First total syntheses of the 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines annoretine and litebamine

Article abstract of DOI:10.1016/S0040-4020(03)01135-9

We describe here the first total synthesis of the two natural 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines, annoretine and litebamine, from [2-(2-styrylphenyl)ethyl]methylcarbamic acid ethyl esters. The key steps were the Bischler-Napieralski cyclization

Full text of DOI:10.1016/S0040-4020(03)01135-9

Tetrahedron 59 (2003) 8057–8065
First total syntheses of the
1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines annoretine
and litebamine
a
M. Carme Pampın, Juan C. Estevez, Ramon J. Estevez, Rafael Suau and Luis Castedo
a
a
b
a
,
*
´
´
´
´
a
´
´
Departamento de Quımica Organica, Universidade de Santiago, E-15782 Santiago de Compostela, Spain
´ ´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Malaga, E-29071 Malaga, Spain
b
Received 15 January 2003; revised 4 July 2003; accepted 22 July 2003
Abstract—We describe here the first total synthesis of the two natural 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines, annoretine and
litebamine, from [2-(2-styrylphenyl)ethyl]methylcarbamic acid ethyl esters. The key steps were the Bischler–Napieralski cyclization to form
the isoquinoline unit and photocyclization of the resulting 2-methyl-5-styryl-3,4-dihydro-2H-isoquinolin-1-ones to 2-methyl-3,4-dihydro-
2H-naphtho[2,1-f]isoquinolin-1-ones.
q 2003 Elsevier Ltd. All rights reserved.
Isoquinolines have received considerable attention because
derivatives of the isoquinoline ring system have been
identified as the major structural motifs in a wide range of
natural compounds of chemical and biological interest.1
However, surprisingly, naphtho[2,1-f]isoquinolines (2-aza-
chrysenes) have received very little attention2 and the
corresponding tetrahydro derivatives (1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinolines) have not been considered prior
to the recent report concerning the isolation of the only two
natural members of this family—litebamine (1b)3 and
annoretine (1a).4
isoquinolines,9 we describe here the first total synthesis of
annoretine10 and litebamine, an exercise that allowed us to
corroborate structures proposed for these natural com-
pounds and to establish a promising method for the large
scale preparation of these and other 1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinolines for chemical and biological
studies.
Our synthetic strategy was based on a sequential construc-
tion of rings C and A, starting from styrylphenylethyl-
urethanes 3 (Scheme 1); these latter compounds contain a
convenient stilbene-like unit for construction of the ring
system of phenanthrenes 2 and so final transformation of
these intermediates into the target compounds 1 should be
achieved by Bischler–Napieralski cyclization, followed by
demethylation and reduction. Alternatively, ring A could be
constructed first, giving 5-styrylisoquinolines 4,7c which
could then be transformed into naphthoisoquinolines 1 by
electrocyclic cyclization followed by demethylation and
reduction.
Litebamine was the first phenanthrenic alkaloid isolated
from Litsea cubeba and its activity as a platelet anti-
aggregant5 and against acetyl choline esterase6 have been
described. Subsequent partial syntheses of litebamine from
the aporphine boldine led to the hypothesis of biogenetic
degradation of aporphines to 1,2,3,4-tetrahydronaphtho[2,1-
f]isoquinolines.7 Annoretine was isolated from the leaves of
Annona montana and it possesses significant cytotoxic
activity against different human cell cultures such as KB, P-
388, A-549 and HT-29.4 No other partial or total synthesis
of these new isoquinoline alkaloids has been reported to
date.
We first studied the preparation of annoretine (1a) starting
from o-styrylphenylethylurethane 3a, which was prepared
by Heck11 coupling of the appropriate halobenzene 5c to
styrene (6a) (Scheme 2). A solution of homoveratrylamine
(5a), ethyl chloroformate and Et3N was stirred at rt for 16 h
to afford the N-carbethoxy derivative 5b in 93% yield. This
compound was subsequently transformed into iodobenzene
In relation to a previous paper8 on this journal and given our
previous exploratory work on the synthesis of naphtho[2,1-f]-
12
derivative 5c in 99% yield after treatment with IPy2BF4
Keywords: Bischler–Napieralski cyclization; demethylation; Heck
reaction; isoquinoline; photocyclization.
and CF3SO3H. When a deoxygenated solution of 5c, styrene
(6a), triethylamine, triphenylphosphine and palladium
acetate was heated at 1008C in a sealed tube for 24 h, the
*
Corresponding author. Tel.: þ34-981-563100x14242; fax: þ34-981-
591014; e-mail: qorjec@usc.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01135-9

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8058
Scheme 1.
desired disubstituted o-styrylphenylethylurethane 3a was
obtained in 70% yield together with 17% of the correspond-
ing a-coupled alkene 7a. The mass spectrum of 3a
confirmed the expected molecular weight (m/z¼355) and
the E configuration of the stilbene double bond was easily
plausible mechanism for the formation of phenanthrene 12
involves electron transfer from the disubstituted aromatic
ring to the unsubstituted ring of 8b, which leads to a cation-
radical/anion-radical (9a) that can also be described by
resonance structures 9b and 9c. The latter species is a
stabilized diradical, the presence of which could explain the
formation of dihydrophenanthrene 10. Oxidation of this
compound by iodine to 11, followed by the concomitant
expulsion of the alkyl chain, allows an aromatization
process to occur and give compound 12.
1
established from its H NMR spectrum, which showed a
doublet at 6.90 ppm (1H, J¼16.1 Hz) due to one proton on
the double bond. The doublet corresponding to the other
vinylic proton was located in one of the complex signals due
to aromatic protons.
We next studied the photochemically induced electrocyclic
cyclization13 of styrylphenylethylurethane 3a in order to
obtain the corresponding phenanthrenylethylurethane 2a
(Scheme 1). However, irradiation of 3a with a 450 W
Hanovia medium-pressure lamp equipped with a Pyrex filter
did not give 2a, but did produce phenanthrene 12 as a
consequence of the removal of the ethylurethane chain of 3a
(Scheme 3).
This unexpected result led us to explore the aforementioned
alternative synthesis of annoretine (1a) from 3a via 5-
styrylisoquinoline 4a (Scheme 1). After an initial
unsuccessful attempt to promote Bischler–Napieralski
cyclization of 3a to 4a with Tf2O (Scheme 4),14 compound
3a was converted into its N-methyl derivative 3b (Scheme 3)
and this was subjected to the above Bichler–Napieralski
cyclization conditions. This reaction readily furnished the
expected 5-styrylisoquinolinone 4b in 77% yield.
The positions of the methoxy substituents on the resulting
phenanthrene 12 clearly show that this compound results
from the cyclization of cis-stilbene 8b through position C(1)
instead of the desired cyclization through position C(3). A
In the next step of our programme the photolysis of
styrylisoquinoline 4b was studied (Scheme 4).9b Irradiation
of this compound under the same conditions as for 3a gave
Scheme 2. (i) Et3N, ClCO2Et, dry CH2Cl2, argon, 08C–.rt, 16 h. (ii) CF3CO2H, IPy2BF4, dry CH2Cl2, argon, 08C, 30 min. (iii) K2CO3, dry DMF, 2-
bromopropane, rt, 48 h. (iv) n-BuLi, CH2vPPhþ3 Br2, THF, argon, 08C–.rt, 4 h. (v) Pd(OAc)2, Ph3P, Et3N, dry MeCN, argon, 808C, 24 h. (vi) (a) NaH, dry
THF, argon, rt, 30 min; MeI, argon, rt, 3 h.

