A traceless, solid-supported synthesis ofβ-turn mimetics based on the hexahydropyrazino[1,2-α ]pyrazine-1,2-dione scaffold

Article abstract of DOI:10.1055/s-0029-1217125

The solid-supported synthesis of a library of-turn mimetics based on the three-component Petasis condensation and 2,5-diketopiperazine formation is reported. The eight-step sequence starts from optically pure (S)-piperazine-2-carboxylic acid dihydrochloride, which is first converted into an orthogonally protected, resin-bound amino derivative. The subsequent transformations lead to compounds having the common hexahydropyrazino[1,2-a] pyrazine-1,2-dione core and diverse side chains, which mimic the-turn structure. This synthetic route includes protection of the initial amino acid with two different protecting groups, followed by attachment to the Wang resin using the Mitsunobu reaction, deprotection of the-nitrogen atom, then Petasis reaction, amidation, deprotection of the-nitrogen atom, coupling with a Boc-protected-amino acid, cleavage of the Boc group, and the cyclizative cleavage from the resin, resulting in the requested bicyclic products obtained in good yields and having good to moderate purities. Six different boronic acids, four amines, and nine-amino acids were applied to this synthetic route, to explore the efficiency and limitations of the described method. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217125

PAPER
221
A Traceless, Solid-Supported Synthesis of b-Turn Mimetics Based on the
Hexahydropyrazino[1,2-a]pyrazine-1,2-dione Scaffold
S
a
ynthesis of
b-Tur
d
n Mimetics am Mieczkowski,a Wiktor Koźmiński,a Janusz Jurczak*a,b
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Fax +48(22)8225996; E-mail: jjurczak@chem.uw.edu.pl
b
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 27 July 2009
out the limitations inherent to peptides. Poor sub-receptor
selectivity, poor biostability, and the fact that interaction
between peptides and macromolecular receptors is highly
depended on the conformation of the peptide means that
Abstract: The solid-supported synthesis of a library of b-turn mi-
metics based on the three-component Petasis condensation and 2,5-
diketopiperazine formation is reported. The eight-step sequence
starts from optically pure (S)-piperazine-2-carboxylic acid dihydro-
chloride, which is first converted into an orthogonally protected, the peptides are not always good materials in drug design.
resin-bound amino derivative. The subsequent transformations lead
to compounds having the common hexahydropyrazino[1,2-a]pyra-
zine-1,2-dione core and diverse side chains, which mimic the b-turn
O
Me
structure. This synthetic route includes protection of the initial ami-
no acid with two different protecting groups, followed by attach-
ment to the Wang resin using the Mitsunobu reaction, deprotection
of the b-nitrogen atom, then Petasis reaction, amidation, deprotec-
tion of the a-nitrogen atom, coupling with a Boc-protected a-amino
acid, cleavage of the Boc group, and the cyclizative cleavage from
the resin, resulting in the requested bicyclic products obtained in
good yields and having good to moderate purities. Six different bo-
ronic acids, four amines, and nine a-amino acids were applied to
this synthetic route, to explore the efficiency and limitations of the
described method.
NH
N
O
N
HN
CCl
NH
3O
N
CCl3
O
Me
1
2
Me
N
HO
O
O
H
N
N
O
OH
NH
Me
3
H
N
Key words: solid-phase synthesis, cyclizative cleavage, multicom-
ponent reactions, b-turn mimetics
O
N
HN
O
O
H
N
4
NH
N
H
HN
The 2,5-diketopiperazine structure is common in many
natural products and can be found as a structural element
of various compounds isolated from many species of mi-
croorganisms. Such compounds include, but are not limit-
ed to, polychlorinated piperazines (e.g., 1) obtained from
cyanobacterial symbionts living on sea sponges Disidea
spp.,1 the Asperigillus ustus metabolite phenylahistin (2),
which exhibits a promising antitumor activity,2 and the N-
methyltyrosine derivative 3 isolated from Streptomyces
griseus, which inhibits calpain, the calcium-activated cys-
teine protease.3 The 2,5-diketopiperazine ring occurs also
in some complex molecules such as tetracyclic roquefort-
ine E (4) isolated from Penicillium roquefortii,4 the penta-
cyclic alkaloids spirotryprostatins5 represented by
spirotryprostatin A (5), or hepta- and octacyclic biologi-
cally active antibiotics okaramines6 isolated from Penicil-
lium simplicissimum such as okaramine N (6) (Figure 1).
O
O
H
H
N
HN
N
5
OH
H
O
6
Figure 1 Naturally occurring compounds possessing a 2,5-diketo-
piperazine fragment
Consequently, much effort has been devoted to the design
and synthesis of metabolically stable and conformational-
ly restricted therapeutic peptide equivalents, which are
called peptidomimetics. The appearance of 2,5-DKPs in
biological natural products inspired and stimulated organ-
ic chemists to investigate the possibility of replacing pep-
tide-based active compounds with 2,5-DKP derivatives to
overcome the limitations of peptides. The use of 2,5-
DKPs improves the resistance of the amide bond to meta-
bolic cleavage reactions and reduces conformational mo-
bility, which strengthens the favorable interactions of 2,5-
DKPs with macromolecules. During the course of drug
discovery, 2,5-diketopiperazine derivatives have been
synthesized that are antagonistic activity to human oxyto-
cin receptor,7 highly cytotoxic,8 selective inhibitors of
collagenase-1,9 and novel neuroprotective compounds.10
However, the 2,5-diketopiperazines (2,5-DKPs) are of
great interest for organic chemists not only because they
are structural elements of many natural compounds. 2,5-
DKPs possess structural similarity to peptides, but with-
SYNTHESIS 2010, No. 2, pp 0221–0232
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217125; Art ID: P10809SS
© Georg Thieme Verlag Stuttgart · New York

222
A. Mieczkowski et al.
PAPER
These results showed a wide range of activity of 2,5-di- and R5 substituents in the designed structure B. The R4
ketopiperazines, thus proving the usefulness of 2,5-DKPs substituent comes from a boronic acid and it is incorporat-
as potent biologically active substances and focusing the ed in the Petasis reaction, the R5 substituent comes from a
attention of medicinal chemists on this class of com- primary or secondary amine and it is incorporated to the
pounds. The design, synthesis, and investigation of bio- structure in the amidation reaction. The R1 and R2 substit-
chemical interactions of mimetics of the peptide turn uents originate from an a-amino acid and they are incor-
structure has captured the interest of scientists and it has porated in the amidation reaction. The R3 substituent of b-
resulted in significant numbers of reviews and opinions turn A is missing in the mimetic structure B. The selected
published in biochemical journals.11
boronic acids, amines, and a-amino acids are presented in
Figure 3.
The b-turn structure A (Figure 2) is defined as any tetra-
peptide sequence with a ten-membered intramolecularly
hydrogen-bonded ring, in which the distance between four
carbon atoms in the peptide chain varies from 4 to 7 Å.
Depending on the dihedral angle values, there are at least
14 types of known b-turn structure. The b-turns are one of
the three major structural elements of the peptides and
play a key role in many molecular recognition events.
These events include, but are not limited to, the interac-
tions between peptide hormones and their receptors, anti-
bodies, and antigens and between regulatory enzymes and
their corresponding substrates. Recently, a solid-support-
ed synthesis of new b-turn structure mimetics, based on
the bicyclic 2,5-diketopiperazine structure B, was an-
nounced by Golebiowski et al. (Figure 2).12
OMe
OCF3
Cl
Cl
B(OH)2
7
B(OH)2
8
B(OH)2
9
B(OH)2
10
MeO
B(OH)2
S
B(OH)2
NH
B(OH)2
11
12
13
NH2
N
O
NH
MeO
16
14
15
NH2
COOH
NH2
COOH
R5
R5
F
NH2 H2N
COOH
R1
O
N
NH
R4
R1
NH
R4
O
18
19
20
17
N
HO
O
HN
R3
NH2
COOH
HN
NH2
COOH
N
R2
H
O
R2
N
O
O
21
22
A
B
Figure 3 Selection of building blocks
Figure 2 b-Turn motif
As shown in Figure 3, seven aromatic boronic acid, hav-
ing either electrophilic or nucleophilic substituents in the
aromatic ring, were chosen: phenylboronic acid (7), 4-
methoxyphenylboronic acid (8), 4-(trifluorometh-
oxy)phenylboronic acid (9), 3,5-dichlorophenylboronic
acid (10), 2-naphthylboronic acid (11), 6-methoxy-2-
naphthylboronic acid (12), and 2-thienylboronic acid
(13). We decided to use four different aromatic or aliphat-
ic, primary or secondary amines: N-phenylpiperazine
(14), morpholine (15), 4-methoxybenzylamine (16), and
4-fluoroaniline (17), as well as five different amino acids:
achiral glycine (18), and chiral L-a-alanine (19), L-a-phe-
nylglycine (20), L-a-phenylalanine (21), and L-a-tyrosine
(22). Where possible, the D-a-enantiomers of the present-
ed amino acids have also been used.
Given the fact that only a few structures of type B have
been reported in the literature, all obtained from racemic
substrates and with no spectral data for the synthesized
compounds, we focused our synthetic efforts on the syn-
thesis of a library of b-turn mimetics of type B based on
the hexahydropyrazino[1,2-a]pyrazine-1,2-dione core. As
opposed to the initial research, we planned to use optically
pure (S)-piperazine-2-carboxylic acid as the major sub-
strate in our synthesis, which should limit to two the num-
ber of the diastereomers of the final product. The use of
optically pure building blocks should make possible the
separation the obtained pairs of diastereomers by column
chromatography and facilitate analysis of the NMR spec-
tra. In this article, we would like to present extensive work
detailed investigation on the synthesis of b-turn mimetics
possessing the 2,5-diketopiperazine moiety from optically
pure amino acids. The use of various building blocks re-
vealed the scope and limitations of the investigation meth-
od and led to a significant number of novel products.
The synthetic route is shown in Scheme 1. In the first step,
the major substrate, optically pure (S)-piperazine-2-car-
boxylic acid dihydrochloride salt (23), was protected with
two different protecting groups that made it possible to
deprotect either of the amine groups selectively. Then it
was attached to the Wang resin. In this step, we used the
Mitsunobu reaction, a very facile and useful method often
utilized in the solid-supported synthesis of esters. The
Planning the synthesis of the library of b-turn mimetics of
type B, we faced the problem of selection of the appropri-
ate building blocks, which could determine the R1, R2, R4,
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

PAPER
Synthesis of b-Turn Mimetics
223
O
R1
O
O
a
b
c
OH
O
N
HO
NH
O
NH
N
e
O
O
HN
N
•2 HCl
Fmoc
Fmoc
25
23
24
R1
R1
O
R1
O
d
R2
R2
R2
O
N
HN
R3
N
O
N
O
N
O
N
O
N
O
Fmoc
26
O
R3
NHBoc
28–56
27
Scheme 1 Reagents and conditions: (a) (i) Boc2O, aq NaOH, dioxane–H2O (2:1), 0 °C to r.t., then FmocCl, Na2CO3 (ii) DEAD, Ph3P, THF–
CH2Cl2 (3:1), 0 °C to r.t.; (iii) 40% TFA–CH2Cl2; (b) OHCCOOH·H2O, R1B(OH)2 7–13, CH2Cl2–MeOH (4:1), r.t.; (c) DIC, HOBt, 14–17,
DMF; (d) (i) 25% piperidine–DMF, r.t.; (ii) DIC, HOBt, R3NH(Boc)CO2H 18–22, DMF, r.t.; (iii) 25% TFA–CH2Cl2; (e) 10% AcOH–i-PrOH,
50 °C.
