1,5-Electrocyclisation of azomethine ylides leading to pyrrolo[2,1-a] isoquinolines - Concise construction of the lamellarin skeleton

Article abstract of DOI:10.1016/j.tetlet.2005.08.165

A new, general route to the 1,2-diaryl-substituted pyrrolo[2,1-a] isoquinolines has been developed via the 1,5-dipolar electrocyclisation reactions of azomethine ylides derived from readily available stilbenic acid derivatives. This method was applied to the concise construction of a lamellarin skeleton.

Full text of DOI:10.1016/j.tetlet.2005.08.165

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7531–7534
1,5-Electrocyclisation of azomethine ylides leading to
pyrrolo[2,1-a]isoquinolines—concise construction of
the lamellarin skeleton
*
}
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´
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Miklos Nyerges and Laszlo Toke
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology,
Technical University of Budapest, PO Box 91, H-1521 Budapest, Hungary
Received 28 June 2005; revised 25 August 2005; accepted 31 August 2005
Available online 19 September 2005
Abstract—A new, general route to the 1,2-diaryl-substituted pyrrolo[2,1-a]isoquinolines has been developed via the 1,5-dipolar elec-
trocyclisation reactions of azomethine ylides derived from readily available stilbenic acid derivatives. This method was applied to the
concise construction of a lamellarin skeleton.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The 1,3-dipolar cycloaddition of azomethine ylides rep-
resents perhaps the most important example of the vari-
ety of reaction pathways available to these dipoles.1
There are, however, many other synthetically useful
reactions of these dipoles, including the 1,5-electrocyclic
ring closure of appropriately substituted dipolar sys-
tems.2 Recently, we3 and others4 published the first
examples of the 1,7-electrocyclisation of azomethine
ylides with a,b:c,d-unsaturation.5 This method was
shown to be general for the annelation of a benzazepine
ring to different heterocycles in one step.6
The starting materials for this study were prepared via
the appropriate stilbenic acids 6 (themselves readily
available from substituted benzaldehydes 4 and phenyl-
acetic acids 5) by the treatment of the corresponding
acid chlorides with a slight excess of 2-(3,4-dimethoxy-
phenyl)ethylamine 7. The cyclisation of amide 8 was car-
ried out using the Bischler–Napieralski procedure,8 in
the presence of POCl3, resulting in the formation of
3,4-dihydroisoquinolines 9. The subsequent reaction of
these isoquinolines 9 with various bromoalkyl deriva-
tives in anhydrous ether gave the quaternary salts 10
(Scheme 2).
We have also demonstrated the first 1,7-electrocyclisa-
tion of azomethine ylides (2, R1 = H, R2 = Ph) stabi-
lised with an electron-withdrawing group (R = e.g.,
CO2Me), providing a useful route to the tetrahydro-
To our surprise, reacting these isoquinolinium salts 10a
(R5 = CO2Et, CH@CH2) with triethylamine at ambient
temperature in dry ethanol, did not give the expected
tetrahydro-benz[5,6]azepino[2,1-a]isoquinolines 3, origi-
nating from a 1,7-electrocyclisation, but the pyrrole
derivatives 12a (R5 = CO2Et, CH@CH2) were obtained,
after column chromatography, in 52–59% yield (Scheme
2).
benz[5,6]azepino[2,1-a]isoquinoline ring system
3
(Scheme 1).7
As a continuation of these studies, we have examined
the reactivity of some closely related azomethine ylides
(2, R1 = Ar, R2 = H) and investigated the effect of the
additional aryl substituents (G) on the course of the
1,7-electrocyclisation process.
We propose that the mechanism for the formation of
these pyrroles involves the 1,5-electrocyclisation of the
azomethine ylide, followed by the aerobic oxidation of
the 11 pyrroline intermediate, which was not isolated
in these cases.
Keywords: Alkaloids; Electrocyclic reactions; Isoquinolines; Pyrroles.
In the reaction of isoquinolinium salt 10a (R5 = Ph)
*
Corresponding author. Tel.: +36 14632213; fax: +36 14633648;
e-mail: mnyerges@mail.bme.hu
with base, using similar conditions, a white precipitate
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.165

