Annulations of isoquinoline and β-carboline ring systems: Synthesis of 8-oxoprotoberberine derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.085

Annulation processes of isoquinoline and β-carboline compounds have been investigated leading to synthetic routes for the preparation of 8-oxoprotoberberine derivatives. The key steps combined a diene formation/Diels-Alder cycloaddition reaction to afford

Full text of DOI:10.1016/j.tetlet.2011.03.085

Tetrahedron Letters 52 (2011) 2733–2736
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Annulations of isoquinoline and b-carboline ring systems: synthesis
of 8-oxoprotoberberine derivatives
Suren Husinec a, Vladimir Savic b, , Milena Simic b, Vele Tesevic c, Dragoslav Vidovic d
⇑
a Institute for Chemistry, Technology and Metallurgy, Centre for Chemistry, PO Box 815, Njegoseva 12, 11000 Belgrade, Serbia
b University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
c University of Belgrade, Faculty of Chemistry, Studentski Trg 12-16, 11000 Belgrade, Serbia
d Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Annulation processes of isoquinoline and b-carboline compounds have been investigated leading to syn-
thetic routes for the preparation of 8-oxoprotoberberine derivatives. The key steps combined a diene for-
mation/Diels–Alder cycloaddition reaction to afford the targeted polycyclic skeletons. Further oxidative
transformations of the cycloadducts produced the 8-oxoprotoberberine type products. The alkaloids of
this class are important natural products with a wide range of biological activity and the synthethic
methodology described in this paper could prove to be useful for the preparation of the D-ring function-
alised derivatives.
Received 27 January 2011
Revised 2 March 2011
Accepted 18 March 2011
Available online 11 April 2011
Keywords:
Isoquinoline
Annulations
Ó 2011 Elsevier Ltd. All rights reserved.
8-Oxoprotoberberine skeletons
Synthesis
MeO
MeO
O
O
Protoberberines are a large class of naturally occurring isoquin-
oline alkaloids derived from tetracyclic structure 1.1 The rings A
and D are usually substituted and aromatised while the oxidation
state of the ring C is variable. These compounds show a broad spec-
trum of biological properties and as such they have been the sub-
ject of intensive research.2
N
O
N
O
OMe
OMe
OMe
8-oxyberberine
8-oxypseudopalmatine
OMe
5
4
Figure 1. Structure of some 8-oxoprotoberberines.
3
6
R
R
R
A
1
B
N
N
7
N
C
8
R
2
tion of the D ring. In addition, we anticipated the synthesis of an
intermediate structure that potentially may be transformed into
various classes of related alkaloids.
14
13
R
R
9
R
R
D
3
12
10
The fact that protoberberines differ in the oxidation state of the
C ring led us retrosynthetically to alkene 2, which was expected to
undergo oxidative transformations to produce the 8-oxoprotoberb-
erine skeleton. Cyclohexene derivative 2 may be accessible via
Diels–Alder cycloaddition reaction of diene 3.
To explore the above strategy, diene 4 was synthesised as out-
lined in Scheme 1. Quaternisation of the isoquinoline ring using
an allyl bromide derivative afforded salt 5 in good yield.5 A second
allylation of the ring was achieved with the appropriate Grignard
reagent producing compound 6.6 The enamino functionality of
the crude product was then reduced under standard conditions
to afford tetrahydroisoquinoline product 7 in 70% overall yield over
two steps.7
1
2
11
These structural variations have attracted attention from organ-
ic chemists and a number of methods for the preparation of these
systems have been reported in the literature.3 Formation of either
ring B or C represents the key step in the majority of these syn-
thetic procedures, while aromatic moieties A and D are usually
incorporated into the structures of the starting materials.
Our interest in the anticancer properties4 of these compounds,
in particular 8-oxoprotoberberines (Fig. 1), has prompted us to de-
sign an approach that would allow straightforward functionalisa-
Finally, the cyclisation process, carried out under typical Heck
⇑
Corresponding author. Tel.: +381 11 3951 243; fax: +381 11 3972 840.
E-mail address: vladimir.savic@pharmacy.bg.ac.rs (V. Savic).
reaction conditions afforded diene 4.8 With diene 4 in hand, we
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.085