Table 1 Compounds Obtained from Phenylboronic Acid (R1 = Ph)
ester-linked, orthogonally protected (S)-piperazine-2-car-
boxylic acid was treated with a trifluoroacetic acid
solution, which resulted in cleavage of the Boc protecting
group and deprotection of the b-nitrogen. In the next step
of the synthesis, the monoprotected amino derivative 24
was subjected to the Petasis reaction with glyoxylic acid
and an appropriate boronic acid. The Petasis product 25
was treated with a diisopropylcarbodiimide/1-hydroxy-
benzotriazole (DIC/HOBt) mixture and then the appropri-
ate amine was added, which led to the amide derivative
26.
Entry Product R2
R3
Yield (%)
Crude Purifieda
1
2
28
29
30
31
32
33
34
35
36b
37b
38b
39b
40
41
42
43
44
45
46
47
4-phenylpiperazinyl
morpholin-4-yl
H
H
H
H
73
87
64
71
68
79
66
69
52
65
57
48
67
74
56
65
22
36
22
28
47
24
21
37
21
35
28
29
22
29
23
18
31
36
28
20
3
4-MeOC6H4CH2NH
4-FC6H4NH
4
5
4-phenylpiperazinyl Me
morpholin-4-yl Me
4-MeOC6H4CH2NH Me
4-FC6H4NH Me
4-phenylpiperazinyl Ph
morpholin-4-yl Ph
4-MeOC6H4CH2NH Ph
4-FC6H4NH Ph
4-phenylpiperazinyl Bn
morpholin-4-yl Bn
4-MeOC6H4CH2NH Bn
4-FC6H4NH Bn
4-phenylpiperazinyl 4-HOBnc 64
morpholin-4-yl
4-HOBnc 58
4-MeOC6H4CH2NH 4-HOBnc 53
4-FC6H4NH
4-HOBnc 43
From among a wide range of coupling reagents, we decid-
ed to use the DIC/HOBt mixture as the most effective and
best fitted to the conditions and requirements of our syn-
thesis. In order to cleave the Fmoc protecting group and
release the remaining a-nitrogen atom, the intermediate
26 was treated with a piperidine solution, followed by
coupling with an appropriate Boc-protected a-amino acid,
which led to the intermediate 27; for the second amide
bond formation, we also decided to use the DIC/HOBt
mixture. In the final part of our synthesis, the amino deriv-
ative 27 was treated with trifluoroacetic acid solution,
which resulted in deprotection of the nitrogen atom of the
coupled a-amino acid. In the final step, the resin was treat-
ed with 10% acetic acid in isopropyl alcohol at 50 °C for
12 hours; the cyclizative cleavage occurred smoothly, giv-
ing final products of type B, 28–56. The obtained com-
6
7
8
9
10
11
12
13
14
15
pounds were purified by column chromatography on 16
silica gel (1–2% MeOH–CH2Cl2).
17
At the beginning of our research, we decided to use un-
substituted phenylboronic acid (7), glycine (18), and four
18
selected amines to synthesize the first series of com-
pounds 28–31 (Table 1, entries 1–4). Encouraged with the
results obtained, we repeated this scheme for each of the
remaining a-amino acids 19–22 (Table 1, entries 5–20).
Then we decided to check the usefulness of other boronic
acids and synthesized a series of compounds from L-a-
phenylglycine (20), N-phenylpiperazine (14), and various
aromatic boronic acids 7–13 (Table 2, entries 1–6). Final-
ly we decided to use three D-a-amino acids (Table 3, en-
tries 1–3).
19
20
a Purified by column chromatography.
b Partial racemization during reaction.
c 4-Hydroxybenzyl.
The following conclusions can be drawn from a compari-
son of the results shown in Tables 1– 3: (1) In most cases
(Table 1, entries 2, 5, 10, 17, 18), the use of secondary
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

224
A. Mieczkowski et al.
PAPER
Table 3 Compounds Obtained from D-a-Amino Acids (R1 = Ph,
R2 = 4-phenylpiperazin-1-yl)
amines [N-phenylpiperazine (14) and morpholine (15)]
slightly decreased the yields of the obtained products,
which could indicate that secondary amines are more suit-
able than primary amines under the amidation reaction
conditions in the presence of HOBt/DIC. (2) The best
crude yields were achieved for reactions with glycine (18)
(Table 1, entries 1–4), the yields for the sterically hin-
dered amino acids were noticeably worse, which could in-
dicate that sterical interactions could play an important
role in cyclization, the last step of the synthesis. (3) In the
most cases, the use of the phenylboronic acids containing
electron-donating groups (Table 2, entries 1, 5, 6) led to
higher yields than the use of unsubstituted boronic acid.
(4) The use of the phenylboronic acids containing elec-
tron-withdrawing groups (Cl, OCF3) did not lead to the
desired products. It was assumed that these reagents were
not effective in the Petasis reaction under the applied con-
ditions. This assumption could be verified by ESI-MS
spectroscopy of the reaction mixture after cleavage,
which, in both cases, indicated the presence of products
with m/z = 245 and 378. These masses could be assigned
to compounds 57 and 58, respectively (Figure 4), which
could be the byproducts when the Petasis reaction failed.
Entry
Product
R3
Yield (%)
Crude
Purifieda
1
2
3
54b
55b
56b
Me
58
59
44
16
22
26
Bn
4-HOBn
a Purified by column chromatography.
b Partial racemization during reaction.
After cleavage with 10% acetic acid in isopropyl alcohol,
we found no traces of any uncyclized products in the reac-
tion mixture.
O
O
O
HN
NH
HN
N
N
N
NH2
O
O
57
58
Table 2 Compounds Obtained from Other Boronic Acids (R2 = 4-
Figure 4
phenylpiperazin-1-yl, R3 = Ph)
Entry
Product R1
Yield (%)
Crude
Due to the partial racemization of phenylglycine, the com-
pounds synthesized from this amino acid were obtained as
a mixture of four diastereomers. The racemization of phe-
nylglycine could occur during Boc protection, coupling
the protecting amino acid by amide bond, or during cy-
clizative cleavage of the final product. Although racem-
ization of phenylglycine under basic conditions, resulting
from the acidity of the benzylic proton, is well described
in literature,13 this process has not been investigated, nei-
ther for the coupling reaction nor for the cyclization. The
compounds obtained from phenylglycine were easily sep-
arated by column chromatography into two pairs of dia-
stereomers, the major and minor pairs. The representative
2D COSY correlation spectrum for the major pair of dia-
stereomers of 39 is shown in Figure 5.
Purifieda
1
2
3
4
5
6
48b
49b
50b
51b
52b
53b
4-MeOC6H4
71
–
32
–
4-F3COC6H4
3,5-Cl2C6H3
2-thienyl
–
–
52
91
50
18
45
31
2-naphthyl
6-MeO-2-naphthyl
a Purified by column chromatography.
b Partial racemization during reaction.
The synthesized products possess either two (when using
glycine) or three (when using other a-amino acids) stereo-
genic centers: the first one originates from optically pure
(S)-piperazine-2-carboxylic acid, the second one is creat-
ed in the Petasis reaction, and the third could be incorpo-
rated with the optically pure chiral a-amino acid. For this
reason all the described compounds were obtained as pairs
of diastereomers in an equimolar ratio (based on 1H NMR
spectra). These pairs are inseparable by chromatographic
methods and they are characterized as mixtures of diaste-
reomers. In order to assign correctly the signals in the 1H
NMR spectra to the appropriate protons in the molecule,
additional correlation spectra (COSY, HSQC, HMBC,
NOE) were recorded for the selected products. These con-
firmed indisputably the assumed structures.
In summary, we have successfully synthesized a library of
b-turn mimetics of type B based on the hexahydropyrazi-
no[1,2-a]pyrazine-1,2-dione core. Starting from optically
pure, orthogonally protected (S)-piperazine-2-carboxylic
acid attached to the Wang resin, and varying the boronic
acids, the amines, and the a-amino acids, we obtained a
wide range of compounds having diverse side chains and
substituents in the heterocyclic core. The use of the opti-
cally pure substrates allows decreases the number of dia-
stereomers of the final products. Unfortunately, the efforts
to separate these diastereomers failed and all products
were described as pairs of diastereomers. In our opinion,
the described synthetic route, which offers the potential
biologically active compounds, deepens the knowledge of
b-turn mimetics. The investigated method could also be
utilized in the synthesis of diketopiperazine derivatives
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

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Synthesis of b-Turn Mimetics
225
(S)-4-(tert-Butoxycarbonyl)-1-(9-fluorenylmethoxycarbon-
yl)piperazine-2-carboxylic Acid
To a soln of 23 (3.0 g, 14.8 mmol) in dioxane (30 mL) and H2O (15
mL), a soln of NaOH (1.5 g, 29.6 mmol) in H2O (5 mL) was added
slowly at 0 °C, followed by (Boc)2O (3.6 g, 16.3 mmol). The mix-
ture was stirred at r.t. for 5 h then solid Na2CO3 (1.7 g, 16.0 mmol)
and FmocCl (4.7 g) were added and the reaction was stirred over-
night. The solvent was removed on a rotary evaporator and the res-
idue obtained was partitioned between EtOAc and 1 M HCl. The
organic layer was washed with brine, dried (MgSO4) and the solvent
was evaporated. The crude product was crystallized once (EtOAc)
to give the product (4.4 g, 43%) as a colorless crystalline solid.
Hexahydropyrazino[1,2-a]pyrazine-1,2-dione Derivatives 28–
56; General Procedure
(a) The Wang resin (1.0 g, 0.82 mmol/g, Novabiochem) was al-
lowed to swell in anhyd CH2Cl2 (10 mL). To this slurry, Ph3P (643
mg, 2.46 mmol) and Na-Fmoc-Nb-Boc-(S)-piperazine-2-carboxylic
acid (111 mg, 2.46 mmol) were added. The mixture was cooled to
0 °C under argon and DEAD (428 mg, 2.46 mmol) in THF (2 mL)
was added slowly. The mixture was stirred for 3 d, then the resin
was filtered off and washed with THF (3 ×), CH2Cl2 (3 ×), MeOH
(3 ×), then alternately with CH2Cl2 and MeOH. The orthogonally
protected piperazinic resin ester was allowed to swell in CH2Cl2 (10
mL) and then TFA (3.3 mL) was added dropwise. After 1 h, the res-
in was filtered off and washed in a standard manner. The resin-
bound amine TFA salt was then neutralized with 10% DIPEA in
CH2Cl2 and washed again in a standard manner.
Figure 5 2D COSY spectrum spectra for the major pair of diaste-
reomers of 39
(b) The resin-bound amino derivative 24 was allowed to swell in
CH2Cl2 (10 mL), and glyoxylic acid (151 mg, 1.64 mmol) and
PhB(OH)2 (200 mg, 1.64 mol) in MeOH (2 mL) were added. The
mixture was agitated for 5 h, then filtered off and washed with
CH2Cl2 (3 ×). The above procedure was repeated again for 12 h after
which the resin was again filtered off and washed in a standard man-
ner.
incorporated into cyclic peptides, as diketopiperazine-
based templates stabilize loop conformations.14 The bio-
logical activity of synthesized compounds will be report-
ed in due course.
All reagents were obtained from Fluka and Merck and were used
without further purification. Anhyd CH2Cl2 and DMF were ob-
tained by distillation from CaH2. The enantiomerically pure (S)-pip-
erazine-2-carboxylic acid was obtained from ChemPacific. The
(c) The piperazinic ester 25 from the previous step was allowed to
swell in anhyd DMF (10 mL) and HOBt (626 mg, 4.1 mmol) was
added followed addition of by DIC (0.63 mL, 4.1 mmol). The reac-
tion was agitated for 3 h, after which the resin was washed with an-
hyd DMF (3 ×). The resin was allowed to swell again in DMF (10
mL) and to this slurry was added N-phenylpiperazine (14, 0.63 mL,
4.1 mmol) and the reaction was agitated for 12 h. The resin 26 was
filtered off and washed with DMF (3 ×) followed by the standard
protocol.