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8059
Scheme 3. (i) UV light, I2, Et2O/CH2Cl2, rt, 5 h.
the expected naphthoisoquinolinone 13a with the tetracyclic
framework of annoretine—which was identified from its
analytical and spectroscopic data. The mass spectrum of this
compoundconfirmedthemolecularmass(Mþ, m/z¼321), two
units less than the starting material. In addition, the 1H NMR
spectrum showed signals for a total of six aromatic protons,
including a multiplet for a proton at 9.67–9.70 ppm due to the
hydrogen at C(10), which is highly deshielded due to steric
interaction with the methoxy substituent at position C(11).
Transformation of naphthoisoquinolinone 13a into annor-
etine was accomplished in a two-step sequence starting with
treatment of 13a with BCl3 at rt during 15 min,15 which led
to compound 16a as a result of regiospecific demethylation
of the methoxy substituent at C(12). Clear evidence for this
process was provided by spectroscopic data—particularly
the H NMR spectrum, which showed a highly deshielded
singlet for one proton at 13.05 ppm. This signal was
assigned to the proton of the hydroxy substituent.
1
Scheme 4. (i) Tf2O, DMAP, dry CH2Cl2, 08C–.rt, 21 h. (ii) UV light, I2, Et2O, rt, 3 h. (iii) BCl3, CH2Cl2, rt, 15 min. (iv) LiAlH4, THF, 08C–.rt, 5 h.

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8060
The marked downfield chemical shift for this proton, due to
its interaction with the carbonyl group, allowed us to
establish that demethylation had occurred at the desired
position. This conclusion was further supported by HMQC
and HMBC experiments, which show a correlation between
the OH proton and carbon atoms C(12a) and C(11), together
with a correlation between the methoxy substituent and the
carbon at C(11) (Fig. 1).
hydroxy group masked as the isopropoxy derivative, a
relatively uncommon protecting group for phenols that is
able to resist the basic, acidic and photochemical conditions
required in this synthesis. The protecting group can be
removed with boron trichloride.18
Treatment of isovanillin (6b) with isopropyl bromide under
basic conditions gave an excellent yield of the correspond-
ing benzaldehyde 6c, which was then converted into the
desired styrene 6d in 93% yield by means of a Wittig
reaction involving treatment of 6c with Ph3PCH3Br and n-
BuLi in THF at rt for 4 h.19 Salient signals in the 1H NMR
spectrum of this compound are two doublet of doublets at
5.58 ppm (J¼17.6, 0.9 Hz) and 6.61 ppm (J¼17.6,
10.9 Hz), together with a doublet at 5.11 ppm, all due to
the protons of the double bond. Subsequent Heck coupling
of iodophenylethylurethane 5c to styrene 6d under the
conditions used for the preparation of 3a allowed us to
obtain a 3:1 mixture of compounds 3c and 7b, the expected
compounds corresponding to the b and a coupling,
Figure 1. Important 1H–13C couplings observed in the HMQC and HMBC
experiments of compound 16a.
1
These correlations clearly indicate that the hydroxy
substituent is located between the carbonyl group and the
methoxy substituent. Furthermore, the main conclusion of
the nOe experiments is that irradiation of the proton at C-10
gives a 5% nOe with the methoxy group and a 2% nOe with
the proton of the hydroxy group.
respectively (global yield 72%). The H NMR spectrum
of 3c contained complex groups of signals corresponding to
the five aromatic protons and the protons of the double
bond. In addition, signals for the aliphatic protons were
observed, including a broad singlet at 4.87 ppm due to the
proton of the NH group. Stilbene 3c was subsequently
reacted with methyl iodide and the resulting N-methyl
derivative 3d was then subjected to the previously described
Bischler–Napieralski cyclization conditions to give the
expected styrylisoquinolinone 4c in 87% yield. Photolysis
of this compound under the conditions described for 4b gave
a 41% yield of naphthoisoquinolinone 13b. This compound
was easily identified from its analytical and spectroscopic
data—particularly from its 1H NMR spectrum, which
showed signals for a total of four aromatic protons (two
fewer than the starting material) including the expected
singlet at 9.26 ppm corresponding to the highly deshielded
proton at C(10).
Selective demethylation of the methoxy substituent at
C(12) can be explained as being the result of the initial
interaction between naphthoisoquinolinone 13a and
BCl3, which leads to a coordination complex 14 in
which the boron atom is coordinated with oxygen atoms
of the carbonyl and methoxy groups; attack on such a
complex by a chloride ion gives a second boron
complex 15, hydrolysis of which furnished the resulting
phenolic naphthoisoquinoline 16a.16
Finally, reduction of compound 16a with LiAlH4 provided
annoretine (1a) in 63% yield. The structure of this
compound was unequivocally confirmed by an X-ray
diffraction experiment (Fig. 2).17
The next step in the planned route involved the
selective demethylation of the methoxy group at C-12
and removal of the isopropyl group at C-8. These
transformations were achieved in a single step when
compound 13b was reacted with BCl3 in dichloro-
methane for 15 min, as described above. Finally,
litebamine (1b) was obtained in 57% yield by reduction
of 16b with LiAlH4 and its structure was unequivocally
confirmed by X-ray diffraction (Fig. 3).20
Figure 2. ORTEP drawing of annoretine (1a).
We next decided to apply the above strategy to the synthesis
of litebamine (1b). This tetrasubstituted 1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinoline possesses two hydroxy groups
(at positions C(8) and C(12)) and we envisaged that only the
latter hydroxy substituent could be generated by a selective
demethylation similar to that used for annoretine (1a). We
therefore decided to start with styrene 6d (Scheme 2), with a
Figure 3. ORTEP drawing of litebamine (1b).

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8061
In summary, we have developed a total synthesis of 1,2,3,4-
tetrahydronaphtho[2,1-f]isoquinolines that has allowed us to
carry out the first total synthesis of annoretine and litebamine.
We would like to highlight the contribution that this study
represents in the chemistry of 5-styrylisoquinolines, which
have hitherto received very little attention.
5.860 mmol) and IPy2BF4 (2.4 g, 6.450 mmol) in dry
dichloromethane (15 mL) at 08C. Stirring was continued
for a further 30 min under argon. The reaction mixture was
poured into saturated sodium thiosulfate, the resulting
suspension was extracted with dichloromethane (3£25 mL),
and the combined organic extracts were washed with water,
dried, filtered and concentrated in vacuo. The resulting solid
residue was purified by column chromatography (eluant: 1:1
ethyl acetate/hexane) to give iodo derivative 5c (2.205 g,
99% yield) as a white solid. Mp 76–788C (methanol). IR
Work is now in progress to prepare a range of non-natural
1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines for chemical
and biological studies.
