Simple approach to highly functionalized trisubstituted tetrahydropyrimidine-2,4-diones from perhydropyrazino[1,2-f]pyrimidine-3,6,8- trione precursors

Article abstract of DOI:10.1055/s-2007-965962

Unprecedented trisubstituted tetrahydropyrimidine-2,4-diones were easily synthesized in two steps involving Boc-amide protection and controlled ring opening, from perhydropyrazino[1,2-f]pyrimidine-3,6,8-triones. These bicyclic derivatives were prepared by

Full text of DOI:10.1055/s-2007-965962

PAPER
1047
Simple Approach to Highly Functionalized Trisubstituted Tetrahydro-
pyrimidine-2,4-diones from Perhydropyrazino[1,2-f]pyrimidine-3,6,8-trione
Precursors
T
etrahydropyrimi
o
dine-2,4-dio
s
ne Deriva
a
tives rio Patiño-Molina,a,b M. Teresa García-López,a Edurne Cenarruzabeitia,c Joaquín Del Río,c
Rosario González-Muñiz*a
a
Instituto de Química Médica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax +34(91)5644853; E-mail: iqmg313@iqm.csic.es
Escuela Técnica Superior de Ingenieros Industriales, Universidad de Valladolid, Paseo del Cauce s/n, 4701 Valladolid, Spain
Departamento de Farmacología-Unidad Asociada al CSIC, Universidad de Navarra, Irunlarrea 1, 31080 Pamplona, Spain
b
c
Received 3 November 2006; revised 24 January 2007
phy defined by the 1,3-dioxoperhydropyrido[1,2-c]pyri-
Abstract: Unprecedented trisubstituted tetrahydropyrimidine-2,4-
midine scaffold is an essential requirement for potent and
diones were easily synthesized in two steps involving Boc-amide
selective binding to CCK1 receptors.14 Thus, the corre-
sponding pyrrolopyrimidine lower homologues (as com-
protection and controlled ring opening, from perhydropyrazino[1,2-
f]pyrimidine-3,6,8-triones. These bicyclic derivatives were pre-
pared by reaction of 2-oxopiperazines derived from dipeptides with pound 2), incorporating a highly constrained five-
isocyanates, followed by cyclization. The monocyclic pyrimidinone
membered ring instead of the perhydropyridine moiety of
1, were completely devoid of affinity at CCK1 receptors.14
derivatives were further elaborated to potential CCK ligands that
have contributed to a better understanding of the structural require-
To further investigate this family of pyridopyrimidine
ments for efficient binding at the CCK1 receptor.
CCK ligands, we were interested in derivatives with high-
er flexibility, but maintaining the essential pyrimidine-
dione ring. Starting from compound 1, selected as a
Key words: heterocycles, peptides, bicyclic compounds, ring
opening, medicinal chemistry
representative model, we designed monocyclic com-
pounds of general formula A (Figure 1), to establish the
Monocyclic and fused dihydropyrimidinones and tetrahy-
significance of the pyrido part of the bicyclic skeleton
dropyrimidin-2-one derivatives have attracted much at-
upon CCK receptors binding. This contribution describes
tention in medicinal chemistry programs due to the large
a convenient synthetic procedure for the preparation of
range of biological activities displayed by these com-
suitable 1,3,6-trisubstituted tetrahydropyrimidin-2,4-di-
pounds.1,2 In a similar way, the related tetrahydropyrimi-
din-2,4-dione is the common heterocycle nucleus in
ones and their application to the preparation of com-
pounds A.
biologically active molecules, such as HIV-integrase in-
Our retrosynthetic planning for compounds A identified
the perhydropyrazino[1,2-f]pyrimidine-3,6,8-triones B as
hibitors,3 anti-epileptic agents,4 ligands for somatostatin
receptors,5 and a-glucosidase inhibitors,6 among others.
key intermediates, and proposed the controlled opening of
Additionally, some tetrahydropyrimidinone derivatives
the pyrazino ring to generate the monocyclic pyrimidin-
have been used as proline mimetics,7 and as temporary
one skeleton (Figure 1). Similar opening of lactams was
chiral scaffolds for asymmetric synthesis.8
described for other related heterocyclic systems.15,16 The
synthesis of bicyclic derivatives B could be envisaged by
elaboration of oxopiperazines C, following synthetic pro-
tocols similar to that reported for the preparation of 1,3-di-
oxoperhydropyrido[1,2-c]pyrimidines.12 2-Oxopiperazines
C can be easily prepared in two steps from commercially
available Z-Xaa-Gly dipeptide derivatives. 17
The most common methods for the synthesis of tetrahy-
dropyrimidin-2,4-diones involve the three-component
condensation of primary amines, isocyanates and b-di-
electrophiles,9 the reduction and photochemical transfor-
mations of dihydropyrimidinone derivatives,10 and the
cyclization of b-amino ester derived ureas.11
The reaction of the 2-oxopiperazines 3–517 with phenyl-
isocyanate at 0 °C afforded the corresponding urea deriv-
atives 6–8 in excellent yield (80–90%, Scheme 1).
However, when the reaction of compound 3 was carried
out at room temperature, the expected urea 6 (43%) was
formed along with an important amount of the bisurea de-
rivative 9 (34%). Compound 6 was obtained as a racemic
mixture starting from racemic 3, while compounds 7 and
8 were enantiopure, and have 3S,5R configuration as their
immediate precursors 4 and 5.17
In recent years, we have dedicated part of our efforts to the
design, synthesis and pharmacological study of a family
of highly selective CCK1 receptor antagonists, having a
1,3-dioxoperhydropyrido[1,2-c]pyrimidine central scaf-
fold (exemplified here by compound 1, Figure 1).12 Struc-
ture–activity relationship studies on these CCK1 receptor
antagonists showed the importance of the 2-substituent
and the Boc-Trp moiety,13 and suggested that the topogra-
SYNTHESIS 2007, No. 7, pp 1047–1053
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965962; Art ID: T16606SS
© Georg Thieme Verlag Stuttgart · New York