1
Wang resin was obtained from Novabiochem. H and 13C spectra
were recorded on Varian 500 MHz using CD3OD as a solvent, with
TMS as an internal standard. The abbreviations used in the descrip-
tions of NMR spectra are as follows: Ha: signal from axial proton,
He: signal from equatorial proton, Hp: signal from the piperazine
substituent, Hm: signal from the morpholine substituent. All ESI-
MS spectra were recorded on Quattro LC Micromass. The IR spec-
tra were recorded on Nicolet Magna 550 FTIR. The IR band posi-
tions are reported in cm–1. The preparative flash chromatographic
experiments were performed using Merck Kieselgel 60, 230–400
mesh. The TLC analyses were done on Merck 60 F254 aluminum
plates and analyzed using iodine vapor and UV light (254 nm), or
by spraying with an aqueous soln of (NH4)6Mo7O24 (2.5%) and
(NH4)4Ce(SO4)4 (1%) in 10% H2SO4 and heating to 110 °C. The
numbering scheme of carbon atoms in the heterocyclic cores is
shown in Figure 6.
(d) The resin 26 was treated with 25% piperidine in DMF, then fil-
tered off and washed in a standard manner. The Boc-protected ami-
no acid (4.1 mmol) was dissolved in anhyd DMF (10 mL) and then
HOBt (626 mg, 4.1 mmol) was added followed by addition of DIC
(0.63 mL, 4.1 mmol). The mixture was agitated for 1 h; in the mean-
time, the resin was allowed to swell in anhyd DMF (10 mL), and the
soln of activated amino acid was added to this heterogeneous slurry.
The reaction was agitated for 5 h and rinsed with anhyd DMF (3 ×)
before repeating the coupling procedure for 15 h. Then the resin was
filtered off and washed in a standard manner. The resin was then
treated with 25% TFA in CH2Cl2 for 1 h and washed in the standard
manner.
O
R1
3
5
R2
(e) The resin-bound intermediate 27 was taken up in 10% AcOH–
i-PrOH and heated at 50 °C for 12 h. The resin was filtered off and
washed several times with MeOH. The filtrate and washings were
combined and concentrated to give a brown solid. The crude prod-
uct was purified by column chromatography (silica gel, 1–2%
MeOH–CHCl3).
2
6
HN
N
1
N
O
4
R3
O
Figure 6
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

226
A. Mieczkowski et al.
PAPER
(S)-8-[2-Oxo-1-phenyl-2-(4-phenylpiperazin-1-yl)ethyl]tetra-
hydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (28)
IR: 3449, 3260, 3061, 2919, 2853, 2822, 1649, 1598, 1495, 1443,
1331, 1274, 1228, 1154, 1114, 1017, 759, 698 cm–1.
(S)-8-[2-(4-Fluorophenylamino)-2-oxo-1-phenylethyl]tetrahy-
dro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (31)
IR: 3442, 3281, 3070, 2923, 2853, 1671, 1510, 1467, 1454, 1407,
1331, 1274, 1211, 1155, 1113, 1028, 838, 810, 765, 729, 701 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.52–7.26 (m, 5 H, HAr), 7.19 (t,
J = 8 Hz, 2 H, HAr), 6.87 (d, J = 8 Hz, 2 H, HAr), 6.83 (t, J = 8 Hz, 1
H, HAr), 4.68, 4.67 (2 s, 1 H, H6), 4.40, 4.35 (2 d, 1 H, H5a), 4.18,
4.13 (2 d, 1 H, H5e), 4.03–3.87 (m, 2 H, H1a,e), 3.86–3.78 (m, 1 H,
HpCH2NC=O), 3.78–3.71 (m, 1 H, HpCH2NC=O), 3.71–3.64 (m, 1
H, HpCH2NC=O), 3.64–3.55 (m, 1 H, HpCH2NC=O), 3.20–3.09 (m,
1 H, HpCH2NPh), 3.08–2.99 (m, 1 H, HpCH2NPh), 2.99–2.92 (m,
1.5 H, HpCH2NPh, 0.5 H3e), 3.47, 3.26 (2 d, J = 11 Hz, 1 H, H3a),
2.87, 2.83 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.76 (d, J = 11 Hz,
0.5 H, 0.5 H3e), 2.62–2.55 (m, 1 H, HpCH2NPh), 2.41, 2.15 (2 t,
J = 11 Hz, 1 H, H2), 2.38, 2.10 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e).
13C NMR (125 MHz, CD3OD): d = 171.06, 171.07, 152.40, 136.33,
136.31, 130.50, 130.48, 130.11, 130.09, 130.07, 129.82, 121.56,
117.81, 70.85, 58.04, 57.94, 55.28, 54.77, 51.09, 50.72, 50.50,
46.67, 45.11, 43.34, 42.46, 42.42.
HRMS (ESI): m/z [M + Na]+ calcd for C25H29N5NaO3: 470.2168;
found: 470.2191.
1H NMR (500 MHz, CD3OD): d = 7.61–7.50 (m, 4 H, HAr), 7.43–
7.30 (m, 3 H, HAr), 7.08–6.98 (m, 2 H, HAr), 4.47, 4.36 (2 d, J = 13
Hz, 1 H, H5a), 4.31, 4.18 (2 d, J = 13 Hz, 1 H, H5e), 4.09 (s, 1 H,
H6), 4.03–3.88 (m, 2 H, H1a,e), 3.57, 3.23 (2 d, J = 11 Hz, 1 H, H3a),
3.10, 2.73 (2 d, J = 11 Hz, 1 H, H3e), 2.99, 2.87 (2 dt, J1 = 3 Hz,
J2 = 13 Hz, 1 H, H4a), 2.32, 2.01 (2 t, J = 11 Hz, 1 H, H2), 2.29, 1.96
(2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.56, 167.20, 167.14, 164.82,
164.76, 161.91, 159.99, 135.44, 135.42, 130.05, 129.98, 129.91,
129.86, 129.79, 129.77, 123.76, 123.70, 123.64, 116.41, 116.39,
116.23, 116.21, 76.40, 76.29, 57.96, 57.74, 55.92, 54.53, 51.94,
50.33, 45.15, 45.10, 42.31, 42.28.
HRMS (ESI): m/z [M + Na]+ calcd for C21H21FN4NaO3: 419.1495;
found: 419.1507.
(3S,9aS)-3-Methyl-8-[2-oxo-1-phenyl-2-(4-phenylpiperazin-1-
yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (32)
IR: 3452, 3205, 3062, 2985, 2921, 2817, 1689, 1659, 1643, 1599,
(S)-8-(2-Morpholin-4-yl-2-oxo-1-phenylethyl)tetrahydro-2H-
pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (29)
1504, 1452, 1432, 1326, 1264, 1232, 1154, 1015, 755, 697 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.56–7.28 (m, 5 H, HAr), 7.19 (t,
J = 8 Hz, 2 H, HAr), 6.90 (d, J = 8 Hz, 2 H, HAr), 6.82 (t, J = 7 Hz, 1
H, HAr), 4.70, 4.69 (2 s, 1 H, H6), 4.37, 4.33 (2 d, J = 13 Hz, 1 H,
H5a), 4.15, 4.11 (2 d, J = 13 Hz, 1 H, H5e), 4.04 (quintet, J = 7 Hz,
1 H, H1), 3.88–3.77 (m, 1 H, HpCH2NC=O), 3.77–3.63 (m, 2 H,
HpCH2NC=O), 3.63–3.52 (m, 1 H, HpCH2NC=O), 3.47, 3.26 (2 d,
J = 11 Hz, 1 H, H3a), 3.18–3.08 (m, 1 H, HpCH2NPh), 3.08–2.98
(m, 1 H, HpCH2NPh), 2.98–2.90 (m, 1.5 H, HpCH2NPh, 0.5 H3e),
2.86, 2.81 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.76 (d, J = 11 Hz,
0.5 H, 0.5 H3e), 2.66–2.54 (m, 1 H, HpCH2NPh), 2.41, 2.13 (2 t,
J = 11 Hz, 1 H, H2), 2.38, 2.11 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e), 1.41 (t, J = 7 Hz, 3 H, CH3).
IR: 3443, 3261, 3092, 2924, 2859, 1675, 1464, 1444, 1334, 1274,
1202, 1179, 1116, 1020, 799, 720 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.49–7.32 (m, 5 H, HAr), 4.63,
4.61 (2 s, 1 H, H6), 4.39–4.35 (2 d, J = 13 Hz, 1 H, H5a), 4.17, 4.12
(2 d, J = 13 Hz, 1 H, H5e), 4.02–3.86 (m, 2 H, H1a,e), 3.71–3.36 (m,
7.5 H, 7 Hm, 0.5 H3a), 3.25 (d, 0.5 H, 0.5 H3a), 3.14 (t, J = 9 Hz, 1
H, Hm), 2.86, 2.82 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.97, 2.74
(2 d, J = 11 Hz, 1 H, H3e), 2.40, 2.14 (2 t, J = 11 Hz, 1 H, H2), 2.38,
2.09 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.20, 171.19, 167.33, 167.25,
164.81, 164.75, 136.19, 136.16, 130.46, 130.44, 130.07, 130.05,
129.81, 79.51, 70.69, 70.63, 67.69, 67.39, 58.03, 57.94, 55.19,
54.72, 50.98, 50.45, 47.36, 47.34, 45.14, 45.10, 43.79, 42.45, 42.41.
13C NMR (125 MHz, CD3OD): d = 171.07, 167.98, 167.92, 152.37,
136.31, 130.48, 130.09, 129.81, 121.53, 117.78, 112.06, 70.72,
58.50, 55.46, 55.17, 51.46, 51.15, 50.68, 50.46, 46.66, 43.29, 42.58,
21.27, 21.20.
HRMS (ESI): m/z [M + Na]+ calcd for C19H24N4NaO4: 395.1695;
found: 395.1713.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31N5NaO3: 484.2325;
(S)-8-[2-(4-Methoxybenzylamino)-2-oxo-1-phenylethyl]tetra-
hydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (30)
IR: 3442, 3300, 3064, 2924, 2836, 1687, 1667, 1613, 1513, 1464,
1443, 1331, 1247, 1174, 1113, 1031, 820, 753, 701 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.47–4.42 (m, 2 H, HAr), 7.37–
7.30 (m, 3 H, HAr), 7.11–7.06 (m, 2 H, HAr), 6.79 (d, J = 8 Hz, 2 H,
HAr), 4.40 (d, J = 13 Hz, 0.5 H, 0.5 H5a), 4.35–4.26 (m, 2.5 H, 2
PhCH2NH, 0.5 H5a), 4.24, 4.12 (2 d, 1 H, H5e), 4.00–3.85 (m, 3 H,
H1a,e, H6), 3.73 (2 s, 3 H, OCH3), 3.56, 3.17 (2 d, J = 11 Hz, 1 H,
H3a), 3.00, 2.66 (2 d, J = 11 Hz, 1 H, H3e), 2.91, 2.80 (2 dt, J1 = 3
Hz, J2 = 13 Hz, 1 H, H4a), 2.22, 1.90 (2 t, J = 11 Hz, 1 H, H2), 2.15,
1.86 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 173.20, 173.18, 167.13, 167.07,
164.78, 164.69, 160.35, 160.30, 137.39, 137.34, 131.87, 131.78,
129.99, 129.92, 129.82, 129.77, 129.73, 129.71, 129.60, 129.58,
114.91, 114.86, 76.23, 76.17, 57.92, 57.67, 56.10, 55.68, 55.67,
54.48, 51.99, 50.30, 45.13, 45.06, 43.41, 42.29, 42.19.
found: 484.2356.
