Diversity-oriented synthesis of polycyclic diazinic scaffolds

Article abstract of DOI:10.1021/ol203364b

An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity.

Full text of DOI:10.1021/ol203364b

ORGANIC
LETTERS
2012
Vol. 14, No. 3
844–847
Diversity-Oriented Synthesis of Polycyclic
Diazinic Scaffolds
Nicolas Gigant, Elise Claveau, Pascal Bouyssou, and Isabelle Gillaizeau*
Institut de Chimie Organique et Analytique, UMR 7311 CNRS, rue de Chartres,
ꢀ
Universite d’Orleans, F-45067 Orleans Cedex 2, France
ꢀ
ꢀ
Isabelle.gillaizeau@univ-orleans.fr
Received December 16, 2011
ABSTRACT
An efficient and versatile synthesis of a polycyclic diazinic system starting from oxazine has been developed using a two-step Michael/retro
Michael and cyclization sequence. The substrates were synthesized with good to high yields giving rapid access to molecular diversity.
The continuing demand to synthesize new and original
collections of small molecules with useful therapeutic
properties1 and also to understand the mechanisms that
control biological processes2 has required the development
of fast and easy synthetic methods. In this context, diversity-
oriented synthesis (DOS) continues to be an essential area
to generate libraries of molecules by varying functional
groups, building blocks, stereochemistry, and molecular
frameworks to obtain molecular diversity.3 By controlling
all of these parameters, the total synthesis of natural
products can be envisaged to find potential new leads for
drug discovery. Considerable research has been carried
out in recent years to develop new and efficient methods
to increase the scaffold diversity present in compound
libraries. Privileged heterocyclic structures are attractive
for drug discovery because of the high hit rates and the
pharmacological profiles of their derivatives relative to
those of other ring systems. Polycyclic diazinic systems are
omnipresent in various alkaloids (i.e., saframycin,
naphthyridinomycin, quinocarcin, etc.) that exhibit a wide
array of biological activities, including antitumor4 and
antiparkinsonian properties.5 Accordingly, these polycyclic
diazinic structures are also attractive targets for the syn-
thesis of pharmaceutical agents.6 As part of our ongoing
research program toward the development of efficient
methodologies to generate biologically relevant molecules,
we recently reported an efficient Michael/retro-Michael
sequence that allows the synthesis of a range of diazinic
frameworks.7,8 Accordingly, the prepared pivotal hemi-
aminal 2 was easily transformed via a nucleophilic addi-
tion into various polycyclic diazinic derivatives (Figure 1).
Although the structures of compounds I and IVÀVII
derived from 2 are mostly known,4À6 little else is known
(5) Moldvai, I.; Temesvari-Major, E.; Incze, M.; Doernyei, G.;
Szentirmay, E.; Szanty, C. Helv. Chim. Acta 2005, 88, 1344–1356.
(6) (a) Tang, H.; Zheng, C.; Lv, J.; Wu, J.; Li, Y.; Yang, H.; Fu, B.; Li,
C.; Zhou, Y.; Zhu, J. Bioorg. Med. Chem. Lett. 2010, 20, 979–982. (b)
Hudack, R. A., Jr.; Barta, N. S.; Guo, C.; Deal, J.; Dong, L.; Fay, L. K.;
Caprathe, B.; Chatterjee, A.; Vanderpool, D.; Bigge, C.; Showalter, R.;
Bender, S.; Augelli-Szafran, C. E.; Lunney, E.; Hou, X. J. Med. Chem.
2006, 49, 1202–1206. (c) Dong, Y.; Chollet, J.; Vargas, M.; Mansour,
N. R.; Bickle, Q.; Alnouti, Y.; Huang, J.; Keiser, J.; Vennerstrom, J. L.
Bioorg. Med. Chem. Lett. 2010, 20, 2481–2484.
(7) Claveau, E.; Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org.
Chem. 2007, 72, 4832–4836.
(8) (a) Claveau, E.; Gillaizeau, I.; Kalinowska-Tluscik, J.; Bouyssou,
P.; Coudert, G. J. Org. Chem. 2009, 74, 2911–2914. (b) Claveau, E.;
Gillaizeau, I.; Coudert, G. Tetrahedron Lett. 2009, 50, 3679–3682.
(1) Schreiber, S. L. Nature 2009, 457, 153–154.
(2) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197–201.
(3) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46–58. (b) Horton, A. H.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893–930. (c) Spandl, R. J.; Bender, A.; Spring, D. R. Org.
Biomol. Chem. 2008, 6, 1149–1158.
(4) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–1730.
(b) Wright, B. J. D.; Chan, C.; Danishefsky, S. J. Nat. Prod. 2008, 71,
409–414. (c) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev.
2008, 37, 2676–2690.
r
10.1021/ol203364b
Published on Web 01/19/2012
2012 American Chemical Society

