Synthesis of chiral 1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines as novel highly functionalized scaffolds for peptidomimetics

Article abstract of DOI:10.1016/S0040-4039(02)00964-4

The synthesis of novel chiral 4,7-disubstituted- and 2,4,7-trisubstituted-1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines from suitably protected TrpΨ[CH(CN)NH]Asp pseudodipeptides is described. This synthesis involves the cyclization of the Ψ[CH(CN)NH] ps

Full text of DOI:10.1016/S0040-4039(02)00964-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4899–4902
Synthesis of chiral
1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines as novel highly
functionalized scaffolds for peptidomimetics
Susana Herrero, Antonio Salgado, M. Teresa Garc´ıa-Lo´pez and Rosario Herranz*
Instituto de Qu´ımica Me´dica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 22 April 2002; revised 17 May 2002; accepted 22 May 2002
Abstract—The synthesis of novel chiral 4,7-disubstituted- and 2,4,7-trisubstituted-1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines
from suitably protected TrpC[CH(CN)NH]Asp pseudodipeptides is described. This synthesis involves the cyclization of the
C[CH(CN)NH] pseudodipeptides, via catalytic hydrogenation and in situ lactamization, to give 3,5-disubstituted-2-oxopiperazine
derivatives, which upon reaction with isocyanates, followed by base-catalyzed cyclization lead to the target 4,7-disubstituted-1,6,8-
trioxoperhydropyrazino[1,2-c]-pyrimidines. The alkylation of these bicyclic heterocycles gives their corresponding 2,4,7-trisubsti-
tuted derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
To circumvent the known drawbacks of peptides as
potential drugs, the search of small nonpeptide
molecules, referred to as peptidomimetics, that are able
to bind to peptide receptors, has been a growing area of
research in recent years.1 In this sense, the design of
scaffold based di- and tripeptidomimetics aimed to
replace the peptide backbone with a cyclic structure
onto which the pharmacophoric amino acid side chains
are attached in an appropriate orientation, has proven
to be a useful strategy.1 To this aim, nitrogen bridged
lactams and cyclic urea based heterocycles are found
to be scaffolds of particular interest.1b,2 Thus, in the
course of our efforts to find novel cholecystokinin
(CCK) mimetics, we have recently reported on a new
series of highly potent and selective CCK1 receptor
antagonists that are based on the 1,3-dioxoperhydropy-
rido[1,2-c]pyrimidine scaffold such as compounds 13
(Fig. 1). This fact and our current interest in versatile
methodology for constructing peptidomimetics directed
our attention to the related 1,6,8-trioxoperhydropy-
razino[1,2-c]pyrimidine analogues 2, where the fused
piperidine of compounds 1 has been replaced with a
2-oxopiperazine ring, also a pharmacologically privi-
leged skeleton.4 Although several related heterocyclic
systems have recently been reported as peptidomimet-
ics,5 to the best of our knowledge, no synthesis of this
6,6-bicyclic heterocycle with pendant substituents on
the ring carbons has been reported to date.
Taking into account the versatility of the cyano group
of C[CH(CN)NH] pseudopeptides for cyclization reac-
tions,6–9 we thought that the use of suitably protec-
ted XaaC[CH(CN)NH]Asp pseudodipeptides could
give access to 5-substituted-2-oxopiperazine-3-acetate
derivatives, via catalytic hydrogenation followed by
d-lactamization, which upon reaction with isocyanates
would lead to the target 4,7-disubstituted nitrogen
bridged compounds bearing the Xaa amino acid residue
at 4 position (Scheme 1). As shown in the scheme,
additional side chains can be appended at the ring N-2,
via alkylation, in order to mimic tripeptides. Besides a
diversity of pendant substituents, this approach allows
CH2In
O
Boc-HN
O
R1
R1
N
N
4
1
6
5N 7N
3
N2
9a
8
9
R2
O
O
O
NH
O
1
2
In = Indol-3-yl
R1 = Ph, CH2-Ph
R2 = CH2Ph, CH2-CO2Me
Keywords:1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines;C[CH(CN)-
NH] pseudodipeptides; 3,5-disubstituted-2-oxopiperazines; nitrogen
bridged bicyclic heterocycles; peptidomimetics; lactams; urea deriva-
tives.
Boc-NH
CH2In
* Corresponding author. Tel.: 34-91-5622900; fax: 34-91-5644853;
e-mail: rosario@iqm.csic.es
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00964-4