1048
R. Patiño-Molina et al.
PAPER
R1
O
R1
O
O
O
O
i
3
N
N
N
4a
S
2 N
N
N
2
4NH
5
H
HN
6
5
HN 1
CO2Et
CO2Et
O
O
R
6: R1 = H (90%)
3: R1 = H (5R,S)
4: R1 = Me (3S,5R)
5: R1 = Bn (3S,5R)
O
NH
NH
O
NH
7: R1 = Me (85%)
8: R1 = Bn (80%)
O
O
O
S
NH
S
O
ii
NH
NH
1
2
R1
O
R1
O
O
O
6
9
4
1
iii
3
N
7N
8
N
N
HN 2
N
R
O
9a
R
O
O
Boc
O
O
MeO2C
O
N
N
13: R1 = H (90%)
14: R1 = Me (86%)
15: R1 = Bn (79%)
10: R1 = H (81%)
11: R
12: R
N
N
1 = Me (79%)
1 = Bn (75%)
HN
O
O
NH
NH
A
B
O
O
iv
R1
O
NH
R
2
MeO2C
Boc
N1 3N
O
NH
6
4
5
O
HN
CO2Me
4, 5, 7, 8, 11, 12, 14, 15, 17
have R-configuration at position
C5, or C9a, or C6
NH
C
16: R1 = H (93%)
17: R1 = Bn (77%)
Figure 1 Model bicyclic CCK ligands and retrosynthetic pathway
to the designed monocyclic analogues A
O
O
The DBU-promoted intramolecular cyclization of the
urea intermediates 6–8 provided the pyrazino[1,2-f]pyri-
midine-3,6,8-triones 10–12 in good yields (Scheme 1).
Then, compounds 13–15 were prepared in 90, 86 and 79%
yield, respectively, by treatment of 10–12 with di-tert-bu-
tyl dicarbonate. The N-urethane substituent in 13–15 has
a double function, as an activating moiety facilitating the
ring cleavage and, after the ring opening, as a protector of
the resulting amino group.
4
3 N
5
O
N1
2
N
N
ii
H
O
O
O
N
CO2Et
NH
CO2Et
HN
HN
9
18 (62%)
Scheme 1 Reagents and conditions: i) PhNCO, THF, 0 °C; ii) DBU,
THF; iii) (Boc)2O, Et3N, DMAP; iv) NH3, MeOH.
Activated pyrazino[1,2-f]pyrimidines 13 and 15 under-
went fast regioselective alcoholysis by treatment with
NH3/MeOH to give the targeted trisubstituted pyrimidine-
2,4-diones 16 (93%) and 17 (77%), respectively. The
pyrazino ring opening was also observed in the attempts
to cyclize compound 9 to the corresponding bicyclic
pyrazino[1,2-f]pyrimidine. In this case, the abstraction of
the 4-urea proton in 9 proceeded with the attack at the 2-
CO group, activated by means of the 1-carbamoyl substit-
uent, with concomitant pyrazino ring opening to yield the
hydantoin derivative 18. Although, most probably, a con-
certed-like process occurs in the formation of 18, a two-
step procedure, involving ring opening followed by cy-
clization to the preferred five-membered cycle, cannot be
discarded.
and 20 were obtained as approximately 1:1.7 and 1.8:1
a:b distereoisomeric mixtures, respectively, which were
resolved into their corresponding C6-epimers by prepara-
tive TLC.18 Although a 1:1 mixture would be expected
from the use of racemic 16, the existence of some kinetic
resolution in the coupling of 16 with the enantiopure Trp
derivatives could explain the higher isomer ratio. A sig-
nificant shielding of the H-5 protons was observed in the
1H NMR spectra of compound 21b compared to the same
protons in the 1¢-unsubstituted analogue 19b, and in the
starting pyrimidine intermediate 17.19 This seems to indi-
cate that compound 21b adopts a preferential conforma-
tion in solution in which the indole nucleus of the Trp
residue folds over the pyrimidine ring. Since this shield-
ing was not observed for compounds 19 and 20, lacking
the 1¢-substituent, the observed behavior could be caused
Compounds 16 and 17 were deprotected, by treatment
with TFA, and coupled to Boc-L- or Boc-D-Trp-OH to af-
ford final compounds 19–21 (Scheme 2). Compounds 19
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York

PAPER
Tetrahydropyrimidine-2,4-dione Derivatives
1049
Table 1 Inhibition of the [3H]pCCK8-Specific Binding to Rat Pan-
creas (CCK1) and Cerebral Cortex Membranes (CCK2) by Pyrimidine
Derivatives
O
MeO2C
O
N
N
S
Product
Config.
Trp
Config.
IC50 (nM)a
CCK1
O
NH
6
CCK2
O
O
*
19a
19b
20a
20b
21b
1
L
L
D
D
L
L
L
S
125.0 13.8
330.0 40.5
>1000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
N
H
R
S
NH
O
19a L-Trp (30%)
20a D-Trp (50%)
R
R
Sb
Rb
>1000
i, ii
MeO2C
N
N
+
>1000
O
O
1.18 0.72c
>1000d
NH
MeO2C
O
N
N
Boc
R
16
2
O
NH
a Values are the mean or mean SEM of at least three experiments,
performed with seven concentrations of test compounds in triplicate.
b In this case the configuration of position 4a of the pyrido[1,2-c]py-
rimidine or the pyrrolo[1,2-c]pyrimidine ring system is indicated.
c Values from reference 13b.
O
O
*
N
H
d Values from reference 14.
NH
19b L-Trp (50%)
20b D-Trp (27%)
In summary, we have described a simple four-step proce-
dure for the synthesis of highly functionalized 1,3,6-
trisubstituted tetrahydropyrimidine-2,4-dione derivatives.
Starting from dipeptide-derived piperazin-2-ones, the
process implies acylation with isocyanates, cyclization to
perhydropyrazino[1,2-f]pyrimidine-3,6,8-triones, activa-
tion with di-tert-butyl dicarbonate, and controlled aper-
ture of the pyrazine ring from the bicyclic skeleton. Some
of these tetrahydropyrimidine-2,4-diones, obtained after
convenient modification, have been evaluated for their af-
finity at CCK receptors. Although low affinities were
found in the best cases, these pyrimidinone derivatives
served to clarify some structural features essential for the
CCK1 receptor recognition.
O
O
1'
MeO2C
O
N
N
i, ii
MeO2C
Boc
N
N
R
O
O
NH
NH
O
O
17
N
H
NH
21b L-Trp (62%)
Scheme 2 Reagents and conditions: i) TFA–CH2Cl2; ii) Boc-L- or
Boc-D-Trp-OH, BOP, Et3N, CH2Cl2.
All reagents were of commercial quality. Solvents were dried and
purified by standard methods. 1H NMR spectra were recorded on a
Varian Gemini 200 or a Varian Unity 300 spectrometer operating at
by the need of suitable accommodation of the two append-
ed hydrophobic residues, benzyl and indole, in compound
21b.
