38.37, 36.76, 31.94,
29.73, 29.60, 29.38, 27.67, 26.32, 22.70, 14.13; minor
conformer δ 156.80, 143.34, 130.30, 126.26, 115.34,
113.63, 54.52, 52.72, 37.65, 36.76, 31.94, 29.73,
29.60, 29.38, 27.36, 26.32, 22.70, 14.13; LSIMS(+):
m/z 107, 222, 462 [M + H]+, 923 [2M + H]+; nega-
tive electrospray MS m/z 385, 428, 460 [M-H]−, pos-
itive electrospray MS m/z 460, 462 [M + H]+, 484
[M + Na]+.
2.6. General procedure for the preparation of
methyl 1-alk(en)yl-6,7-dimethoxy-3,4-dihydro-
2(1H)-isoquinolinecarboxylates (6a–6d)
Substrates 5a–5d were dried overnight in a vac-
uum dessicator over phosphorous pentoxide before
the reaction. To a stirred solution of compound
5a–5d (0.50 mmol) in dry acetone (50 ml), contain-
ing anhydrous potassium carbonate (1.0 g), a sam-
ple of iodomethane (3.0 ml) was added in two por-
tions during 1 h under reflux. After 4 h the mix-
ture was cooled, filtered and the filtrate was concen-
trated in vacuo. The residue was subjected to col-
umn chromatography on silica gel. Elution with chlo-
roform gave products as yellow oils, crystallizing
on standing. The crude products were recrystallized
from hexane giving pure compounds 6a–c as colorless
solids.
2.5.4. Data for methyl 1-[(Z)-8-heptadecenyl]-6,
7-dihydroxy-3,4-dihydro-2(1H)-isoquinolineca-
rboxylate (5d)
Starting from 4d (0.46 g) the product 5d (0.26 g,
yield 71.0%) was obtained applying the above proce-
dure. m.p. 96–99 ◦C; 1H NMR (two stable conformers
present, ratio ca. 2:1). Major conformer: δ 7.42 and
5.81 (two br s, two OH), 6.62 and 6.61 (two s, H-
8, H-5), 5.33 (m, H-8ꢀ, H-9ꢀ), 5.00 (dd, H-1, J1 = 8.2,
J2 = 5.2 Hz), 3.93 (m, H-3), 3.76 (s, NCOO-CH3), 3.32
(m, H-3), 2.78 (m, H-4), 2.62 (m, H-4), 2.00 (m, H-
7ꢀ, H-10ꢀ), 1.72 (m, H-1ꢀ), 1.63 (m, H-1ꢀ), 1.18–1.42
(m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-11ꢀ, H-12ꢀ, H-
13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz);
minor conformer: δ 6.59 and 6.58 (two s, H-8, H-
2.6.1. Data for methyl 1-tridecyl-6,7-dimethoxy-
3,4-dihydro-2(1H)-isoquinolinecarboxylate (6a)
Starting from 5a (0.20 g) the product 6a (0.15 g,
yield 68.0%) was obtained applying the above pro-
1
cedure. m.p. 99–101 ◦C; H NMR (two stable con-
formers present, ratio ca. 1:1) δ 6.66, 6.64, 6.56
and 6.53 (four s, H-5, H-8), 5.07 and 4.95 (two dd,

138
I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
cedure. m.p. 58–60 ◦C; 1H NMR (two stable con-
formers present, ratio ca. 1:1) δ 6.59, 6.57 and 6.55
(three s, intensity ratio 2:1:1, H-5, H-8), 5.10 and
4.97 (two dd, H-1, J1 = 9.3, J2 = 5.0 and J1 = 9.9,
J2 = 3.9 Hz, respectively), 4.23, 4.01, 3.29 and 3.20
(dd and three m, H-3), 3.86 and 3.85 (two s, two
CH3), 3.72 (br s, CH3), 2.87 and 2.62 (two m,
H-4), 1.77 and 1.68 (two m, H-1ꢀ), 1.20–1.42 (m,
H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-
10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88
(t, H-17ꢀ, J = 6.8 Hz); 13C NMR δ 156.32, 147.33,
130.32, 129.94, 126.00, 125.66, 111.55, 111.36,
110.13, 109.82, 56.02, 55.89, 54.54, 54.38, 52.53,
52.51, 37.95, 37.27, 36.89, 36.73, 31.94, 29.72,
29.69, 29.67, 29.63, 29.50, 29.37, 28.08, 27.77, 26.41,
26.34, 22.70, 14.14; LSIMS(+) m/z 81, 95, 250,
490 [M + H]+; positive electrospray MS m/z 165,
208, 458, 490 [M + H]+, 512 [M + Na]+; HR MS
calcd. for C30H51NNaO4 [M + Na]+: 512.3716. Found:
512.3700.