1
(n, cm21, NaCl): 3345 (–NH), 1683 (CO). H NMR (d,
ppm): 7.19(s, 1H, ArH), 6.74(s, 1H, ArH), 5.12 (bs, 1H, –NH),
4.11 (q, J¼7.1 Hz, 2H, –OCH2CH3), 3.83 (s, 3H, –OCH3),
3.82 (s, 3H, –OCH3), 3.42–3.34 (m, 2H, –CH2–), 2.90–2.84
(m, 2H, –CH2–), 1.22 (t, J¼7.1 Hz, 3H, –OCH2CH3). 13C
NMR (d, ppm): 156.35 (CO); 148.97 (ArOCH3); 147.78
(ArOCH3); 133.57 (C); 121.29 (ArH); 112.34 (ArH); 87.77
(C); 60.34 (–OCH2CH3); 55.78 (–OCH3); 55.55 (–OCH3);
40.66 (–CH2–); 39.96 (–CH2–); 14.39 (–OCH2CH3). MS
(m/z, %): 379 (Mþ, 44), 277 (100). Anal. calcd for
C13H18INO4, C 41.18, H 4.78, I 33.47, N 3.69; found, C
40.96, H 4.89, I 33.12, N 3.85.
1. Experimental
1.1. General
Melting points were determined on a Kofler Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear
magnetic resonance spectra, unless otherwise specified,
were recorded on a Bruker WM-250 apparatus using
deuterochloroform solutions containing tetramethylsilane
as internal standard. Mass spectra were obtained on a
Kratos MS 50 TC mass spectrometer. Thin layer
chromatography (TLC) was performed using Merck GF-
254 type 60 silica gel and dichloromethane/methanol
mixtures as eluant; the tlc spots were visualized with
ultraviolet light or iodine vapour. Column chromato-
graphy was carried out using Merck type 9385 silica gel.
Solvents were purified according to Ref. 21. Solutions of
extracts in organic solvents were dried with anhydrous
sodium sulfate.
1.1.3. [2-(4,5-Dimethoxy-2-styrylphenyl)ethyl]carbamic
acid ethyl ester (3a). A deoxygenated mixture of iodo-
phenylethylamine derivative 5c (1 g, 2.635 mmol), styrene
(0.605 mL, 5.270 mmol), palladium acetate (59 mg,
0.263 mmol, 10% molar), triphenylphosphine (138 mg,
0.572, 20% molar) and triethylamine (0.441 mL,
3.162 mmol) in dry acetonitrile (14 mL) was heated in a
sealed tube at 808C for 24 h under argon. The suspension
was filtered through celite, the filtrate was washed with
water (50 mL), dried and concentrated in vacuo. The
resulting oily residue was purified by column chromato-
graphy (eluant: 99:1 dichloromethane/methanol) to give
1.1.1. [2-(3,4-Dimethoxyphenyl)ethyl]carbamic acid
ethyl ester (5b). Triethylamine (14.5 mL, 110 mmol) and
then ethyl chloroformate (7.2 mL, 75.038 mmol) were
added dropwise under argon to a solution of homoveratryl-
amine (5a) (4 g, 22.070 mmol) in dry dichloromethane
(25 mL) at 08C. The mixture was stirred for 16 h under
argon at rt. The reaction mixture was concentrated in vacuo,
the residue was suspended in water (25 mL) and the
suspension was extracted with dichloromethane (3£20 mL).
The combined organic extracts were washed with water,
dried, filtered and concentrated in vacuo. The resulting oily
residue was purified by column chromatography (eluant: 1:1
ethyl acetate/hexane) to give compound 5b (5.198 g, 93%
yield) as a white solid. Mp 53–558C (methanol). IR
compound 3a (571 mg, 70% yield) as an oil. IR (n, cm21
,
NaCl): 3370 (–NH), 1713 (CO). 1H NMR (d, ppm): 7.53–
7.50 (m, 2H, 2£ArH), 7.37–7.19 (m, 4H, 4£ArH), 7.12
(s, 1H, ArH), 6.90 (d, J¼16.0 Hz, 1H, –CHvCH–), 6.65
(s, 1H, ArH), 4.94 (m, 1H, –NH), 4.04 (q, J¼7.0 Hz, 2H,
–OCH2CH3), 3.91 (s, 3H, –OCH3), 3.85 (s, 3H, –OCH3),
3.37–3.32 (m, 2H, –CH2–), 2.94–2.88 (m, 2H, –CH2–),
1.24 (t, J¼7.0 Hz, 3H, –OCH2CH3). 13C NMR (d, ppm):
155.44 (CO), 148.54 (ArOCH3), 147.58 (ArOCH3), 137.36
(C), 129.35 (C), 128.40 (3£ArH), 128.33 (C), 127.15 (ArH),
126.14 (2£ArH), 125.19 (ArH), 112.72 (ArH), 108.19
(ArH),60.40(–OCH2CH3), 55.67(–OCH3), 55.61(–OCH3),
41.91 (–CH2–), 32.87 (–CH2–), 14.34 (–OCH2CH3). MS
(m/z, %): 355 (Mþ, 31), 253 (100). HRMS: C21H25NO4
(Mþ), calcd 355.1784; found 355.1782.
(n, cm21, NaCl): 3304 (–NH), 1683 (CO). H NMR (d,
1
ppm): 6.80–6.69 (m, 3H, 3£ArH), 5.27 (bs, 1H, –NH), 4.08
(q, J¼7.0 Hz, 2H, –OCH2CH3), 3.84 (s, 3H, –OCH3), 3.82
(s, 3H, –OCH3), 3.42–3.34 (m, 2H, –CH2–), 2.77–2.71
(m, 2H, –CH2–), 1.20 (t, J¼7.0 Hz, 3H, –OCH2CH3). 13
C
Further elution allowed us to isolate compound 7a (139 mg,
17% yield) as an oil. IR (n, cm21, NaCl): 3365 (–NH), 1715
(CO). 1H NMR (d, ppm): 7.54–7.51 (m, 2H, 2£ArH), 7.38–
7.21 (m, 3H, 3£ArH), 7.00 (s, 1H, ArH), 6.74 (s, 1H, ArH),
5.78 (d, J¼1.4 Hz, 1H, CvCHH); 5.21 (d, J¼1.4 Hz, 1H,
CvCHH); 4.81 (m, 1H, –NH), 4.09 (q, J¼7.0 Hz, 2H,
–OCH2CH3), 3.84 (s, 3H, –OCH3), 3.83 (s, 3H, –OCH3),
3.25–3.16 (m, 2H, –CH2–), 2.91–2.86 (m, 2H, –CH2),
1.24 (t, J¼7.0 Hz, 3H, –OCH2CH3). 13C NMR (d, ppm):
155.45 (CO), 150.08 (C), 148.61 (ArOCH3), 147.63
(ArOCH3), 137.63 (C), 129.40 (C), 128.76 (3£ArH),
128.44 (C), 127.51 (ArH), 126.20 (ArH), 112.80 (ArH),
NMR (d, ppm): 156.19 (CO); 148.38 (ArOCH3); 147.03
(ArOCH3); 130.98 (C); 120.13 (ArH); 111.45 (ArH); 110.83
(ArH); 59.98 (–OCH2CH3); 55.26 (–OCH3); 55.17 (–OCH3);
41.76 (–CH2–); 35.16 (–CH2–); 14.09 (–OCH2CH3). MS
(m/z, %): 253 (Mþ, 14), 151 (100). HRMS (CI): C13H20NO4
(MþþH), calcd 254.1314; found 254.1321.
1.1.2. [2-(2-Iodo-4,5-dimethoxyphenyl)ethyl]carbamic
acid ethyl ester (5c). Trifluoromethanesulfonic acid
(1.15 mL, 12.900 mmol) was added dropwise under argon
to a stirred solution of N-carbethoxy derivative 5b (1.485 g,

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8062
108.23 (ArH), 102.96 (vCH2), 60.41 (–OCH2CH3), 55.68
(–OCH3), 55.63 (–OCH3), 41.47 (–CH2–), 32.89 (–CH2–),
14.33 (–OCH2CH3). MS (m/z, %, FAB): 356 [(MþþH),
100]. HRMS (FAB): C21H26NO4 (MþþH) calcd 356.1784;
found 356.1789.