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M. Nyerges, L. Toke / Tetrahedron Letters 46 (2005) 7531–7534
7532
MeO
MeO
MeO
MeO
MeO
MeO
Br
R
H
R
i
N
R
N
N
R1 = H
H
R2 = Ph
R1
R1
R2
R2
G
Ph
G
G
3
2
1
Scheme 1. Reagents and conditions: (i) Et3N, EtOH, rt.
CHO
R3
CO2H
R3
R4
CO2H
ii. then
i
4
MeO
+
R4
NH2
R1
MeO
R2
7
6
R1
5
R2
MeO
MeO
MeO
R3
3
R
N
O
N
iv
iii
MeO
R1
H
R4
R4
R1
R2
R2
8
9
MeO
MeO
MeO
Br
R5
N
v
N
R5
MeO
R1
R3
R4
R4
11
R2
R3
10
1
R
R2
MeO
MeO
"O"
N
R5
a R1 = MeO, R2 = R3 = R4 = H
b R1 = MeO, R2 = R4 = H, R3 = NO2
c R1 = MeO, R2 = R4 = H, R3 = MeO
d R1 = R2 = MeO, R3 = H, R4 = OCH2CH=CH2
R4
R3
R5 = CO2Et, Ph, CH=CH2
R1
R2
12
Scheme 2. Reagents and conditions: (i) Et3N, Ac2O, reflux (48–66%); (ii) SOCl2, reflux (90–95%); (iii) POCl3, toluene, reflux (90–96%); (iv) BrCH2R5,
Et2O, rt (95–98%); (v) Et3N, EtOH, rt (52–68%).
was collected (in 55–68% yield) and the expected pyr-
role derivative 12a (R5 = Ph) was isolated from the
filtrate, but only in 5–12% yield. The main crystalline
product proved to be the pyrroline derivative 11a
(R5 = Ph). The relative stereochemistry of this cyclo-
adduct was deduced by NOE studies. Similar results
were obtained with two isoquinolinium bromide ana-
logues (10b and 10c).
We next examined the synthesis of the lamellarin skele-
ton using this 1,5-electrocyclisation methodology.
The lamellarins, described for the first time in 1985 by

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M. Nyerges, L. Toke / Tetrahedron Letters 46 (2005) 7531–7534
7533
MeO
MeO
MeO
MeO
HO
N
CO2Et
O
O
i
N
N
O
MeO
O
O
MeO
OH
OMe
MeO
MeO
OMe
OMe
OH
Lamellarin D
12d
13
Scheme 3. Reagents and conditions: (i) 10% Pd/C, TsOH, EtOH, H2O, reflux (68%).
Faulkner and co-workers,9 are a group of approxi-
mately 40 compounds, isolated from marine inverte-
ject No. T 046196). N.M. thanks the Hungarian Acad-
emy of Sciences, for a Bolyai J. fellowship.
brates such as sponges, tunicates and molluscs.10
A
wide array of interesting biological activity has been
found in the lamellarins, including inhibition of cell divi-
sion, cytotoxicity (against several multidrug-resistant
cell lines),11 HIV-1 integrase inhibition12 and immuno-
modulatory activity.10a Lamellarin D (Scheme 3) was
also found to be a novel potent inhibitor of topoisomer-
ase I.13 To establish some structure–activity relation-
ships (SAR) and to find out the mechanism of action
of these alkaloids, relatively large quantities of lamella-
rins are required. However, because the natural sources
of lamellarins provide these compounds in only small
quantities, total synthesis is a vital alternative in provid-
ing these compounds. In order to satisfy this demand, a
number of research groups have reported elegant strate-
gies for total syntheses of lamellarins14 including solid-
phase methods.15
References and notes
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129.
Based on the results depicted in Scheme 2, we have
developed a simple, general method for the synthesis
of the core of the lamellarin alkaloids. The synthesis
starts from O-allylsalicylaldehyde 4d and in five steps
gives the pyrrole derivative (12d, R5 = CO2Et) in 31%
yield. Removal of the allylic protecting group by Pd/C
in the presence of TsOH16 resulted in the formation of
pyrroloisoquinoline 13, containing the 8,9-dihydro-6H-
chromeno[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one skele-
ton of some of the lamellarin alkaloids (Scheme 3),17
in one step via simultaneous lactone formation.
´
}
´
´
6. (a) Nyerges, M.; Pinter, A.; Viranyi, A.; Bitter, I.; Toke, L.
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¨
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¨
´
}
´
´
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Lett. 2003, 44, 793–794.
´
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In summary, we have explored a convenient reaction
sequence which provides a useful route to pyrrolo[2,1-
a]isoquinoline ring system via the 1,5-dipolar electrocy-
clisation reactions of azomethine ylides derived from eas-
ily available stilbenic acid derivatives.18 The synthesised
pyrrolo[2,1-a]isoquinolines—as we have demonstrated
in one example—could be novel building blocks for
the synthesis of otherwise difficultly obtainable lamella-
rin alkaloids and analogues.
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Acknowledgements
This work was financially supported by the National
Fund for Science and Research, Hungary (OTKA Pro-

