First total synthesis of the 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinoline annoretine

Article abstract of DOI:10.1016/S0040-4039(01)00168-X

Here we describe the first total synthesis of the 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinoline (6) annoretine from N-carbethoxy-o-styrylphenylethylamines 2. The key steps were the Bischler-Napieralski reaction to form the isoquinoline unit and photocycliz

Full text of DOI:10.1016/S0040-4039(01)00168-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2307–2308
First total synthesis of the
1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline annoretine
M. Carme Pamp´ın, Juan C. Este´vez, Luis Castedo and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica and Unidad Asociada al Instituto de Investigaciones Qu´ımicas (CSIC),
University of Santiago, 15706 Santiago de Compostela, Spain
Received 25 January 2001; accepted 29 January 2001
Abstract—Here we describe the first total synthesis of the 1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline (6) annoretine from
N-carbethoxy-o-styrylphenylethylamines 2. The key steps were the Bischler–Napieralski reaction to form the isoquinoline unit and
photocyclization of the resulting 5-styrylisoquinoline 3 to naphtoisoquinoline 4. © 2001 Elsevier Science Ltd. All rights reserved.
The only natural products containing the 1,2,3,4-tetra-
hydronaphtho[2,1-f ] isoquinoline skeleton are the rela-
tively recently discovered alkaloids annoretine (6)1 and
litebamine.2 This explains why the 1,2,3,4-tetra-
hydronaphtho[2,1-f ] isoquinoline skeleton has received
little chemical attention apart from a preliminary study
of synthetic approaches3 and a biomimetic synthesis
from its probably biogenetic precursor boldine.4,5 How-
ever, pharmacological studies have established the
antiplatelet effects and the anti-acetylcholinesterase
activity of litebamine and the cytotoxic properties of
annoretine.6 Additionally, tetrahydronaphtho[2,1-f ]-
isoquinolines are potential antibacterials and antitu-
morals because they have a tetracyclic ring system that
i, ii
iii
I
N
N
MeO
Me
MeO
R
CO2Et
N
MeO
H
1
CO2Et
MeO
O
MeO
MeO
2a, R= H
3
2b, R= Me
iv
v
vi
N
N
N
MeO
Me
MeO
Me
MeO
Me
OH
O
MeO
O
OH
6
5
4
Scheme 1. Pd(OAc)2 (10% molar), Ph3P, Et3N, MeCN, argon, 80°C, 24 h; (ii) (a) NaH, THF, rt, 30 min; (b) MeI, rt, 3 h; (iii)
5:3 Tf2O/DMAP, CH2Cl2, argon, 0°C, 1 h; (iv) UV light, I2, O2, 95:5 Et2O/CH2Cl2, 2 h; (v) BCl3, CH2Cl2, argon, rt, 15 min; (vi)
LiAlH4, THF, rt, 5 h.
* Corresponding author. Tel.: +34 981 563100 ext. 14242; fax: +34 981 591014; e-mail: qorjec@usc.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00168-X