regarding the biological activity of compounds having the
analogue substructures II or III. Therefore, the present
article is devoted to the investigations in our laboratory on
a further expansion of our initial discovery that provides
ready access to various privileged structures containing a
diazinic framework.
Table 1. Reaction with Varying Heteroaromatic-3-alkylamines
addition step
yielda (%)
cyclization step
yielda (%)
entry
n
X
1
2
3
4
5
0
1
2
1
1
NH
NH
NH
O
2a (84)
2b (95)
2c (80)
2d (74)
2e (74)
3a (0)
3b (78)
3c (11)
3d (82)
3e (46)
S
a Yield of pure product after purification by column chromatography.
the Michael/retro-Michael sequence with heteroaromatic
3-alkylamines containing either a nitrogen, an oxygen or
a sulfur atom (Table 1). Sequential treatment of 1 with
tryptamine (1 equiv) and with TFA (2 equiv) in the
presence of pyridine (1 equiv) provided in two steps, the
desired adduct 2b in 95% yield and then the cyclized
product3bin78%yield (entry2). The presenceofpyridine,
in the cyclization step, was required to buffer the reaction
medium and to avoid the concomitant Boc group cleavage
which will lead otherwise to a rapid decomposition of
the unstable enamine intermediate. Indole-3-alkylamines
bearing different sizes of chains were also investigated.
Although the Michael/retro-Michael sequence afforded
in each case the desired hemiaminal intermediate
(respectively 2a or 2c) in good yields (entries 1 and 3),
poor yields were unfortunately obtained for the cyclization
step (product 3a or 3c). It is noticeable that at room
temperature, this step was slow to form five- or seven-
membered rings, and competing substrate decomposition
was observed prior to the complete consumption of the
starting material. By applying harsher reaction conditions,
using a large excess of TFA, and/or by removing pyridine
and/or by varying the time or the temperature of the
reaction, decomposition was favored in all cases. Other-
wise, the change of heteroatom in the starting heteroaro-
matic-2-alkylamine11 afforded a molecular framework
embodied in 3d or 3e not described yet in the liter-
ature. In this case, disappointing results were obtained
for the cyclization step even in the favorable case of the
six-membered ring. The benzothiophene derivative 3e was
isolated with a poor yield of only 46% (entry 5) due
probably to its lesser reactivity in electrophilic aromatic
substitution compared to benzofuran 3d (entry 4) or indole
derivative 3b (entry 2).12 As before, harsh acidic conditions
were not helpful.
Figure 1. Diversity-oriented strategy.
We chose the methyl4H-1,4-oxazine-3-carboxylate 17,8
as the common input for this Michael/retro-Michael se-
quence (Figure 1) as it allows the preparation of various
1,4-diazinicsystems depending on the choice of the starting
nucleophilic amine. To this end, the reactivity of various
primary amines such as heteroaromatic-3-alkylamines,
heteroaromatic-2-alkylamines, ω- functionalized alkyla-
mines, aromatic alkylamines and 2-functionalized benzy-
lamines was investigated. The amines were prepared
according to the literature or according to the reported
experimental procedure. Consequently, when the obtained
key intermediate 2 was treated with acid, the potential
iminium ion intermediate could be trapped by a range
of nucleophiles to afford various polycyclic diazinic cores
(for instance, derivatives IÀVII in Figure 1).9 The dihy-
dropyrazine scaffold obtained could then be easily further
functionalized.10 To simplify the following discussion, for
each primary amine studied, the Michael/retro-Michael
sequence and the cyclization step will be addressed
concomitantly.
Primarily, we wanted to explore access to heterocyclic
analogues of quinolizidine derivatives I, II or III contain-
ing different heteroatoms (Figure 1, X = O, S, N) at
various positions with respect to the diazinic core. In the
light of previously reported results,8 we thus first explored
(9) Martinez-Estibalez, U.; Gomez-SanJuan, A.; Garcia-Calvo, O.;
Aranzamendi, E.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011,
3610–3633.
(11) Mewshaw, R. E.; Zhou, D.; Zhou, P.; Shi, X.; Hornby, G.;
Spangler, T.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T. H.
J. Med. Chem. 2004, 47, 3823–3842.
(10) (a) Chaignaud, M.; Gillaizeau, I.; Ouhamou, N.; Coudert, G.
Tetrahedron 2008, 64, 8059–8066. (b) Aparicio, D.; Attanasi, O. A.;
Filippone, P.; Ignacio, R.; Lillini, S.; Mantellini, F.; Palacios, F.; de los
Santos, J. M. J. Org. Chem. 2006, 71, 5897–5905.
(12) Gotta, M. F.; Mayr, H. J. Org. Chem. 1998, 63, 9769–9775.
Org. Lett., Vol. 14, No. 3, 2012
845

