Synthesis of 5 H -Pyrrolo[3,4- b ]pyrazine-Based Peptidomimetics

Article abstract of DOI:10.1055/s-0035-1560184

A range of 5H-pyrrolo[3,4-b]pyrazine-based peptidomimetics were designed, and their efficient synthesis starting from 5-imino-5H-pyrrolo[3,4-b]pyrazin-7-amine by subsequent interaction with N-protected amino acid hydrazides and amino acid esters with N,N-carbonyldiimidazole as the coupling agent was elaborated.

Full text of DOI:10.1055/s-0035-1560184

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3733–3740
paper
3733
A. V. Biitseva et al.
Paper
Synthesis
Synthesis of 5H-Pyrrolo[3,4-b]pyrazine-Based Peptidomimetics
Angelina V. Biitsevaa
Igor V. Rudenkoa
urea
linkage
R3
O
OMe
Olga V. Hordiyenko*a
Iryna V. Omelchenkob
Axelle Arraultc
MeO
N
H
N
NH
N
OMe
N
N
N
N
N
CN
CN
N
N
N
N
O
2 steps
NH
O
X
N
a Department of Chemistry, Taras Shevchenko National
University of Kyiv, 64/13 Volodymyrs’ka str., Kyiv 01601,
Ukraine
R2
N
NH2
NH2
N
H
hydrazide
linkage
R1
ov_hordiyenko@univ.kiev.ua
6 examples
b SSI ‘Institute for Single Crystals’, National Academy of
Science of Ukraine, 60 Lenina ave., Kharkiv 61072,
Ukraine
c Laboratoire de Chimie Physique Macromoléculaire,
ENSIC, Université de Lorraine, 1 rue Grandville, BP 20451,
54001 Nancy, France
Dedicated to Professor Mykhailo Yu. Kornilov on the occasion of his retirement
Received: 28.05.2015
Accepted after revision: 30.07.2015
Published online: 16.09.2015
known to be higher in peptidomimetics that contain het-
erocyclic cores as non-peptidic fragments. Peptidomimetics
of this type have been studied extensively.8 Recently,9 we
described a convenient preparation of a new range of pepti-
domimetics 1, bearing a 1H-isoindole fragment as an amino
acid unit surrogate in a peptide chain (Figure 1).
DOI: 10.1055/s-0035-1560184; Art ID: ss-2015-z0339-op
Abstract A range of 5H-pyrrolo[3,4-b]pyrazine-based peptidomimet-
ics were designed, and their efficient synthesis starting from 5-imino-
5H-pyrrolo[3,4-b]pyrazin-7-amine by subsequent interaction with N-
protected amino acid hydrazides and amino acid esters with N,N-car-
bonyldiimidazole as the coupling agent was elaborated.
R3
O
H
N
CO2Me
N
H
N
Key words amino acids, peptidomimetics, nitrogen heterocycles,
coupling, hydrazones, ureas
O
R4
R2
NH
O
H
N
Peptidomimetics are small organic molecules that are
chemically designed to mimic natural peptides. They inter-
act with various receptors in a manner similar to those of
the natural peptides, and often exhibit the same biological
activities.1 The design of novel peptidomimetics and struc-
tural modifications of natural peptides has generated sub-
stantial interest in the scientific community, particularly in
the area of synthesis and development of new drug-like
molecules.2 Various synthetic approaches have been devel-
oped to generate molecules with the desired ADME proper-
ties that mimic natural peptides.3 The design principles in-
volve side-chain modifications, isosteric replacement of
peptide bonds, transition-state mimics, and constrained
mimics for amino acids or peptides, peptoids, cyclic pep-
tides, and privileged substructures.4 Another strategy is the
creation of hybrid peptides by combining small organic
fragments such as aromatic rings or heterocycles with a
peptide motif. These fragments could be introduced at the
C-terminus5 or the N-terminus6 as well as into the peptide
chains.7 The insertion of a non-peptidic fragment that can
conformationally constrain the peptide backbone could sta-
bilize a biologically active conformation, thus increasing
the selectivity of biological action and decreasing toxicity.
