Radical cyclization of N-acylcyanamides: Total synthesis of luotonin A

Article abstract of DOI:10.1002/anie.200602940

(Chemical Equation Presented) As radical chain cascade precursors, N-acylcyanamides give rise to amide-iminyl radicals which, when appropriately substituted, can finally yield pyrroloquinazolines. The versatility of these new radical acceptors is illustrated by the formation of N-heterocycles with wide structural variation and by the total synthesis of luotonin A.

Full text of DOI:10.1002/anie.200602940

Communications
DOI: 10.1002/anie.200602940
Polynitrogenated Heterocycles
Radical Cyclization of N-Acylcyanamides: Total Synthesis of
Luotonin A**
Aurore Servais, MØriam Azzouz, David Lopes, Christine Courillon,* and Max Malacria*
In memory of Marcial Moreno-Maæas
Heterocyclic compounds are of particular interest in medic-
inal science. This has accelerated the quest for new methods
in heterocyclic chemistry. A particular class of alkaloids that
incorporate the pyrroloquinazoline chromophore have been
isolated from natural sources[1] and display a wide range of
biological activities.[2] Amongthem, luotonin A is a human
DNA topoisomerase I poison, which has been isolated from
Peganum nigellastrum, a Chinese medicinal plant.[3] Ma et al.
have examined the biological activity of luotonin A and its
analogues,[4] and Jahnget al. have described structure–activity
studies on this class of compounds.[5] Luotonin A is cytotoxic
toward the murine leukemia P388 cell line[3] by stabilizingthe
topoisomerase I/DNA complex.[6] This has established luoto-
nin A as an attractive pyrroloquinazoline target for total
synthesis. It appeared to us that we could build the
pyrroloquinazoline moiety from N-acylcyanamide radical
precursors.
N-acyl-N-(2-iodobenzyl)-cyanamides 3 were obtained by
two different synthetic methods. Acylation of 2-iodobenzyl-
amine (1) gave 2-iodobenzylamides 2a–k, which reacted with
cyanogen bromide under basic conditions to yield N-acylcya-
namides 3a–k in generally good yields (method A, Tab-
le 1).The electrophilic character of the cyanogen bromide
reagent limits this acylation/cyanation sequence when nucle-
Table 1: Preparation of N-acyl-N-(2-iodobenzyl)cyanamides 3a–k by an
acylation/cyanation sequence (method A).
R
Amide
Yield [%]
N-acylcyanamide
2
3
Yield [%]
Our interest in radical cyclization cascades,[7,8] especially
in the field of heterocyclic synthesis[9,10,11] prompted us to
examine an unprecendented strategy introducing N-acylcya-
namides as novel radical acceptors. Indeed, to the best of our
knowledge, no radical reaction involving these moieties has
appeared in the literature. Synthesizingthe N-acylcyanamides
substrates was challenging: the preparation of N-acetyl- and
N-benzoylcyanamides and some of their derivatives has been
reported, but those molecules often show a lack of stabil-
ity.[12–15] As N-acylcyanamides display properties in other
fields, for instance, as prodrugs of cyanamide,[13] enzymatic
inhibitors[16] and heteroanalogues of ethylenes,[17] there is also
an interest in their practical synthesis. We report herein the
preparation of stable N-acyl-N-(2-iodobenzyl)cyanamides
and their use as radical partners in cyclization cascade
processes, which led to the total synthesis of luotonin A.
C6H5
2a
2b
2c
2d
2e
2 f
2g
2h
2i
86
44
60
73
90
78
57
73
3a
3b
3c
3d
3e
3 f
3g
3h
3i
73
68
58
33
86
47
28
61
49
17
p-NO2-C6H5
p-CF3-C6H5
p-CN-C6H5
p-CO2Me-C6H5
p-Br-C6H5
p-OMe-C6H5
p-C5H5N
m-C5H5N
56
>98[6]
2j
3j
2k
>98[6]
3k
20
ophiles are present in the molecule. For example, N-acylcya-
namides 3g and 3j,k were obtained in lower yields, probably
because of the possible reaction of cyanogen bromide with the
the electron-rich unsaturated compounds 2g and 2j,k.[18]
Sensitive substrates were obtained by installingthese unsa-
turated bonds in the last step.
When the steps were reversed, 2-iodobenzylamine (1)
provided the desired substrates in much better yields through
a cyanation/acylation pathway (method B, Table 2).[19] The
vinylic precursors 3j–l were obtained in good yields, and so
were N-acylcyanamides 3m,n, in which the amide function is
in conjugation with furyl (73%) and thienyl substituents
(74%).
[*] A. Servais, M. Azzouz, D. Lopes, Prof. C. Courillon, Prof. M. Malacria
Laboratoire de Chimie Organique, UMR CNRS 7611
Institut de Chimie MolØculaire, FR 2769
UniversitØ Pierre et Marie Curie, Paris 6, case 229
4, place Jussieu, 75252 Paris (France)
Fax: (+33)1-4427-7360
E-mail: christine.courillon@paris7.jussieu.fr
max.malacria@upmc.fr
[**] M.M. is a senior member of the Institut Universitaire de France. The
authors thank IUF, Minist›re de la Recherche, CNRS, and Institut de
Recherche Pierre Fabre (grant to A.S.) for financial support. Dr.
Emmanuel Lacôte (UPMC-CNRS) is gratefully acknowledged for his
suggestions concerning the organization of this manuscript.
We wanted to probe whether the aryl radical obtained
from 3a–m could be trapped by the triple bond of the
cyanamide in a 5-exo-digcyclization process, and whether the
resultingradical could be captured by an unsaturated bond
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
576
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Angew. Chem. Int. Ed. 2007, 46, 576 –579