(178 mg, 1.461 mmol) in dry dichloromethane (5 mL) at
08C. The mixture was stirred for 21 h under argon at rt. The
reaction mixture was then diluted with dichloromethane
(10 mL) and the resulting solution was successively washed
with saturated potassium carbonate (20 mL), 10% aq.
hydrochloric acid (30 mL) and water (50 mL). The solution
was dried, filtered and concentrated in vacuo to give a
yellow oil, which was purified by column chromatography
(eluant: 95:5 dichloromethane/methanol) to give isoquino-
linone 4b (106 mg, 77% yield) as a colorless oil. IR
1.1.4. 2,3-Dimethoxyphenanthrene (12). Air was bubbled
for 10 min through a stirred solution of stilbene derivative
3a (105 mg, 0.295 mmol) in diethyl ether (180 mL) and
dichloromethane (5 mL). A catalytic amount of iodine
(12 mg, 0.03 mmol) was added and the mixture was then
irradiated for 5 h in a photochemical reactor equipped with a
Pyrex condenser and a Hanovia 450 W medium-pressure
Hg vapour lamp. Saturated sodium thiosulfate (100 mL)
was added and the organic layer was dried, filtered and
concentrated in vacuo. The residue was purified by column
chromatography (eluant 4:1 dichloromethane/hexane) to
afford phenanthrene 12 (11 mg, 15% yield). Mp 166–1688C
(methanol). IR (n, cm21, NaCl): 2925 (ArH), 1269 (C–O).
1H NMR (d, ppm): 8.53 (d, J¼8.0 Hz, 1H, ArH), 8.00 (s,
1H, ArH), 7.88–7.85 (m, 1H, ArH), 7.72–7.49 (m, 4H,
4£ArH), 7.25 (s, 1H, ArH), 4.11 (s, 3H, –OCH3), 4.04 (s, 3H,
–OCH3). 13C NMR (d, ppm): 149.23 (2£ArOCH3); 131.29
(C); 129.68 (C); 128.65 (ArH); 127.09 (C); 126.15 (ArH);
125.92 (ArH); 125.52 (ArH); 125.19 (ArH); 124.78 (C);
122.09 (ArH); 108.24 (ArH); 103.16 (ArH); 55.96 (–OCH3);
55.89 (–OCH3). MS (m/z, %): 238 (Mþ, 100). Anal. calcd
for C16H14O2, C 80.65, H 5.92; found, C 80.32, H 5.69.
1
(n, cm21, NaCl): 1639 (CO). H NMR (d, ppm): 7.50 (d,
J¼8.6 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.39–7.16 (m, 5H,
5£ArH), 6.89 (d, J¼16.1 Hz, 1H, –CHvCH–), 3.99 (s, 3H,
–OCH3), 3.91 (s, 3H, –OCH3), 3.47–3.42 (m, 2H, –CH2–),
3.15 (s, 3H, –NCH3), 2.96–2.91 (m, 2H, –CH2–). 13C
NMR (d, ppm): 162.85 (CO), 152.43 (ArOCH3), 149.59
(ArOCH3), 136.89 (C), 130.78 (ArH), 129.88 (C), 129.57
(C), 128.53 (2£ArH), 127.68 (ArH), 126.28 (2£ArH),
124.88 (ArH), 124.29 (C), 112.20 (ArH), 61.36 (–OCH3),
55.97 (–OCH3), 47.49 (–CH2 –), 34.61 (–NCH3), 25.39
(–CH2–). MS (m/z, %): 323 (Mþ, 64), 294 (100). HRMS:
C20H21NO3 (Mþ) calcd 323.1521; found 323.1518.
1.1.7. 11,12-Dimethoxy-2-methyl-3,4-dihydro-2H-
naphtho[2,1-f]isoquinolin-1-one (13a). Irradiation of stil-
bene isoquinolinone 4b (115 mg, 0.355 mmol) under the
same conditions as for the cyclization of 4a afforded
naphthoisoquinolinone 13a (60 mg, 52% yield). Mp 134–
1
1368C (ethyl acetate). IR (n, cm21, NaCl): 1648 (CO). H
1.1.5. [2-(4,5-Dimethoxy-2-styrylphenyl)ethyl]methyl-
carbamic acid ethyl ester (3b). A solution of stilbene 3a
(490 mg, 1.379 mmol) in dry THF (6 mL) was added
dropwise under argon to a stirred suspension of sodium
hydride (290 mg, 12 mmol) in dry THF (6 mL). The stirring
was continued at rt for 30 min and methyl iodide (2.92 mL,
46.900 mmol) was added. The resulting mixture was stirred
for a further 3 h and diluted with water (20 mL). The THF
was removed in vacuo and the remaining aqueous suspen-
sion was extracted with dichloromethane (3£20 mL), the
combined organic extracts were washed with water
(40 mL), dried, filtered and concentrated in vacuo to give
N-methylcarbamic acid derivative 3b (510 mg, 100% yield)
as an oil. This compound was used directly without further
purification. IR (n, cm21, NaCl): 1688 (CO). 1H NMR
(d, ppm, 331 K): 7.52–7.49 (m, 2H, 2£ArH), 7.35–7.21
(m, 4H, 4£ArH), 7.12 (s, 1H, ArH), 6.90 (d, J¼16.0 Hz,
1H, –CHvCH–), 6.66 (s, 1H, ArH), 4.07 (q, J¼7.0 Hz,
2H, –OCH2CH3), 3.89(s, 3H, –OCH3), 3.86(s, 3H, –OCH3),
3.45–3.39 (m, 2H, –CH2–), 2.95–2.89 (m, 2H, –CH2–),
2.81 (s, 3H, –NCH3), 1.17 (t, J¼7.0 Hz, 3H, –OCH2CH3).
13C NMR (d, ppm, 331 K): 156.14 (CO), 149.15 (ArOCH3),
148.13 (ArOCH3), 137.73 (C), 129.89 (C), 128.88 (C),
128.65 (ArH), 128.43 (2£ArH), 127.15 (ArH), 126.22
(2£ArH), 125.62 (ArH), 113.61 (ArH), 109.37 (ArH),
60.88 (–OCH2CH3), 55.01 (–OCH3), 55.91 (–OCH3),
50.43 (–CH2–), 34.71 (–NCH3), 31.83 (–CH2–), 14.56
(–OCH2CH3). MS (m/z, %): 369 (Mþ, 35), 116 (100).
HRMS: C22H27NO4 (Mþ) calcd 369.1940; found 369.1943.
NMR (d, ppm): 9.70–9.67 (m, 1H, ArH), 7.88–7.79 (m, 2H,
2£ArH), 7.72–7.60 (m, 3H, 3£ArH), 4.16 (s, 3H, –OCH3),
3.97 (s, 3H, –OCH3), 3.64–3.59 (m, 2H, –CH2–), 3.36–
3.31 (m, 2H, –CH2–), 3.23 (s, 3H, –NCH3). 13C NMR
(d, ppm): 163.01 (CO), 151.89 (ArOCH3), 157.74 (ArOCH3),
132.95 (C), 132.89 (C), 129.52 (C), 128.27 (2£ArH), 127.44
(ArH), 127.26 (ArH), 127.06 (ArH), 126.46 (C), 123.49 (C),
121.65 (ArH), 61.93 (–OCH3), 55.94 (–OCH3), 47.59
(–CH2–), 34.84 (–NCH3), 25.69 (–CH2–). MS (m/z, %):
321 (Mþ, 39), 57 (100). Anal. calcd for C20H19NO3, C
74.75, H 5.96, N 4.36; found, C 75.02, H 5.81, N 4.59.