200 and 300 MHz, respectively, using TMS as internal standard. 13
C
NMR spectra were recorded on a Varian Gemini 200 (50 MHz) or
a Varian Unity 300 (75 MHz) spectrometer. COSY and HSQC two-
dimensional experiments were used for 1H and 13C assignments, re-
spectively. The H-assignments marked with a superscript ‘i’ in
compounds 19a,b and 21b belong to the indole fragment of the mol-
ecule. Optical rotations were measured at 25 °C using a Perkin-Elm-
er 141 polarimeter. Elemental analyses were obtained on a CHN-O-
RAPID instrument. Analytical TLC was performed on aluminum
sheets coated with a 0.2 mm layer of silica gel 60 F254 (Merck). Sil-
When these compounds were assayed for their binding
properties at CCK1 receptors, derivatives 19a and 19b
showed two-orders of magnitude lower affinities than the
model compound 1 (Table 1). D-Trp-containing ana-
logues 20a,b and the 1¢-benzyl substituted derivative 21a
were totally ineffective. These results provide further ev-
idence for the significant role of the perhydropyridine ring ica gel 60 (230400 mesh, Merck) was used for column chromatog-
raphy. Analytical HPLC was performed on a Waters Nova-pak C18
in the bicyclic 1,3-dioxoperhydropyrido[1,2-c]pyrimidine
(3.9 × 150 mm, 4 mm) column, with a flow rate of 1 mL/min, using
a tunable UV detector set at 214 nm. Mixtures of MeCN (solvent A)
and 0.05% TFA in H2O (solvent B) were used as mobile phase.
Starting 2-oxopiperazine derivatives 3–5 were prepared as de-
scribed.17
skeleton. The importance of the perhydropyridine C6 and
C7 methylene groups for the interaction with a hydropho-
bic cavity of the CCK1 receptor had been anticipated by a
three-dimensional model complex between the CCK1 re-
ceptor and the pyridopyrimidine antagonists.20
Abbreviations: BOP: benzotriazol-l-yloxytris(dimethylamino)phos-
phonium hexafluorophosphate; CCK: cholecystokinin.
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York

1050
R. Patiño-Molina et al.
PAPER
Reaction of 2-Oxopiperazines 3–5 with Phenyl Isocyanate; Gen-
eral Procedure
3.97 (d, J = 18.2 Hz, 1 H, H-3), 3.92 (dd, J = 14.0, 4.1 Hz, 1 H, H-
6), 2.79 (dd, J = 17.6, 9.1 Hz, 1 H, 5-CH2), 2.64 (dd, J = 17.6, 3.2
Hz, 1 H, 5-CH2), 1.29 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (300 MHz, CDCl3): d = 172.6, 170.7, 154.7, 150.4 (C=O),
138.8, 137.0, 128.9, 128.8, 124.5, 123.0, 120.4, 119.5 (C6H5), 62.0
(CH2CH3), 48.8 (C-5), 46.4 (C-3), 44.9 (C-6), 36.9 (5-CH2), 13.9
(CH2CH3).
A solution of the corresponding 2-oxopiperazine 3–5 (3.3 mmol) in
anhyd THF (24 mL) at 0 °C, was treated with phenyl isocyanate
(0.36 mL, 3.3 mmol) and stirred at the indicated temperature for 30
min. The white solid that formed was filtered and, after evaporation,
the resulting residue was purified on a silica gel column, using
CH2Cl2–MeOH (100:1) as eluent.
Anal. Calcd for C22H24N4O5: C, 62.25; H, 5.70; N, 13.20. Found: C,
61.99; H, 5.71; N, 13.13.
(5RS)-5-(1¢-Ethoxycarbonyl)methyl-4-(N-phenyl)carbamoyl-
piperazin-2-one (6)
Yield: 90% (from 3); white foam.
1H NMR (300 MHz, CDCl3): d = 7.74 (s, 1 H, H-1), 7.41–7.01 (m,
5 H, C6H5), 6.86 (s, 1 H, 4-CONH), 4.80–4.78 (m, 1 H, H-5), 4.68
(d, J = 18.4 Hz, 1 H, H-3), 4.19 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.80
(d, J = 18.4 Hz, 1 H, H-3), 3.71 (dd, J = 18.4, 4.0 Hz, 1 H, H-6),
3.32–3.26 (m, 1 H, H-6), 2.91 (dd, J = 16.7, 8.8 Hz, 1 H, 5-CH2),
2.63 (dd, J = 16.7, 4.9 Hz, 1 H, 5-CH2), 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3).
Pyrazino[1,2-f]pyrimidine-3,6,8-triones 10–12, 18; General
Procedure
A stirred solution of the corresponding compound 6–9 (2.5 mmol)
in anhyd THF (23 mL) was treated with DBU (0.95 mL, 6.3 mmol).
Stirring was continued for 6 days at r.t. The solid that formed was
filtered and the solvent was concentrated in vacuo. The resulting
residue was chromatographed on a silica gel column eluting with
CH2Cl2–MeOH (100:1).
13C NMR (75 MHz, CDCl3): d = 171.9, 167.9, 154.3 (C=O), 138.9,
128.7, 123.0, 119.8 (C6H5), 61.5 (CH2CH3), 46.0 (C-5), 44.5 (C-3),
44.0 (C-6), 35.3 (5-CH2), 13.9 (CH2CH3).
(9aRS)-7-Phenyl-4-H-tetrahydropyrazino[1,2-f]pyrimidine-
3,6,8-trione (10)
Yield: 81% (from 6); white foam.
Anal. Calcd for C15H19N3O4: C, 59.01; H, 6.27; N, 13.76. Found: C,
58.97; H, 6.29; N, 13.70.
1H NMR (300 MHz, DMSO-d6): d = 8.24 (s, 1 H, H-2), 7.42–7.14
(m, 5 H, C6H5), 4.07 (d, J = 17.6 Hz, 1 H, H-4), 4.01–3.97 (m, 1 H,
H-9a), 3.84 (d, J = 17.6 Hz, 1 H, H-4), 3.34–3.21 (m, 2 H, H-1),
2.93 (dd, J = 16.5, 5.0 Hz, 1 H, H-9), 2.80 (dd, J = 16.5 10.2 Hz, 1
H, H-9).
(3S,5R)-5-(1¢-Ethoxycarbonyl)methyl-3-methyl-4-(N-phe-
nyl)carbamoylpiperazin-2-one (7)
Yield: 85% (from 4); white foam; [a]D –1.5 (c = 0.99, CHCl3).