(3S,9aS)-3-Methyl-8-(2-morpholin-4-yl-2-oxo-1-phenyleth-
yl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione
(33)
IR: 3475, 3243, 2969, 2923, 2857, 1683, 1651, 1453, 1322, 1269,
1230, 1154, 1114, 1025, 733, 701 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.60–7.31 (m, 5 H, HAr), 4.65,
4.64 (2 s, 1 H, H6), 4.38, 4.33 (2 d, J = 13 Hz, 1 H, H5a), 4.15, 4.11
(2 d, J = 13 Hz, 1 H, H5e), 4.05 (quintet, J = 7 Hz, 1 H, H1), 3.70–
3.34 (m, 7.5 H, 7 Hm, 0.5 H3a), 3.25 (d, 0.5 H, 0.5 H3a), 3.14 (t, J = 9
Hz, 1 H, Hm), 2.98, 2.76 (2 d, J = 11 Hz, 1 H, H3e), 2.85, 2.81 (2 dt,
J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.41, 2.13 (2 t, J = 11 Hz, 1 H, H2),
2.38, 2.10 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 1.41 (t, J = 7 Hz,
3 H, CH3).
13C NMR (125 MHz, CD3OD): d = 171.10, 167.96, 167.90, 167.05,
166.96, 136.09, 130.44, 130.42, 130.07, 130.05, 129.83, 129.81,
70.55, 70.53, 67.65, 67.35, 58.44, 58.40, 58.31, 55.38, 55.09, 51.45,
51.44, 51.08, 50.62, 47.33, 47.31, 43.73, 42.55, 42.51, 21.25, 21.19.
HRMS (ESI): m/z [M + Na]+ calcd for C23H26N2NaO4: 445.1852;
found: 445.1850.
HRMS (ESI): m/z [M + H]+ calcd for C20H26N4NaO4: 387.2032;
found: 387.2036.
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

PAPER
Synthesis of b-Turn Mimetics
227
(3S,9aS)-8-[2-(4-Methoxybenzylamino)-2-oxo-1-phenylethyl]-
3-methyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (34)
117.71, 115.39, 115.35, 79.70, 69.93, 60.20, 60.14, 58.76, 55.80,
55.78, 55.72, 55.46, 51.22, 50.65, 50.62, 50.37, 46.58, 43.20, 42.81.
HRMS (ESI): m/z [M + Na]+ calcd for C31H33N5NaO3: 546.2482;
IR: 3456, 3282, 3065, 2928, 2835, 1683, 1661, 1613, 1513, 1453,
found: 546.2497.
1322, 1247, 1175, 1151, 1303, 1030, 700 cm–1.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.50–7.41 (m, 2 H, HAr), 7.38–
7.28 (m, 3 H, HAr), 7.12–7.05 (m, 2 H, HAr), 6.85–6.76 (m, 2 H,
HAr), 4.35–4.26 (m, 2.5 H, PhCH2NH, 0.5 H5a), 4.37 (d, 0.5 H, 0.5
H5a), 4.23, 4.10 (2 d, 1 H, H5e), 4.02 (q, J = 7 Hz, 1 H, H1), 3.95,
3.94 (2 s, 1 H, H6), 3.73, 3.72 (2 s, 3 H, OCH3), 3.58, 3.18 (d, J = 11
Hz, 1 H, H3a), 3.00, 2.67 (2 d, J = 11 Hz, 1 H, H3e), 2.90, 2.79 (2 dt,
J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.19, 1.86 (2 t, J = 11 Hz, 1 H, H2),
2.14, 1.84 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 1.38, 1.41 (2 d,
J = 7 Hz, 3 H, CH3).
13C NMR (125 MHz, CD3OD): d = 173.16, 168.00, 167.91, 166.94,
166.86, 160.35, 160.31, 137.39, 137.45, 131.87, 131.78, 129.98,
129.92, 129.83, 129.78, 129.73, 129.61, 129.58, 114.91, 114.87,
76.19, 76.17, 76.09, 58.39, 58.16, 56.41, 55.69, 55.68, 55.67, 55.66,
54.92, 52.14, 51.46, 51.42, 50.50, 43.41, 42.46, 42.35, 21.20, 21.13.
1H NMR (500 MHz, CD3OD): d = 7.52–7.45 (m, 2 H, HAr), 7.45–
7.28 (m, 8 H, HAr), 7.19 (t, J = 8 Hz, 2 H, HAr), 6.88 (d, J = 9 Hz, 2
H, HAr), 6.83 (t, J = 7.5 Hz, 1 H, HAr), 5.05, 5.04 (2 s, 1 H, H1), 4.71,
4.69 (2 s, 1 H, H6), 4.40–4.20 (m, 2 H, H5), 3.88–3.79 (m, 1 H,
HpCH2NC=O), 3.79–3.72 (m, 1 H, HpCH2NC=O), 3.72–3.64 (m, 1
H, HpCH2NC=O), 3.64–3.58 (m, 1 H, HpCH2NC=O), 3.56, 3.36 (2
d, J = 11 Hz, 1 H, H3a), 3.18–3.10 (m, 1 H, HpCH2NPh), 3.08–2.90
(m, 2.5 H, 2 HpCH2NPh, 0.5 H3e), 2.89, 2.83 (2 dt, J1 = 3 Hz,
J2 = 13 Hz, 1 H, H4a), 2.75 (d, J = 11 Hz, 0.5 H, 0.5 H3e), 2.59 (t,
J = 8.5 Hz, 1 H, HpCH2NPh), 2.46, 2.21 (2 t, J = 11 Hz, 1 H, H2),
2.42, 2.13 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.30, 171.29, 167.31, 167.23,
165.87, 165.83, 152.36, 152.35, 140.04, 140.01, 131.68, 131.65,
130.12, 129.95, 129.94, 129.61, 128.28, 1228.25, 127.93, 121.51,
117.77, 115.41, 115.38, 79.48, 70.12, 60.26, 60.22, 57.79, 57.67,
55.68, 55.03, 51.15, 50.69, 50.44, 46.62, 43.27, 42.60.
HRMS (ESI): m/z [M + Na]+ calcd for C24H28N4NaO4: 459.2008;
found: 459.2014.
(3S,9aS)-8-[2-(4-Fluorophenylamino)-2-oxo-1-phenylethyl]-3-
methyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-di-
one (35)
IR: 3456, 3277, 3071, 2977, 2925, 2851, 1683, 1668, 1509, 1453,
1408, 1366, 1322, 1266, 1212, 1155, 1030, 838, 810, 788, 764, 699
cm–1.
(9aS)-8-(2-Morpholin-4-yl-2-oxo-1-phenylethyl)-3-phenyltet-
rahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (37)
Major pair of diastereomers
IR: 3456, 3242, 3063, 2960, 2922, 2856, 1652, 1494, 1454, 1340,
1303, 1270, 1230, 1114, 1022, 757, 702 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.50–7.28 (m, 10 H, HAr), 5.07,
5.06 (2 s, 1 H, H1), 4.66 (s, 1 H, H6), 4.36–4.18 (m, 2 H, H5a,e),
3.73–3.32 (8 H, 7 Hm, H3a), 3.20–3.08 (m, 1 H, Hm), 2.87, 2.85 (2
dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.96, 2.74 (2 d, J = 11 Hz, 1 H,
H3e), 2.56, 2.26 (2 t, J = 11 Hz, 1 H, H2), 2.33 Hz), 2.08 (2 dt, J1 = 3
Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.22, 171.19, 166.83, 166.79,
165.49, 165.44, 140.11, 140.08, 136.20, 130.46, 130.45, 130.09,
130.06, 129.84, 129.82, 129.57, 128.65, 128.59, 70.51, 70.47,
67.67, 67.38, 60.23, 60.17, 58.82, 55.73, 55.56, 51.15, 50.78, 47.35,
43.75, 42.85, 42.84.
1H NMR (500 MHz, CD3OD): d = 7.62–7.50 (m, 4 H, HAr), 7.44–
7.30 (m, 3 H, HAr), 7.04 (t, 2 H, HAr), 4.45, 4.38 (2 d, J = 13 Hz, 1
H, H5a), 4.30, 4.18 (2 d, J = 13 Hz, 1 H, H4e), 4.09, 4.08 (2 d, J = 13
Hz, 1 H, H4e), 4.05 (q, J = 7 Hz, 1 H, H1), 3.59, 3.24 (2 d, J = 11
Hz, 1 H, H3a), 3.12, 2.75 (2 d, J = 11 Hz, 1 H, H3e), 2.99, 2.87 (2 dt,
J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.29, 1.96 (2 t, J = 11 Hz, 1 H, H2),
2.27, 1.95 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 1.41, 1.43 (2 d,
J = 7 Hz, 3 H, CH3).
13C NMR (125 MHz, CD3OD): d = 171.61, 168.10, 168.03, 167.03,
166.95, 160.03, 137.10, 135.45, 130.05, 130.00, 129.95, 129.89,
129.84, 129.81, 123.78, 123.71, 123.66, 116.43, 116.41, 116.25,
116.23, 76.43, 76.28, 58.43, 58.22, 56.26, 54.98, 52.17, 51.50,
50.56, 42.48, 42.44, 21.19, 21.09.
HRMS (ESI): m/z [M + H]+ calcd for C25H28N4O4: 449.2189; found:
449.2189.
HRMS (ESI): m/z [M + H]+ calcd for C22H23FN4O3: 411.1833;
found: 411.1846.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.48–7.30 (m, 10 H, HAr), 5.05,
5.04 (2 s, 1 H, H1), 4.65, 4.63 (2 s, 1 H, H6), 4.43–2.28 (m, 2 H,
H4a,e), 3.72–3.37 (m, 7.5 H, 7 Hm, 0.5 H3a), 3.34 (d, J = 11 Hz, 0.5
H, 0.5 H3a), 3.19–3.11 (m, 1 H, Hm), 2.98, 2.75 (2 d, J = 11 Hz, 1
H, H3e), 2.87, 2.82 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.45, 2.19
(2 t, J = 11 Hz, 1 H, H2), 2.41, 2.12 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1
H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.21, 167.31, 167.22, 165.92,
165.89, 140.06, 140.04, 136.15, 130.47, 130.45, 130.11, 130.09,
129.97, 129.96, 129.84, 129.64, 128.30, 128.27, 70.68, 70.65,
67.70, 67.40, 60.27, 57.80, 57.71, 55.66, 55.12, 50.46, 47.36, 43.83,
43.80, 42.63, 42.60.
(9aS)-8-[2-Oxo-1-phenyl-2-(4-phenylpiperazin-1-yl)ethyl]-3-
phenyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-di-
one (36)
Major pair of diastereomers
IR: 3457, 3229, 2922, 2854, 2818, 1681, 1651, 1598, 1495, 1452,
1303, 1271, 1228, 1152, 1124, 1016, 757, 698 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.53–7.44 (m, 2 H, HAr), 7.44–
7.29 (m, 8 H, HAr), 7.20 (t, J = 8 Hz, 2 H, HAr), 6.89 (d, J = 9 Hz, 2
H, HAr), 6.83 (t, J = 7 Hz, 1 H, HAr), 5.08, 5.06 (2 s, 1 H, H1), 4.72
(s, 1 H, H6), 4.38–4.20 (m, 2 H, H5), 3.92–3.77 (m, 1 H,
HpCH2NC=O), 3.77–3.64 (m, 2 H, HpCH2NC=O), 3.64–3.54 (m,
1.5 H, HpCH2NC=O, 0.5 H3a), 3.36 (d, J = 11 Hz, 0.5 H, 0.5 H3a),
3.20–3.08 (m, 1 H, HpCH2NPh), 3.08–2.91 (m, 2.5 H, 2 HpCH2NPh,
0.5 H3e), 2.89, 2.85 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.75 (d,
J = 11 Hz, 0.5 H, 0.5 H3e), 2.66–2.52 (m, 1.5 H, HpCH2NPh, 0.5
H2), 2.34, 2.10 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 2.27 (t, J = 11
Hz, 0.5 H, 0.5 H2).