1.1.8. 12-Hydroxy-11-methoxy-2-methyl-3,4-dihydro-
2H-naphtho[2,1-f]isoquinolin-1-one (16a). A 1 M solution
of boron trichloride in dichloromethane (0.800 mL,
0.781 mmol) was added dropwise under argon to a stirred
solution of isoquinolinone 13a (25 mg, 0.078 mmol) in
dichloromethane (5 mL) and the mixture was stirred for
15 min. Water (5 mL) was added to the reaction mixture and
this was stirred for a further 15 min. The product was
extracted with dichloromethane (3£10 mL) and the com-
bined organic extracts were washed with water (15 mL),
dried, filtered and concentrated in vacuo. The resulting solid
residue was purified by column chromatography (eluant: 1:1
ethyl acetate/hexane) to give phenolic naphthoisoquinoli-
none 16a (24 mg, 100%) as a yellow solid. Mp 120–1228C
(ethyl acetate). IR (n, cm21, NaCl): 1647 (CO). 1H NMR (d,
ppm, 500 MHz): 13.05 (s, 1H, –OH), 9.71–9.67 (m, 1H,
ArH), 7.81–7.77 (m, 1H, ArH), 7.67 (d, J¼9.2 Hz, 1H,
ArH), 7.63–7.58 (m, 2H, 2£ArH), 7.52 (d, J¼9.2 Hz, 1H,
ArH), 3.98 (s, 3H, –OCH3), 3.63 (t, J¼6.9 Hz, 2H, –CH2–),
1.1.6. 7,8-Dimethoxy-2-methyl-5-styryl-3,4-dihydro-2H-
isoquinolin-1-one (4b). Triflic anhydride (0.410 mL,
2.436 mmol) was added dropwise over 5 min to a solution
of compound 3b (180 mg, 0.487 mmol) and DMAP
3.35 (t, J¼6.9 Hz, 2H, –CH2–), 3.16 (s, 3H, –NCH3). 13
C
NMR (d, ppm, 125.72 MHz): 168.64 (CO), 152.35 (C),
144.61 (C), 133.41 (C), 130.70 (C), 129.34 (C), 128.69

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8063
(ArH), 128.12 (ArH), 127.49 (ArH), 126.77 (ArH), 125.48
(ArH), 122.20(C), 121.66(ArH), 112.66(C), 59.34 (–OCH3),
47.77 (–CH2–), 34.62 (–NCH3), 24.06 (–CH2–). MS (m/z,
%): 307 (Mþ, 100), 292 (80), 249 (34). Anal. calcd for
C19H17NO3, C 74.25, H 5.58, N 4.56; found, C 73.99, H
5.86, N 4.31.
20.595 mmol) in dry THF (20 mL) was added dropwise.
The resulting mixture was stirred for 4 h at rt. The solvent
was removed in vacuo, the residue was suspended in
water (100 mL) and the suspension was extracted with
dichloromethane (3£70 mL). The combined organic
extracts were washed with a 1:2 methanol/water mixture,
dried, filtered and concentrated in vacuo. The resulting
solid residue was purified by column chromatography
(eluant: 1:9 ethyl acetate/hexane) to give styrene 6d
(3.69 g, 93% yield) as a yellow oil, which was used
without further purification. IR (n, cm21, NaCl): 1510
(C–O), 1261 (C–O). 1H NMR (d, ppm): 6.99 (d, J¼2.2 Hz,
1H, ArH), 6.93 (dd, J¼8.5, 1.5 Hz, 1H, ArH), 6.78 (dd,
J¼8.5, 1.5 Hz, 1H, ArH), 6.61 (dd, J¼17.6, 10.9 Hz, 1H,
–CHvCHH), 5.58 (dd, J¼17.6, 0.9 Hz, 1H, –CHvCHH),
5.11 (d, J¼10.9 Hz, 1H, –CHvCHH), 4.52 (m, J¼6.1 Hz,
1H, –CH–), 3.79 (s, 3H, –OCH3), 1.35 (d, J¼6.1 Hz, 6H,
2£–CH3). 13C NMR (d, ppm): 150.20 (C), 146.94 (C),
136.22 (ArH), 130.36 (C), 119.56 (ArH), 113.29 (ArH),
111.49 (ArH), 111.35 (–CHvCH2), 71.18 (–CH–),
55.59 (–OCH3), 21.82 (2£–CH3). MS (m/z, %): 192 (Mþ,
22), 135 (100). HRMS: C12H16O2 (Mþ) calcd 192.1150;
found 192.1146.
1.1.9. 11-Methoxy-2-methyl-1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinolin-12-ol (annoretine) (1a). Lithium
aluminium hydride (12 mg, 0.325 mmol) was added to a
stirred solution of naphthoisoquinolinone 16a (20 mg,
0.065 mmol) in THF (3 mL) at 08C. The reaction mixture
was stirred at rt for 5 h and the excess lithium aluminium
hydride was destroyed by consecutive addition of water
(0.013 mL), 15% aq. sodium hydroxide (0.13 mL) and
water (0.039 mL). The resulting suspension was filtered
under vacuum, the solid residue was washed with a 95:5
dichloromethane/methanol mixture, the filtrate was con-
centrated in vacuo and the solid residue was purified by
preparative TLC (eluant: 9:1 dichloromethane/methanol) to
give annoretine (1a) (12 mg, 63% yield) as a white solid.
Mp 160–1628C (MeOH, sublimation). IR (n, cm21, NaCl):
1
3435 (–OH). H NMR (d, ppm): 9.38–9.34 (m, 1H, ArH),
7.87–7.82 (m, 2H, 2£ArH), 7.78–7.55 (m, 3H, 3£ArH),
3.79 (s, 3H, –OCH3), 3.77 (s, 2H, –CH2–), 3.27
(t, J¼5.9 Hz, 2H, –CH2–), 2.85 (t, J¼5.9 Hz, 2H, –CH2–),
2.57 (s, 3H, –NCH3). 13C NMR (d, ppm): 144.73 (C),
141.47 (C), 132.37 (C), 128.91 (C), 128.19 (ArH), 127.15
(C), 127.00 (ArH), 126.63 (ArH), 126.17 (ArH), 125.42 (C),
124.94 (ArH), 123.15 (C), 121.89 (ArH), 121.85 (C), 60.08
(–OCH3), 53.04 (–CH2–), 52.48 (–CH2–), 45.92 (–NCH3),
26.76 (–CH2–). MS (m/z, %): 293 (Mþ, 97), 250 (100).
Anal. calcd for C19H19NO2, C 77.79, H 6.53, N 4.77; found,
C 78.11, H 6.32, N 4.93.