Moreover, metabolic stability and biological activity are
N
NHBoc
N
H
R1
O
1
R3
O
OMe
N
H
N
N
N
O
NH
O
X
N
R2
N
N
H
R1
2
Figure 1 General structure of peptidomimetics 1 and 2
In a continuation of our research on the synthesis of
heterocycle–peptide hybrid molecules, we developed in
this work the synthesis of peptidomimetics 2, which con-
tain the 5H-pyrrolo[3,4-b]pyrazine moiety incorporated
into a peptide backbone (Figure 1). Previously, a range of bi-
ological activities have been observed for 5H-pyrrolo[3,4-
b]pyrazine-based compounds.10a–c Nitrogen atoms of the
pyrazine heterocycle have the potential to be involved in in-
termolecular hydrogen-bond networks leading to addition-
al structural motifs.10d
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3734
A. V. Biitseva et al.
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Synthesis
The initial part of our work focused on synthetic ap-
proaches that allowed the amino acid residues to be com-
bined with the 5H-pyrrolo[3,4-b]pyrazine heterocycle in
one molecule. The protocol that was developed previously
to prepare compounds 1 could be applied to introduce the
amino acid residues into the molecule by reaction of N-pro-
tected amino acid hydrazides with pyrazine-2,3-dicarboni-
trile (3) or 5-imino-5H-pyrrolo[3,4-b]pyrazin-7-amine (4).
Compound 4 was reported to act as an oxidizing-agent-
free dye precursor in dyeing human keratin fibers.11 It was
obtained in 96.5% yield by reaction of gaseous anhydrous
ammonia with a methanolic solution of dinitrile 3 (1 h, r.t.);
reflux of the reaction mixture (3 h) in the presence of a cat-
alytic amount of MeONa accomplished the synthesis.12 We
found that amine 4 could be obtained more easily in 95%
yield by stirring a mixture of dinitrile 3 and a catalytic
amount of MeONa in 7N ammonia solution in methanol for
one hour at room temperature (Scheme 1). We observed
that 5,5-dimethoxy-5H-pyrrolo[3,4-b]pyrazin-7-amine (5)
was formed as an intermediate in this reaction, which was
characterized for the first time.
By following a previously published procedure,9 a set of
dipeptides 6a–e was synthesized by reacting pyrrolopyra-
zine 4 with the corresponding N-protected hydrazides. A
selection of amino acids either with or without a function-
alized side chain (glycine, L-alanine, L-methionine, L-ser-
ine(OBn), and Cbz-L-proline) was used (Table 1).
Table 1 Synthesis of 6
O
NXR2
H2N
NH2
N
NH2
N
N
H
N
N
R1
O
MeOH
75–92%
X
N
N
N
R2
N
NH
N
H
4
6a–e
R1
Entry
6
R1
R2
X
Yield (%) Z/E in CDCl3
1
2
3
4
5
6a
H
H
Boc
Boc
Boc
Boc
Cbz
92
85
75
89
90
1:0.75
1:0.55
1:0.40
1:0.30
1:0.60
6b
6c
6d
6e
Me
H
H
H
–
(CH2)2SMe
CH2OBn
(CH2)3
MeO
NH
NH3
OMe
N
CN
CN
N
N
N
(7 N soln in MeOH)
Na
N
N
MeOH
90%
98%
N
N
Vigorous stirring of equimolar methanolic mixtures of
starting compounds for three hours at 50 °C or overnight at
room temperature led to the formation of the desired prod-
ucts 6a–e in high yields. Notably, side-chain steric hin-
drance had no influence on the yields of the couplings.
It should be mentioned that both nitrile 314 and dimeth-
oxypyrrolopyrazine 5 could be used as starting materials
for the preparation of peptidomimetics 6a–e. However,
these routes afforded lower yields than those starting from
4.
The NMR spectra of all peptidomimetics 6 revealed two
sets of signals for most of the atoms. This indicated that
compounds exist as mixtures of Z and E amide isomers (Ta-
ble 1) because of restricted rotation about the C(O)–N bond
at the hydrazide residue, similar to those found in pyrazine-
based carboxylic acid derivatives14 and isoindole carbohy-
drazides.9,15
NH2
NH2
3
5
4
MeONa, NH3 (7 N soln in MeOH)
95%
Scheme 1 Synthesis of 4
Compound 5 has rarely been used as a precursor for the
synthesis of bispyrrolopyrazine dyes, despite its great po-
tential.13 According to our X-ray diffraction study, dimeth-
oxy derivative 5 exists in the crystal in the tautomeric ami-
no form (Figure 2).
