Construction of functionalized tricyclic dihydropyrazino-quinazolinedione chemotypes via an Ugi/N-acyliminium ion cyclization cascade

Article abstract of DOI:10.1016/j.tetlet.2013.06.042

Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of biological interest, being found in the marine alkaloids such as brevianamide M-N and fumiquinazolines A-C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction sequence. Additional structural diversification for further library enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation.

Full text of DOI:10.1016/j.tetlet.2013.06.042

Tetrahedron Letters 54 (2013) 4467–4470
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of functionalized tricyclic dihydropyrazino-
quinazolinedione chemotypes via an Ugi/N-acyliminium
ion cyclization cascade
Steven Gunawan a,b, Christopher Hulme b,
⇑
a Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States
b Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, BIO5 Oro Valley, Tucson, AZ 85737, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of
biological interest, being found in the marine alkaloids such as brevianamide M–N and fumiquinazolines
A–C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an
Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecu-
lar nucleophilic addition reaction sequence. Additional structural diversification for further library
enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 April 2013
Revised 5 June 2013
Accepted 11 June 2013
Available online 19 June 2013
Keywords:
Peptidomimetics
Ugi reaction
Multi-component reaction
N-acyliminium ion
Heterocycles
The compelling quest to discover novel small molecules that
modulate protein function has enabled access to ever-growing re-
gions of chemical space.1 Over the past 20 years, isocyanide-based
MCRs (IMCRs) have proven to be a convenient and versatile ap-
proach toward expeditious molecular diversity generation, allow-
ing the generation of numerous unique, drug-like small
molecules for biological evaluation.2 In particular, the Ugi IMCR
(Scheme 1), which proceeds through reaction of an aldehyde or
ketone, amines, isocyanides, and carboxylic acids to produce the
dipeptide-like adduct 1, has undergone many post-condensation
modifications, accessing numerous new scaffolds. To cite a few
examples, these post-MCR transformations comprise Ugi/depro-
tection/cyclization (UDC),3 Ugi/Heck,4 Ugi/Pictet-Spengler,5 Ugi/
RCM,6 Ugi/Knoevenagel,7 Ugi/cycloaddition,8 Ugi/Diels–Alder,9
Ugi/Pd-catalyzed arylation,10 Ugi/Mitsunobu11 and, most recently,
elegant Ugi/Aldol methodologies.12 In this Letter, Ugi/N-acylimini-
R2
NH2
R1
R1
R2
H
O
O
R3
OH
R4NC
N
R3
R4NC
R5
R5
N
O
R1
N
O
R4
O
O
H
N
O
R5
H
N
R3
R2
N
R5
R4
R3
R2
Mumm
rearrangement
N
H
R1
R1
R2 R3
O
R4
H
1
Scheme 1. The Ugi MCR.
⇑
Corresponding author.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.042