1.1.12. (2-{2-[2-(3-Isopropoxy-4-methoxyphenyl)vinyl]-
4,5-dimethoxyphenyl}ethyl)carbamic acid ethyl ester
(3c). Compound 3c was prepared in 55% yield from
compound 5c (1.2 g, 3.165 mmol) and styrene 6d
(730 mg, 3.797 mmol) following the same procedure as
for compound 3a. Mp 121–1228C (methanol). IR (n, cm21
,
NaCl): 3421 (–NH), 1676 (CO). 1H NMR (d, ppm): 7.28–
7.07 (m, 4H, ArH), 6.88 (s, 1H, ArH), 6.83 (d, J¼7.5 Hz,
1H, ArH), 6.56 (s, 1H, ArH), 4.87 (bs, 1H, –NH), 4.69 (m,
J¼5.9 Hz, 1H, –CH–), 4.07 (q, J¼6.9 Hz, 2H, –OCH2CH3),
3.93 (s, 3H, –OCH3), 3.87 (s, 3H, –OCH3), 3.86 (s,
3H, –OCH3), 3.36 (t, J¼6.8 Hz, 2H, –CH2–), 2.93 (t,
J¼6.8 Hz, 2H, –CH2–), 1.41 (d, J¼5.9 Hz, 6H, 2£–CH3),
1.18 (t, J¼6.9 Hz, 3H, –OCH2CH3). 13C NMR (d, ppm):
156.52 (CO), 150.06 (C), 148.31 (C), 147.65 (C), 147.15
(C), 130.58 (C), 128.91 (C), 128.81 (C), 128.32 (ArH),
123.31 (ArH), 119.85 (ArH), 113.62 (ArH), 112.79
(ArH), 111.74 (ArH), 108.14 (ArH), 71.25 (–CH–), 60.51
(–OCH2CH3), 55.79 (–OCH3), 55.76 (–OCH3), 55.73
(–OCH3),42.05(–CH2–),33.20(–CH2–),21.94(2£–CH3),
14.44 (–OCH2CH3). MS (m/z, %): 443 (Mþ, 100). Anal.
calcd for C25H33NO6, C 67.70, H 7.50, N 3.16; found, C
67.56, H 7.69, N 3.12.
1.1.10. 3-Isopropoxy-4-methoxybenzaldehyde (6c). Potas-
sium carbonate (12.717 mg, 92.014 mmol) was added to a
solution of isovanillin (6b) in dry DMF (100 mL) and
to this mixture was added 2-bromopropane (15.12 mL,
161.024 mmol). The reaction mixture was stirred for 48 h at
rt and then poured into water (100 mL). The resulting
suspension was extracted with diethyl ether (3£100 mL),
the combined organic extracts were washed with water
(4£150 mL), dried, filtered and concentrated in vacuo to
give compound 6c (8.869 g, 99% yield) as a yellow oil,
which was used without further purification. IR (n, cm21
,
NaCl):1689(–CHO).1HNMR(d, ppm):9.84(s, 1H, –CHO),
7.47 (d, J¼7.9 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 6.98 (d,
J¼7.9 Hz, 1H, ArH), 4.64 (m, J¼6.1 Hz, 1H, –CH–), 3.94
(s, 3H, –OCH3), 1.39 (d, J¼6.1 Hz, 6H, 2£–CH3). 13C
NMR (d, ppm): 190.28 (CHO), 155.09 (C), 147.25 (C),
129.49 (C), 125.88 (ArH), 112.18 (ArH), 110.48 (ArH),
70.67 (–CH–), 55.49 (–OCH3), 21.35 (2x–CH3). MS (m/z,
%): 194 (Mþ, 16), 151 (100). HRMS: C11H14O3 (Mþ) calcd
194.0943; found 194.0944.
Proceeding as for 7a, compound 7b was isolated in a 17%
yield, as an oil. IR (n, cm21, NaCl): 3410 (–NH), 1690
(CO). 1H NMR (d, ppm): 7.28–7.10 (m, 2H, 2£ArH), 6.86
(s, 1H, ArH), 6.82–6.76 (m, 2H, 2£ArH)5.67 (d, J¼1.1 Hz,
1H, –CvCHH), 5.10 (d, J¼1.1 Hz, 1H, –CvCHH), 4.87
(bs, 1H, –NH), 4.46 (h, J¼6.1 Hz, 1H, –CH–), 4.07 (q,
J¼6.9 Hz, 2H, OCH2CH3), 3.90 (s, 3H, –OCH3), 3.86 (s,
3H, –OCH3), 3.84 (s, 3H, –OCH3), 3.21 (t, J¼6.8 Hz, 2H,
–CH2–), 2.53 (t, J¼6.8 Hz, 2H, –CH2–),1.32 (d, J¼6.1 Hz,
6H, 2£CH3), 1.18 (t, J¼6.9 Hz, 3H, –OCH2CH3). 13C NMR
(d, ppm): 156.51 (CO), 150.62 (C), 149.48 (C), 148.33 (C),
147.68 (C), 147.17 (C), 130.61 (C), 129.01 (C), 128.47
(C), 119.89 (ArH), 113.60 (ArH), 112.78 (ArH), 111.66
(ArH), 108.05 (ArH), 103.11 (vCH2), 71.26 (–CH–),
60.48 (–OCH2CH3), 55.81 (–OCH3), 55.78 (–OCH3),
1.1.11. 2-Isopropoxy-1-methoxy-4-vinylbenzene (6d). A
1.6 M solution of n-BuLi in hexane (27 mL) was added
under argon to a stirred suspension of methyltriphenylphos-
phonium bromide (14.72 g, 41.190 mmol) in dry THF
(70 mL) at 2788C (dry ice/acetone bath). The mixture
was allowed to warm up to rt, stirred for 20 min, cooled
again to 2788C, and a solution of benzaldehyde 6c (4 g,

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M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8064
55.74 (–OCH3), 42.08 (–CH2–), 33.23 (–CH2–), 21.93
(2£–CH3), 14.41 (–OCH2CH3). MS (m/z, %, FAB): 444
[(MþþH), 100]. HRMS (FAB): C25H34NO6 (MþþH) calcd
444.2308; found 444.2313.
ArH), 7.60 (d, J¼9.1 Hz, 1H, ArH), 7.23 (s, 1H, ArH), 4.80
(m, J¼5.9 Hz, 1H, –CH–), 4.16 (s, 3H, –OCH3), 4.09 (s, 3H,
–OCH3), 3.98 (s, 3H, –OCH3), 3.63–3.58 (m, 2H, –CH2–),
3.34–3.28 (m, 2H, –CH2–), 3.22 (s, 3H, –NCH3), 1.50 (d,
J¼5.9 Hz, 6H, 2£–CH3). 13C NMR (d, ppm): 163.08 (CO),
151.12 (C), 150.87 (C), 149.76 (C), 147.63 (C), 133.09 (C),
128.56 (C), 126.38 (ArHþC), 125.71 (C), 123.78 (C), 122.45
(C), 119.88 (ArH), 110.56 (ArH), 109.22 (ArH), 70.64
(–CH–), 61.84 (–OCH3), 59.93 (–OCH3), 55.80 (–OCH3),
47.45 (–CH2–), 34.68 (–NCH3), 25.56 (–CH2–), 21.85
(2£–CH3). MS (m/z, %): 409 (Mþ, 100). Anal. calcd for
C24H27NO5, C 70.40, H 6.65, N 3.42; found, C 70.63, H
6.47, N 3.24.