H-1, J1 = 9.2, J2 = 4.9 and J1 = 9.7, J2 = 3.7 Hz, re-
spectively), 4.18, 3.95, 3.29 and 3.20 (four m, H-
3), 3.86 (s, two CH3), 3.72 (s, CH3), 2.74–2.94
and 2.61 (two m, H-4), 1.77 and 1.67 (two m,
H-1ꢀ), 1.20–1.44 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-
6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ), 0.88
(t, H-13ꢀ, J = 6.8 Hz); 13C NMR δ 156.35, 144.95,
144.15, 144.06, 129.77, 129.43, 126.79, 126.51,
114.46, 114.20, 109.43, 109.07, 56.06, 54.67, 54.48,
52.59, 52.52, 38.08, 37.38, 37.08, 36.90, 31.93,
29.70, 29.68, 29.66, 29.62, 29.50, 29.37, 27.84,
27.53, 26.41, 26.32, 22.70, 14.14; LSIMS(+) m/z
151, 236, 250, 434 [M + H]+, 456 [M + Na]+; posi-
tive electrospray MS m/z 151, 163, 359, 420; neg-
ative electrospray MS m/z 386, 403, 418; HR MS
calcd. for C26H43NNaO4 [M + Na]+: 456.3090. Found:
456.3080.
2.6.2. Data for methyl 1-pentadecyl-6,7-dimeth-
oxy-3,4-dihydro-2(1H)-isoquinoline carboxylate
(6b)
Starting from 5b (0.22 g) the product 6b (0.18 g,
yield 76.3%) was obtained applying the above proce-
2.6.4. Data for methyl 1-[(Z)-8-heptadecenyl]-6,
7-dimethoxy-3,4-dihydro-2(1H)-isoquin-
olinecarboxylate (6d)
1
dure. m.p. 62–63 ◦C; H NMR (two stable conform-
ers present, ratio ca. 1:1) δ 6.59, 6.58 and 6.55 (three
s, H-5, H-8), 5.10 and 4.97 (two dd, H-1, J1 = 9.0,
J2 = 5.0 and J1 = 9.5, J2 = 3.7 Hz, respectively), 4.24,
4.00, 3.29 and 3.20 (four m, H-3), 3.86 and 3.84
(two s, CH3), 3.72 (br s, CH3), 2.87 (m, H-4), 2.62
(dt, H-4, J1 = 15.9, J2 = 3.2 Hz), 1.62–1.84 (m, H-1ꢀ),
1.20–1.40 (m, H-2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-
8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ), 0.88
(t, H-15ꢀ, J = 6.8 Hz); 13C NMR δ 156.31, 147.34,
130.32, 129.95, 126.00, 125.67, 111.56, 111.37,
110.14, 109.84, 56.03, 56.01, 55.89, 55.88, 54.52,
54.39, 52.55, 37.95, 37.28, 36.89, 36.74, 31.94, 29.71,
29.68, 29.67, 29.62, 29.50, 29.37, 28.09, 27.77, 26.41,
26.34, 22.70, 14.13; LSIMS(+) m/z 250, 462 [M + H]+,
923 [2M + H]+; positive electrospray m/z 165, 208,
387, 430, 462 [M + H]+, 484 [M + Na]+; HR MS
calcd. for C28H47NNaO4 [M + Na]+: 484.3403. Found:
484.3427.
Starting from 5d (0.23 g) the product 6d (0.19 g,
yield 78.5%) was obtained as a colorless oil applying
the above procedure. H NMR (two stable conform-
1
ers present, ratio 11:10) δ 6.59, 6.57 and 6.55 (three
s, intensity ratio 2:1:1, H-5, H-8), 5.34 (m, H-8ꢀ, H-
9ꢀ), 5.10 and 4.97 (two dd, H-1, J1 = 10.2, J2 = 3.5
and J1 = 8.9, J2 = 4.6 Hz, respectively), 4.23 (dd, H-3,
J1 = 13.3, J2 = 4.2 Hz), 4.01, 3.28 and 3.20 (three m, H-
3), 3.86 and 3.85 (two s, two CH3), 3.72 and 3.71 (two s,
CH3), 2.79–2.95 and 2.59–2.66 (two m, H-4), 2.01 (m,
H-7ꢀ, H-10ꢀ), 1.64–1.82 (m, H-1ꢀ), 1.22–1.46 (m, H-
2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ,
H-15ꢀ, H-16ꢀ), 0.88 (t, H-17ꢀ, J = 6.8 Hz); 13C NMR
δ 156.31, 147.65, 147.53, 147.33, 130.29, 129.99,
129.93, 129.86, 129.78, 125.99, 125.65, 111.54,
111.35, 110.11, 109.80, 56.01, 55.88, 54.52, 54.37,
52.59, 52.53, 37.93, 37.27, 36.89, 36.73, 31.91, 29.77,
29.60, 29.53, 29.47, 29.33, 29.31, 29.27, 28.08, 27.76,
27.23, 27.21, 26.40, 26.33, 22.69, 14.13;LSIMS(+)m/z
165, 250, 488 [M + H]+, 510 [M + Na]+, 975 [2M + H]+;
positive electrospray MS m/z 165, 208, 413, 428, 488
[M + H]+, 510 [M + Na]+, 997 [2M + Na]+; HR MS
calcd. for C30H49NNaO4 [M + Na]+: 510.3559. Found:
510.3554.