Angewandte
Chemie
Table 2: Preparation of N-acyl-N-(2-iodobenzyl)cyanamides 3a–n by a
cyanation/acylation sequence (method B).
Table 3: Radical cyclization cascade of N-acyl-N-(2-iodobenzyl)cyana-
mides 3 to give heterocyclic compounds 9 and 10.
Entry R, Precursor
1
Product
Yield [%]
71
R
Product
Yield
[%]
R
Product
Yield
[%]
3a
3c
3d
3e
3h
9a
9c
9d
9e
9h
3a
3j
74
70
67
3l
54
73
74
2
3
4
5
72
99
74
56
3m
3n
3k
conjugated to the amide function. Iminyl radical chemistry
has been thoroughly studied in the last decade[20] and was
recently applied to the synthesis of heteroarenes,[21] notably
by means of radical cascade cyclizations.[22] Nevertheless, N-
acylcyanamides differ from both nitriles and ynamides[10] in
that they have an additional nitrogen atom. Original reac-
tivities and access to polynitrogenated alkaloid stuctures
might be anticipated.
79
9i/10
2.2:1
6
7
8
9
3i
Under standard radical conditions, simple N-acetylcyana-
mide 6 was transformed into 2-cyanobenzylacetamide (8)
(53% yield, Scheme 1). Radical 7 is formed after an initial 5-
3j
9j
66
71
cis/trans
1.56:1
3k
3n
9k
9n
57
Scheme 1. 5-exo-dig cyclization of substrate 6.
the unsaturated moiety and subsequent aromatization (or
reduction in the case of vinylic derivatives); 2) [1,5] ipso
substitution followed by rearrangement, thus providing
cyclization compounds 9.[24] Our preliminary studies in this
direction remain inconclusive. Further investigations are
beyond the scope of this report and will be the subject of
future reports.
We then decided to use this new access to pyrroloquinazo-
lines as the key step for the total synthesis of luotonin A.[25,2d]
A few strategies reported so far involve radical cyclization.
For example, Bowman et al. used an intramolecular cascade
radical cyclization involving4-oxo-3,4-dihydroquinazoline-2-
carbonitrile in the step leadingto the luotonin frame-
work.[26,9a] Curran et al. synthesized luotonin A and a small
library of AB-ring-substituted analogues using a bimolecular
radical cascade employingarylisonitrile and propargylquina-
zolones.[27]
À
exo-digcyclization and undergoes N C bond cleavage prior
to reduction. This transfer has been observed with nitriles.[23]
This preliminary result made us confident that N-acylcyana-
mides 3a–m could be designed precursors for domino
processes. Indeed, they generally reacted smoothly, giving
rise to new pyrroloquinazoline heterocycles in 56–99% yield
(Table 3). Only N-(2-iodobenzyl)-N-(4-nitrobenzoyl)cyana-
mide (3b) and furanoyl cyanamide 3m did not react under
radical conditions. The nitro group in 3b was reduced by
tributyltin hydride and degraded upon further exposure to the
radical conditions.
N-(2-iodobenzyl)-N-(cyclohexanoyl)cyanamide
3k
cyclized in good (71%) yield (1.56:1 mixture of the two
diastereomers of tetracyclic compound 9k). The minor
diastereomer crystallized out. X-ray diffraction analysis
showed that the minor product has a trans ringjunction,
indicatingthat the major diastereomer is the cis one (entry 8,
Table 3).
The intermediate radical resultingfrom the attack of the
aromatic radical on the cyanamide triple bond could react
further followingtwo pathways: 1) 6- endo-trigaddition onto
We considered creatingthe pyrroloquinazoline skeleton
of luotonin A by cyclization of N-acylcyanamide 13
(Scheme 2). Azide 11 was prepared from commercially
available quinoline chlorocarbaldehyde in four steps (56%
overall yield).[28] Staudinger reduction of the azide delivered
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577

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Scheme 2. Total synthesis of luotonin A. Reaction conditions: a) PPh3,
THF, H2O; b) benzoyl chloride, Et3N, CH2Cl2, 47% (two steps);
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an amine, which was benzoylated to give amide 12 in 47%
yield (two steps). Cyanation of amide 12 usingmethod A
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refluxingtoluene under irradiation for 6 h successfully
yielded luotonin A in 43% yield.
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Received: July 21, 2006
Revised: October 5, 2006
Published online: December 8, 2006
Keywords: alkaloids · cyanamides · cyclization ·
.
nitrogen heterocycles · radicals
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