13C NMR (75 MHz, DMSO-d6): d = 167.6 (C-3), 166.3 (C-8), 152.1
(C-6), 135.9, 129.0, 128.2, 127.5 (C6H5), 46.6 (C-9a), 46.4 (C-4),
43.8 (C-1), 33.6 (C-9).
1H NMR (300 MHz, CDCl3): d = 7.49–6.91 (m, 5 H, C6H5), 6.27 (s,
1 H, H-1), 5.89 (s, 1 H, 4-CONH), 4.63–4.58 (m, 1 H, H-3), 4.52–
4.49 (m, 1 H, H-5), 4.14 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.93–3.87
(m, 1 H, H-6), 3.80–3.73 (m, 1 H, H-6), 3.08 (dd, J = 17.3, 3.6 Hz,
1 H, 5-CH2), 2.61 (dd, J = 17.3, 7.6 Hz, 1 H, 5-CH2), 1.50 (d,
J = 7.3 Hz, 1 H, 3-CH3), 1.25 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 170.3, 169.0, 157.2 (C=O), 138.9,
128.7, 122.6, 119.2 (C6H5), 61.2 (CH2CH3), 51.3 (C-3), 46.7 (CH-
5), 40.9 (C-6), 35.0 (5-CH2), 20.0 (3-CH3), 14.1 (CH2CH3).
Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C,
60.07; H, 5.27; N, 16.24.
(4S,9aR)-4-Methyl-7-phenyl-4-H-tetrahydropyrazino[1,2-f]py-
rimidine-3,6,8-trione (11)
Yield: 79% (from 7); white foam; [a]D 2.4 (c = 1.05, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.49–6.99 (m, 6 H, C6H5, H-2),
4.65 (q, J = 6.9 Hz, 1 H, H-4), 4.03–3.95 (m, 1 H, H-9a), 3.71 (dd,
J = 14.0, 4.5 Hz, 1 H, H-1), 3.48–3.41 (m, 1 H, H-1), 2.87 (dd,
J = 16.2, 3.5 Hz, 1 H, H-9), 2.72 (dd, J = 16.2, 13.2 Hz, 1 H, H-9),
1.58 (d, J = 7.0 Hz, 3 H, 4-CH3).
13C NMR (75 MHz, CDCl3): d = 171.7 (C-3), 167.4 (C-8), 152.3 (C-
6), 136.3, 129.1, 128.6 (C6H5), 53.6 (C-4), 48.2 (C-9a), 43.7 (C-1),
35.9 (C-9), 20.2 (4-CH3).
Anal. Calcd for C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C,
60.11; H, 6.39; N, 13.02.
(3S,5R)-3-Benzyl-5-(1¢-ethoxycarbonyl)methyl-4-(N-phe-
nyl)carbamoylpiperazin-2-one (8)
Yield: 80% (from 5); white foam; [a]D 70.2 (c = 0.70, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.48 (s, 1 H, H-1), 7.34–6.98 (m,
10 H, C6H5), 6.84 (br s, 1 H, 4-CONH), 5.03 (t, J = 5.0 Hz, 1 H, H-
3), 4.60–4.53 (m, 1 H, H-5), 4.21–4.03 (m, 2 H, CH2CH3), 3.64 (dd,
J = 12.8, 3.4 Hz, 1 H, H-6), 3.42 (dd, J = 13.7, 4.6 Hz, 1 H, 3-CH2),
3.25 (dd, J = 13.7, 5.4 Hz, 1 H, 3-CH2), 3.15 (ddd, J = 12.8, 5.4, 2.8
Hz, 1 H, H-6), 2.22 (dd, J = 18.1, 3.1 Hz, 1 H, 3-CH2), 1.98 (dd,
J = 18.1, 9.1 Hz, 1 H, 3-CH2), 1.27 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 173.3, 170.0, 155.7 (C=O), 139.3,
138.3, 130.5, 128.8, 128.4, 126.8, 119.1 (C6H5), 61.4 (CH2CH3),
57.5 (C-3), 48.4 (C-5), 45.8 (C-6), 37.1 (3-CH2), 35.9 (5-CH2), 13.9
(CH2CH3).
Anal. Calcd for C14H15N3O3: C, 61.53; H, 5.53; N, 15.38. Found: C,
61.40; H, 5.31; N, 15.44.
(4S,9aR)-4-Benzyl-7-phenyl-4-H-tetrahydropyrazino[1,2-f]py-
rimidine-3,6,8-trione (12)
Yield: 75% (from 8); white foam; [a]D 86.0 (c = 1.09, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.52–7.17 (m, 11 H, C6H5, H-2),
4.85 (dd, J = 5.8 Hz, 2.8, 1 H, H-4), 3.84–3.79 (m, 1 H, H-9a), 3.48
(dd, J = 13.7, 2.8 Hz, 1 H, 4-CH2), 3.23 (dd, J = 13.7, 5.8 Hz, 1 H,
4-CH2), 2.88–2.80 (m, 1 H, H-1), 2.58 (dd, J = 16.3, 3.2 Hz, 1 H, H-
9), 2.31 (dd, J = 16.3, 13.4 Hz, 1 H, H-9), 1.60 (dd, J = 14.5, 11.4
Hz, 1 H, H-1).
Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C,
66.92; H, 6.36; N, 10.51.
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C-3), 167.5 (C-8), 152.7
(C-6), 136.3, 134.8, 130.0, 129.2, 128.6, 128.4, 127.6 (C6H5), 59.2
(C-4), 46.9 (C-9a), 42.4 (C-1), 37.9 (4-CH2), 35.5 (C-9).
(3S,5R)-5-(1¢-Ethoxycarbonyl)methyl-1,4-bis(N-phenyl)car-
bamoylpiperazine-2-one (9)
Yield: 34% (from 3, in a reaction performed at r.t.); white foam.
1H NMR (300 MHz, CDCl3): d = 11.12 (s, 1 H, NH), 8.56 (s, 1 H,
NH), 7.53–7.03 (m, 10 H, C6H5), 4.76–4.70 (m, 2 H, H-3, H-5), 4.32
(dd, J = 14.0, 5.2 Hz, 1 H, H-6), 4.25 (q, J = 7.1 Hz, 2 H, CH2CH3),
Anal. Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found: C,
68.48; H, 5.53; N, 12.08.