4900
S. Herrero et al. / Tetrahedron Letters 43 (2002) 4899–4902
R3
H
N
O
N
O
2
CN CO2Me
3
4
1
5
N
6
Boc-NH
Boc-NH
Boc-NH
9a
N
H
N
H
9
8
R1
CO2Me
R1
R1
CO2Me
7
N
R2
O
O
4
Boc-XaaΨ[CH(CN)NH]Asp(OMe)-OMe
3
2
Scheme 1. General approach for the synthesis of 1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidines.
the construction of enantiopure 4,7-disubstituted- and
2,4,7-trisubstituted-1,6,8-trioxoperhydropyrazino[1,2-c]
pyrimidines with stereocontrol at C4 and at the ring-
fusion C9a centers. Because of the importance of the
stereochemistry in tryptophan- and indolyl-based CCK
receptor ligands,3a,10 we have used pseudodipeptides
As shown in Scheme 3, reaction of the resolved 2-
oxopiperazine derivatives (5R)-, (5S)-4a and (5R)-,
(5S)-4b with phenyl or benzyl isocyanate in dry THF,
at room temperature for 24 h, led to the corresponding
urea derivatives 5a, 5b, and 6a, 6b in 85–95% yield. In
the case of the compounds derived from Boc-D-tryp-
(R,S)-3a and (R,S)-3b, containing
L- and D-Trp,
tophan 4b, traces of the 1,4-diacylated compounds were
also obtained. In contrast to the 1,4-unsubstituted 2-
oxopiperazines 4, the low J5,6 values for the urea
derivatives 5 and 6 (3–4 and 3–5 Hz) indicated that 5-H
adopts an equatorial disposition in these compounds,
independently of the stereochemistry at this position.
respectively, as starting materials for the work herein
reported. These pseudodipeptides were obtained, as
(1:2) and (2:3) (R,S)-epimeric mixtures at the peptide
bond surrogate, from the reaction of Boc-
L
-Trp-H and
Boc-
D
-Trp-H, respectively, with H-Asp(OMe)-OMe
and trimethylsilyl cyanide (TMSCN).11 The catalytic
hydrogenation of the epimeric mixtures (R,S)-3a and
(R,S)-3b at room temperature and 1 atm of H2 pres-
sure, in the presence of Raney nickel, led to the corre-
sponding 2-oxopiperazine derivatives (5R,S)-4a and
(5R,S)-4b, which were chromatographically resolved
into both (5R)- and (5S)-epimers (Scheme 2).
The treatment of the
L-tryptophan urea derivatives
(5R)-, (5S)-5a and (5R)-, (5S)-6a with an equimolar
amount of DBU, at room temperature in dry THF,
produced the desired intramolecular condensation to
give the 1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidine
derivatives 7a and 8a in good yields (>90%). However,
in the case of the -tryptophan derivatives 5b and 6b, it
D
was necessary to heat at refluxing temperature to
achieve their cyclization to 7b and 8b. Finally, the
alkylation of all these bicyclic compounds, by reaction
with benzyl bromide or methyl bromoacetate, yielded
the desired 2,4,7-trisubstituted-1,6,8-trioxoperhydropy-
razino[1,2-c]-pyrimidines 9a,b–12a,b. Traces of com-
pounds dialkylated, at position 2 and at the indol NH,
were detected in this reaction. To minimize the addi-
tional alkylation at the indolic NH, molar excesses of
alkylating agent and base (Cs2CO3) higher than 50%
were not used, although some of the starting material
was recovered unchanged (30–50%). Epimerization at
any of the three stereogenic centers of the starting
pseudodipeptides 3a and 3b was not observed in any of
the synthetic steps. In the NMR spectra of compounds
(4S)-9a, (4S)-11a, (4R)-11b, and (4R)-12b some signals
appeared duplicated in an (ꢀ1:1) ratio, indicating the
presence of two rotamers, probably due to restricted
The J5,6 coupling constant values (2–4 and 9–12 Hz) in
the 1H NMR spectra of all these 2-oxopiperazine
derivatives indicated that 5-H adopts an axial disposi-
tion. Furthermore, a weak NOE effect (0.5–1%) was
observed between 3-H and 5-H in the 3,5-cis isomers
(5S)-4a and -4b, indicative of
a
3,5-cis-diaxial
disposition.
1
rotation at the N2ꢀC or C4ꢀC bonds. In the H NMR
spectra in DMSO these duplicated signals did not com-
pletely collapse at the highest spectrometer work tem-
perature (90°C).
Independently of the stereochemistry, the 1H NMR
spectra of the 1,6,8-trioxoperhydropyrazino[1,2-c]py-
rimidine derivatives 7–12 showed J9,9a values (4–5 and
9–11 Hz) indicative of an axial disposition for 9a-H
proton, while the low values for J3,4 (1–4 and 3–5 Hz)
showed that the proton at position 4 adopts an equato-
rial orientation, and, therefore, the voluminous sub-
stituent at this position, 1-(tert-butyloxycarbonyl-
Scheme 2. Synthesis of 5-substituted-2-oxopiperazine-3-
acetates. According to the CIP system, the ligand preference
for the stereogenic center denoted with * changes after the
CN reduction. Thus, the (R)-3 epimers would be denoted
(5S)-4 after the hydrogenation.
a

S. Herrero et al. / Tetrahedron Letters 43 (2002) 4899–4902
4901
Scheme 3. Synthesis of 4,7-disubstituted- and 2,4,7-trisubstituted-1,6,8-trioxoperhydropyrazino[1,2-c]pyrimidine. Reagents and
conditions: (a) R1NCO, THF, 85–95%; (b) DBU, THF, >90%; (c) BrCH2Ph, Cs2CO3, acetone, 50°C, 50–65%; (d) BrCH2CO2Me,
Cs2CO3, acetone, 50°C, 50–65%.
amino)-2-(indol-3-yl)ethyl, would be situated in an axial
disposition.
Acknowledgements
All the new compounds herein described were evaluated
as CCK1 and CCK2 receptor ligands, by measuring the
inhibition of the specific [3H]propionyl-CCK-8 binding
to rat pancreas and cerebral cortex homogenates,12
respectively. Unfortunately, none of them showed sig-
nificant affinity for any of the CCK receptors at con-
centrations below 10−6 M. The lack of affinity in the
This work has been supported by CICYT (SAF2000-
0147).
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