Previous work in our research group9 resulted in the de-
velopment of a general procedure for introducing the sec-
ond amino acid residue into benzo analogues of 6 by apply-
ing the methodology of the present amino group transfor-
mation using highly reactive amino acid ester isocyanates.
Isoindole analogues of tripeptides 2 were synthesized in
high yields through coupling of the corresponding hydra-
zide derivatives with amino acid methyl ester isocyanates
generated in situ from amino acid esters and triphosgene.
However, an attempt to apply the developed reaction
protocol to the pyrazine series was unsuccessful; in this
case, the conversion of 6 into the products 2 did not exceed
10%. This could be attributed to the significantly lower sol-
Figure 2 Molecular structure of 5 according to the X-ray diffraction
data
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A. V. Biitseva et al.
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Synthesis
Table 2 Synthesis of Peptidomimetics 2
R3
O
OMe
NH2
N
H
N
R3
N
N
O
+
CDI, DBU, DMF
69–85%
OMe
N
O
NH
H3N
+
O
X
N
N
X
N
N
Cl–
O
R2
N
N
R2
N
N
H
H
R1
6
2a–f
R1
Entry
2
R1
R2
R3
X
Yield (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
H
Me
Boc
Boc
Boc
Boc
Cbz
Cbz
85
69
80
71
78
82
H
H
H
H
(CH2)2SMe
CH2OBn
CH2OBn
(CH2)3
Me
(CH2)2SMe
Me
(CH2)3
CH2OBn
ubility of 6 compared with their benzo analogues. Solubili-
ty tests revealed that N,N-dimethylformamide (DMF) was
the best solvent for dipeptides 6. However, the formation of
Vilsmeier type intermediates in the reaction of triphosgene
with DMF16 prevented the use of this solvent for the syn-
thesis of the target compounds 2.
whereas the low chemical shift value of BocNH is charac-
teristic of a non-hydrogen-bonded amide proton.19 Four
other broad singlets correspond to hydrazide NH and endo-
cyclic NH of two amide conformers.
To obtain preliminary information on the H-bonds in 2,
a hydrogen–deuterium exchange experiment was carried
out for peptide 2a in CDCl3 (in this solvent we observed best
resolution of NH signals). A small aliquot of D2O was added
to a sample of 2a to give an approximately 5% v/v mixture
with CDCl3. Monitoring the rate of H/D exchange of NH pro-
The results described above prompted us to elaborate an
alternative protocol for the preparation of urea-tethered
peptidomimetics 2 by employing N,N-carbonyldiimidazole
(CDI), which is a widely used coupling reagent for urea di-
peptide synthesis.17 Similar to the published one-pot proto-
col,18 compounds 6 were coupled with a set of amino acid
methyl esters with CDI in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in DMF at 0 °C with stirring
overnight from 0 °C to room temperature (Table 2). Peptid-
omimetics 2a–f were isolated in good yields (69–85%) after
purification by flash column chromatography on silica.
As in the case of 6, the NMR spectra of all peptidomi-
metics 2 presented two sets of signals for most of the at-
oms, corresponding to Z and E amide isomers. The assign-
ment of signals by means of 1D and 2D NMR spectroscopy
was challenging because of the overlap of the signals of iso-
meric forms and because of the structural features of pep-
tides 2. Molecules 2 contain three isolated spin systems
(protons of pyrazine cycle, hydrazide, and urea residues),
which does not allow the correlations needed for assign-
ment of signals in the NMR spectra to be observed.
1
tons in the H NMR spectrum after D2O addition revealed
that Ala NH resonances exchanged relatively slowly com-
pared with the other NH resonances. It could be suggested
that they correspond to the NH groups that participate in
intramolecular H-bonds to the C=O group of the hydrazide
fragment.