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York

PAPER
Tetrahydropyrimidine-2,4-dione Derivatives
1051
(2¢RS)-3-Phenyl-1-[3¢-(phenylcarbamoyl)-1¢-ethoxycarbonyl-
prop-2¢-yl]hydantoin (18)
(C6H5), 84.6 [C(CH3)3], 61.0 (C-4), 47.2 (C-9a), 45.1 (C-1), 38.9 (4-
CH2), 35.3 (C-9), 27.8 [C(CH3)3].
Yield: 62% (from 9); syrup.
Anal. Calcd for C25H27N3O5: C, 66.80; H, 6.05; N, 9.35. Found: C,
66.51; H, 5.87; N, 9.25.
1H NMR (300 MHz, CDCl3): d = 11.12 (s, 1 H, NH), 8.56 (s, 1 H,
NH), 7.49–6.91 (m, 10 H, C6H5), 4.61–4.58 (m, 1 H, H-2¢), 4.49 (d,
J = 16.8 Hz, 1 H, H-5), 4.16 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.92 (d,
J = 16.8 Hz, 1 H, H-5), 3.81–3.70 (m, 1 H, H-3¢), 3.10–3.06 (m, 1
H, H-3¢), 2.61 (d, J = 7.3 Hz, 2 H, H-1¢), 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13C NMR (75 MHz, CDCl3): d = 170.3, 157.1, 155.9 (C=O), 150.4
(C-2), 138.8, 131.5, 129.1, 129.0, 128.8, 128.3, 126.5 (Ar), 61.2
(CH2CH3), 51.3 (C-2¢), 46.8 (C-5), 40.9 (C-3¢), 35.0 (C-1¢), 14.1
(CH2CH3).
Ring Opening of Boc-Protected Pyrazino[1,2-f]pyrimidine-
3,6,8-triones 13,15; General Procedure
Sat. NH3/MeOH (5 mL) was added to the corresponding 2-tert-but-
oxycarbonylpyrazino[1,2-f]pyrimidine-3,6,8-trione derivative 13,
15. After being stirred for 10 min at r.t., the solution was evaporated
and the residue was purified by silica gel column chromatography
(CH2Cl2–MeOH, 100:1).
(6RS)-6-(tert-Butoxycarbonyl)aminomethyl-1-(methoxycarbo-
nyl)methyl-3-phenyltetrahydropyrimidine-2,4-dione (16)
Yield: 93% (from 13); white foam.
Anal. Calcd for C22H24N4O5: C, 62.25; H, 5.70; N, 13.20. Found: C,
62.15; H, 5.61; N, 13.07.
1H NMR (300 MHz, CDCl3): d = 7.47–7.19 (m, 5 H, C6H5), 5.36 (t,
J = 6.1 Hz, 1 H, NHBoc), 4.27 (d, 1 H, J = 17.6 Hz, 1-CH2), 4.13
(d, 1 H, J = 17.6 Hz, 1-CH2), 3.78 (s, 3 H, OCH3), 3.77–3.67 (m, 1
H, H-6), 3.64–3.55 (m, 1 H, 6-CH2), 3.31–3.19 (m, 2 H, H-5, 6-
CH2), 2.91 (d, J = 16.7 Hz, 1 H, H-5), 1.44 (s, 9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 170.0 (CO2CH3), 167.9 (C-4),
155.8 (C-2), 153.1 (CO2Boc), 135.2, 129.1, 128.9, 128.8, 128.3,
125.9 (C6H5), 80.2 [C(CH3)3], 53.7 (C-6), 52.4 (OCH3), 49.5 (1-
CH2), 42.9 (6-CH2), 34.8 (C-5), 28.3 [C(CH3)3].
Boc-Protected Pyrazino[1,2-f]pyrimidine-3,6,8-triones 13–15;
General Procedure
To a solution of the pyrazino[1,2-f]pyridine-3,6,8-triones deriva-
tives 10–12 (1.2 mmol) in anhyd THF (11 mL), were added Et3N
(0.17 mL, 1.22 mmol), DMAP (15 mg, 0.123 mmol) and di-tert-bu-
tyl dicarbonate (546 mg, 2.5 mmol). The mixture was stirred at r.t.
for 15 min and then concentrated under reduced pressure. The crude
mixture was purified by silica gel column chromatography
(EtOAc–hexane, 1:6).
Anal. Calcd for C19H25N3O6: C, 58.30; H, 6.44; N, 10.74. Found:
C, 58.49; H, 6.67; N, 10.61.
(9aRS)-2-tert-Butoxycarbonyl-7-phenyl-4H-tetrahydropyrazi-
no[1,2-f]pyrimidine-3,6,8-trione(13)
yield: 90% (from 10); syrup.
(6R,1¢S)-6-(tert-Butoxycarbonyl)aminomethyl-1-[1¢-(methoxy-
carbonyl)-2¢-phenyl]ethyl-3-phenyltetrahydropyrimidine-2,4-
dione (17)
1H NMR (300 MHz, DMSO-d6): d = 7.43–7.15 (m, 5 H, C6H5), 4.28
(d, J = 17.3 Hz, 1 H, H-4), 4.22–4.18 (m, 2 H, H-1, H-9a), 4.12 (d,
J = 17.3 Hz, 1 H, H-4), 3.74 (dd, J = 13.4, 7.7 Hz, 1 H, H-1), 2.92–
2.86 (m, 2 H, H-9), 1.48 (s, 9 H, t-C4H9).
13C NMR (75 MHz, DMSO-d6): d = 168.3 (C-3), 165.9 (C-6), 151.8
(C-8), 150.8 (CO2Boc), 136.1, 129.2, 128.5, 127.8 (C6H5), 82.9
[C(CH3)3], 46.8 (CH-9a), 45.6 (C-4), 37.9 (C-1), 33.8 (C-9), 27.3
[C(CH3)3] .
Yield: 77% (from 15); white foam; [a]D 2.8 (c = 0.68, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.48–7.16 (m, 10 H, C6H5), 5.59
(t, J = 6.4 Hz, 1 H, NHBoc), 3.93 (dd, J = 11.3, 4.9 Hz, 1 H, H-1¢),
3.82 (s, 3 H, OCH3), 3.54–3.43 (m, 2 H, H-2¢, 6-CH2), 3.36 (dd,
J = 13.9, 4.9 Hz, 1 H, H-2¢), 3.25–3.17 (m, 1 H, 6-CH2), 2.87–2.82
(m, 1 H, H-6), 2.44 (d, J = 16.5 Hz, 1 H, H-5), 2.08 (dd, J = 16.5,
7.5 Hz, 1 H, H-5), 1.42 (s, 9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 170.7 (CO2Me), 167.6 (C-2), 155.7
(C-4), 152.1 (CO2Boc), 137.7, 134.8, 129.0, 128.9, 128.7, 128.4,
127.2 (C6H5), 80.0 [C(CH3)3], 65.4 (C-1), 56.1 (C-6), 52.9 (OCH3),
42.8 (6-CH2), 34.4 (C-5), 33.8 (C-1¢), 33.8 (C-2¢), 28.3 [C(CH3)3].
Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.89; N, 11.69. Found: C,
60.04; H, 5.85; N, 11.70.
(4S,9aR)-2-tert-Butoxycarbonyl-4-methyl-7-phenyl-4H-tetra-
hydropyrazino[1,2-f]pyrimidine-3,6,8-trione (14)
Yield: 86% (from 11); syrup; [a]D 12.6 (c = 0.90, CHCl3).
1H NMR (300 MHz, DMSO-d6): d = 7.4–7.14 (m, 5 H, C6H5), 4.84
(q, J = 7.1 Hz, 1 H, H-4), 4.48 (dd, J = 13.8, 3.1 Hz, 1 H, H-1),
4.08–4.02 (m, 1 H, H-9a), 3.42 (dd, J = 13.8, 11.1 Hz, 1 H, H-1),
2.93 (dd, J = 16.2, 3.4 Hz, 1 H, H-9), 2.74 (dd, J = 16.2, 3.3 Hz, 1
H, H-9), 1.58 (m, 12 H, 4-CH3, t-C4H9).
Anal. Calcd for C26H31N3O6: C, 64.85; H, 6.49; N, 8.73. Found: C,
64.63; H, 6.26; N, 8.77.
Coupling of 16 and 17 with Boc-L- or Boc-D-Trp-OH; General
Procedure
TFA (3 mL) was added to a solution of the corresponding N-Boc-
protected dihydropyrimidine-2,4-dione derivative 16 or 17 (0.4
mmol) in CH2Cl2 (6 mL). After 30 min at r.t., the solvents were
evaporated to dryness and the residue was co-evaporated several
times with CH2Cl2. The residue was dissolved in anhyd CH2Cl2 (5
mL) and Boc-L- or D-Trp-OH (162 mg, 0.5 mmol), BOP (235 mg,
0.5 mmol) and Et3N (0.14 mL, 1 mmol) were added successively to
the solution. After being stirred overnight at r.t., the solvent was
evaporated. The residue was dissolved in EtOAc (25 mL) and
washed successively with 10% citric acid (10 mL), aq 10%
NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL). The organic
layer was separated, dried (Na2SO4), and evaporated. The resulting
Boc-tryptophyl derivative was purified by preparative TLC
(CHCl3–MeOH, 100:1). Using this chromatographic procedure,
compounds 19 and 20 were also resolved into diastereoisomers a
(6S) and b (6R).
Anal. Calcd for C19H23N3O5: C, 61.11; H, 6.21; N, 11.25. Found: C,
60.78; H, 6.00; N, 11.12.
(4S,9aR)-4-Benzyl-2-tert-butoxycarbonyl-7-phenyl-4H-tetra-
hydropyrazino[1,2-f]pyrimidine-3,6,8-trione (15)
Yield: 79% (from 12); syrup.
1H NMR (300 MHz, CDCl3): d = 7.52–7.13 (m, 10 H, C6H5), 5.02
(dd, J = 5.6, 3.3 Hz, 1 H, H-4), 3.91–3.83 (m, 1 H, H-9a), 3.72 (dd,
J = 13.6, 3.4 Hz, 1 H, H-1), 3.45 (dd, J = 13.8, 5.7 Hz, 1 H, 4-CH2),
3.28 (dd, J = 13.8, 3.3 Hz, 1 H, 4-CH2), 2.66 (dd, J = 16.4, 3.3 Hz,
1 H, H-9), 2.37 (dd, J = 16.4, 13.4 Hz, 1 H, H-9), 1.63 (dd, J = 13.6,
11.3 Hz, 1 H, H-1), 1.55 (s, 9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 167.2 (C-3), 167.0 (C-6), 152.2 (C-
8), 150.5 (CO2 Boc), 136.1, 134.6, 129.8, 129.2, 128.7, 128.6, 127.8
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York

1052
R. Patiño-Molina et al.
PAPER
(6S)-6-[N-(tert-Butoxycarbonyl)-L-tryptophyl]aminomethyl-1-
(methoxycarbonyl)methyl-3-phenyltetrahydropyrimidine-2,4-
dione (19a)
5.19 (d, J = 7.9 Hz, 1 H, NHBoc), 4.43–4.37 (m, 1 H, a-CH), 3.71
(s, 3 H, OCH3), 3.55–3.46 (m, 1 H, 6-CH2), 3.36–2.94 (m, 4 H, b-
CH2, H-1¢, H-2¢, 6-CH2), 2.51–4.49 (m, 1 H, H-6), 2.05 (d, J = 19.3
Hz, 1 H, H-5), 1.45 (s, 9 H, t-C4H9), 1.33–1.19 (m, 1 H, H-5).
Yield: 30% (from 16); white foam; HPLC: tR = 69.60 min (25:75);
[a]D –17.9 (c = 1.45, CHCl3).
13C NMR (75 MHz, CDCl3): d = 172.1, 171.1, 168.0 (C=O), 155.2
(CO2Boc), 151.2 (C-2), 136.0, 134.5, 129.1, 129.0, 128.9, 128.5,
127.4, 127.2, 123.2, 122.5, 119.8, 118.9, 111.2, 110.9 (Ar), 80.0
[C(CH3)3], 64.8 (C-1¢), 55.9 (a-CH), 53.0 (OCH3), 53.0 (C-6), 41.6
(6-CH2), 33.8 (C-2¢), 33.7 (C-5), 28.8 (b-CH2), 28.3 [C(CH3)3].
1H NMR (300 MHz, CDCl3): d = 8.25 (s, 1 H, NHi), 7.61 (d, J = 7.9
Hz, 1 H, H-4i), 7.43–7.34 (m, 3 H, C6H5, H-7i), 7.22 (t, J = 7.9 Hz,
1 H, H-6i), 7.15–7.07 (m, 4 H, C6H5, H-5i), 7.02 (d, J = 2.2 Hz, 1 H,
H-2i), 6.72 (br t, 1 H, a-NH), 5.06 (d, J = 7.0 Hz, 1 H, NHBoc),
4.38–4.34 (m, 1 H, a-CH), 3.83–3.78 (m, 2 H, H-1¢), 3.69 (s, 3 H,
OCH3), 3.41–3.27 (m, 4 H, b-CH2, H-6, 6-CH2), 3.13 (dd, J = 14.3,
7.4 Hz, 1 H, b-CH2), 2.89 (dd, J = 16.7, 5.8 Hz, 1 H, H-5), 2.40 (d,
J = 16.7 Hz, 1 H, H-5), 1.44 (s, 9 H, t-C4H9).
