3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation

Article abstract of DOI:10.1016/j.bmcl.2011.03.115

The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and

Full text of DOI:10.1016/j.bmcl.2011.03.115

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3384–3389
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists
for the treatment of pain and inflammation
Jian Jeffrey Chen a, , Thomas Nguyen a, Derin C. D’Amico a, Wenyuan Qian a, Jason Human a, Toshihiro Aya a,
⇑
Kaustav Biswas a, Christopher Fotsch a, Nianhe Han a, Qingyian Liu a, Nobuko Nishimura a,
Tanya A. N. Peterkin a, Kevin Yang a, Jiawang Zhu a, Babak Bobby Riahi b, Randall W. Hungate a,
Neil G. Andersen b, John T. Colyer b, Margaret M. Faul b, Augustus Kamassah c, Judy Wang c,
Janan Jona d, Gondi Kumar e, Eileen Johnson c, Benny C. Askew f,
a Department of Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
b Department of Process Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
c Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
d Department of Pharmaceutical Science, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
e Department of Pharmacokinetics & Drug Metabolism, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
f Department of Medicinal Chemistry, Serono Research Institute, Rockland, MA, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described.
Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the
current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-
1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-
1-naphthalenyl)acetamide, showed EC50 of 10.3 nM in a rabbit biochemical challenge model. The
practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 5 March 2011
Revised 28 March 2011
Accepted 31 March 2011
Available online 7 April 2011
Keywords:
Bradykinin B1
Antagonist
Pain
Inflammation
GPCR
Oxopiperazine
Tetralin
Bradykinin-1 (B1) receptor is a G-protein coupled receptor.1 It is
activated by the longer acting des-Arg [9/10] metabolites of brady-
kinin (BK) and kallidin (Lys-BK). The receptor is normally absent or
expressed at very low levels but is induced during tissue injury and
inflammation. Pre-clinical studies suggested that B1 receptor is
implicated in establishing and maintaining the signaling of chronic
pain.2,3 The rationale for and discovery of B1 receptor antagonists
as potential treatment of pain and inflammation has been exten-
sively discussed in the literature.4–8
We recently reported a number of novel B1 antagonists contain-
ing bicyclic chromans and tetralins as the key subunit.9–13 Both
acyclic and cyclic arylsulfonylated b-amino acids represented by
1–310,11,13 were investigated. Early leads such as 1–2 suffered from
high human microsomal clearance or moderate functional
potencies. Dihydroquinoxalinone acetic acid based compounds
such as 3 exhibited much improved functional potency and in
some cases improved metabolic stability.13 We prepared the ana-
log of 3 without the fused benzo ring (i.e., compound 4 as a mix-
ture of two diastereomers) and found that both binding and
functional potency for B1 receptor was maintained (Table 1). This
report discusses the structure–activity relationships (SAR) studies
of these oxopiperazine based B1 antagonists, which led to com-
pound 17 with improved in vivo efficacy over initial lead 1.
In order to facilitate quick exploration of structure–activity
relationships we used commercially available ethyl 2-(3-oxopi-
perazin-2-yl)acetate to prepare analogs of 4 as 1:1 diastereomeric
mixtures. The synthesized compounds were tested in a human B1
receptor binding assay to give various Ki values. They were also
tested in a human B1 agonist-induced aqueorin-based calcium
efflux assay in Chinese hamster ovary cells to measure their func-
tional potency (reported as IC50).9,11 In this paper we will focus the
discussion on functional activities, although similar SAR trends
⇑
Corresponding author. Tel.: +1 805 447 8498; fax: +1 805 480 1337.
E-mail address: jianc@amgen.com (J.J. Chen).