2.6.3. Data for methyl 1-heptadecyl-6,7-dimeth-
oxy-3,4-dihydro-2(1H)-isoquinoline carboxylate
(6c)
Staring from 5c (0.23 g) the product 6c (0.20 g,
yield 81.7%) was obtained applying the above pro-

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
139
J2 = 1.9 Hz, 1H-6ꢀ), 6.72 (br s, 1H-2ꢀ), 5.66 (br s,
NH), 3.87 and 3.86 (two s, 6H-OCH3), 3.50 (q,
J = 6.8 Hz, 2H-1ꢀꢀ), 2.77 (t, J = 6.8 Hz, 2H-2ꢀꢀ), 2.14
(t, J = 7.7 Hz, 2H-2), 1.59 (quintet, J = 7.5, 2H-3),
1.20–1.32 (m, 28H, H-4, H-5, H-6, H-7, H-8, H-
9, H-10, H-11, H-12, H-13, H-14, H-15, H-16, H-
17), 0.88 (t, J = 6.9 Hz, 3H-18); 13C NMR δ 173.43,
149.02, 147.67, 131.35, 120.63, 111.83, 111.27, 55.90,
55.85, 40.73, 36.76, 35.26, 31.94, 29.72, 29.70, 29.68,
29.65, 29.52, 29.38, 29.31, 25.85, 22.71, 14.15; pos-
itive electrospray MS m/z 470 [M + Na]+; HR MS
calcd. for C28H49NNaO3 [M + Na]+: 470.3610. Found:
470.3605.
2.7. General procedure for the preparation of
N-[2-(3,4-dimethoxyphenyl)ethyl]amides (9e–9g)
and( 9c)
To a stirred mixture of homoveratrylamine 7
(1.09 g, 6.00 mmol) in dry THF (50 ml) BOP (2.65 g,
6.00 mmol) and an equimolar amount of acid 8e–8g or
8c (pelargonic, stearic, linolenic or arachidonic) were
added. The mixture was then stirred at room tempera-
ture for 10 min, cooled to 5 ◦C and a solution of triethy-
lamine (2.5 ml) in THF (10 ml) was added dropwise.
The cooling bath was then removed and the solution
was stirred at room temperature for 12 h. The volatiles
were then evaporated and brine (20 ml) and diethyl
ether (150 ml) were added to the residue. The aque-
ous layer was extracted with ether and the combined
extracts were washed with saturated sodium hydrogen
carbonate solution, dried and evaporated to dryness.
The residue was subjected to column chromatography
using chloroform–methanol (98:2, v/v) mixture as elu-
ent. The solid products were recrystallized from diethyl
ether-hexane to give pure compounds 9e–9g or 9c, re-
spectively with yields 84–88%.
2.7.3. Data for (9Z,12Z,15Z)-N-[2-(3,4-dimethox-
yphenyl)ethyl]octadeca-9,12,15-trienamide (9f)
Starting from linolenic acid 8f (1.67 g) the product
9f (2.25 g, yield 85.0%) as a yellow oil was obtained
1
following the procedure 2.7. H NMR δ 6.81 (dAB
,
J = 7.7 Hz, 1H-5ꢀ), 6.73 (ddAB, J1 = 7.7, J2 = 1.6 Hz,
1H-6ꢀ), 6.72 (br s, 1H-2ꢀ), 5.48 (br t, NH), 5.28–5.43
(m, 6H, H-9, H-10, H-12, H-13, H-15, H-16), 3.87
and 3.86 (two s, 6H-OCH3), 3.50 (q, J = 6.7 Hz, 2H-
1ꢀꢀ), 2.71–2.83 (m, 6H, 2H-11, 2H-14, 2H-2ꢀꢀ), 2.12
(t, J = 7.7 Hz, 2H-2), 2.05 (m, 4H, 2H-8, 2H-17),
1.59 (apparent quintet, 2H-3), 1.23–1.38 (m, 8H, 2H-
4, 2H-5, 2H-6, 2H-7), 0.97 (t, J = 6.9 Hz, 3H-18));
13C NMR δ 173.10, 149.04, 147.68, 131.97, 131.43,
130.25, 128.30, 128.24, 127.74, 127.10, 120.63,
111.87, 111.31, 55.91, 55.87, 40.62, 36.86, 35.32,
29.60, 29.27, 29.13, 27.20, 25.77, 25.62, 25.53, 20.55,
14.29; positive electrospray MS m/z 905 [2M + Na]+,
883 [2M + H]+, 480 [M+K]+, 464 [M + Na]+, 442
[M + H]+.