To evaluate the possibility of peptide aggregation in
CDCl3, the concentration dependence of the NH chemical
shifts for 2a was determined. Studies were conducted over
the concentration range of 2 to 50 mM. Three NH groups of
the major isomeric form (including Ala NH and BocNH)
were insensitive to concentration change. One could con-
clude that these protons may either be involved in intramo-
lecular interactions or remain as solvent-exposed NH
groups. The fourth NH proton signal moved downfield with
increasing concentration, indicating that this group partici-
pates in the formation of intermolecular hydrogen bonds.20
This fact promoted us to assign this singlet to hydrazide NH.
We also carried out temperature dependence studies of
The 1H NMR spectrum of 2a in CDCl3 revealed eight NH
proton signals of two amide conformers with a ratio of
1:0.2. The resonances at δ = 9.98 and 10.54 ppm were as-
signed to the Ala NH group, because this proton exhibited a
splitting of the NMR signal into a doublet. The resonance of
the BocNH group was observed as two broad singlets at δ =
5.34 and 5.64 ppm. The substantial downfield shift of Ala
NH resonance indicates a high degree of hydrogen bonding,
1
the H NMR chemical shifts of NH protons, which also re-
flects their state of hydrogen bonding. The temperature de-
pendence of the NH Ala proton chemical shift for peptide
2a falls within the range of values typical for intramolecu-
larly hydrogen-bonded protons Δδ(NH)/ΔT = –4.2 ppb/K. At
the same time, hydrazide NH proton shows a relatively
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A. V. Biitseva et al.
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Synthesis
NHBoc
O
N
O
NH
NH
N
X
X
O
X
X
H2NHN
MeOH
O
+
N
N
N
NH2
NH2
NHBoc
X = CH, N (4)
7 X = CH, 95%
8 X = N, 92%
Scheme 2
large temperature dependence Δδ(NH)/ΔT = –19.8 ppb/K,
suggesting that it is in equilibrium between intermolecular
hydrogen-bonded and non-hydrogen-bonded states.21
As shown earlier,9 dipeptide hydrazides could also be
used effectively as starting materials in the reaction with 1-
imino-1H-isoindol-3-amine, which is a benzo analogue of
4. Given the success of this reaction protocol for the synthe-
sis of linear tripeptides, we became interested in its appli-
cation to the formation of analogues of the D-Phe-Pro-Arg
thrombin inhibitor due to the presence of the NCN amidine
triad in 6 and their benzo analogues. Structure optimiza-
tion of the D-Phe-Pro-Arg tripeptide led to the discovery of
a new generation of noncovalent thrombin inhibitors in
which arginine residue was effectively replaced by amidine
containing groups.22 A number of inhibitors have been re-
ported that utilize nitrogen-containing heterocycles pos-
sessing a cyclic amidine, in particular, 2-aminopyridine22a
and 2-aminoquinazoline23 derivatives, as arginine surro-
gates in the inhibitor templates. Thereby, compounds 7 and
8, containing substituted 1H-isoindole and 5H-pyrrolo[3,4-
b]pyrazine moieties, were easily prepared from the hydra-
zide of Boc-D-Phe-Pro and corresponding amines in high
yields (Scheme 2).
formationally constrained template that may find useful
application in the development of novel peptidomimetics
with promising structures and properties.
Melting points were determined with a Boetius microscope hot-plate
apparatus. Elemental analyses (C, H, N) were conducted with a Vario
Micro Cube. Mass spectra were recorded with an Agilent 1100 LCMSD
SL instrument by chemical ionization (CI). NMR spectra were mea-
sured with a Bruker Avance 500 spectrometer (at 500 MHz, 1H and
125 MHz, for 13С) and a Mercury (Varian) 400 spectrometer (400
1
MHz, H and 100 MHz, for 13С) with tetramethylsilane as a standard.