(9aS)-8-[2-(4-Methoxybenzylamino)-2-oxo-1-phenylethyl]-3-
phenyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-di-
one (38)
Major pair of diastereomers
IR: 3462, 3300, 3063, 2925, 2835, 1664, 1613, 1513, 1454, 1303,
1247, 1176, 1124, 1030, 817, 752, 701 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.50–7.41 (m, 2 H, HAr), 7.40–
7.27 (m, 8 H, HAr), 7.12–7.07 (m, 2 H, HAr), 6.84–6.76 (m, 2 H,
13C NMR (125 MHz, CD3OD): d = 171.27, 171.22, 166.80, 166.76,
165.39, 165.33, 152.31, 152.30, 140.08, 140.05, 131.67, 131.64,
130.10, 129.82, 129.80, 129.54, 128.62, 128.57, 127.95, 121.46,
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228
A. Mieczkowski et al.
PAPER
HAr), 5.04, 5.02 (2 s, 1 H, H1), 4.40–4.25 (m, 3 H, 2 NHCH2Ar,
H5a), 4.21 (d, J = 13 Hz, 1 H, H5e), 3.96, 3.95 (2 s, 1 H, H6), 3.72,
3.71 (2 s, 3 H, OCH3), 3.69, 3.28 (2 d, J = 11 Hz, 1 H, H3a), 2.97,
2.64 (2 d, J = 11 Hz, 1 H, H3e), 2.91, 2.80 (2 dt, J1 = 3 Hz, J2 = 13
Hz, 1 H, H4a), 2.32, 1.98 (2 t, J = 11 Hz, 1 H, H2), 2.08, 1.79 (2 dt,
J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 173.12, 166.68, 166.64, 165.48,
165.40, 160.34, 160.31, 139.94, 137.37, 137.29, 131.86, 131.80,
129.97, 129.95, 129.82, 129.76, 129.73, 129.64, 129.58, 128.59,
128.53, 128.23, 128.18, 114.93, 114.87, 76.09, 76.00, 60.20, 60.10,
58.71, 56.79, 55.68, 55.33, 52.21, 50.63, 52.21, 50.63, 43.43, 43.41,
42.71, 42.59.
(3S,9aS)-3-Benzyl-8-[2-oxo-1-phenyl-2-(4-phenylpiperazin-1-
yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (40)
IR: 3454, 3243, 3062, 3028, 2919, 2822, 1682, 1651, 1599, 1495,
1454, 1442, 1339, 1274, 1228, 1154, 1017, 759, 701 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.44–7.33 (m, 4 H, HAr), 7.33–
7.24 (m, 4 H, HAr), 7.24–7.16 (m, 2 H, HAr), 7.16–7.08 (m, 3 H,
HAr), 6.92–6.80 (m, 2 H, HAr), 4.42–4.26 (m, 2 H, H1, H5a), 4.15,
4.12 (2 s, 1 H, H6), 3.98, 3.87 (2 d, J = 13 Hz, 1 H, H5e), 3.84–3.50
(m, 4 H, 4 HpCH2NC=O), 3.30–3.24 (m, 1 H, PhCH2CH), 3.18–
2.80, 2.79–2.60, 2.60–2.48 (3 m, 8 H, 4 (m, 1 H, HpCH2NPh, H3a,e,
H4a, PhCH2CH), 1.80, 1.50 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e),
0.42, 0.22 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 170.69, 170.55, 166.81, 164.85,
152.39, 152.37, 136.38, 136.32, 135.91, 135.90, 130.44, 130.31,
130.14, 130.12, 130.10, 130.05, 129.81, 129.79, 129.76, 129.74,
128.63, 128.60, 121.58, 71.04, 58.44, 58.27, 56.75, 55.52, 54.05,
51.56, 50.85, 50.64, 50.44, 49.88, 46.71, 43.44, 42.24, 40.89.
HRMS (ESI): m/z [M + H]+ calcd for C29H30N4O4: 499.2345; found:
499.2350.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.50–7.43 (m, 2 H, HAr), 7.42–
7.26 (m, 8 H, HAr), 7.13–7.06 (m, 2 H, HAr), 6.83–6.76 (m, 2 H,
HAr), 5.05, 5.02 (2 s, 1 H, H1), 4.40–4.20 (m, 4 H, 2 NHCH2Ph,
H5a,e), 3.96 (s, 1 H, H6), 3.74, 3.73 (2 s, 3 H, OCH3), 3.65, 3.27 (2
d, J = 11 Hz, 1 H, H3a), 2.99, 2.66 (2 d, J = 11 Hz, 1 H, H3e), 2.92,
2.81 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.28, 1.96 (2 t, J = 11
Hz, 1 H, H2), 2.20, 1.90 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 173.27, 167.27, 167.15, 166.03,
165.93, 160.39, 139.97, 137.38, 137.35, 131.90, 131.82, 129.98,
129.96, 129.90, 129.85, 129.81, 129.77, 129.69, 129.64, 128.61,
128.56, 128.26, 128.21, 114.95, 114.89, 76.21, 76.17, 60.26, 57.69,
57.42, 56.48, 55.71, 55.68, 54.85, 52.01, 50.29, 46.28, 44.94, 44.01,
43.44, 42.56, 42.41.
HRMS (ESI): m/z [M + H]+ calcd for C32H35N5O3: 538.2818; found:
538.2840.
(3S,9aS)-3-Benzyl-8-(2-morpholin-4-yl-2-oxo-1-phenyleth-
yl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione
(41)
IR: 3459, 3242, 3086, 3029, 2961, 2923, 2856, 1683, 1650, 1495,
1454, 1442, 1340, 1323, 1272, 1229, 1205, 1113, 1020, 750, 702
cm–1.
1H NMR (500 MHz, CD3OD): d = 7.45–7.31 (m, 4 H, HAr), 7.30–
7.18 (m, 4 H, HAr), 7.13–7.05 (m, 2 H, HAr), 4.40–4.34 (m, 1.5 H,
H1, 0.5 H5a), 4.29 (d, 0.5 H, 0.5 H4a), 4.08, 4.06 (2 s, 1 H, H6), 3.97,
3.86 (2 d, J = 13 Hz, 1 H, H5e), 3.68–3.33 (m, 7 H, 7 Hm), 3.29–3.26
(m, 1 H, PhCH2CH), 3.24–3.16, 3.12–3.04 (2 m, 1 H, Hm), 2.94,
2.66 (2 d, J = 11 Hz, 1 H, H3a), 2.92–2.84 (m, 1 H, PhCH2CH),
2.82, 2.53 (2 d, J = 11 Hz, 1 H, H3e), 2.74, 2.64 (2 dt, J1 = 3 Hz,
J2 = 13 Hz, 1 H, H4a), 1.79, 1.49 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e), 0.40, 0.19 (2 t, J = 11 Hz, 1 H, H2).
(9aS)-8-[2-(4-Fluorophenylamino)-2-oxo-1-phenylethyl]-3-phe-
nyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione
(39)
Major pair of diastereomers
IR: 3463, 3279, 3064, 3032, 2921, 2826, 1672, 1509, 1454, 1407,
1304, 1269, 1211, 1125, 1029, 838, 810, 763, 739, 700 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.59–7.50 (m, 4 H, HAr), 7.42–
7.30 (m, 8 H, HAr), 7.07–7.00 (m, 3 H, HAr), 4.45–4.24 (m, 2 H,
H5a,e), 5.09, 5.07 (2 s, 1 H, H1), 4.12, 4.10 (s, 1 H, H6), 3.70, 3.35
(2 d, J = 11 Hz, 1 H, H3a), 3.10, 2.73 (2 d, J = 11 Hz, 1 H, H3e),
3.01, 2.89 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.42, 2.08 (2 t,
J = 11 Hz, 1 H, H2), 2.22, 1.90 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e).
13C NMR (125 MHz, CD3OD): d = 172.99, 171.52, 166.76, 166.75,
165.58, 165.52, 161.92, 160.01, 159.99, 140.01, 139.97, 137.03,
137.00, 135.44, 135.42, 135.39, 130.05, 130.01, 129.94, 129.86,
129.85, 129.84, 129.77, 129.62, 129.61, 128.61, 128.55, 123.80,
123.74, 123.66, 116.40, 116.23, 76.30, 76.17, 61.54, 60.23, 60.16,
58.75, 58.58, 56.62, 55.37, 52.20, 50.67, 42.75, 42.69.
13C NMR (125 MHz, CD3OD): d = 170.83, 170.68, 166.81, 164.88,
164.87, 136.37, 136.30, 135.75, 132.25, 132.19, 130.42, 130.30,
130.12, 130.06, 129.85, 129.81, 129.75, 129.73, 128.63, 128.58,
70.98, 70.91, 67.70, 67.66, 67.51, 67.35, 58.41, 58.27, 56.75, 56.73,
5545, 53.97, 51.56, 47.41, 47.35, 43.90, 42.23, 40.88, 40.85.
HRMS (ESI): m/z [M + Na]+ calcd for C26H30N4NaO4: 485.2165;
found: 485.2183.
(3S,9aS)-3-Benzyl-8-[2-(4-methoxybenzylamino)-2-oxo-1-phe-
nylethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (42)
IR: 3281, 3063, 3029, 2926, 2835, 1683, 1659, 1614, 1513, 1454,
1441, 1339, 1322, 1301, 1247, 1206, 1117, 1108, 1031, 820, 783,
749, 701 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C27H25FN4NaO3: 495.1808;
1H NMR (500 MHz, CD3OD): d = 7.42–7.18 (m, 8 H, HAr), 7.16–
7.00 (m, 4 H, HAr), 6.82–6.76 (m, 2 H, HAr), 4.40–4.17 (m, 4 H, 2
PhCH2H, H1, H5a), 4.01, 3.83 (2 d, J = 13 Hz, 1 H, H5e), 3.74 (s, 3
H, OCH3), 3.51, 3.49 (2 s, 1 H, H6), 3.30–3.26 (m, 1 H, PhCH2CH),
2.99, 2.49 (2 d, J = 11 Hz, 1 H, H3a), 2.94–2.81 (m, 1 H,
PhCH2CH), 2.76, 2.40 (2 d, J = 11 Hz, 1 H, H3e), 2.74, 2.62 (2 dt,
J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 1.68, 1.38 (2 dt, J1 = 3 Hz, J2 = 13
Hz, 1 H, H4e), 0.34, –0.07 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 173.24, 173.01, 166.81, 166.78,
164.85, 164.79, 160.38, 160.24, 137.14, 137.10, 136.26, 132.28,
132.24, 131.89, 131.84, 130.03, 129.86, 129.81, 129.79, 129.6,
129.74, 129.67, 129.62, 129.60, 128.75, 128.69, 114.89, 114.84,
76.30, 76.11, 58.46, 58.22, 56.78, 56.72, 55.68, 55.62, 53.71, 51.92,
3.37, 43.34, 42.24, 42.14, 40.990, 40.84.
found: 495.1830.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.58–7.51 (m, 4 H, HAr), 7.44–
7.30 (m, 8 H, HAr), 7.08–7.00 (m, 3 H, HAr), 4.47–4.31 (m, 2 H,
H5a,e), 5.07, 5.05 (2 s, 1 H, H1), 4.12 (s, 1 H, H6), 3.66, 3.32 (2 d,
J = 11 Hz, 1 H, H3a), 3.10, 2.74 (2 d, J = 11 Hz, 1 H, H3e), 3.00,
2.88 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.38, 2.06 (2 t, J = 11
Hz, 1 H, H2), 2.33, 1.99 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 172.96, 171.58, 167.13, 166.59,
165.80, 165.59, 161.92, 161.91, 159.99, 159.98, 140.03, 137.04,
137.02, 135.46, 135.44, 135.42, 130.05, 130.00, 129.98, 129.96,
129.89, 129.88, 129.78, 129.68, 129.65, 128.61, 128.56, 123.77,
123.71, 123.65, 116.41, 116.24, 116.24, 76.37, 76.27, 61.53, 60.29,
60.22, 58.64, 56.31, 54.54, 51.97, 50.32, 43.44, 42.61, 42.47.