for the cyclization step, the use of 2 equivalents of TFA in
the presence of 1 equivalent of pyridine afforded first the
desired 3,4-dimethoxyphenyl derivatives 3j in only 33%
yield. The removal of the pyridine decreased the yield to
0%, because of the Boc group cleavage. Finally, the use of
12 equivalents of TFA at 0 °C for only one minute allowed
us to isolate the desired compound 3jin90% yield (entry1).
Table 2. Reaction with Varying Heteroaromatic-2-ethylamines
entry
X
addition step yielda (%) cyclization step yielda (%)
Table 3. Reaction with Varying Aromatic Alkyl Amines
1
2
3
NH
O
2f (62)
2g (67)
2h (74)
3f (92)
3g (79)
3h (74)
S
a Yield of pure product after purification by column chromatography.
It should be pointed out at this stage that the advantage
of our methodology lies in the fact that different hits can be
targeted by introducing various functionalities on the
substituents borne by the starting primary amine in order
to obtain derivatives that exhibit potentially favorable
biological properties. To further expand the scope of the
reaction, modification of the heterocyclic primary amines
containing the alkylamino group branched in position 213
was therefore tested (Table 2). Satisfying yields were ob-
tained with the nitrogen (entry 1), the oxygen (entry 2) or
the sulfur derivatives (entry 3) affording after the cycliza-
tion step respectively the tetracycles 3f,14 3g, or 3h. It is
important to mention that, to the best of our knowledge, 3g
and 3h constitute two original and unpublished tetracyclic
compounds. The biological relevance of compound such as
3farisesfromtheobservationthatderivativeswithidentical
frameworks exhibit central nervous system activities.15
When the ethylamino side chain is attached directly to
the indole nitrogen atom, the above-mentioned Michael/
retro-Michael sequence afforded the hemiaminal precursor
2i which upon acid-catalyzed cyclization led in satisfactory
yields to an original and unpublished tetracyclic scaffold 3i,
a triaza-benzo[a]fluorene skeleton (Scheme 1).
addition
cyclization
entry
R1
R2
R3
step yielda (%)
step yielda (%)
1
2
3
4
5
OMe
OMe
OMe
H
OMe
OMe
H
H
2j (100)
2k (65)
2l (84)
3j (90)
3k (96)
3l (93)
3m (0)
3n (0)
OMe
H
F
H
2m (93)
2n (95)
H
H
H
a Yield of pure product after purification by column chromatography.
Then, as expected, derivatives 3jÀl bearing electron-
donating aryl groups were isolated in good yields, giving
access to high potential target molecules (entries 1À3).6
However it should be noted that the intermediate 2m
bearing a deactivating substituent, a fluorine atom, on
the para-position of the aryl group did not make it possible
to isolate the corresponding cyclized derivative 3m (entry 4),
as for derivative 2n bearing no substituent (entry 5). We
can also point out that no regioisomer was observed by
NMR analysis for compounds 3j and 3l. With these results
inhand, wenextexplored the cyclization stepwith different
functionalized benzylamines bearing an alkylamino or
alkylhydroxy side chain in ortho position (Table 4). With
a derivative bearing two primary amine functionalities, a
one-pot Michael/retro-Michael/cyclization sequence was
accomplishedin highyields affording, without purification
of the intermediate 2oÀp, the triaza-derivative 3o or 3p
(entries 1À2) whose framework is present in many quina-
zoline alkaloids or analogues.16
Scheme 1. Reaction with 2-(1H-Indol-1-yl)ethanamine
Starting from an amino alcohol substrate, oxygenated
analogues were isolated in two steps with good yield giving
the original products 3q or 3r, not described yet in the
literature (entries 3À4). In both series, the six-membered
ring was unsurprisingly favored compared to the five-
membered ring. In addition, we also focused on exploring
ω- functionalized alkylamines in order to obtain the
ergotamine central skeleton or analogues (Table 5).17
Diversification was also introduced by carrying out
reactions with primary amines bearing different aryl sub-
stituents (Table 3). In all cases, the Michael/retro-Michael
sequence gave satisfactory yields up to 100%. However,
(13) Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; Di
Giacomo, B.; Tontini, A.; Tarzia, G. J. Med. Chem. 1998, 41, 3624–3634.
(14) For compound 3f, it is important to note that a spontaneous
cyclization occurred with 2f in the NMR tube using CDCl3 as solvent.
(15) Varady, J.; Wu, X.; Fang, X.; Min, J.; Hu, Z.; Levant, B.; Wang,
S. J. Med. Chem. 2003, 46, 4377–4392.
(16) D’yakonov, A. L.; Telezhenetskaya, A. V. Chem. Nat. Compd.
1997, 33, 221–267.
ꢁ
(17) (a) Pazoutova, S.; Olsovska, J.; Sulc, M.; Chudickova, M.;
Flieger, M. J. Nat. Prod. 2008, 71, 1085–1088. (b) Wallwey, C.; Li,
S.-M. Nat. Prod. Rep. 2011, 28, 496–510.
846
Org. Lett., Vol. 14, No. 3, 2012