Present address.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.115

J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
3385
Table 1
Discovery of a new class of oxopiperazine based B1 antagonists
Table 3
Characterization of the four diastereomers of compound 10
O
O
O
S
HN
O
F3C
S
N
S
O
H
2
O
H
N
F3C
H
N
N
N
1
O
O
O
O
N
H
O
N
H
F
N
N
2
1
a
Compd # (stereochemistry at 1, 2)
hB1 Kia (nM)
hB1 IC50 (nM)
17 (R,R)
18 (R,S)
19 (S,R)
20 (S,S)
0.16 0.08
31.8 2.8
5.3 0.1
0.22 0.07
248 10
3.6 0.1
Cl
Cl
Cl
541 129
1165 69
Cl
a
O
O
Ki and IC50 reported are average SD of at least two or more determinations.
O
O
S
N
S
N
H
N
H
N
O
were observed in the binding assay. We also assessed the meta-
bolic stability of these compounds by incubation in human liver
microsomal preparation. The rate of the disappearance of the par-
O
N
H
O
N
H
O
ent was measured and expressed in unit of lL/min/mg.
N
N
Substitution on the sulfonamide portion was studied (Table 2).
In general various mono and disubstitution by halogen, methyl,
methoxy, and trifluoromethyl group on benzenesulfonamides were
well tolerated. Although more lipophilic groups increased the
binding affinity slightly, the functional potency was compromised
in certain cases compared to simple phenyl sulfonamide (e.g., com-
pare 14 and 6). Furthermore these compounds were also metabol-
ically more labile. Substituted thiophene or benzothiophene
sulfonamides were also well tolerated. However, replacement of
the phenylsulfonamide by methyl sulfonamide resulted in 1000-
fold drop in functional potency.
4
3
a
Compd #
hB1 Kia (nM)
hB1 IC50 (nM)
HLMb
(lL/min/mg)
1
2
3
4
0.4 0.1
0.8 0.1
330
900
417
369
23
8
13
8
0.1 0.01
0.17 0.03
0.55 0.08
1.2 0.7
a
Ki and IC50 reported are average SD of at least two or more determinations.
The experiments are performed wth two replicates for each compound. The
percent difference between replicates must be less than or equal to 20% in order for
the results to be considered valid.
b
Table 2
SAR studies on the sulfonamide portion
R
SO2
H
N
N
O
N
H
O
N
HLMb
(lL/min/mg)
a
Compd #
R
hB1 Kia (nM)
hB1 IC50 (nM)
4
5
6
7
8
3,4-Cl2Ph
Me
Ph
2-ClPh
4-ClPh
2,4-Cl2Ph
4-MePh
4-OMePh
4-CF3Ph
0.17 0.03
522 75
1.2 0.2
1.2 0.7
475 108
0.48 0.31
0.55 0.06
0.49 0.05
0.64 0.08
0.30 0.13
0.43 0.02
1.76 0.3
0.94 0.46
2.3 0.4
369
<50
<50
104
137
198
176
<50
215
193
722
415
326
0.41 0.09
0.60 0.08
0.21 0.02
0.30 0.18
0.55 0.04
0.46 0.01
0.15 0.01
0.12 0.02
0.10 0.01
0.10 0.02
9
10
11
12
13
14
15
16
3-CF3Ph
4-Me-3-CF3Ph
3-Br-5-Cl-thiophen-2-yl
5-Cl-benzothiophen-2-yl
0.33 0.02
3.3 0.01
a
Ki and IC50 reported are average SD of at least two or more determinations.
The experiments are performed wth two replicates for each compound. The percent difference between replicates must be less than or equal to 20% in order for the
b
results to be considered valid.

3386
J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
Table 4
Modification of the oxopiperazine ring
O
O
O
O
S
N
O
O
S
N
S
N
NHR
NHR
NHR
O
O
O
N
H
O
N
O
N
H
O
21
23
22
H
N
O
O
S
N
NHR
=
NHR
O
O
N
H
N
24
a
Compd #
hB1 Kia (nM)
hB1 IC50 (nM)
10
21
22
23
24
0.30 0.18
17.6 1.8
442 255
718 79
0.30 0.13
136 40
98.6 34
NDb
5.10 0.02
2.2 0.7
a
Ki and IC50 reported are average SD of at least two or more determinations.