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Synthesis of b-Turn Mimetics
229
HRMS (ESI): m/z [M + H]+ calcd for C30H32N4O4: 513.2502; found:
513.2512.
13C NMR (125 MHz, CD3OD): d = 170.60, 170.53, 166.94, 164.96,
158.15, 158.11, 136.28, 136.19, 133.67, 133.65, 132.48, 130.22,
130.16, 129.98, 129.93, 127.03, 127.01, 116.79, 116.67, 71.65,
71.43, 67.66, 67.44, 64.76, 58.29, 57.97, 57.01, 56.98, 55.86, 54.40,
51.78, 49.95, 47.39, 44.01, 42.11, 42.05, 40.21, 40.15.
HRMS (ESI): m/z [M + H]+ calcd for C26H30N4O5: 479.2294; found:
479.2316.
(3S,9aS)-3-Benzyl-8-[2-(4-fluorophenylamino)-2-oxo-1-phenyl-
ethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-di-
one (43)
IR: 3455, 3269, 3064, 3030, 2924, 2838, 1683, 1510, 1454, 1442,
1407, 1339, 1322, 1272, 1210, 1188, 1155, 1101, 1030, 838, 810,
764, 748, 701 cm–1.
(3S,9aS)-3-(4-Hydroxybenzyl)-8-[2-(4-methoxybenzylamino)-
2-oxo-1-phenylethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-
1,4(3H,6H)-dione (46)
IR: 3280, 3030, 2927, 2836, 1664, 1613, 1513, 1455, 1442, 1337,
1304, 1269, 1247, 1207, 1175, 1114, 1030, 817, 783, 754, 727, 700
cm–1.
1H NMR (500 MHz, CD3OD): d = 7.40–7.28 (m, 5 H, HAr), 7.10–
7.02 (m, 4 H, HAr), 6.97–6.87 (m, 2 H, HAr), 6.86–6.70 (m, 2 H,
HAr), 4.42–4.20 (m, 4 H, 2 PhCH2N, H1, H5a), 4.02, 3.81 (2 d,
J = 13 Hz, 1 H, H5e), 3.74 (s, 3 H, OCH3), 3.45, 3.41 (2 s, 1 H, H6),
3.25–3.17 (m, 1 H, PhCH2CH), 3.04, 2.41 (2 d, J = 11 Hz, 1 H,
H3a), 2.86–2.68 (m, 2 H, PhCH2CH, 0.5 H4a, 0.5 H3e), 2.60 (dt,
J1 = 3 Hz, J2 = 13 Hz, 0.5 H, H4a), 2.32 (d, J = 11 Hz, 0.5 H, H3e),
1.74, 1.40 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 0.49 (t, J–11 Hz,
0.5 H, 0.5 H2), the other ‘half’ of the H2 signal probably overlap-
ping with TMS signal.
1H NMR (500 MHz, CD3OD): d = 7.56–7.48 (m, 2 H, HAr), 7.40–
7.21 (m, 8 H, HAr),, 7.13–7.08 (m, 2 H, HAr), 7.05–6.98 (m, 2 H,
HAr), 4.34, 4.32 (2 d, 1 H, H1), 4.42, 4.31 (2 d, 1 H, H5a), 4.07, 3.90
(2 d, 1 H, H5e), 3.70, 3.69 (2 s, 1 H, H6), 3.33–3.27 (m, 1 H,
PhCH2CH), 3.02, 2.57 (2 d, J = 11 Hz, 1 H, H3a), 2.93–2.84 (m, 1.5
H, PhCH2CH, 0.5 H3a), 2.80, 2.68 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4a), 2.48 (d, J = 11 Hz, 0.5 H, H3e), 1.80, 1.45 (2 dt, J1 = 3 Hz,
J2 = 13 Hz, 1 H, H4e), 0.49, 0.07 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 171.46, 171.32, 166.79, 166.72,
164.80, 164.76, 161.92, 161.88, 156.99, 159.96, 136.75, 136.56,
136.24, 136.21, 135.41, 135.39, 135.30, 135.28, 132.24, 132.16,
130.14, 129.88, 129.85, 129.73, 129.66, 128.69, 128.64, 123.89,
123.83, 123.71, 123.64, 116.39, 116.35, 116.21, 116.17, 76.21,
76.19, 76.09, 76.07, 58.50, 58.22, 56.75, 56.72, 55.51, 53.72, 51.76,
49.89, 42.22, 40.86, 40.82.
HRMS (ESI): m/z [M + H]+ calcd for C28H27FN4O3: 487.2145;
found: 487.2130.
13C NMR (125 MHz, CD3OD): d = 173.40, 173.18, 166.96, 166.84,
164.97, 160.39, 160.34, 158.07, 157.95, 137.43, 137.31, 133.44,
133.35, 132.47, 131.89, 131.77, 129.89, 129.85, 129.79, 129.71,
129.67, 126.96, 126.73, 116.77, 116.64, 116.42, 114.91, 114.84,
77.08, 76.76, 58.57, 58.09, 56.03, 55.68, 53.80, 52.141, 43.35,
42.27, 42.12, 40.19, 40.08.
(3S,9aS)-3-(4-Hydroxybenzyl)-8-[2-oxo-1-phenyl-2-(4-phe-
nylpiperazin-1-yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyra-
zine-1,4(3H,6H)-dione (44)
IR: 3240, 3063, 3025, 2921, 2822, 1680, 1639, 1598, 1414, 1495,
HRMS (ESI): m/z [M + Na]+ calcd for C30H32N4NaO5: 551.2271;
found: 551.2294.
1443, 1337, 1272, 1229, 1186, 1152, 1115, 1016, 759, 698 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.46–7.28 (m, 6 H, HAr), 7.25–
7.16 (m, 2 H, HAr), 7.02–6.94 (m, 2 H, HAr), 6.93–6.78 (m, 4 H,
HAr), 4.39 (d, J = 13 Hz, 0.5 H, 0.5 H5a), 4.32–4.26 (m, 1.5 H, H1,
0.5 H5a), 4.00 (d, J = 13 Hz, 0.5 H, H5e), 3.94, 3.91 (2 s, 1 H, H6),
3.88–3.56 (m, 4.5 H, 4 HpCH2NC=O, 0.5 H5e), 3.27–3.19 (m, 1 H,
PhCH2CH), 3.15–3.03 (m, 2 H, 2 HpCH2NPh), 3.00, 2.38 (2 d,
J = 11 Hz, 1 H, H3a), 2.97–2.84 (m, 1.5 H, HpCH2NPh, 0.5 H3e),
2.83–2.74 (m, 1 H, PhCH2CH), 2.74–2.68 (m, 1 H, HpCH2NCPh),
2.60 (dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.24 (d, J = 11 Hz, 0.5 H,
0.5 H3e), 1.73, 1.55 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 0.31,
0.09 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 170.50, 170.40, 166.94, 164.94,
158.16, 158.14, 152.38, 152.34, 136.40, 136.33, 133.70, 133.65,
130.25, 130.17, 130.13, 129.97, 129.92, 127.04, 127.01, 121.57,
117.82, 117.79, 116.82, 116.71, 71.80, 71.57, 58.28, 57.95, 57.04,
55.95, 54.44, 51.86, 51.01, 50.80, 50.45, 49.96, 46.72, 43.55, 42.11,
42.07, 40.21, 40.15.
(3S,9aS)-8-[2-(4-Fluorophenylamino)-2-oxo-1-phenylethyl]-3-
(4-hydroxybenzyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-
1,4(3H,6H)-dione (47)
IR: 3265, 3088, 2960, 2925, 1843, 1677, 1646, 1614, 1510, 1454,
1444, 1408, 1337, 1309, 1269, 1210, 1175, 1156, 1114, 838, 813,
765, 726, 700 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.60–7.48 (m, 5 H, HAr), 7.46 (d,
J = 7 Hz, 2 H, HAr), 7.41–7.26 (m, 2 H, HAr), 7.09–6.86 (m, 2 H,
HAr), 6.83–6.70 (m, 2 H, HAr), 4.45 (d, J = 13 Hz, 0.5 H, H5a), 4.33–
4.23 (m, 1.5 H, H1, 0.5 H5a), 4.09, 3.90 (2 d, J = 13 Hz, 1 H, H5e),
3.58, 3.55 (2 s, 1 H, H6), 3.23–3.18 (m, 1 H, PhCH2CH), 3.06, 2.45
(2 d, J = 11 Hz, 1 H, H3a), 2.90, 2.38 (2 d, J = 11 Hz, 1 H, H3e),
2.88–2.77 (m, 1.5 H, PhCH2CH, 0.5 H4a), 2.67 (dt, J1 = 3 Hz,
J2 = 13 Hz, 0.5 H, H4a), 1.86, 1.48 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e), 0.60, 0.09 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 172.73, 172.59, 171.80, 171.50,
166.96, 166.85, 165.01, 161.97, 160.05, 158.07, 157.94, 127.12,
136.99, 135.24, 135.22, 133.46, 133.38, 129.96, 129.94, 129.89,
129.86, 127.00, 126.78, 123.98, 123.91, 116.72, 116.65, 116.38,
116.35, 116.21, 116.17, 77.34, 76.92, 58.54, 58.11, 57.02, 56.96,
55.90, 53.74, 52.36, 42.23, 42.15, 40.13, 40.09.
(3S,9aS)-3-(4-Hydroxybenzyl)-8-(2-morpholin-4-yl-2-oxo-1-
phenylethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-
1,4(3H,6H)-dione (45)
IR: 3241, 2967, 2924, 2855, 1683, 1637, 1613, 1592, 1514, 1464,
1441, 1338, 1264, 1232, 1206, 1185, 1147, 1113, 1032, 1018, 863,
817, 757, 700 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.44–7.29 (m, 5 H, HAr), 7.0–
6.93 (m, 2 H, HAr), 6.84–6.77 (m, 2 H, HAr), 4.39 (d, J = 13 Hz, 0.5
H, H5a), 4.32–4.22 (m, 1.5 H, H1, 0.5 H5a), 4.00, 3.81 (2 d, J = 13
Hz, 1 H, H5e), 3.87, 3.84 (2 s, 1 H, H6), 3.74–3.36 (m, 7 H, Hm),
3.27–3.17 (m, 1.5 H, PhCH2CH, 0.5 Hm), 3.18–3.08 (m, 0.5 H, Hm),
2.84–2.70 (m, 1.5 H, PhCH2CH, 0.5 H4a), 2.99, 2.35 (2 d, J = 11
Hz, 1 H, H3a), 2.88, 2.22 (2 d, J = 11 Hz, 1 H, H3e), 2.59 (dt, J1 = 3
Hz, J2 = 13 Hz, 0.5 H, H4a), 1.73, 1.53 (2 dt, J1 = 3 Hz, J2 = 13 Hz,
1 H, H4e), 0.28, 0.10 (2 t, J = 11 Hz, 1 H, H2).
HRMS (ESI): m/z [M + H]+ calcd for C28H27FN4O4: 503.2095;
found: 503.2078.
(9aS)-8-[1-(4-Methoxyphenyl)-2-oxo-2-(4-phenylpiperazin-1-
yl)ethyl]-3-phenyltetrahydro-2H-pyrazino[1,2-a]pyrazine-
1,4(3H,6H)-dione (48)
Major pair of diastereomers
IR: 3457, 3239, 3031, 2929, 2853, 2834, 1684, 1655, 1609, 1598,
1512, 1495, 1454, 1440, 1339, 1304, 1250, 1229, 1177, 1154, 1124,
1017, 808, 758, 694 cm–1.