1.1.13. (2-{2-[2-(3-Isopropoxy-4-methoxyphenyl)vinyl]-
4,5-dimethoxyphenyl}ethyl)methylcarbamic acid ethyl
ester (3d). Treatment of stilbene 3c (705 mg, 1.1589 mmol)
with sodium hydride (480 mg, 19.868 mmol) and methyl
iodide (3.46 mL, 55.635 mmol) under the same conditions
as for the methylation of 3a provided a solid residue that
was purified by column chromatography (eluant: 99:1
dichloromethane/methanol) to give stilbene derivative 3d
(712 mg, 98% yield) as a white solid. Mp 113–1158C
1
(methanol). IR (n, cm21, NaCl): 1695 (CO). H NMR (d,
1.1.16. 8,12-Dihydroxy-9,11-dimethoxy-2-methyl-3,4-
dihydro-2H-naphtho[2,1-f]isoquinolin-1-one (16b). Naph-
thoisoquinolinone 13b (45 mg, 0.109 mmol) was reacted
with boron trichloride (1.1 mL of a 1 M solution in
dichloromethane) following the same conditions as for
compound 13a to give diphenolic naphthoisoquinolinone
ppm, 331 K): 7.18–7.05 (m, 4H, ArH), 6.86 (d, J¼8.5 Hz,
1H, ArH), 6.82 (d, J¼15.7 Hz, 1H, –CHvCH–), 6.66 (s,
1H, ArH), 4.60 (m, J¼5.9 Hz, 1H, –CH–), 4.09 (q,
J¼6.9 Hz, 2H, –OCH2CH3), 3.91 (s, 3H, –OCH3), 3.87
(s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 3.43 (t, J¼7.5 Hz,
2H, –CH2–), 2.93 (t, J¼7.5 Hz, 2H, –CH2 –), 2.83 (s,
3H, –NCH3), 1.37 (d, J¼5.9 Hz, 6H, 2£–CH3), 1.20 (t,
J¼6.9 Hz, 3H, –OCH2CH3). 13C NMR (d, ppm, 331 K):
156.33 (CO), 150.80 (C), 149.00 (C), 148.25 (C), 147.81
(C), 131.24 (C), 129.64 (C), 129.33 (C), 128.66 (ArH),
123.91 (ArH), 120.24 (ArH), 115.09 (ArH), 113.75
(ArH), 112.83 (ArH), 109.39 (ArH), 71.97 (–CH–), 61.03
(–OCH2CH3), 56.17 (2£–OCH3), 56.08 (–OCH3), 50.61
(–CH2–),34.84(–NCH3),31.47(–CH2–),22.17(2£–CH3),
14.62 (–OCH2CH3). MS (m/z, %): 457 (Mþ, 100). Anal.
calcd for C26H35NO6, C 68.25, H 7.71, N 3.06; found, C
67.89, H 7.78, N 2.89.
16b in 77% yield. Mp 232–2348C (methanol). IR (n, cm21
,
NaCl): 3450 (–OH), 1617 (CO). 1H NMR (d, ppm,
500 MHz, DMSO): 13.25 (s, 1H, –OH), 9.73 (s, 1H, –OH),
9.11 (s, 1H, ArH), 7.70 (d, J¼9.1 Hz, 1H, ArH), 7.47 (d,
J¼9.1 Hz, 1H, ArH), 7.22 (s, 1H, ArH), 3.95 (s, 3H, –OCH3),
3.94 (s, 3H, –OCH3), 3.70–3.67 (m, 2H, –CH2–), 3.38–3.36
(m, 2H, –CH2–), 3.09 (s, 3H, –NCH3). 13C NMR (d, ppm,
125.72 MHz, DMSO): 167.97 (CO), 150.96 (C), 147.77 (C),
147.47 (C), 142.24 (C), 131.88 (C), 129.09 (C), 126.94 (C),
124.13 (ArH), 121.84 (C), 120.99 (C), 120.35 (ArH), 111.74
(ArH), 111.22 (C), 109.11 (ArH), 58.82 (–OCH3), 55.24
(–OCH3), 46.95 (–CH2–), 34.04 (–NCH3), 23.27 (–CH2–
). MS (m/z, %): 353 (Mþ, 71), 338 (100). Anal. calcd for
C20H19NO5, C 67.98, H 5.42, N 3.96; found, C 68.13, H
5.19, N 4.07.
1.1.14. 5-[2-(3-Isopropoxy-4-methoxyphenyl)vinyl]-7,8-
dimethoxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one
(4c). Naphthoisoquinolinone 4c was prepared in 87% yield
from stilbene derivative 3d (410 mg, 0.896 mmol) follow-
ing the same procedure as for its analogue 4b. Mp 59–628C
1.1.17. 9,11-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinoline-8,12-diol (litebamine) (1b).
Reduction of naphthoisoquinolinone 16b (11 mg,
0.031 mmol) with lithium aluminium hydride (12 mg,
1.550 mmol) under the same conditions as for 1a provided
57% yield of litebamine (1b) as a white solid. Mp 133–
1
(methanol). IR (n, cm21, NaCl): 1653 (CO). H NMR (d,
ppm): 7.19 (s, 1H, ArH), 7.09–7.06 (m, 2H, ArH), 7.04
(d, J¼16.0 Hz, 1H, –CHvCH–), 6.88 (d, J¼8.8 Hz, 1H,
ArH), 6.83 (d, J¼16.0 Hz, 1H, –CHvCH–), 4.59 (m,
J¼5.9 Hz, 1H, –CH–), 4.11 (q,J¼6.9 Hz, 2H, –OCH2CH3),
3.99 (s, 3H, –OCH3), 3.92 (s, 3H, –OCH3), 3.88
(s, 3H, –OCH3), 3.49–3.44 (m, 2H, –CH2–), 3.17 (s, 3H,
–NCH3), 2.98–2.93 (m, 2H, –CH2–), 1.40 (d, J¼5.9 Hz,
6H, 2£–CH3), 1.25 (t, J¼6.9 Hz, 3H, –OCH2CH3). 13C
NMR (d, ppm): 163.01 (CO), 152.46 (C), 150.58 (C),
149.33 (C), 147.19 (C), 130.69 (ArH), 130.24 (C), 130.02
(C), 129.32 (C), 124.32 (C), 123.04 (ArH), 120.08 (ArH),
114.16 (ArH), 112.12 (ArH), 111.86 (ArH), 71.59 (–CH–),
61.43 (–OCH3), 56.01 (–OCH3), 55.84 (–OCH3), 47.60
(–CH2–), 34.70 (–NCH3), 25.49 (–CH2–), 21.99 (2£–H3).
MS (m/z, %): 411 (Mþ, 100). Anal. calcd for C24H29NO5, C
70.05, H 7.10, N 3.40; found, C 69.76, H 7.22, N 3.71.
1
1368C (methanol). IR (n, cm21, NaCl): 3434 (–OH). H
NMR (d, ppm, 500 MHz, DMSO): 9.51 (s, 1H, –OH), 9.24
(s, 1H, –OH), 8.93 (s, 1H, ArH), 7.62 (d, J¼9.0 Hz, 1H,
ArH), 7.45 (d, J¼9.0 Hz, 1H, ArH), 7.20 (s, 1H, ArH), 3.94
(s, 3H, –OCH3), 3.72 (s, 3H, –OCH3), 3.58 (s, 2H, –CH2–
), 3.11–3.09 (m, 2H, –CH2–), 2.75–2.73 (m, 2H, –CH2–),
2.44 (s, 3H, –NCH3). 13C NMR (d, ppm, 125.72 MHz,
DMSO): 147.81 (C), 146.26 (C), 144.87 (C), 140.99 (C),
127.81 (C), 126.43 (C), 123.44 (C), 123.28 (ArH), 123.02
(C), 122.16 (C), 121.61 (C), 119.76 (ArH), 111.47 (ArH),
107.84 (ArH), 59.59 (–OCH3), 55.19 (–OCH3), 53.07
(–CH2–), 51.98 (–CH2–), 45.60 (–NCH3), 26.26 (–CH2–).