ND: not determined.
b
Table 5
SAR study of optically pure oxopiperazines
R
O
O
S
N
H
N
O
Y
N
H
O
X
a
Compd #
R
Y
X
hB1 Kia (nM)
hB1 IC50 (nM)
HLM (lL/min/mg)
17
25
26
27
4-Me
H
4-Cl
CH2
CH2
CH2
O
0.16 0.08
0.5 0.2
0.3 0.1
0.22 0.07
0.8 0.2
0.2 0.1
0.4 0.2
<50
<50
124
N
4-Me
0.18 0.04
<100
N
28
4-Me
4-Me
CH2
0.11 0.11
1.98 0.44
0.14 0.02
<50
371
29
CH2
2.6 0.1
N
N
N
30
31
4-Me
4-Me
CH2
CH2
3.0 0.3
2.4 0.9
1.2 1.4
<100
<50
O
1.46 1.2
NMe
32
33
34
35
36
37
38
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
CH2
CH2
CH2
CH2
CH2
CH2
CH2
–NH2
60 43
1.09 0.01
0.52 0.08
4.1 0.9
0.22 0.07
0.29 0.08
1.6 1.5
238 253
4.3 0.4
<50
<100
<100
<5
113
<100
113
–NHcPr
–NH2cPen
–NHtBu
–NHCH2cPr
–NHCH2iPr
–NHCH2tBu
0.60 0.04
1.28 0.22
0.33 0.23
0.48 0.46
2.3 1.6
a
Ki and IC50 reported are average SD of at least two or more determinations.

J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
3387
Table 6
Ar
Ar
SO2
N
SO2
N
PK profiles of representative oxopiperazines
H
N
OEt
OEt
OH
a
b
Compd Rat IV
#
Rat IV
Vss (L/
kg)
Rat CYP 3A4 IC50
CYP 3A4 IC50
30-min pre-
incubation
(lM)
Cla (L/h/
kg)
F%b
(lM) no
incubation
a
O
40
O
O
N
H
O
N
H
O
N
H
O
17
25
26
27
35
31
38
7.4
5.4
6.7
6.7
3.4
6.1
1.8
9.3
9.9
6
>30
NA
NA
NA
>30
NA
>30
>30
NA
NA
NA
>30
NA
2.2
39
38
NA
19
6.5
0.3
NA
16
c
H2N
11.9
12.5
8.34
15.2
3.4
2HCl
Ar
SO2
N
H
N
O
N
H
O
N
a
After IV bolus dose of 1 mg/kg in DMSO to Sprague–Dawley rats (n = 2).
b
After po administration of 10 mg/kg in 2% HPMC/1% Tween 80 to Sprague–
4-16
Dawley rats (n = 2). NA: not available.
N
Scheme 1. Synthetic sequence for oxopiperazine acetamides. Reagents and condi-
tions: (a) RSO2Cl, pyridine; (b) LiOH, water, methanol and dioxane (1:1:1); (c)
DIPEA, EDCI, HOAt, IPA.
120
100
80
60
40
20
0
3-oxo in 10 to 5-oxo analog 24 reduced the functional potency
by sixfold. These data indicated the modification of oxopiperazine
ring dramatically affected the affinity for the B1 receptor and the
parent 3-oxopiperazine core provided the highest antagonistic po-
tency at the B1 receptor.
We subsequently prepared a number of optically pure (R)-2-
oxopiperazine acetamides with modifications at aryl sulfonamide,
bicyclic and terminal amine portions to establish the SAR pattern
in the series (Table 5).
-11
-10
-9
-8
-7
-6
Log(M)
Figure 1. Effect of compound 17 on B1 agonist DAK induced hypotension. Each data
point represented the % hypotensive response due to DAK administration either at
30- or 75-min post subcutaneous dose of 17. The x-axis represented the measured
plasma concentration of 17 at different doses or time points.