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

230
A. Mieczkowski et al.
PAPER
1H NMR (500 MHz, CD3OD): d = 7.43–7.28 (m, 7 H, HAr), 7.23–
7.18 (m, 2 H, HAr), 6.97–6.91 (m, 2 H, HAr), 6.87 (d, J = 8 Hz, 2 H,
HAr), 6.82 (t, J = 7 Hz, 1 H, HAr), 5.04, 5.03 (2 s, 1 H, H1), 4.62, 4.61
(2 s, 1 H, H6), 4.33–4.17 (m, 2 H, H5a,e), 3.84–3.75 (m, 4 H, OCH3,
HpCH2NC=O), 3.73–3.60 (m, 2 H, HpCH2NC=O), 3.60–3.49 (m,
1.5 H, HpCH2NC=O, 0.5), 3.35 (2 d, J = 11 Hz, 0.5 H, 0.5 H3a),
3.16–3.06 (m, 1 H, HpCH2NPh), 3.06–2.98 (m, 1 H, HpCH2NPh),
2.97–2.90 (m, 1.5 H, HpCH2NPh, 0.5 H3e), 2.86, 2.82 (2 dt, J1 = 3
Hz, J2 = 13 Hz, 1 H, H4a), 2.73 (d, J = 11 Hz, 0.5 H, 0.5 H3e), 2.65–
2.58 (m, 1 H, HpCH2NPh), 2.57, 2.24 (2 t, J = 11 Hz, 1 H, H2), 2.30,
2.06 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.27, 171.22, 166.80, 166.76,
165.39, 165.33, 161.38, 161.35, 152.31, 152.30, 140.08, 140.05,
131.67, 131.64, 130.10, 129.82, 129.80, 129.54, 128.62, 128.57,
127.95, 121.46, 117.71, 115.39, 115.35, 60.20, 60.14, 60.11, 58.76,
55.80, 55.78, 55.72, 55.46, 51.22, 50.65, 50.62, 50.37, 46.58, 43.20,
42.81.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.47–7.44 (m, 1 H, HAr), 7.39–
7.29 (m, 5 H, HAr), 7.21 (t, J = 8 Hz, 2 H, HAr), 7.10, 7.12 (2 d,
J = 3.5 Hz, 1 H, HAr), 7.04–7.00 (m, 1 H, HAr), 6.92 (d, J = 9 Hz, 2
H, HAr), 6.84 (t, J = 7.5 Hz, 1 H, HAr), 5.16, 5.14 (2 s, 1 H, H1), 5.05
(2 s, 1 H, H6), 4.37–4.28, 4.26–4.18 (2 m, 2 H, H4a,e), 3.90–3.63 (m,
4 H, HpCH2NC=O), 3.56, 3.48 (2 d, J = 11 Hz, 1 H, H3a), 3.20–3.10
(m, 2 H, HpCH2NPh), 3.10–3.04 (m, 1 H, HpCH2NPh), 2.97 (d,
J = 11 Hz, 0.5 H, 0.5 H3e), 2.94–2.76 (m, 2.5 H, HpCH2NPh, H5a,
0.5 H3e), 2.57 (t, J = 11 Hz, 0.5 H, 0.5 H2), 2.38–2.24 (m, J = 11
Hz, 1 H, 0.5 H2, 0.5 H5a), 2.14 (dt, J1 = 3 Hz, J2 = 13 Hz, 0.5 H, 0.5
H5e).
13C NMR (125 MHz, CD3OD): d = 170.26, 167.25, 165.88, 152.44,
140.07, 140.06, 137.98, 137.95, 130.16, 129.97, 129.82, 29.77,
129.65, 128.49, 128.47, 128.33, 128.31, 127.56, 127.53, 121.59,
117.88, 65.48, 60.29, 60.26, 57.96, 57.91, 55.33, 54.39, 50.96,
50.74, 50.53, 47.04, 43.47, 42.77, 42.72;
HRMS (ESI): m/z [M + Na]+ calcd for C32H35N5NaO4: 576.2587;
found: 576.2584.
(9aS)-8-[1-(2-Naphthyl)-2-oxo-2-(4-phenylpiperazin-1-yl)eth-
yl]-3-phenyltetrahydro-2H-pyrazino[1,2-a]pyrazine-
1,4(3H,6H)-dione (52)
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.43–7.28 (m, 7 H, HAr), 7.23–
7.18 (m, 2 H, HAr), 6.97–6.91 (m, 2 H, HAr), 6.87 (d, J = 8 Hz, 2 H,
HAr), 6.82 (t, J = 7 Hz, 1 H, HAr), 5.04, 5.03 (2 s, 1 H, H1), 4.62, 4.63
(2 s, 1 H, H6), 4.41–4.28 (m, 2 H, H5a,e), 3.85–3.75 (m, 4 H, OCH3,
HpCH2NC=O), 3.75–3.62 (m, 2 H, HpCH2NC=O), 3.61–3.56 (m, 1
H, HpCH2NC=O), 3.54, 3.36 (2 d, J = 11 Hz, 1 H, H3a), 3.18–3.08
(m, 1 H, HpCH2NPh), 3.08–3.00 (m, 1 H, HpCH2NPh), 3.00–2.91
(m, 1.5 H, HpCH2NPh, 0.5 H3e), 2.86, 2.80 (2 dt, J1 = 3 Hz, J2 = 13
Hz, 1 H, H4a), 2.74 (d, J = 11 Hz, 0.5 H, 0.5 H3e), 2.66–2.56 (m, 1
H, HpCH2NPh), 2.44, 2.17 (2 t, J = 11 Hz, 1 H, H2), 2.37, 2.10 (2
dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.30, 171.29, 167.31, 167.23,
165.87, 165.83, 152.36, 152.35, 140.04, 140.01, 131.68, 131.65,
130.12, 129.95, 129.94, 129.61, 128.28, 128.25, 127.93, 121.51,
117.77, 115.41, 115.38, 79.48, 70.12, 60.26, 60.22, 57.79, 57.67,
55.81, 55.78, 55.68, 55.03, 51.15, 50.69, 50.44, 50.34, 46.62, 43.27,
42.60.
Major pair of diastereomers
IR: 3468, 3229, 3057, 2914, 2854, 2828, 1651, 1598, 1495, 1453,
1440, 1303, 1271, 1227, 1154, 1127, 1018, 753, 695 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.94–7.81 (m, 4 H, HAr), 7.63,
7.60 (2 d, J = 8.5 Hz, 1 H, HAr), 7.52–7.48 (m, 2 H, HAr), 7.37–7.26
(m, 5 H, HAr), 7.17–7.12 (m, 2 H, HAr), 6.82–6.75 (m, 3 H, HAr),
5.04, 5.03 (2 s, 1 H, H1), 4.89, 4.88 (2 s, 1 H, H6), 4.31 (d, J = 13
Hz, 0.5 H, 0.5 H5a), 4.28–4.20 (m, 1.5 H, H5a,e), 3.86–3.67 (m, 3 H,
3 HpCH2NC=O), 3.58–3.49 (m, 1 H, HpCH2NC=O), 3.60, 3.38 (2 d,
J = 11 Hz, 1 H, H3a), 3.13–3.03 (m, 1 H, HpCH2NPh), 3.02–2.91
(m, 2.5 H, 2 HpCH2NPh, 0.5 H3e), 2.88, 2.84 (2 dt, J1 = 3 Hz,
J2 = 13 Hz, 1 H, H4a), 2.76 (d, J = 11 Hz, 0.5 H, H3a), 2.67, 2.34 (2
t, J = 11 Hz, 1 H, H2), 2.63–2.55 (m, 1 H, HpCH2NPh), 2.39, 2.15
(2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e).
13C NMR (125 MHz, CD3OD): d = 171.07, 171.00, 166.84, 166.78,
165.43, 165.37, 152.27, 152.26, 140.08, 140.03, 134.78, 134.74,
134.71, 134.68, 133.82, 130.07, 129.94, 129.88, 129.82, 129.80,
129.56, 129.08, 128.79, 128.63, 128.56, 127.75, 127.65, 127.57,
127.52, 121.47, 117.74, 60.22, 60.19, 60.13, 58.89, 55.71, 55.59,
51.11, 50.94, 50.65, 50.47, 46.69, 43.27, 42.92.
(9aS)-8-[2-Oxo-2-(4-phenylpiperazin-1-yl)-1-(2-thienyl)ethyl]-
3-phenyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (51)
Major pair of diastereomers
HRMS (ESI): m/z [M + Na]+ calcd for C35H35N5NaO3: 596.2637;
IR: 3469, 3223, 3090, 3064, 2921, 2853, 2822, 1651, 1598, 1495,
1454, 1442, 1339, 1304, 1271, 1231, 1155, 1129, 1016, 759, 696
cm–1.
found: 596.2639.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.95–7.82 (m, 4 H, HAr), 7.62 (t,
J = 8.5 Hz, 1 H, HAr), 7.53–7.46 (m, 2 H, HAr), 7.40–7.27 (m, 5 H,
HAr), 7.17–7.12 (m, 2 H, HAr), 6.84–6.76 (m, 3 H, HAr), 5.04, 5.02
(2 s, 1 H, H1), 4.44–4.34 (m, 1.5 H, H5a,e), 4.30 (d, J = 13 Hz, 0.5
H, 0.5 H5e), 3.86–3.68 (m, 3 H, 3 HpCH2NC=O), 3.65–3.54 (m, 1.5
H, HpCH2NC=O, 0.5 H3a), 3.38 (d, 0.5 H, 0.5 H3a), 3.14–3.05 (m,
1 H, HpCH2NPh), 3.05–2.92 (m, 2.5 H, 2 HpCH2NPh, 0.5 H3e),
2.88, 2.82 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4a), 2.77 (d, J = 11 Hz,
0.5 H, H3a), 2.66–2.58 (m, 1 H, HpCH2NPh), 2.54, 2.27 (2 t, J = 11
Hz, 1 H, H2), 2.47, 2.19 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), the
signal of H6 covered by the signal of MeOH at 4.87.
13C NMR (125 MHz, CD3OD): d = 171.05, 171.03, 167.32, 167.21,
165.88, 165.85, 152.31, 140.03, 134.80, 134.78, 135.74, 134.74,
134.72, 133.81, 133.78, 130.09, 129.90, 129.63, 129.09, 128.81,
128.30, 128.27, 127.77, 127.69, 127.53, 127.50, 121.52, 117.78,
60.25, 57.84, 57.79, 55.56, 55.26, 51.06, 50.70, 50.62, 50.52, 46.72,
43.35, 42.68.
1H NMR (500 MHz, CD3OD): d = 7.46 (d, J = 5 Hz, 1 H, HAr),
7.42–7.28 (m, 5 H, HAr), 7.22 (t, J = 8 Hz, 2 H, HAr), 7.13 (d, J = 3.5
Hz, 1 H, HAr), 7.03, 7.01 (2 d, J = 3.5 Hz, 1 H, HAr), 6.93 (d, J = 9
Hz, 2 H, HAr), 6.84 (t, J = 7.5 Hz, 1 H, HAr), 5.14, 5.13 (2 s, 1 H,
H1), 5.04, 5.03 (2 s, 1 H, H6), 4.42–4.32 (m, 2 H, H4a,e), 3.88–3.68
(m, 4 H, HpCH2NC=O), 3.53, 3.47 (2 d, J = 11 Hz, 2 H, H3a), 3.19–
3.07 (m, 2 H, HpCH2NPh), 3.07–3.01 (m, 1 H, HpCH2NPh), 2.96 (d,
J = 11 Hz, 0.5 H, 0.5 H3e), 2.91–2.78 (m, 2.5 H, HpCH2NPh, H5a,
0.5 H3e), 2.46, 2.20 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H5e).
13C NMR (125 MHz, CD3OD): d = 170.24, 166.79, 165.50, 165.46,
140.05, 140.03, 137.99, 137.93, 130.14, 129.84, 129.77, 129.58,
128.61, 128.56, 128.50, 128.48, 127.50, 121.55, 117.83, 65.32,
60.22, 60.18, 60.15, 58.93, 58.91, 55.37, 54.71, 50.92, 50.83, 50.46,
49.91, 47.00, 43.41, 42.96, 42.92.