4468
S. Gunawan, C. Hulme / Tetrahedron Letters 54 (2013) 4467–4470
CHO
O
NC
mide M–N15 8 and 9 and fumiquinazolines A–C16 10, 11, and 12
possessing insecticidal and antineoplastic activity, respectively
(Fig. 1).
O
R1
R1
R2
R3
O
R2
N
OEt
OEt
N
Thus, studies began with evaluation of reagent compatibility for
the Ugi MCR (Scheme 4). Specifically, mixing an aldehyde, 2-flu-
oro-5-nitro-benzoic acid 4, the ammonia surrogate 2,4-dimethoxy-
benzylamine 517 and 1,1-diethoxy-2-isocyanoethane 618 rendered
Ugi products 13 upon overnight stirring at ambient temperature in
moderate to good yields (43–82%, Table 1). It is worth noting that
isocyanide 6 can be readily synthesized in two steps and has also
been reported to be an extremely valuable building block for the
preparation of several families of heterocycles that include imida-
zoles19 and thiazoles.20 Subsequent displacement of the fluorine
group in 13 by a primary amine was achieved under mild condi-
tions in DCE and afforded 14, which was subjected without purifi-
cation to an acid-mediated double cyclization generating tricyclic
system 7 (Table 1). Mechanistically, this pathway is presumably
initiated by the generation of an oxonium ion and concomitant re-
moval of the acid labile 2,4-dimethoxybenzyl moiety 15
(Scheme 4). Closure of the amidic nitrogen onto the oxonium ion
thus leads to the formation of hemiaminal 16, which under the
acidic reaction conditions affords N-acyliminium ion 18 with the
associated loss of a molecule of ethanol. The sequence concludes
through nucleophilic attack of the anilinic amine onto the newly
formed N-acyliminium ion 18 to give the desired dihydropyrazi-
no-quinazolinedione 7.
H2N
R3
OH
3
2
Scheme 2. Synthesis of
D
5-2-oxopiperazines 3.
CHO
O
NH2
R1
F
O
R1
a
MeO
OMe
O2N
NH2
O
N
R2
5
6
b H
NH
OH
N
R2
OEt
H
CN
4
OEt
7 ( )
NO2
Scheme 3. General Ugi/N-acyliminium ion cyclization sequences.
um ion sequences used to expand our toolbox of heterocyclic
chemotypes are relatively underexploited, and only one article
has been published that describes the synthesis of
azines 3 (Scheme 2) using aminoacetaldehyde diethylacetal 2 as
the carbonyl surrogate.13 However, reports do exist on N-acylimin-
ium ion strategies being employed with other MCRs.14 Herein,
post-condensation modifications of the Ugi adduct driven by
N-acyliminium ion cascade reactions are reported to prepare keto-
piperazine containing tricyclic chemotypes 7 (Scheme 3) whose
unusual core structure is found in the marine alkaloids breviana-
D
5-2-oxopiper-
Scaffold 7 is likely to exist as an anti-diastereomer in which the
two hydrogens of the two chiral centers, ‘a’ and ‘b’, are predicted to
be in a pseudo-trans relationship (Fig. 2). Molecular dynamics
studies reveal that both enantiomers of 7a exist in a lower energy
state than the corresponding pair of enantiomers (20 and 22) of the
Me
HN
Me
HN
O
O
N
N
O
N
O
N
O
O
O
N
O
N
N
N
OH
O
H
H
O
O
O
NH
OH
NH
N
N
H
H
NH
R1 R2
Fumiquinazoline
NH
Me
Fumiquinazoline C (
8)
9
Brevianamide N ( )
Brevianamide M (
12
)
A (10) R1 = H, R2 = Me
B ( ) R1 = Me, R2 = H
11
Figure 1. Brevianamide M–N (8 and 9) and fumiquinazolines A–C (10–12).
R2
F
O
R1
OEt
OEt
NH
O
R1
OEt
OEt
H
N
H
N
NH2
R2
DCE, r.t.
4, 5, 6
CHO
HCOOH
N
N
R1
O
O
MW 100 °C
10 min
MeOH, r.t.
13
14
OMe
NO2
NO2
MeO
R2
OMe
MeO
R2
R2
R2
NH
O
R1
NH
O
R1
NH
O
R1
NH
O
R1
OEt
H
O
O
O
N
N
N
N
7
N
H
NH
NH
NH
O
EtO
NO2
EtO
NO2
H
NO2
NO2
15
16
17
18
Scheme 4. Synthesis of dihydropyrazino-quinazolinedione 7.

S. Gunawan, C. Hulme / Tetrahedron Letters 54 (2013) 4467–4470
4469
Table 1
Tricyclic analogs 7a–f
Entry
Ugi product
R1
Yield (%)
7
R2
Yielda (%)
1
2
3
4
13a
13b
13c
13d
Propyl
Phenyl
3-(Methylthio)ethyl
Cyclopropyl
67
78
43
82
7a
7b
7c
7d
Isobutyl
Isobutyl
Isobutyl
2-Methoxyethyl
67
79
41
41
a
Two-step yield for fluoride displacement and acid treatment.
alternate diastereomer, thus suggesting preferential formation of
7a.21 Observed stereoselectivity may be explained by the steric
hindrance between the propyl group and the approaching anilinic
nitrogen of intermediate 19 (R-enantiomer) at the si-face that ne-
gates formation of 20 (R,R), affording 7a (R,S) as the strongly pre-
ferred product (Fig. 2). In analogous fashion, si-attack on the
intermediate 21 (S-enantiomer) affording 7a (S,R) (Fig. 2) is sug-
gested to be favored [Note that comparison of the relative energies
of two diastereomers is only justified when assuming reversibility
of reactions going through either 19 or 21, with product 7 pre-
ferred over 20 under thermodynamic control]. This configuration
is in accordance with a report by Patek et al. describing the assem-
bly of 1-acyl-3-oxopiperazines via a multi-step solid-phase synthe-
sis.21Unequivocal structural confirmation of 7a was also provided
by X-ray crystallography (Fig. 3).
With 7a in hand as the ‘model study’ molecule, a small collec-
tion of compounds was prepared to demonstrate the generality
of the reaction sequence utilizing different aldehydes and primary
amines (Table 1). Concurrently, further functionalization of 7 was
also enabled via N-alkylation on the amidic nitrogen and by N-
O
O
N
O
O2N
O
O2N
O
O2N
O
N
Si
X
N
Re
N
H
H
H
NH
NH
NH
N
NH
H
H
20
19
(R)
7a
(R,R)
(R,S)
78.856 kcal/mol
75.493 kcal/mol
O
O
O
O2N
O
O2N
O
O2N
O
N
Si
N
Re
X
N
H
H
H
NH
NH
NH
N
NH
N
H
H
7a
21
(S)
22
(S,R)
(S,S)
75.850 kcal/mol
80.122 kcal/mol
Figure 2. Stereoselectivity and calculated energy for each diastereomer.
Figure 3. Definitive structural confirmation by X-ray crystallography of 11a.