Anal. Calcd for C37H41N5O7: C, 66.55; H, 6.19; N, 10.49. Found: C,
66.64; H, 6.21; N, 10.44.
Binding Assays
Anal. Calcd for C30H35N5O7: C, 62.38; H, 6.11; N, 12.12. Found: C,
62.27; H, 5.93; N, 12.03.
CCK1 and CCK2 receptor binding assays were performed using rat
pancreas and cerebral cortex homogenates, respectively, according
to the method previously described.12b
(6R)-6-[N-(tert-Butoxycarbonyl)-L-tryptophyl]aminomethyl-1-
(methoxycarbonyl)methyl-3-phenyltetrahydropyrimidine-2,4-
dione (19b)
Acknowledgment
Yield: 50% (from 16); white foam; HPLC: tR = 73.97 min (25:75);
[a]D –17.3 (c = 0.12, CHCl3).
We thank the Plan Nacional de Biomedicina (SAF 2003-07207-
C02) for financial support.
1H NMR (300 MHz, CDCl3): d = 8.22 (s, 1 H, NHi), 7.61 (d, J = 7.9
Hz, 1 H, H-4i), 7.42–7.34 (m, 3 H, C6H5, H-7i), 7.26 (t, J = 7.9 Hz,
1 H, H-6i), 7.22–7.06 (m, 4 H, C6H5, H-5i), 7.03 (d, J = 2.2 Hz, 1 H,
H-2i), 6.67 (br t, 1 H, NH), 5.01 (br s, 1 H, NHBoc), 4.40–4.35 (m,
1 H, a-CH), 3.91–3.79 (m, 2 H, H-1¢), 3.72 (s, 3 H, OCH3), 3.48–
3.43 (m, 1 H, 6-CH2), 3.36–3.29 (m, 2 H, b-CH2, H-6), 3.24–3.21
(m, 1 H, 6-CH2) 3.15 (dd, J = 14.5, 7.8 Hz, 1 H, b-CH2), 2.89 (dd,
J = 16.7, 5.6 Hz, 1 H, H-5), 2.41 (d, J = 16.7 Hz, 1 H, H-5), 1.44 (s,
9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 172.6, 170.0, 168.4 (C=O), 155.4
(CO2Boc), 152.5 (C-2), 136.1, 134.8, 129.0, 128.4, 127.2, 123.1,
122.4, 119.7, 118.8, 111.3, 110.4 (Ar), 80.4 [C(CH3)3], 55.5 (a-
CH), 52.6 (C-6), 52.5 (OCH3), 49.4 (C-1¢), 41.1 (6-CH2), 34.2 (C-
5), 29.6 (b-CH2), 28.2 [C(CH3)3].
References
(1) Selected applications in medicinal chemistry of
dihydropyrimidinones include: Antivirals: (a) Botta, M.;
Occhionero, F.; Nicoletti, R.; Mastromarino, P.; Conti, C.;
Magrini, M.; Saladino, R. Bioorg. Med. Chem. Lett. 1999, 7,
1925. (b) Botta, M.; Corelli, F.; Maga, G.; Manetti, F.;
Renzulli, M.; Spadari, S. Tetrahedron 2001, 57, 8357.
(c) Balzarini, J.; McGuigan, C. J. Antimicrob. Chemother.
2002, 50, 5. (d) McGuigan, C.; Pathirana, R. N.; Snoeck, R.;
Andrei, G.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2004,
47, 1847. (e) Stray, S. J.; Bourne, C. R.; Punna, S.; Lewis,
W. G.; Finn, M. G.; Zlotnick, A. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 8138. (f) Semaine, W.; Johar, M.; Lorne,
D.; Tyrrell, J.; Kumar, R.; Agrawal, B. J. Med. Chem. 2006,
49, 2049. Calcium channel blockers: (g) Atwal, K. S.;
Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.;
Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem.
1990, 33, 1510. a1a-Antagonists: (h) Barrow, J. C.;
Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.;
Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R.
M.; Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.;
Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.;
Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.;
Anal. Calcd for C30H35N5O7: C, 62.38; H, 6.11; N, 12.12. Found: C,
62.10; H, 5.95; N, 12.00.
(6R)-6-[N-(tert-Butoxycarbonyl)-D-tryptophyl]aminomethyl-1-
(methoxycarbonyl)methyl-3-phenyltetrahydropyrimidine-2,4-
dione (20a)
Yield: 50% (from 16); white foam; [a]D = 16.4 (c = 0.65, CHCl3).
This compound showed analytical and spectroscopic data identical
to those of its enantiomer 19b.
Anal. Calcd for C30H35N5O7: C, 62.38; H, 6.11; N, 12.12. Found: C,
62.43; H, 6.04; N, 12.15.
Nagarathnam, D.; Forray, C. J. Med. Chem. 2000, 43, 2703.
(i) Patanè, E.; Pittalà, V.; Guerrera, F.; Salerno, L.; Romeo,
G.; Siracusa, M. A.; Russo, F.; Manetti, F.; Botta, M.;
Mereghetti, I.; Cagnotto, A.; Mennini, T. J. Med. Chem.
2005, 48, 2420. Angitensin II receptor antagonists:
(6S)-6-[N-(tert-Butoxycarbonyl)-D-tryptophyl]aminomethyl-1-
(methoxycarbonyl)methyl-3-phenyltetrahydropyrimidine-2,4-
dione (20b)
(j) Atwal, K. S.; Ahmed, S. Z.; Bird, J. E.; Delaney, C. L.;
Dickinson, K. E.; Ferrara, F. N.; Hedberg, A.; Miller, A. V.;
Moreland, S.; O’Reilly, B. C. J. Med. Chem. 1992, 35, 4751.
(2) Tetrahydropyrimidin-2-ones have shown to exhibit a range
of interesting biological activities: Anti-HIV (a) De Lucca,
G. V.; Liang, J.; De Lucca, I. J. Med. Chem. 1999, 42, 135.
Antitumoral: (b) Adams, J. L.; Meek, T. D.; Mong, S.-M.;
Johnson, R. K.; Wetcalf, B. W. J. Med. Chem. 1988, 31,
1355. Antiallergic agents: (c) Cohan, V. L.; Pettipher, E. R.
Eur. Pat. Appl. E.P. 636369, 1995; Chem. Abstr. 1995, 122,
178386.