In the sulfonamide portion, removal of 4-Me from 17 to give 25
resulted in threefold drop in potency. The 4-Cl analog 26 is equally
potent to the 4-Me analog 17. Changing the tetralin in 17 to chro-
man had only minor effect on potency (see 27). Modification of the
piperidine in 17 was studied next. Adding a methyl group at 4-po-
sition slightly increased the functional potency. Addition of gem-
dimethyl group at 3-position, however, reduced the potency by
10-fold. Changing the piperidine ring to a more polar group such
as morpholine or N-methylpiperazine ring decreased the potency
by four to fivefold. Truncation of piperidine to simple amino group
dramatically reduced the potency. The potency could be restored
by introduction of a lipophilic alkyl or cycloalkyl group on the
nitrogen. The cyclopropylmethylamine and isobutylamine analogs
(36–37) were almost equally potent to the piperidine analog 17.
Most compounds in the series, except 29, had dramatically reduced
human microsomal clearance compared to earlier leads 1–3.
The in vivo pharmacokinetics of representative examples of
oxopiperazines in rat are shown in Table 6. Generally most
compounds in this series possessed high IV clearance and high
Vss. Compound 38 had the lowest in vivo clearance among the
compounds profiled. Additional PK experiments on 38 showed
the compound to be a time dependent CYP 3A4 inhibitor (TDI,
see Table 6).
Table 7
Pharmacokinetic profiles of 17 in pre-clinical species
a
a
Species
CLa (L/h/kg)
Vss (L/kg)
t1/2 (h)
Fb (%)
Mouse
Rat
Rabbit
Cynomolgus monkey
Rhesus monkey
Dog
8.0
7.4
3.2
0.6
1.8
3.8
6.0
9.3
6.4
1.6
5.9
1.4
4.8
2.4
5.6
3.2
4.6
6
6
5c
17
23c
24e
16.2
d
Dosed orally 5 mg/kg in 2% HPMC/1% Tween 80.
a
Dosed iv at 1 mg/kg in 100% DMSO (rat) or PBS (other species).
b
Dosed orally 10 mg/kg (rat and Rat) in 2% HPMC/1% Tween 80 (rat) or PBS
(mouse).
c
Dosed orally 5 mg/kg po in PBS.
Dosed orally at 3 mg/kg in 2% HPMC/1% Tween 80.
e
Next we prepared the four single diastereomers of compound
Several analogs of 38 were screened for TDI and N-neopentyl
group was identified to be responsible for the observed TDI.
Replacing neopentylamino group by tertbutylamino (compound
35) or piperidine (compound 17) solved the TDI issue (see Table
6).
We next examined the in vivo activity of 17. Several B1 antag-
onists such as 1 were previously tested in a rabbit biochemical
challenge model.11,12 Briefly, treatment with lipopolysaccharide
upregulates B1 receptors in animals like rabbits and subsequent
injection with a B1 agonist such as DAK (des-Arg10-Kallidin)
induces hypotensive response. This effect could be reversed by
administration of B1 antagonists in a pharmacodynamic assay of
in vivo activity.11,12
10 to study the effect of stereochemistry at the amino acid and
amine sites (Table 3). Consistent with previous SAR the (R)
stereochemistry is preferred at both sites.9 Switching the stereo-
chemistry at either site reduced the functional potency by at least
10-fold. The potency was reduced further when both centers were
changed to (S) configuration.