2.7.1. Data for N-[2-(3,4-dimethoxyphenyl)ethyl]-
nonanamide (9e)
Starting from pelargonic acid 8e (0.95 g) the prod-
uct 9e (1.62 g, yield 84.0%) was prepared following the
1
procedure 2.7. m.p. 73–75 ◦C; H NMR δ 6.81 (dAB
,
J1 = 7.8 Hz, 1H-5ꢀ), 6.73 (ddAB, J1 = 7.8, J2 = 1.7 Hz,
1H-6ꢀ), 6.72 (br s, 1H-2ꢀ), 5.43 (br s, NH), 3.87 and
3.88 (two s, 6H-OCH3), 3.50 (q, J = 6.8 Hz, 2H-1ꢀꢀ),
2.76 (t, J = 6.8 Hz, 2H-2ꢀꢀ), 2.12 (t, J = 7.6 Hz, 2H-2),
1.60 (m, 2H-3), 1.20–1.35 (m, 10H, H-4, H-5, H-6, H-
7, H-8), 0.88 (t, J = 6.8 Hz, 3H-9); 13C NMR δ 173.16,
149.04, 147.68, 131.47, 120.64, 111.88, 111.32, 55.91,
55.87, 40.62, 36.89, 35.33, 31.83, 29.33, 29.31, 29.16,
25.80, 22.65, 14.10; positive electrospray MS m/z 665
[2M + Na]+, 360 [M+K]+, 322 [M + H]+; HR MS calcd.
for C38H62N2NaO6 [2M + Na]+: 665.4506. Found:
665.4522.
2.7.4. Data for (5Z,8Z,11Z,14Z)-N-[2-(3,4-dime-
thoxyphenyl)ethyl]icosa-5,8,11,14-tetraenamide
(9g)
Starting from arachidonic acid 8g (1.83 g) the
product 9g (2.47 g, yield 88.0%) as an oil was ob-
1
tained following the procedure 2.7. m.p. <20 ◦C. H
2.7.2. Data for N-[2-(3,4-dimethoxyphenyl)-
ethyl]octadecanamide (9c)
Starting from stearic acid 8c (1.71 g) the prod-
uct 9c (2.27 g, yield 84.9%) was prepared follow-
ing the procedure 2.7. m.p. 93–95 ◦C; 1H NMR δ
6.81 (dAB, J1 = 8.0 Hz, 1H-5ꢀ), 6.73 (ddAB, J1 = 8.0,
NMR δ 6.81 (dAB, J = 7.7 Hz, 1H-5ꢀ), 6.72–6.75 (m,
2H, H-6ꢀ, H-2ꢀ), 5.29–5.46 (m, 9H, H-5, H-6, H-
8, H-9, H-11, H-12, H-14, H-15, NH), 3.87 and
3.86 (two s, 6H-OCH3), 3.50 (q, J = 6.7 Hz, 2H-
1ꢀꢀ), 2.74–2.86 (m, 8H, H-2ꢀꢀ, H-7, H-10, H-13),
2.02–2.18 (m, 6H, H-2, H-4, H-16), 1.69 (quin-

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I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
tet, J = 7.6 Hz, 2H-3), 1.22–1.40 (m, 6H, H-17, H-
18, H-19), 0.89 (t, J = 6.8 Hz, 3H-20); 13C NMR
δ 172.77, 149.07, 147.71, 131.38, 130.54, 129.11,
128.76, 128.62, 128.25, 128.16, 127.85, 127.52,
120.62, 111.86, 111.33, 55.93, 55.87, 40.65, 36.17,
35.33, 31.52, 29.33, 27.23, 26.68, 25.64, 25.55,
22.58, 14.09; positive electrospray MS m/z 934
[2M + H]+, 490 [M + Na]+, 468 [M + H]+; HR MS
calcd. for C30H45NNaO3 [M + Na]+: 490.3297. Found:
490.3307.
2.8.2. Data for 1-heptadecyl-6,7-dimethoxy-3,4-
dihydroisoquinoline (10c)
Starting from amide 9c (0.90 g) compound 10c
(0.47 g, yield 55.3%) was isolated as a yellow oil
following the procedure 2.8. 1H NMR δ 7.02 (s,
H-8), 6.71 (s, H-5), 3.93 and 3.91 (two s, 6H,
OCH3), 3.66 (t, J = 7.7 Hz, 2H-3), 2.75 (t, J = 7.5 Hz,
2H-1ꢀ or 2H-4), 2.66 (t, J = 7.7 Hz, 2H-4 or 2H-
1ꢀ), 1.67 (quintet, J = 7.5 Hz, 2H-2ꢀ), 1.40 (m, 2H-
3ꢀ), 1.19–1.36 (m, 26H, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ, H-
8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ, H-14ꢀ, H-
15ꢀ, H-16ꢀ), 0.88 (t, J = 6.8 Hz, 3H-17ꢀ); 13C NMR
δ 167.12, 150.87, 147.60, 131.82, 122.12, 110.53,
109.06, 56.42, 56.11, 47.08, 36.30, 32.10, 29.70,
29.68, 29.66, 29.64, 29.57, 29.55, 29.46, 29.37, 27.41,
26.09, 22.86, 14.29; positive electrospray MS m/z 430
[M + H]+.