Yield: 27% (from 16); white foam.
This compound showed analytical and spectroscopic data identical
to those of its enantiomer 19a.
Anal. Calcd for C30H35N5O7: C, 62.38; H, 6.11; N, 12.12. Found: C,
62.29; H, 5.97; N, 12.21.
(6R)-6-[N-(tert-Butoxycarbonyl)-L-tryptophyl]aminomethyl-
1-[1¢-(methoxycarbonyl)-2¢-phenyl]ethyl-3-phenyltetrahydro-
pyrimidine-2,4-dione (21b)
Yield: 62% (from 17); white foam; HPLC: tR = 11.95 min (45:55);
[a]D –118.7 (c = 0.29, CHCl3).
(3) Embrey, M. W.; Wai, J. S.; Funk, T. W.; Homnick, C. F.;
Perlow, D. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J.;
Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.;
Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I.-W.; Ellis,
1H NMR (300 MHz, CDCl3): d = 8.23 (s, 1 H, NHi), 7.63 (d, J = 7.8
Hz, 1 H, H-4i), 7.52 (br s, 1 H, NH), 7.44–7.00 (s, 14 H, C6H5, Hi),
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York

PAPER
J. D.; Wong, B. K.; Lin, J. H.; Leonard, Y. M.; Tsou, N. N.;
Zhuang, L. Bioorg. Med. Chem. Lett. 2005, 15, 4550.
(4) Jones, K. A.; Weaver, D. F.; Tiedje, K. E. Pat. Appl. WO
2004009559, 2004; Chem. Abstr. 2004, 140, 146155.
(5) Poitout, L.; Thurieau, C.; Brault, V. Pat. Appl. WO
2001009090, 2001; Chem. Abstr. 2001, 134, 163050.
(6) Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.;
Srivastava, A. K.; Ahmad, R.; Srivastava, R.; Srivastava, B.
S. Bioorg. Med. Chem. Lett. 2003, 11, 2911.
(7) Konopelski, J. P.; Filonova, L. K.; Olmstead, M. M. J. Am.
Chem. Soc. 1997, 119, 4305.
(8) Hopkins, S. A.; Ritsema, T. A.; Konopelski, J. P. J. Org.
Chem. 1999, 64, 7885.
(9) Martins, M. A. P.; Teixeira, M. V. M.; Cunico, W.; Scapin,
E.; Mayer, R.; Pereira, C. M. P.; Zanatta, N.; Bonacorso, H.
G.; Peppe, C.; Yuan, Y.-F. Tetrahedron Lett. 2004, 45, 8991.
(10) (a) Agami, C.; Dechoux, L.; Melaimi, M. Tetrahedron Lett.
2001, 42, 8629. (b) Scannell, M. P.; Prakash, G.; Falvey, D.
E. J. Phys. Chem. A 1997, 101, 4332.
Tetrahydropyrimidine-2,4-dione Derivatives
1053
Martínez, M.; Gómez-Monterrey, I.; García-López, M. T.;
González-Muñiz, R.; Cenarruzabeitia, E.; Latorre, M.; Del
Río, J.; Herranz, R. J. Med. Chem. 2001, 44, 2219.
(14) Bartolomé-Nebreda, J. M.; García-López, M. T.; González-
Muñiz, R.; Cenarruzabeitia, E.; Latorre, M.; Del Río, J.;
Herranz, R. J. Med. Chem. 2001, 44, 4196.
(15) Martín-Martínez, M.; García-López, M. T.; Herranz, R.;
González-Muñiz, R. Tetrahedron Lett. 1996, 37, 2471.
(16) Gerona-Navarro, G.; García-López, M. T.; González-
Muñiz, R. Tetrahedron Lett. 2003, 44, 6145.
(17) Compounds 3, 4, and 5 were synthesized by reductive
amination of b-keto esters derived from Z-Xaa-Gly
dipeptides (Xaa = Gly, Ala, and Phe, respectively).
Compounds 4 and 5 were obtained as separable mixtures of
diastereoisomers due to the induction by the Ala and Phe
stereogenic centers. However, analogue 3 was obtained as
racemic due to the achiral nature of the starting b-keto ester:
Patiño-Molina, R.; Herranz, R.; García-López, M. T.;
González-Muñiz, R. Tetrahedron 1999, 55, 15001.
(18) An authentic sample of compound 19b, prepared by an
alternative stereospecific synthetic route, allows the
unequivocal assignment of the configuration at C6 in the
diastereoisomeric pairs 19a,b and 20a,b: Patiño-Molina, R.;
Cubero, J.; Pérez de Vega, M. J.; García-López, M. T.;
González-Muñiz, R., unpublished results.
(11) Hakkou, H.; Vanden Eynde, J. J.; Hamelin, J.; Bazureau, J.
P. Tetrahedron 2004, 60, 3745.
(12) (a) Martín-Martínez, M.; Bartolomé-Nebreda, J. M.;
Gómez-Monterrey, I.; González-Muñiz, R.; García-López,
M. T.; Ballaz, S.; Barber, A.; Fortuño, A.; Del Río, J.;
Herranz, R. J. Med. Chem. 1997, 40, 3402. (b) Ballaz, S.;
Barber, A.; Fortuño, A.; Del Río, J.; Martín-Martínez, M.;
Gómez-Monterrey, I.; Herranz, R.; González-Muñiz, R.;
García-López, M. T. Br. J. Pharmacol. 1997, 121, 759.
(13) (a) Bartolomé-Nebreda, J. M.; Gómez-Monterrey, I.;
García-López, M. T.; González-Muñiz, R.; Martín-
Martínez, M.; Ballaz, S.; Cenarruzabeitia, E.; Latorre, M.;
Del Río, J.; Herranz, R. J. Med. Chem. 1999, 42, 4659.
(b) Bartolomé-Nebreda, J. M.; Patiño-Molina, R.; Martín-
(19) The increased shielding (Db = d19b – d21b) was 0.36 ppm
for the H-5eq and 1.67 ppm for the H-5ax.
(20) Martín-Martínez, M.; Marty, A.; Jourdan, M.; Escrieut, C.;
Archer, E.; González-Muñiz, R.; García-López, M. T.;
Maigret, B.; Herranz, R.; Fourmy, D. J. Med. Chem. 2005,
48, 4842.
Synthesis 2007, No. 7, 1047–1053 © Thieme Stuttgart · New York