The oxopiperazine portion of compound 10 was examined (Ta-
ble 4). Introduction of the gem-dimethyl group at the carbon adja-
cent to the internal amide NH to give compound 21 reduced the
functional potency by 412-fold. N-Methylation of the ring amide
NH in 10 also decreased the potency by 300-fold. The a-methyla-
tion of the carbon next to the internal carbonyl group to give 23 ad-
versely impacted the binding affinity. The translocation of the

3388
J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
MeO
NH2
Ar
Ar
O2S
HN
OMe
b
O2S
HN
H2N
HO
OBn
OBn
OBn
a
O
MeO
O
O
O
N
H
O
43
HO
O
OMe
41
42
c
Ar
O2S
N
Ar
SO2
N
d
OBn
OH
O
N
H
O
O
N
H
O
44
45
H2N
Ar
SO2
N
H
N
X
45
25-27
O
O
X
e
N
H
N
X = O, CH2
N
Ar
H2N
SO2
N
45
H
N
e
46
O
N
H
O
g
HO
OH
Ar
SO2
H
N
N
O
28-38
N
H
O
R1
N
R1
Scheme 2. Chiral synthesis of oxopiperazines. Reagents and conditions: (a) Na2CO3, THF/water; (b) EDCI, HOBt, THF; (c) p-TsOH, dioxane, 60 °C; (d) TFA, Et3SiH, CH2Cl2, then
10% Pd/C, EtOAc; (e) EDCI, HOBt, DMF; (f) MnO2, CH2Cl2, then R1R2NH, CHCl3, NaBH(OAc)3.
Compound 17 had functional IC50 of 4.1 nM against rabbit B1
receptor. In the rabbit biochemical challenge model it was able
to reduce the B1 agonist (DAK) induced hypotension in rabbit in
a plasma-concentration dependent manner (see Fig. 1). In contrast
to compound 1 (only 47% reduction in the hypotensive response at
the highest plasma concentration tested with the calculated EC50 of
1700 nM)11 it almost completely reversed the hypotension at a
much lower concentration. From Fig 1, the EC50 value was calcu-
lated to be 10.3 nM (R2 = 0.81, 95%CI: 4.3–24.7 nM). This correlated
well with IC50 value in the rabbit functional assay divided by the
free fraction (4.1 nM/0.28 fu = 14.6 nM). Since the difference in
functional IC50 against rabbit B1 receptor was only 2.5-fold
(4.1 nM for 17 vs 10.4 nM for 1) the enhanced PD effect of 17 could
be partially attributed to significantly lower plasma protein bind-
ing (72% for 17 vs 94.5% for 1).
Based on the close correlation between rabbit PD EC50 and
in vitro functional potency it is reasonable to assume that in
human the EC50 for 17 could be approximated by its functional
potency divided by its free fraction in human plasma. In order to
obtain more relevant functional activity of 17 we tested its activity
in an ex vivo isolated tissue bath assay using human umbilical vein
(HUV).14 The stress of tissue isolation up-regulated the B1 receptor
in umbilical vein segments and administration of a B1 agonist
produced smooth muscle contractions in dose-dependent
manner. In this native tissue preparation, 17 had Kb value of
0.34 nM (n = 3). Using this value we could estimate the human
EC50 of 1.21 nM.
a
The pharmacokinetics of 17 was profiled in several pre-clinical
species (Table 7). In mouse, rat, rabbit and dog, CL of 17 was very
high, with a large volume of distribution and a terminal half-life
ranging from 1.4 to 4.8 h (see Table 7). In cynomolgus monkey, it
had lower clearance, and a moderate volume of distribution, with
a 5.6 h terminal half-life. In rhesus monkey, clearance was higher
compared to cynomolgus monkey. The oral bioavailability of 17
ranged from low in rodents to moderate in dog and monkey (Table
7). In allometric scaling a more conservative estimate (excluding
non-human primate data) provided 1.2 L/h/kg of human clearance
and 6.5 L/kg of volume distribution. Using these projected human
PK values and assuming oral bioavailability of 10% in humans, it
was estimated that either 100 mg QD or 20 mg BID would allow
24 h coverage of estimated human EC50 of 1.21 nM.