2.8. General procedure for the preparation of 1-
alk(en)yl-6,7-dimethoxy-3,4-dihydroisoquinolines
(10e–10g) and( 10c)
Phosphorus pentachloride (0.41 g, 3.0 mmol) was
added to the cooled to 0 ◦C dry dichloromethane
(20 ml), containing amide 9e–9g or 9c (2.0 mmol). The
solutionwasstirredfor20 minandthenthecoolingbath
was removed. The mixture was stirred at room temper-
ature under argon atmosphere for 6 h and subsequently
wasaddedtoasolutionof1.50 g(18.0 mmol)ofsodium
hydrogen carbonate in water (20 ml). This mixture was
stirredfor 5 min and then the layerswere separated. The
aqueous layer was extracted twice with 20-ml portions
of dichloromethane. The combined organic extracts
were washed with brine (30 ml) and dried. The residue,
whichwasobtainedafterevaporation, wasthenpurified
by column chromatography using 3% (v/v) methanol
in chloroform as eluent. The imines thus obtained were
quite unstable and should be taken immediately to the
next step.
2.8.3. Data for 1-[(8Z,11Z,14Z)-heptadeca-8,
11,14-trienyl]-6,7-dimethoxy-3,4-dihydroisoq-
uinoline (10f)
Starting from amide 9f (0.88 g) compound 10f
(0.53 g, yield 62.5%) was isolated as a colorless oil
following the procedure 2.8. 1H NMR δ 6.71 and 6.70
(two s, 2H, H-5 and H-8), 5.35–5.51 (m, 6H, H-8ꢀ, H-
9ꢀ, H-11ꢀ, H-12ꢀ, H-14ꢀ, H-15ꢀ), 3.92 and 3.91 (two
s, 6H, OCH3), 3.88 and 3.73 (two m, 2H-3), 2.78
(m, 4H, 2H-10ꢀ, 2H-13ꢀ), 2.63 (m, 4H, 2H-4 and 2H-
1ꢀ), 2.09 (m, 4H, 2H-7ꢀ, 2H-16ꢀ), 1.58 (m, 4H, 2H-
2ꢀ, 2H-6ꢀ), 1.36 (m, 6H, 2H-3ꢀ, 2H-4ꢀ, 2H-5ꢀ), 0.97
(t, J = 7.0 Hz, 3H-17ꢀ); 13C NMR δ 164.25, 151.08,
147.39, 132.17, 131.98, 130.23, 128.30, 128.29,
127.76, 127.10, 120.11, 110.42, 108.87, 56.28, 55.97,
47.27, 36.88, 35.28, 29.71, 29.61, 29.11, 27.19, 26.89,
25.68, 25.60, 20.56, 14.29; positive electrospray MS
m/z 424 [M + H]+.
2.8.1. Data for 1-octyl-6,7-dimethoxy-3,
4-dihydroisoquinoline (10e)
Starting from amide 9e (0.64 g) the product 10e
(0.41 g, yield 67.8%) was isolated as a yellow oil fol-
1
lowing the procedure 2.8. H NMR δ 7.03 (s, 1H-8),
2.8.4. Data for 1-[(4Z,7Z,10Z,13Z)-nonadeca-4,
7,10,13-tetraenyl]-6,7-dimethoxy-3,4-dihydro-
isoquinoline (10g)
The conversion of amide 9g (0.94 g) into imine
10g was effected following the procedure 2.8. The
chromatographically pure compound 10g (0.85 g,
94.8% yield) was obtained as very unstable yellow
oil. The product without spectral investigations was
immediately reduced in the next step into amine
11g.
6.72 (s, 1H-5), 3.94 (s, 3H-OCH3), 3.91 (s, 3H-OCH3),
3.69 (t, J = 7.7 Hz, 2H-4), 2.79 (t, J = 7.7 Hz, 2H-3 or
2H-1ꢀ), 2.68 (t, J = 7.7 Hz, 2H-3 or 2H-1ꢀ), 1.60–1.70
(m, 2H-2ꢀ), 1.20–1.42 (m, 10H, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ,
H-7ꢀ), 0.88 (t, J = 7.0 Hz, 3H-8ꢀ); 13C NMR δ 169.64,
151.91, 147.70, 132.14, 120.84, 110.50, 109.50, 56.29,
56.07, 44.77, 34.87, 31.88, 29.45, 29.41, 29.32, 27.82,
25.83, 22.66, 14.11; positive electrospray MS m/z 304
[M + H]+; HR MS calcd. for C19H30NaO2 [M + H]+:
304.2277. Found: 304.2284.

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
141
H-14ꢀ, H-15ꢀ, H-16ꢀ), 0.88 (t, J = 6.8 Hz, 3H-17ꢀ);
13C NMR δ 147.61, 147.43, 129.66, 126.26, 111.63,
109.24, 56.02, 55.86, 55.04, 40.28, 36.01, 35.34, 31.94,
29.77, 29.72, 29.67, 29.65, 29.60, 29.56, 29.42, 29.37,
28.34, 25.94, 25.41, 22.70, 14.13; positive electro-
spray MS m/z 454 [M + Na]+, 432 [M + H]+; HR MS
calcd. for C28H50NO2 [M + H]+: 432.3842. Found:
432.3825.