For compounds 2 and 6–8, signals of both Z and E amide conformers
are given. Preparative column chromatography was carried out with
silica gel 60 (40–63 μm). Boc-protected amino acid hydrazides and
Boc-D-Phe-Pro hydrazide were obtained from the corresponding
methyl esters and excess hydrazine monohydrate in MeOH by stirring
the reaction mixture overnight at r.t., and then evaporation to dryness
(yields 95–99%), similar to a reported procedure.25
X-ray Diffraction Study of 5
The anti-arrangement of methoxy substituents at the C(6) atom
[C(2)–C(6)–O–C torsion angles are 168.6(1)° for O(1)–C(7) and
61.3(2)° for O(2)–C(8) groups] is stabilized by weak attractive intra-
molecular contacts C–H···N [C(7)–H(7A)···N(3) of 2.58 Å and C(8)–
H(8C)···N(2) of 2.56 Å compared with the van der Waals radii sum26 of
2.67 Å]. The C(1)–C(5) bond length of 1.485(2) Å does not reveal extra
conjugation of the C(5)–N(3) bond with aromatic pyrazine ring, de-
spite their coplanar arrangement. The C(5)–N(4) bond of 1.324(3) Å is
slightly shorter than the mean value27 1.336 Å, but the C(5)=N(3)
double bond of 1.300(2) Å is also shortened slightly (1.313 Å), which
indicates a lack of conjugation between the double bond and the ami-
no group. Thus, the planar configuration of the N(4) atom (sum of va-
lence angles centered on N(4) is 359°) should not be referred to as in-
tramolecular π-interactions but rather to the formation of intermo-
lecular hydrogen bonds N(4)–H(4A)···N(3)′ (H···N′ 2.11 Å, N–H···N′
163°) and N(4)–H(4B)···N(1)′ (H···N′ 2.17 Å, N–H···N′ 173°). These hy-
drogen bonds organize molecules in the crystal into chains along the
(010) crystallographic direction.
Starting dipeptide Boc-D-Phe-Pro-OMe was prepared by
following a standard protocol24 in high yield (90%) and then
further transformed into the corresponding hydrazide in
excellent yield (98%).
In summary, we have reported the design and synthetic
strategies that can be used to generate new peptidomimet-
ics containing the pyrrolo[3,4-b]pyrazine template. CDI was
found to be the reagent of choice for the coupling reaction
of dipeptide analogues with amino acid esters. The ob-
tained tripeptide analogues possess two strands derived
from an amino acid hydrazide and a urea scaffold linked
through a pyrrolopyrazine unit, which are designed to al-
low further incorporation into longer strands through their
protected NH2 and COOH groups. The rigid scaffold of the
pyrrolo[3,4-b]pyrazine described here can serve as a con-
Crystals of 5 (C8H10N4O2, Mr = 194.20) are monoclinic; P21/c; a =
8.4609(6), b = 8.4049(5), c = 13.0466(8) Å, β = 98.931(6)°; V =
916.54(9) Å3; Z = 4; dcalc = 1.407 g·sm–1; μ = 0.105 mm–1; F(000) = 408.
4308 reflections (2331 independent, Rint = 0.024) were collected with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3733–3740

3737
A. V. Biitseva et al.
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Synthesis
an Xcalibur-3 diffractometer (Mo-Kα radiation, ССD-detector, graph-
ite monochromator, ω-scanning, 2θmax= 55°). The structure was
solved by direct methods and refined against F2 within anisotropic
approximation for all non-hydrogen atoms by full-matrix least
squares procedure using the OLEX2 program package28 with SHELXS
and SHELXL modules.29 All hydrogen atoms were located from the
differential density map and refined using isotropic approximation,
except for H atoms of the methyl groups, which were placed in ideal-
ized positions (C–H = 0.96 Å) and constrained to ride on their parent
Synthesis of 6a–e; General Procedure
A suspension of pyrrolopyrazine 4 (0.294 g, 2 mmol) and the corre-
sponding N-protected amino acid hydrazide (2.1 mmol) in methanol
(25 mL) was stirred for 3 h at 50 °C or overnight at r.t. After cooling,
the precipitate was filtered off, washed with cold MeOH (10 mL) and
dried in vacuo.
(Z)-tert-Butyl 2-[2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)hydrazinyl]-2-oxoethylcarbamate (6a)
atoms with Uiso = 1.5Uequiv. Final refinement was converged at wR2
=
Yield: 0.59 g (92%); yellow solid; mp 205 °C (dec).
0.119 for all 2094 reflections (R1 = 0.045 for 1452 reflections with
F>4σ (F), S = 1.03).
1H NMR (400 MHz, DMSO-d6): δ = 1.41 (br s, 9 H, Boc), 3.73 and 4.12
(2 × br s, 2 H, CH2), 6.82 and 7.24 (2 × br s, 1 H, NHBoc), 8.66 and 8.71
(2 × br s, 2 H, 2 × HPyraz).