Table 4. Reaction with Varying 2-Functionalized Benzylamines
Table 5. Reaction with Varying ω-Functionalized Alkylamines
addition step
yielda (%)
cyclization step
yielda (%)
entry
n
R
X
addition step cyclization step
1
2
3
4
1
2
1
1
H
O
2s (79)
3s (83)
entry
X
R1
R2
R3
yielda (%)
yielda (%)
H
O
2t (96)
3t (88)
1
2
3
4
NH
NH
O
H
H
H
2o (À)b
2p (À)b
2q (87)
2r (73)
3o (76)
3p (86)
3q (89)
3r (93)
Me
H
O
2u (28) 48:52
2v (À)b
3u (78) trans
3v (53)
NH
H
H
H
H
H
OMe
a Yield of pure product after purification by column chromatography.
O
OMe OMe OMe
b Directly used in the next step without further purification.
a Yield of pure product after purification by column chromatography.
b Directly used in the next step without further purification.
Scheme 2. Synthesis of a Pyrazino[1,2-b]isoquinoline Core
The five- and the six- membered oxygenated rings readily
delivered the desired products 3s and 3t (entries 1À2).
Introducing a substituent alpha to the primary amine
function by using L-Alaninol dramatically decreased the
yield of the Michael/retro-Michael sequence (only 28%
yields) (entry 3). Attempts were made to increase this yield
bymodifyingcertain parameters(solvent, temperatureand
base), however without any success. As with hindered
alkylamines the nucleophilic addition is slow, decomposi-
tion occurred prior to the complete consumption of the
starting material. However, for the cyclization step, the
desired bicyclic derivative 3u was isolated as a single trans
diastereoisomer (determined by 2D Noesy NMR) thanks
to the chiral pool. Moreover, the one-pot Michael addi-
tion/cyclization was carried out with ethylenediamine in
moderate yield (entry 4).
The last challenge was the construction of the pyrazino-
[1,2-b]isoquinoline core which is present in many essential
natural alkaloids4 (Scheme 2). Synthesis of the intermedi-
ate 4 was performed following the previously described
sequence. Using TMSCN and BF3.Et2O at À78 °C then
allowed the conversion of the hemiaminal 4 to the amino-
nitrile 5 in good yield. Reduction of the nitrile with Red-
Al,18 followed by treatment of the resulting aldehyde with
TFA19 gave the desired cyclized product 6 in moderate
yield over two steps.
Performing the Michael/retro Michael and cyclization
sequence on the 1,4-oxazine skeleton allowed us, by chan-
ging the nature of the starting nucleophile, to create
molecules with alternative scaffolds. Diversity could also
be introduced through Michael acceptors. The polycyclic
diazinic skeletons obtained may be further functionalized
to generate small compound libraries for submission to
pharmacological studies. Further development of this
methodology is currently in progress in our laboratory.
ꢀ
Acknowledgment. Wethank Gerard Coudert, Professor
Emeritus of the University of Orleans, for fruitful
discussions.
In conclusion, we have described an elegant method for
the efficient synthesis of natural product-like molecules
containing a diazinic framework, a privileged structure,
by using a diversity-oriented synthesis (DOS) approach.
Supporting Information Available. Fullcharacterization
details including 1H and 13C NMR, IR, MS, and HRMS.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
6810–6812.
(19) Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Org. Lett. 2004,
6, 3095–3097.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
847