2.9. General procedure for preparation of
1-alk(en)yl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinolines (11e–11g) and( 11c)
To a stirred and cooled (0 ◦C) solution of imine
10e–10f or 10c (1.0 mmol) in ethanol (5 ml), NaBH4
(0.25 g, 6.6 mmol) was added in two portions. Af-
ter removing of the cooling bath, the reaction mix-
ture was stirred at room temperature for 2 h. Water
(10 ml) was then added to the solution and ethanol
was evaporated under reduced pressure. The aqueous
layer was extracted with three portions (5 ml each) of
dichloromethane and the combined organic extracts
were washed with brine (10 ml), dried and evaporated.
The residue was subjected to column chromatography
using 5–8% (v/v) methanol in chloroform as eluent.
Compounds 11e–11g and 11c were isolated as pale yel-
low oils.
2.9.3. Data for 1-[(8Z,11Z,14Z)-heptadeca-8,11,
14-trienyl]-6,7-dimethoxy-1,2,3,4-tetrahydroi-
soquinoline (11f)
Starting from imine 10f (0.42 g) compound 11f
(0.35 g, 83.2% yield) was isolated following the pro-
cedure 2.9. 1H NMR δ 6.60 and 6.57 (two s, H-8 and
H-5), 5.50–5.58 and 5.28–5.44 (two m, 1H and 5H,
H-8ꢀ, H-9ꢀ, H-11ꢀ, H-12ꢀ, H-14ꢀ, H-15ꢀ), 3.97 (m, 1H-
1), 3.85 (s, 6H-OCH3), 3.27 and 3.01 (two m, 2H-4),
2.54–2.86 (m, 6H, 2H-4, 2H-10ꢀ, 2H-13ꢀ), 2.07 (m,
4H, 2H-7ꢀ, 2H-16ꢀ), 1.70–1.90 (m, 3H), 1.256–1.55
(m, 10H), 0.97 (t, J = 7.5 Hz, 3H-17ꢀ); 13C NMR
δ 147.42, 147.29, 131.97, 130.32, 128.29, 128.26,
127.70, 127.11, 126.71, 124.43, 111.71, 109.20, 56.03,
55.83, 55.42, 40.88, 36.34, 29.80, 29.66, 29.54, 29.31,
28.94, 27.25, 26.17, 25.62, 25.53, 20.56, 14.29.
Positive electrospray MS m/z 448 [M + Na]+, 426
[M + H]+;HR MS calcd. for C28H44NO2 [M + H]+:
426.3372. Found: 426.3362.
2.9.1. Data for 1-octyl-6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinoline (11e)
Starting from imine 10e (0.30 g) compound 11e
(0.27 g, 88.8% yield) was isolated following the pro-
cedure 2.9. 1H NMR δ 6.62 and 6.57 (two s, 2H,
H-5 and H-8), 3.90 (m, H-1), 3.85 and 3.84 (two s,
6H, OCH3), 3.23 (dt, 1H, J1 = 12.3, J2 = 5.4 Hz, H-
3), 2.97 (ddd, 1H, J1 = 12.6, J2 = 7.9, J3 = 5.5 Hz, H-
3), 2.60–2.80 (m, 2H-4), 2.16 (br s, NH), 1.63–1.78
and 1.46–1.61 (two m, 2H-1ꢀ), 1.14–1.46 (m, 12H, H-
2ꢀ, H-3ꢀ, H-4ꢀ, H-5ꢀ, H-6ꢀ, H-7ꢀ), 0.86 (t, J = 7.0 Hz,
3H-8ꢀ); 13C NMR δ 147.23, 147.16, 131.51, 127.09,
111.73, 109.21, 56.01, 55.83, 55.46, 41.09, 35.85,
31.91, 30.20, 29.70, 29.40, 29.15, 26.27, 22.99, 14.07;
positive electrospray MS m/z 306 [M + H]+; HR MS
calcd. for C19H32NO2 [M + H]+: 306.2433. Found:
306.2444.
2.9.4. Data for 1-[(4Z,7Z,10Z,13Z)-nonadeca-4,7,
10,13-tetraenyl]-6,7-dimethoxy-1,2,3,4-tetrahyd-
roisoquinoline (11g)
Starting from imine 10g (0.45 g) compound 11g
(0.36 g, 79.1% yield) was isolated following the proce-
dure 2.9. 1H NMR δ 6.60 and 6.57 (two s, 1H-8 and 1H-
5), 5.37 (m, 8H, H-4ꢀ, H-5ꢀ, H-7ꢀ, H-8ꢀ, H-10ꢀ, H-11ꢀ,
H-13ꢀ, H-14ꢀ), 3.85 (s, 6H-OCH3), 3.96 (m, 1H-1), 3.22
(br s, NH), 2.52–3.01 (m, 10H, H-3, H-4, H-6ꢀ, H-9ꢀ, H-
12ꢀ), 2.00–2.25(m, 4H, H-3ꢀ, H-15ꢀ), 1.45–1.93(m, 4H,
H-1ꢀ, H-2ꢀ), 1.15–1.45 (m, 6H, H-16ꢀ, H-17ꢀ, H-18ꢀ),
0.89 (t, J = 7.0 Hz, 3H-19ꢀ); 13C NMR δ 147.33, 147.24,
131.14, 130.50, 129.92, 128.57, 128.32, 128.13,
127.89, 127.53, 127.04, 111.76, 109.20, 56.02, 55.84,
55.36, 41.06, 35.96, 31.52, 29.33, 27.23, 26.8, 25.70,
25.65, 22.58, 14.09; LSIMS(+) m/z 474 [M + Na]+, 452
[M + H]+; HR MS calcd. for C30H45NNaO2 [M + Na]+:
474.3348. Found: 474.3371.
2.9.2. Data for 1-heptadecyl-6,7-dimethoxy-1,2,3,
4-tetrahydroisoquinoline (11c)
Starting from imine 10c (0.43 g) compound 11c
(0.33 g, 77.0% yield) was isolated following the pro-
cedure 2.9. 1H NMR δ 6.60 and 6.57 (two s, 1H-
8 and 1H-5), 4.03 (dd, J1 = 8.8, J2 = 3.9 Hz, 1H-1),
3.86 and 3.85 (two s, 6H-OCH3), 3.48 (br s, NH),
3.30 (dt, 1H), 3.04 (m, 1H) and 2.70–2.86 (m, 2H)
(2H-3 and 2H-4), 1.72–1.90 (m, 2H-1ꢀ), 1.58 (quin-
tet, 2H-2ꢀ), 1.18–1.52 (m, 28H, H-3ꢀ, H-4ꢀ, H-5ꢀ,
H-6ꢀ, H-7ꢀ, H-8ꢀ, H-9ꢀ, H-10ꢀ, H-11ꢀ, H-12ꢀ, H-13ꢀ,

142
I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
Fig. 2. Some biologically active 1-substitute-1,2,3,4-tetrahydroisoquinoline.
3. Results and discussion
We have already successfully applied this approach
for the radio-labeling of dopamides and we concluded
that N-oleoyl-dopamine (the analogue of compounds
9c, and 9e–9f) had an appreciable ability to cross the
blood–brain barrier (Pokorski et al., 2003). Our study
suggested a potential pharmacological role for exoge-
nously delivered selected dopamides in helping reg-
ulate the brain function and that N-oleoyl-dopamine
might enhance the normally limited dopamine trans-
port into the brain, which would be of therapeutic po-
tential in the pathological states characterized by de-
ranged brain neurotransmitter profile.
Aldehydes 2a–2d were prepared from commer-
cially available alcohols using the Swern oxidation
methodology (Mancuso and Swern, 1981) following
the procedure optimized by us for the oxidation of other
primary alcohols (Czarnocki et al., 1986).1 Dopamine
was then subjected to the Pictet–Spengler reaction
with aldehydes 2a–2d in boiling 1-propanol to afford
directly 1-substituted-1,2,3,4-tetrahydroisoquinolines
3a–3d in isolated 52–60% yield (Scheme 1).
Alkaloids and their analogues possessing 1-subst-
ituted tetrahydroisoquinoline skeleton include sev-
eral biologically active compounds as (S)-salsolidine,
(S)-calycotomine, (S)-laudanosine, and (S)-xylopinine
(Fig. 2). Therefore, the synthesis of these compounds,
recently also in stereoselective manner, has attracted
much attention of several research groups.
Among a variety of methods available for the
construction of tetrahydroisoquinoline skeleton, es-
pecially two of them seem to be most of-
ten applied: the Pictet–Spengler condensation and
the Bischler–Napieralski cyclization (Rozwadowska,
1994; Chrzanowska and Rozwadowska, 2004). Both
methods involve the use of different starting materials
and processes with different intermediates.
Planning further in vivo investigations with regiose-
lectively radio-labeled substrates, we found both meth-
ods very promising in planned incorporation of the ra-
dioactivity into selected parts of the molecule.
The Pictet–Spengler reaction is the most frequently
used method in the chemistry of isoquinolines. In
this process dopamine 1 is reacted, sometimes under
very mild biomimetic conditions with the carbonyl
compound (often aldehyde), furnishing directly the
1-substituted-1,2,3,4-tetrahydroisoquinoline skeleton.
The product contains two phenolic groups that allow
the introduction of tritium atoms into the aromatic ring.
Compounds 3a–3d proved to be relatively prone to
aerial oxidation and slow decomposition, probably due
to the presence of two phenolic groups and secondary
amine functionality. In order to increase the stability of
the molecule, both phenolic groups were methylated
1
The conditions of Swern oxidation ensures the stability of very
sensitive components.

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
143
Scheme 1. The synthesis of tetrahydroisoquinoline via the Pictet–Spengler reaction.
by a two-step procedure. Thus, the treatment of 3a–3d
with an excess of methyl chloroformate in the presence
of pyridine gave per-acyl derivatives 4a–4d in fair to
good yields after purification by column chromatogra-
phy and crystallization.