Syntheses of compounds mentioned in this manuscript are
described in Scheme 1–3. Compounds 4–16 were made from
commercially available ethyl 2-(3-oxopiperazin-2-yl)acetate (38)

J. J. Chen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3384–3389
3389
H
N
(R)-6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-
OMe
NH2
NH2
OMe
a
amine or (R)-7-(piperidin-1-ylmethyl)chroman-4-amine was cou-
pled with acid 45 gave the amides 25–35. Alternatively, acid 45
was coupled to (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-
yl)methanol to give the alcohol intermediate 46. It was oxidized
with MnO2 to give the aldehyde which was reductively aminated
with various amines to give the final compounds 36–46. Similarly
(R)-2-(4-methyl-3-oxo-1-tosylpiperazin-2-yl)acetic acid was pre-
pared and coupled with (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-
hydronaphthalen-1-amine to give compound 22.
An alternative chiral resolution based synthesis was developed
for arylsulfonylated oxopiperazine acetic acids (Scheme 3). The
racemic methyl 2-(3-oxopiperazin-2-yl)acetate 47 was prepared
from ethylenediamine and dimethyl maleate. Hydrolysis followed
by tosylation efficiently gave the racemic acid 50. Salt pairs were
formed from 50 and (R)-1-phenylethanamine. The (R)-oxopiper-
azine and (R) amine complex 52 was significantly less soluble
(16.5 mg/mL in MeOH, 28 °C) than the (S)-oxopiperazine and (R)
amine complex. The crystallized material (52) was obtained in
good ee (>98.5%). The complex 52 was treated with sulfuric acid
to afford the acid 53, which was recrystallized from methanol to
further improve the ee (>99.9%). Other arylsulfonylated oxopiper-
azine acetic acids were also similarly prepared with high ee %.
In summary, a series of highly potent B1 antagonists with im-
proved metabolic stability were identified. Based on in vitro po-
tency, protein binding, in vivo pharmacokinetics, and pre-clinical
animal safety assessment compound 17 was chosen for further
pre-clinical evaluation.
+
O
O
MeO
O
N
H
47
O
b
H
N
ClO2S
OLi
O2S
N
OH
O
c
N
H
O
O
N
H
O
H2N
48
50
Ph
d
O2S
N
O2S
N
+
+
H N
H N
3
OH
OH
3
+
O
Ph
Ph
O
N
H
O
51
N
H
O
52
e, f
O2S
N
OH
References and notes
O
N
H
O
53
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Scheme 3. Chiral resolution approach to prepare oxopierazine acetic acid. Reagents
and conditions: (a) iPrOH, 50 °C, 73%; (b) LiOHÁH2O, H2O, 40 °C; (c) Na2CO3, H2O,
acetone, 77% (from 47) (d) MeOH (9.5 Â volume); (e) H2SO4, H2O; (f) MeOH, 50 °C,
31% (from 50).
5. Kuduk, S. D.; Bock, M. G. Curr. Top. Med. Chem. 2008, 8, 1420.
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as mixture of 1:1 diastereomers. Compound 38 was sulfonylated
with various sulfonyl chlorides to give the ester 39. Basic hydroly-
sis of the ester 39 gave the corresponding acid 40. Coupling of
the acid 40 with (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra-
hydronaphthalen-1-amine13 gave amides 4–16. Compounds 21,
23, and 24 were prepared similarly from the corresponding oxo-
piperazines: ethyl 2-(5,5-dimethyl-3-oxopiperazin-2-yl)acetate,15
ethyl 2-(2-methyl-3-oxopiperazin-2-yl)acetate,16 and ethyl 2-(5-
oxopiperazin-2-yl)acetate.17
Optically pure aryl sulfonylated 2-oxopiperazine acetic acids
were first prepared from the chiral aspartic acid derivative 41
(Scheme 2). Compound 41 was sulfonylated with aryl sulfonyl
chloride in THF/water in the presence of sodium carbonate to give
42. EDCI-mediated coupling of 42 with 2,2-dimethoxyethanamine
afforded amide 43. The p-toluenesulfonic acid (PTSA) catalyzed
cyclization of 43 gave the dehydrooxopiperazine 44. Sequential
reduction of the dehydrooxopiperazine double bond (Et3SiH/TFA)
followed by removal of the benzyl ester through hydrogenolysis
afforded 45 in high enantioselectivity (>99.5% ee).