2308
M. C. Pamp´ın et al. / Tetrahedron Letters 42 (2001) 2307–2308
is similar to that of the carcinogenic hydrocarbon chry-
sene but, like the ring system of antibacterial and
antitumoral benzophenanthridine alkaloids, includes a
nitrogen atom.7 Here we briefly describe the first total
synthesis of annoretine starting from the key N-car-
bethoxy-o-styrylphenylethylamines 2.
2. Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
Tetrahedron Lett. 1991, 32, 4169.
3. Mart´ınez, E.; Este´vez, J. C.; Este´vez, R. J.; Villaverde, M.
C.; Castedo, L. Tetrahedron Lett. 1998, 39, 1231.
4. Lee, S.-S.; Lin, Y.-J.; Chen, M.-Z.; Wu, Y.-C.; Chen,
C.-H. Tetrahedron Lett. 1992, 33, 6309.
5. Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
N-Carbethoxy-o-iodohomoveratrylamine (1) was easily
prepared in 75% yield in a two-step sequence starting
from homoveratrylamine.8 Heck coupling9 of 1 to sty-
rene gave the E isomer of N-carbethoxy-o-styryl-
phenylethylamine 2a (Scheme 1) as a yellow oil (yield
70%). Treatment of this carbamate with MeI then
afforded a 100% yield of N-methylcarbamate 2b, which
when subjected to Bischler–Napieralski10 cyclization
conditions (5:3 Tf2O/DMAP) gave isoquinolinone 3 in
75% yield. Construction of the phenanthrene ring sys-
tem was completed by photocyclization11 of isoquinoli-
none 3 in oxygenated 95:5 ether–dichloromethane
containing one equivalent of iodine. The resulting
1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinolinone 4 was
obtained in 40% yield as a yellow solid, mp 134–136°C
(AcOEt).
Tetrahedron Lett. 1991, 32, 4169.
6. Hara, H.; Kaneko, K.-I.; Endoh, M.; Uchida, H.;
Hoshino, O. Tetrahedron 1995, 51, 10189.
7. Cheng, C. C. In Progress in Medicinal Chemistry; Ellis,
G. P.; West, G. B., Eds. Structural aspects of antineo-
plastic agents—a new approach. Elsevier Science BV
(Biomedical Division): Amsterdam, 1988; Vol. 25, pp.
35–83.
8. (a) Barluenga, J.; Campos, P. J.; Gonza´lez, J. M.; Asen-
sio, G. J. Chem. Soc., Perkin Trans. 1 1984, 2623; (b)
Barluenga, J.; Rodr´ıguez, M. A.; Campos, P. J. J. Org.
Chem. 1990, 55, 3104.
9. (a) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 46,
4416; (b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995,
28, 2.
10. Banwell, M. G.; Bissett, 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, 2551.
11. Koszyk, F. J.; Lenz, G. R. J. Chem. Soc., Perkin Trans.
1 1984, 1273.
The substitution pattern of annoretine was easily estab-
lished by treatment of 4 with BCl3, which selectively
and quantitatively removed the methyl group of the
methoxy substituent at position 12 (a process favored
by the carbonyl group). NOEs and NMR correlation
experiments (HMBC and HMQC) allowed unambigu-
ous identification of the structure of compound 5. Final
treatment of 5 with LiAlH4 afforded annoretine12 in
75% yield as a white solid, mp 160–163°C (MeOH,
sublimation). We note that this synthesis confirms the
structure proposed for annoretine.1
12. All new compounds gave satisfactory analytical and spec-
troscopic data.
(a) Selected spectroscopic data for annoretine (6): 1H
NMR (l, ppm, Cl3CD): 2.57 (s, 3H, -NCH3), 2.85 (t,
J=5.9 Hz, 2H, -CH2-), 3.27 (t, J=5.9 Hz, 2H, -CH2-),
3.77 (s, 2H, -CH2-), 3.79 (s, 3H, -OCH3), 7.55–7.78 (m,
3H, 3×Ar-H), 7.82–7.87 (m, 2H, 2×Ar-H), 9.34–9.38 (m,
1H, Ar-H). 13C NMR (l, ppm, Cl3CD): 26.76 (-CH2-),
45.92 (-NCH3), 52.48 (-CH2-), 53.04 (-CH2-), 60.08 (-
OCH3), 121.85 (C), 121.89 (Ar-H), 123.15 (C), 124.94
(Ar-H), 125.42 (C), 126.17 (Ar-H), 126.63 (Ar-H), 127.00
(Ar-H), 127.15 (C), 128.19 (Ar-H), 128.91 (C), 132.37 (C),
141.47 (C), 144.73 (C). MS (m/z, %): 293 (M+, 97), 250
(100).
The above route to annoretine is currently being
applied to the synthesis of litebamine and a series of
non-natural tetrahydronaphtho[2,1-f ]isoquinolines with
a view to systematic study of their chemical and biolog-
ical properties.
(b) Crystallographic data for annoretine (6): C19H19NO2,
(
M=293.35, T=293(2) K. Triclinic, space group P1 with
,
a=11.5575(17), b=12.0696(16), c=13.271(3) A; h=
Acknowledgements
112.933(13), i=111.403(14), k=97.794(14)°; U=
3
1501.7(4) A , Dcalcd (Z=4)=1.298 g cm−3. F(000)=624,
,
v(Cu Ka)=6.66 cm−1; 6453 unique data (2qmax=150°),
6177 with I>2|(I); conventional R1[I>2|(I)]=0.0413,
wR2 [all data]=0.1323, GOF [all data]=1.017. Data were
obtained on an Enraf–Nonius CAD4-Mach3 diffractome-
The authors would like to thank the Xunta de Galicia
and the Spanish Ministry of Education, Culture and
Sports for financial support.
,
ter (graphite crystal monochromator, u=1.5418 A) using
the ꢀ=2q 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 F2 (SHELXL-93)
References
1. Wu, Y.-C.; Chang, G.-Y.; Duh, C.-Y.; Wang, S.-K.
2
2 2
2 2 1/2
Phytochemistry 1993, 33, 497.
using all data; wR2=[(ꢀw(Fo −Fc ) /ꢀw(Fo ) ]
.
.
.