The removal of the carbonate protecting groups was
performed via ammonolysis under very mild condi-
tions to afford amides 5a–5d that were immediately
di-O-methylated with methyl iodide in the presence
of potassium carbonate to give final 1-substituted-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines 6a–6d
in good isolated yields.
polyphosphoric acid) to give 3,4-dihydroisoquinoline
or dihydroisoquinolinium salt, subsequently reduced
by complex metal hydrides or by hydrogenation to af-
ford 1,2,3,4-tetrahydroisoquinolines. In our case, we
started from homoveratrylamine and the appropriate
fatty acid 8e–8g to form amides 9e–9g in a mild,
BOP-mediated coupling (Czarnocki et al., 1998). This
method was chosen to ensure optimal yield of the prod-
uct and chemical and stereochemical stability of the
acid used. Also, the subsequent cyclization was opti-
mized to eliminate unwanted transformations of sensi-
tive parts of the molecules (Scheme 2).
The Bischler–Napieralski cyclization constitutes
another important method for the construction of
isoquinoline skeleton (Rozwadowska, 1994; Chrza-
nowskaandRozwadowska, 2004). Startingfromdiffer-
ent substrates, employing different reagents and going
through another types of intermediate compounds, the
method provides an important, complementary alter-
native to the former approach, also in respect of con-
sidered labeling experiments.
Upon treatment with phosphorous pentachloride in
dichloromethane at 0 ◦C, amides 9e–9g gave relatively
unstable imines 10e–10g in fair yields in a pure form
without any contamination of chlorinated products.2
The imine double bond in compounds 10e–10g gives
not only the possibility to introduce the radioactive la-
beling (e.g. by the reduction with NaB3H4) but also
2
We observed that compounds 10e–10g were quite sensitive to-
Usually, arylethylamides of carboxylic acids were
treated with acidic reagents (e.g., POCl3, PCl5,
wards air oxidation and moisture and should be taken immediately
to the next step.

144
I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
Scheme 2. The synthesis of tetrahydroisoquinoline via the Bischler–Napieralski reaction.
provides a prochiral environment for the enantioselec-
tive synthesis. When reduced with sodium borohydride
in ethanol, imines 10e–10g afforded secondary amines
11e–11ginover80%isolatedyields. Thesecompounds
appeared quite stable and could be stored without ob-
servable decomposition at room temperature except in
the case of amine 11g, which should be kept in the cold.
The most indicative and significant absorption in the
NMR spectra in both series 6a–6d and 11e–11g were
attributed to carbon and hydrogen in methoxy groups
and the aromatic ring. In the series of amides both
signals of proton and the C-1 carbon atoms appeared
deshieldedintheregion4.9–5.2and52.7–55.2 ppm, re-
spectively. Absorptions of methoxy substituents in all
final compounds at 55.8–56.1 ppm for 13C NMR and
The conformer ratio in the series of compounds var-
ied from about 1:1 in 4a–4d, through 2:1 in 5a–5d,
back to ca. 1:1 in 6a–6d, that reflects the increasing
polarity of interacting substituents.
1
Since a temperature dependent H NMR experi-
ments did not give a conclusive answer, we had to rely
on the room temperature spectra. Thus, in the case of
the spectrum of compound 4a, we observed three pairs
of “one-proton” signals: doublet of doublets at 5.05 and
5.17 ppm (H-1 in both conformers), multiplets at 4.25
and 4.03 (H-3), and multiplets at 3.18 and 3.28 ppm
(H-3). The integration ratios of all former signals ver-
sus the later ones in all three pairs were approximately
in the same order (6:5). On the other hand, the singlets
at 3.90 and 3.89 ppm (OCOOCH3, four methyl groups)
were located too close to each other to allow direct in-
tegration comparison. The same was also observed in
the case of signals at 3.71 and 3.72 ppm (NCOOCH3),
as well as for signals at 7.02 and 7.00 ppm (H-5 and
H-8).
1
3.84–3.95 ppm for H NMR in the form of isolated
peaks seem to be quite characteristic and may serve as
a future reference for analogues.
The interpretation of both 1H and 13C NMR spec-
tra in the series of compounds 4a–4d, 5a–5d, and
6a–6d was not straightforward. The inspection of com-
plicated patterns of signals has prompted us to as-
sume the presence of two relatively stable (with re-
spect to the NMR time scale) conformers in CDCl3
solution. It seems quite clear that restricted rotation
around the amide bond in all twelve 1-substituted iso-
quinolinecarboxylates might be responsible for the ob-
served phenomenon. Alternatively, a steric type A in-
teraction in 1,2-arrangement of methoxycarbonyl and
alk(en)yl substituents may generate relatively stable ro-
tamers (Eliel and Wilen, 1994).
4. Conclusions
Two series of novel tetrahydroisoquinoline deriva-
tives bearing at C-1 atom a carbon chain derived
from fatty acids were prepared employing two comple-
mentary synthetic methodologies: the Pictet–Spengler
condensation and the Bischler–Napieralski cycliza-
tion. The ability to use both methods allows our fur-
ther experiments for various labeling of the final 1-

I. Matuszewska et al. / Chemistry andPhysics of Lipids 135 (2005) 131–145
145
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studies. These will involve the determination of the
brain uptake and distribution of lipophilic dopamine
and isoquinoline derivatives that can freely penetrate
the blood–brain barrier and serve as slow-release pre-
cursor of dopamine which play a crucial role in devel-
oping different pathologic states like Parkinson’s dis-
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