2734
S. Husinec et al. / Tetrahedron Letters 52 (2011) 2733–2736
Br
Br
I
_
+
Br
N
I
N
N
MeCN
Δ
85%
Mg
Et2O
6
5
I
MeOH
HCl
NaBH3CN
70%
Pd(OAc)2
N
N
I
PPh3
K2CO3
MeCN
70%
4
7
Scheme 1.
Figure 2. X-ray (SHELXL/XP) crystal structure of 10.
The Diels–Alder cycloaddition9 reaction employing dimethyl
acetylenedicarboxylate (DMAD) under thermal conditions afforded
cyclohexadiene 9 which was then submitted to oxidative transfor-
mation in the presence of MnO2.10 This reaction produced 8-oxo-
protoberberine derivative 10 in 45% yield. Analysis of the NMR
data supported the above structure.
R
R
R
N
R
R
N
O
R
MnO2
N
DMAD
1,4-dioxane
toluene
Δ
COOMe
COOMe
9 R = H
COOMe
COOMe
10 R = H
Δ
Compared to the starting material 9, the 13C NMR data of prod-
uct 10 suggested the presence of an additional carbonyl group (d
161.3). Analysis of the 1H NMR spectrum showed three singlets
for protons belonging to the rings C and D, with a signal at d 7.03
(C13-H) which is typical for these compounds. The structure of
compound 10 was also confirmed by single crystal X-ray analysis,
Figure 2.11
45%
90%
4 R = H
8 R = OMe
Scheme 2.
explored further transformations towards 8-oxoprotoberberine
structures (Scheme 2).
Table 1
Synthesis of 8-oxoprotoberberine derivatives
Entry
Diene
Dienophile
Producta
Yieldc (%)
Productb
Yieldc (%)
N
a
4
EtOOC–N@N–COOEt
66
N
COOEt
11a
N
COOEt
O
N
N
O
O
N
Ph
O
O
b
4
85d
66
12a
11b
NPh
NPh
O
O
O
O
N
N
N
N
45
43
50
12b
11c
COOMe
COOMe
COOMe
c
4
8
75e
65
COOMe
COOMe
12b'
11c'
MeOOC
COOMe
O
d
N
N
MeO
MeO
MeO
MeO
COOMe
COOMe
Reaction conditions: diene (0.2 mmol), dienophile (0.24 mmol), toluene (5 mL), 12 h, 110 °C.
COOMe
COOMe
12c
11d
a
b
c
Reaction conditions: 11 (0.1 mmol), MnO2 (10 mmol), 1,4-dioxane (20 mL), 70 °C (oil bath temperature), 72 h.
Isolated yield after column chromatography.
Isolated as a mixture of diastereomers.
11c: 11c0 product ratio = 1:1.2.
d
e

S. Husinec et al. / Tetrahedron Letters 52 (2011) 2733–2736
2735
Br
Br
Pd(OAc)2
I
_
+
Br
N
I
N
N
I
N
N
N
MeCN
Δ
N
Mg
N
PPh3
K2CO3
MeCN
48%
H
H
H
H
Et2O
80%
14
13
15
42%
toluene
Δ
DMAD
70%
MnO2
N
O
N
N
N
H
H
1,4-dioxane
23%
16
17
COOMe
COOMe
COOMe
COOMe
Scheme 3.
Using the above described procedure, several 8-oxoprotoberbe-
rines were synthesised as outlined in Scheme 2 (Table 1). The
cycloaddition steps were carried out with a slight excess of dieno-
phile (1.2 equiv), under thermal conditions, affording the products
in yields ranging from 65% to 85%. In the reaction with N-phenyl-
maleinimide (entry b, Table 1) a mixture of exo and endo cycload-
ducts was isolated. The products were obtained in a 2:1 ratio, but
analysis of the NMR data did not suggest unambiguously the struc-
ture of the major component. The nonsymmetrical dienophile,
methyl propiolate (entry c, Table 1), produced two regioisomeric
products, 10- and 11-substituted, in a 1:1.2 ratio. The structures
of the regioisomers were elucidated by NOESY experiments. The
cycloaddition reaction with diethyl azodicarboxylate (entry a,
Table 1) can also be performed at room temperature giving compa-
rable results to those shown. The unoptimised oxidation step was
carried out using an excess of MnO2 to afford the 8-oxoprotoberb-
erine products in moderate to good yields.
Acknowledgements
Financial support from the Serbian Ministry of Science (Grant
no 172009) is greatly appreciated. We thank the Faculties of Phar-
macy and Chemistry, Belgrade University, for their assistance. D.V.
would like to thank NTU (SPMS and CBC) for the start-up grant. We
also thank Dr. Alexander E.A. Porter for helpful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.085.
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