4470
S. Gunawan, C. Hulme / Tetrahedron Letters 54 (2013) 4467–4470
O
R1
O
R1
H
O
R1
H
H
N
a
O2N
O
O2N
O
O
1. Pd/C, N2H4
NaH/DMF
R3Br
N
H
N
H
R4
N
H
b H
NH
N
N
2. R4Cl, DIPEA
DCM
N
R2
N
R2
R3
N
R2
R3
7
23
24
( )
( )
( )
Scheme 5. Synthesis of dihydropyrazino-quinazolinedione 7.
2. (a) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135; (b)
Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80.
Table 2
Functionalized tricyclic chemotype 23
3. (a) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R.
Tetrahedron Lett. 1998, 39, 7227–7230; (b) Marcaccini, S.; Torroba, T. Post-
Condensation Modifications of the Passerini and Ugi Reactions. In
Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2005; pp 33–75.
4. (a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417–420;
(b) Umkehrer, M.; Kalinski, C.; Kolb, J.; Burdack, C. Tetrahedron Lett. 2006, 47,
2391–2393.
Entry
7
R3
23
Yield (%)
1
2
3
4
5
7a
7a
7a
7b
7b
3-Methoxybenzyl
4-Fluorophenethyl
Cyclobutylmethyl
3-Methoxybenzyl
4-Fluorophenethyl
23a
23b
23c
23d
23e
94
87
87
71
46
5. (a) El Kaim, L.; Gageat, M.; Gaultier, L.; Grimaud, L. Synlett 2007, 500–502; (b)
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Table 3
Functionalized tricyclic chemotype 24
Entry
23
R4
24
Yielda (%)
1
2
3
4
5
23a
23b
23b
23c
23c
CO-Ph
SO2Me
CO-Ph
SO2Me
CO-Ph
24a
24b
24c
24d
24e
85
83
75
80
89
7. Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcıa-Valverde, M.; Torroba,
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Eur. J. Org. Chem. 2011, 2011, 100–109.
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1621–1624.
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Jones, S. D.; Murray, C. W.; Franciskovich, J. B.; Engel, D. B.; Weber, W. W., II;
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a
Two-step yield for hydrogenation and N-acylation.
acylation and/or sulfonation upon reduction of the nitro group,
leading to the addition of two further diversity points (Scheme 5).
Tables 2 and 3 summarize selected alkyl bromides and acyl/sulfo-
nyl chlorides employed to attain 23 and 24, respectively, in high
overall yields.
In summary, a concise three-step synthesis of a collection of tri-
cyclic dihydropyrazino-quinazolinediones 7 has been successfully
established with only one diastereomer formed utilizing an Ugi/
N-acyliminium ion cyclization-intramolecular nucleophilic addi-
tion reaction cascade. Moreover, this scaffold can be readily diver-
sified via sequential N-alkylation and N-acylation and/or
sulfonation, adding two further variety points by means of com-
mercially available alkyl bromides and acyl and/or sulfonyl chlo-
rides. Due to the uniqueness of the chemotypes produced, their
favorable drug-like properties, and the potential for structural
diversification, this procedure represents a practical and enticing
approach for the enrichment of small molecule libraries in a
high-throughput and operationally friendly manner.
17. Tangirala, R. S.; Curran, D. P. Org. Synth. 2005, 82, 18–21.
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1993, 1229–1231.
19. Kazmaier, U.; Ackermann, S. Org. Biomol. Chem. 2005, 3, 3184–3187.
20. Molecular dynamics calculations were performed on ChemBio3D Ultra 12.0.
MMF94 was performed on each molecule with maximum number of iterations
of 5000 and minimum RMS gradient of 0.100, followed by energy and gradient
calculations. Finally, MMF94 molecular dynamics were performed at 2 fs (step
interval), 1000 fs (frame interval), 100,000 steps (number of iterations), 1 kcal/
atom/ps (heating/cooling rate) and 300 K (target temperature). Upon
completion, MMF94 energy minimizations were reiterated and provided the
numbers displayed in Figure 2.
Acknowledgments
The authors thank Dr. Sue Roberts for X-ray crystallography
work, Drs. Fabio De Moliner and David M. Bishop for proofreading,
and the National Institutes of Health (P41GM086190) for financial
support.
´
21. Vojkovsky, T.; Weichsel, A.; Pátek, M. J. Org. Chem. 1998, 63, 3162–3163.
References and notes
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Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613–618.