HRMS (ESI): m/z [M + Na]+ calcd for C29H31N5NaO3S: 552.2045;
found: 552.2061.
Synthesis 2010, No. 2, 221–232 © Thieme Stuttgart · New York

PAPER
Synthesis of b-Turn Mimetics
231
(9aS)-8-[1-(6-Methoxy-2-naphthyl)-2-oxo-2-(4-phenylpiper-
azin-1-yl)ethyl]-3-phenyltetrahydro-2H-pyrazino[1,2-a]pyra-
zine-1,4(3H,6H)-dione (53)
0.5 H, 0.5 H3e), 2.64–2.53 (m, 1 H, HpCH2NPh), 2.39, 2.13 (2 t,
J = 11 Hz, 1 H, H2), 2.37, 2.10 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H,
H4e), 1.43, 1.41 (2 d, J = 7 Hz, 3 H, CH3).
Major pair of diastereomers
13C NMR (125 MHz, CD3OD): d = 171.05, 167.88, 167.85, 166.92,
166.86, 152.38, 136.26, 130.49, 130.46, 130.11, 130.08, 129.83,
121.57, 117.81, 70.83, 70.80, 57.91, 57.80, 55.42, 54.88, 51.82,
51.78, 51.17, 50.71, 50.49, 46.66, 43.33, 42.51, 42.48, 21.29, 21.26.
IR: 3453, 3241, 3060, 2919, 2822, 1682, 1657, 1600, 1504, 1495,
1454, 1440, 1391, 1339, 1303, 1267, 1228, 1156, 1121, 1020, 757,
696 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.90–7.79 (m, 2 H, HAr), 7.77,
7.75 (2 d, J = 9 Hz, 1 H, HAr), 7.57, 7.55 (2 d, J = 8.5 Hz,1 H, HAr),
7.43–7.28 (m, 6 H, HAr), 7.26–7.20 (m, 1 H, HAr), 7.20–7.12 (m, 2
H, HAr), 6.89–6.76 (m, 3 H, HAr), 5.08, 5.06 (2 s, 1 H, H1), 4.85,
4.84 (2 s, 1 H, H6), 4.34 (d, J = 13 Hz, 0.5 H, H5e), 4.32–4.22 (m,
1.5 H, H5a,e), 3.91, 3.90 (2 s, 3 H, OCH3), 3.86–3.70 (m, 3 H,
HpCH2NC=O), 3.64–3.56 (m, 1.5 H, HpCH2NC=O, 0.5 H3a), 3.38
(d, J = 11 Hz, 0.5 H, 0.5 H3a), 3.18–3.07 (m, 1 H, HpCH2NPh),
3.07–2.94 (m, 2.5 H, 2 HpCH2NPh, 0.5 H3e), 2.92, 2.87 (2 dt, J1 = 3
Hz, J2 = 13 Hz, 1 H, H5a), 2.79 (d, J = 11 Hz, 0.5 H, H3e), 2.64–2.56
(m, 1 H, HpCH2NPh), 2.66, 2.32 (2 t, J = 11 Hz, 1 H, H2), 2.39, 2.18
(2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4).
13C NMR (125 MHz, CD3OD): d = 171.27, 171.19, 166.91, 166.85,
165.55, 165.49, 159.88, 159.89, 152.37, 152.36, 140.12, 136.23,
136.18, 131.24, 130.54, 130.20, 130.16, 130.09, 129.86, 129.84,
129.74, 129.61, 129.59, 128.91, 128.85, 128.67, 128.60, 128.03,
127.97, 121.55, 120.50, 117.83, 117.81, 106.73, 79.51, 70.69,
60.27, 60.21, 58.89, 55.85, 55.73, 51.36, 50.94, 50.74, 50.60, 46.76,
43.35, 42.92.
HRMS (ESI): m/z [M + H]+ calcd for C26H31N5O3: 462.2427; found:
462.2485.
(3R,9aS)-3-Benzyl-8-[2-oxo-1-phenyl-2-(4-phenylpiperazin-1-
yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (55)
IR: 3457, 3243, 3061, 3028, 2921, 2858, 2820, 1685, 1656, 1599,
1495, 1453, 1439, 1335, 1321, 1272, 1228, 1154, 1017, 758, 701
cm–1.
1H NMR (500 MHz, CD3OD): d = 7.40–7.24 (m, 8 H, HAr), 7.22–
7.14 (m, 2 H, HAr), 7.12–7.04 (m, 2 H, HAr), 6.88–6.78 (m, 3 H,
HAr), 4.56, 4.50 (2 s, 1 H, H6), 4.32–4.18 (m, 2 H, H5a, H1), 3.80–
3.44 (m, 5 H, 4 HpCH2NC=O, H5e), 3.26–3.20 (m, 1 H, PhCH2CH),
3.12–3.02, 3.02–2.80, 2.70–2.48 (m, 7 H, 4 HpCH2NPh, PhCH2CH,
H3a, 0.5 H5a, 0.5 H3e), 2.48–2.36 (m, 1 H, 0.5 H4a, 0.5 H3e), 2.25
(dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e), 2.10 (t, J = 11 Hz, 0.5 H, H2),
1.97–1.86 (m, 1 H, 0.5 H4e, 0.5 H2).
13C NMR (125 MHz, CD3OD): d = 170.80, 170.73, 167.72, 167.66,
166.93, 166.90, 152.28, 136.02, 135.96, 131.38, 130.41, 130.39,
130.08, 130.07, 129.96, 129.93, 129.71, 129.68, 129.60, 129.58,
128.71, 128.68, 121.47, 117.72, 117.70, 79.47, 70.85, 70.49, 57.05,
56.75, 56.59, 55.13, 54.37, 50.61, 50.52, 50.29, 50.07, 46.59, 46.52,
43.23, 43.16, 42.12, 41.97, 41.66.
HRMS (ESI): m/z [M + H]+ calcd for C36H37N5O4: 604.2924; found:
604.2954.
Minor pair of diastereomers
1H NMR (500 MHz, CD3OD): d = 7.90–7.80 (m, 2 H, HAr), 7.76 (d,
J = 9 Hz, 1 H, HAr), 7.56 (t, J = 8.5 Hz, 1 H, HAr), 7.44–7.29 (m, 6
H, HAr), 7.25 (m, 1 H, HAr), 7.20–7.12 (m, 2 H, HAr), 6.90–6.76 (m,
3 H, HAr), 5.06, 5.04 (2 s, 1 H, H1), 4.84 (s, 1 H, H6), 4.46–4.36 (m,
1.5 H, H5a,e), 4.33 (d, J = 13 Hz, 0.5 H, H5e), 3.91, 3.90 (2 s, 3 H,
OCH3), 3.86–3.70 (m, 3 H, HpCH2NC=O), 3.67–3.56 (m, 1.5 H,
HpCH2NC=O, 0.5 H3a), 3.37 (d, J = 11 Hz, 0.5 H, 0.5 H3a), 3.18–
3.09 (m, 1 H, HpCH2NPh), 3.09–2.95 (m, 2.5 H, 2 HpCH2NPh, 0.5
H3e), 2.92, 2.85 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H5a), 2.79 (d,
J = 11 Hz, 0.5 H, H3e), 2.68–2.58 (m, 1 H, HpCH2NPh), 2.54, 2.27
(2 t, J = 11 Hz, 1 H, H2), 2.48, 2.21 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1
H, H4).
13C NMR (125 MHz, CD3OD): d = 171.30, 171.15, 167.34, 167.22,
165.94, 165.90, 159.89, 159.87, 152.37, 152.35, 140.05, 136.24,
136.20, 131.21, 130.54, 130.20, 130.15, 130.10, 129.99, 129.97,
129.74, 129.66, 129.55, 128.93, 128.87, 128.31, 128.29, 128.01,
127.93, 121.57, 120.53, 117.83, 117.81, 106.73, 79.50, 70.87,
60.23, 57.81, 55.85, 55.69, 55.21, 51.29, 50.75, 50.61, 46.75, 43.34,
42.63.
HRMS (ESI): m/z [M + Na]+ calcd for C32H35N5NaO3: 560.2637;
found: 560.2665.
(3R,9aS)-3-(4-Hydroxybenzyl)-8-[2-oxo-1-phenyl-2-(4-phe-
nylpiperazin-1-yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyra-
zine-1,4(3H,6H)-dione (56)
IR: 3251, 3024, 2922, 2821, 1645, 1598, 1515, 1495, 1441, 1333,
1272, 1228, 1175, 1154, 1017, 757, 697 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.42–7.28 (m, 5 H, HAr), 7.22–
7.12 (m, 2 H, HAr), 6.94–6.78 (m, 5 H, HAr), 6.76–6.63 (m, 2 H,
HAr), 4.57, 4.51 (2 s, 1 H, H6), 4.32–4.22 (m, 1 H, H4a), 4.20, 4.19
(2 s, 1 H, H1), 3.92–3.46 (m, 5 H, 4 HpCH2NC=O, H5e), 3.27, 3.05
(2 d, 1 H, H3a), 3.21–3.07 (m, 2 H, HpCH2NPh, PhCH2CH), 3.04–
2.85 (m, 2.5 H, 2 HpCH2NPh, 0.5 H3e), 2.85–2.76 (m, 1 H,
PhCH2CH), 2.72–2.51 (m, 1.5 H, HpCH2NPh, 0.5 H3e), 2.51–2.39
(m, 1 H, H4a), 2.27, 1.96 (2 dt, J1 = 3 Hz, J2 = 13 Hz, 1 H, H4e),
2.10, 1.92 (2 t, J = 11 Hz, 1 H, H2).
13C NMR (125 MHz, CD3OD): d = 170.94, 170.80, 168.00, 167.94,
167.37, 167.28, 158.38, 158.34, 152.36, 136.21, 136.10, 132.49,
130.42, 130.40, 130.10, 130.04, 130.02, 129.77, 126.22, 126.20;
121.54, 117.80, 116.45, 116.41, 71.03, 70.64, 57.32, 57.29, 56.76,
56.54, 55.18, 54.57, 50.65, 50.42, 50.14, 46.64, 46.59, 43.35, 43.27,
42.11, 41.92, 40.97.
(3R,9aS)-3-Methyl-8-[2-oxo-1-phenyl-2-(4-phenylpiperazin-1-
yl)ethyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-
dione (54)
IR: 3460, 3243, 3061, 2923, 2855, 2821, 1684, 1650, 1599, 1495,
1450, 1322, 1273, 1228, 1153, 1020, 758, 697 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C32H35N5O4: 554.2767; found:
554.2785.
1H NMR (500 MHz, CD3OD): d = 7.52–7.44 (m, 2 H, HAr), 7.44–
7.30 (m, 3 H, HAr), 7.19 (t, J = 8 Hz, 2 H, HAr), 6.88 (d, J = 8 Hz, 2
H, HAr), 6.82 (t, J = 7 Hz, 1 H, HAr), 4.68, 4.67 (2 s, 1 H, H6), 4.40,
4.36 (2 d, J = 13 Hz, 1 H, H5a), 4.22, 4.16 (2 d, J = 13 Hz, 1 H, H5e),
4.01 (quintet, J = 7 Hz, 1 H, H1), 3.87–3.78 (m, 1 H, HpCH2NC=O),
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