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M. Nyerges, L. Toke / Tetrahedron Letters 46 (2005) 7531–7534
7534
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H-10), 6.72 (d, 2H, J 8.8 Hz, Ar1–3 and 5H), 6.60 (s, 1H,
H-7), 4.17 and 4.16 (2 · d, 2H, J 11.9 Hz, H-2 and H-3),
3.83 (s, 3H, 8-OMe), 3.66 (s, 3H, OMe), 3.32 (s, 3H, 9-
OMe), 3.19 (m, 1H, H-6), 3.07 (m, 1H, H-5), 2.84 (m, 1H,
H-5), 2.78 (m, 1H, H-6); 13C NMR (125 MHz, CDCl3):
157.9 (q), 148.6 (q), 146.6 (q), 142.2 (q), 141.6 (q), 140.3
(q), 131.3 (2 · CH), 130.5 (q), 129.3 (2 · CH), 128.2
(2 · CH), 128.1 (q), 127.9 (2 · CH), 127.3 (2 · CH),
127.2 (CH), 126.3 (CH), 121.2 (q), 113.7 (2 · CH), 112.4
(q), 110.6 (CH), 109.3 (CH), 78.6 (CH), 64.0 (CH), 55.7
(CH3), 55.0 (CH3), 54.95 (CH3), 46.9 (CH2), 29.9 (CH2).
Compound 12d (R5 = CO2Et): 1H NMR (500 MHz,
CDCl3): 7.50 (d, 1H, J 7.8 Hz, Ar2–30H), 7.25 (t, 1H, J
7.8 Hz, Ar2–40H), 7.13 (t, 1H, J 7.8 Hz, Ar2–50H), 7.02 (d,
1H, J 7.8 Hz, Ar2–60H), 6.79–6.69 (m, 5H, H-7, H-10, and
Ar1–H), 5.82 (m, 1H, allyl–CH), 5.14 (m, 2H, allyl–CH2),
4.53 (m, 2H, allyl–CH2), 4.00 (m, 2H, H-6), 3.90 (s, 3H,
OMe), 3.86 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.59 (s, 3H,
OMe), 3.36 (s, 3H, OMe), 3.05 (t, 2H, J 6.6 Hz, H-5); 13C
NMR (125 MHz, CDCl3): 162.0 (q), 156.5 (q), 148.4 (q),
148.0 (q), 147.5 (q), 147.2 (q), 138.7 (CH), 133.9 (CH),
132.2 (CH), 130.8 (q), 129.0 (q), 128.4 (q), 127.8 (CH),
127.4 (q), 125.9 (q), 124.4 (CH), 123.1 (CH), 121.7 (q),
121.2 (q), 119.8 (q), 116.4 (CH2), 116.3 (CH), 114.1 (CH),
111.9 (CH), 110.8 (CH), 108.8 (CH), 69.0 (CH2), 59.5
(CH2), 56.1 (CH3), 55.9 (CH3), 55.8 (CH3), 55.3 (CH3),
42.8 (CH2), 29.1 (CH2), 13.6 (CH3). Compound 13: 1H
NMR (500 MHz, CDCl3): 7.37 (d, 1H, J 8 Hz, H-4), 7.27
(t, 1H, J 8 Hz, H-3), 7.23 (d, 1H, J 8 Hz, H-1), 7.07 (m,
2H, Ar14–50 and 60H), 7.02 (s, 1H, Ar14–20H), 7.00 (t, 1H,
J 8 Hz, H-2), 6.76 (s, 1H, H-13), 6.66 (s, 1H, H-10), 4.81
(m, 2H, H-8), 3.99 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.85
(s, 3H, OMe), 3.36 (s, 3H, OMe), 3.12 (t, 2H, J 7.0 Hz, H-
9); 13C NMR (125 MHz, CDCl3): 155.2 (q), 151.2 (q),
149.8 (q), 149.0 (q), 148.9 (q), 147.5 (q), 136.1 (q), 127.8
(q), 127.5 (q), 127.3 (CH), 126.6 (q), 123.7 (CH), 123.3
(CH), 123.25 (CH), 120.0 (q), 118.3(q), 117.1 (CH), 115.8
(q), 114.5 (q), 113.7 (CH), 112.0 (CH), 110.9 (CH), 108.7
(CH), 56.1 (2 · CH3), 55.9 (CH3), 55.1 (CH3), 42.5 (CH2),
28.7 (CH2).
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CDCl3): 7.29–7.25 (m, 5H, Ph3–H), 7.18–7.12 (m, 5H,
Ph2–H), 7.09 (d, 2H, J 8.8 Hz, Ar1–2 and 6H), 6.92 (s, 1H,
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