MS (m/z, %): 339 (Mþ, 63), 63 (100). Anal. calcd for
C20H21NO4, C 70.78, H 6.24, N 4.13; found, C 70.83, H
6.02, N 4.37.
1.1.15. 8-Isopropoxy-9,11,12-trimethoxy-2-methyl-3,4-
dihydro-2H-naphtho[2,1-f]isoquinolin-1-one (13b). Irra-
diation of stilbene isoquinolinone 4c (110 mg, 0.267 mmol)
under the same conditions as for the cyclization of 4b afforded
41% yield of the corresponding naphthoisoquinolinone 13b.
Mp 160–1628C (methanol). IR (n, cm21, NaCl): 1653 (CO).
1H NMR (d, ppm): 9.26 (s, 1H, ArH), 7.71 (d, J¼9.1 Hz, 1H,
Acknowledgements
We thank the Spanish Ministry of Science and Technology
and the Xunta de Galicia for financial support.

´
M. C. Pampın et al. / Tetrahedron 59 (2003) 8057–8065
8065
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 166420 (1a, solvent: MeOH). Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44-
1223-336-033; e-mail: deposit@ccdc.cam.ac.uk]. Crystallo-
graphic data for annoretine (1a). C19H19NO2, M¼293.35,
References
1. Bentley, K. Nat. Prod. Rep. 2000, 17, 247.
2. (a) Whaley, W. M.; Meadow, M. J. Org. Chem. 1954, 19, 661.
(b) Galiazzo, G.; Bortolus, P.; Masetti, F. J. Chem. Soc.,
Perkin Trans. 2 1975, 1712. (c) Masetti, F.; Bartocci, G.;
Mazzucato, U. Gazz. Chim. Ital. 1982, 112, 255. (d) Tanga,
M. J.; Almquist, R. G.; Smith, T. H. J. Heterocycl. Chem.
1985, 22, 1597.
T¼293(2) K. Triclinic, space group P1 with a¼11.5575(17),
˚
b¼12.0696(16),
c¼13.271(3) A,
a¼112.933(13)8,
3
˚
3. Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
Tetrahedron Lett. 1991, 32, 4169.
b¼111.403(14)8, g¼97.794(14)8, U¼1501.7(4) A , Dc
(Z¼4)¼1.298 g cm23. F(000)¼624, m(Cu Ka)¼6.66 cm21
;
4. Wu, Y.-C.; Chang, G.-Y.; Duh, C.-Y.; Wang, S.-K. Phyto-
chemistry 1993, 33, 497.
6453 unique data (2umax¼1508), 6177 with I.2s(I), conven-
tional R1[I.2s(I)]¼0.0413, wR2 [all data]¼0.1323, GOF [all
data]¼1.017. Data were obtained on an Enraf-Nonius CAD4-
Mach3 diffractometer (graphite crystal monochromator,
5. Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
J. Pharm. Pharmacol. 1997, 49, 706.
6. Chiou, C.-M.; Kang, J.-J.; Lee, S.-S. J. Nat. Prod. 1998, 61,
46.
˚
l¼1.5418 A) using the v¼2u scan method; absorption
corrections were applied. Refinement, with anisotropic
displacement parameters applied to each of the non-hydrogen
atoms, was by full-matrix least squares on F 2 (SHELXL-93)
7. (a) Lee, S.-S.; Lin, Y.-J.; Chen, M.-Z.; Wu, Y.-C.; Chen, C.-H.
Tetrahedron Lett. 1992, 33, 6309. (b) Lee, S.-S.; Chiou, C.-M.;
Lin, H.-Y.; Chen, C.-H. Tetrahedron Lett. 1995, 36, 1531. (c)
Hara, H.; Kaneko, K.; Endoh, M. Tetrahedron 1995, 37,
10189. (d) Chiou, C.-M.; Kang, J.-J.; Lee, S.-S. J. Nat. Prod.
1998, 61, 46.
P
P
using all data; wR 2¼[( w(Fo22Fc2)2/ w(Fo2)2]1/2
.
18. Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979,
2593.
19. Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996,
61, 3561.
´ ´ ´
8. Pampın, M. C.; Estevez, J. C.; Estevez, R. J.; Maestro, M.;
Castedo, L. Tetrahedron 2003, 59, 7231.
´
20. Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publications no. CCDC 166421 (1b, solvent: MeOH). Copies
of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44-
1223-336-033; e-mail: deposit@ccdc.cam.ac.uk]. Crystallo-
graphic data for litebamine (1b). C20H21NO4, M¼339.38,
T¼293(2) K. Triclinic, space group P1 with a¼23.264(8),
´ ´
9. (a) Martınez, E.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
´
Tetrahedron 2001, 57, 1973. (b) Martınez, E.; Estevez, J. C.;
´
´
Estevez, R. J.; Castedo, L. Tetrahedron 2001, 57, 1981.
10. For a preliminary communication on the total synthesis of
´ ´
annoretine see: Pampın, M. C.; Estevez, J. C.; Castedo, L.;
´
Estevez, R. J. Tetrahedron Lett. 2001, 42, 2307.
11. (a) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 46, 4416.
(b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
´
12. (a) Barluenga, J.; Campos, P. J.; Gonzalez, J. M.; Asensio, G.
J. Chem. Soc., Perkin Trans. 1 1984, 2623. (b) Barluenga, J.;
˚
b¼7.392(2), c¼10.152(3) A, a¼908, b¼114.975(7)8, g¼908,
U¼1582.7(9) A , Dc (Z¼4)¼1.424 g cm23. F(000)¼720,
3
˚
´
Rodrıguez, M. A.; Campos, P. J. J. Org. Chem. 1990, 55, 3104.
m(Mo Ka)¼0.099 cm21; 1725 unique data (2umax¼1508),
1233 with I.2s(I), conventional R1[I.2s(I)]¼0.0656, wR2
[all data]¼0.1426, GOF [all data]¼0.968. Data were obtained
on a SMART Bruker diffractometer (graphite crystal mono-
13. (a) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76,
509. (b) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30,
1. (c) Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org.
Chem. 1991, 56, 3769.
˚
chromator, l¼0.71073 A) using the v¼2u scan method;
14. Banwell, M. G.; Bisset, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.
J. Chem Soc., Chem. Commun. 1995, 24, 2551.
absorption corrections were applied. Refinement, with aniso-
tropic displacement parameters applied to each of the non-
hydrogen atoms, was by full-matrix least squares on F 2
15. Kim, D. H. J. Heterocycl. Chem. 1992, 29, 11.
16. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.;
Morton, R. B.; Parton, B.; Price, A. W.; Somvichien, N.
Tetrahedron Lett. 1996, 35, 4153.
P
(SHELXL-97) using all data; wR 2¼[( w(Fo22Fc2)2/
P
w(F2o)2]1/2
.
21. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals. Pergamon: 1988.
17. Crystallographic data (excluding structure factors) for the