13C NMR (100 MHz, DMSO-d6): δ = 28.0 [C(CH3)3], 41.5 and 43.1 (CH2),
78.0 [C(CH3)3], 143.6, 144.0, 145.2, 147.9, 151.0, 152.0, 155.7, 163.9,
165.9.
Atom coordinates and crystallographic parameters have been depos-
ited to the Cambridge Crystallographic Data Centre (CCDC 1061021).
These data can be obtained free of charge from the Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
5-Imino-5H-pyrrolo[3,4-b]pyrazin-7-amine (4)
Anal. Calcd for C13H17N7O3: C, 48.90; H, 5.37; N, 30.70. Found: C,
48.81; H, 5.32; N, 30.79.
LC/MS (CI): m/z = 320.3 [M + H]+.
Sodium methylate (0.108 g, 2 mmol) was added to a solution of am-
monia (7 N in MeOH, 30 mL). The resulting mixture was cooled on an
ice-water bath and dinitrile 3 (2.60 g, 20 mmol) was added in one
portion with vigorous stirring. The solution became yellow and then
orange-brown. In 5 min the dimethoxy derivative 5 precipitated as a
white solid. After stirring for 1 h, compound 5 dissolved and precipi-
tation of product 4 was observed in a few minutes. The precipitate
formed was filtered off, washed with MeOH (10 mL) and dried in vac-
uo to give the desired product.
(S,Z)-tert-Butyl 1-[2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)hydrazinyl]-1-oxopropan-2-ylcarbamate (6b)
Yield: 0.57 g (85%); yellow solid; mp 186–187 °C.
1H NMR (500 MHz, DMSO-d6): δ = 1.25–1.39 (m, 12 H, Boc + CH3),
4.15–4.23 and 4.90–4.95 (2 × m, 1 H, CH), 7.07 and 7.33 (2 × br s, 1 H,
NHBoc), 8.58–8.81 (m, 4 H, 2 × HPyraz + NH2), 9.82 and 10.63 (2 × br s,
1 H, NHHydraz).
13C NMR (125 MHz, DMSO-d6): δ = 17.2 and 17.9 (Me), 28.5 and 28.6
[C(CH3)3], 47.0 and 49.8 (CH), 78.3 and 78.8 [C(CH3)3], 144.4 (CH),
146.2 (CH), 148.1, 151.8, 155.7, 163.9, 164.0, 169.6, 174.1.
Yield: 2.79 g (95%); beige solid; mp 240 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 8.77 (s, 2 H, 2 × HPyraz), 8.90 (br s,
3 H, 3 × NH).
13C NMR (100 MHz, CF3CO2D): δ = 150.9 (2 × C), 153.3 (2 × CH), 174.7
(2 × C).
Anal. Calcd for C14H19N7O3: C, 50.44; H, 5.75; N, 29.41. Found: C,
50.59; H, 5.84; N, 29.57.
LC/MS (CI): m/z = 334.4 [M + H]+.
Anal. Calcd for C6H5N5: C, 48.98; H, 3.43; N, 47.60. Found: C, 49.07; H,
3.55; N, 47.78.
LC/MS (CI): m/z = 148 [M + H]+.
(S,Z)-tert-Butyl 1-[2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)hydrazinyl]-4-(methylthio)-1-oxobutan-2-ylcarbamate
(6c)
5,5-Dimethoxy-5H-pyrrolo[3,4-b]pyrazin-7-amine (5)
Sodium methylate (108 mg, 2 mmol) was dissolved in MeOH (30 mL),
and dinitrile 3 (2.60 g, 20 mmol) was added in one portion with vig-
orous stirring. Compound 3 dissolved within a few seconds and the
solution became yellow and then orange-brown. After 15 min stirring
at r.t., the title compound 5 precipitated. The precipitate formed was
filtered off, washed with cold MeOH (10 mL) and dried in vacuo to
give the desired product 5 (2.90 g, 75%) as a white solid. An additional
portion of pure product 5 (0.58 g, 15%; mp 157–159 °C) was obtained
by concentration at r.t. of the methanolic solution under reduced
pressure.
Yield: 0.59 g (75%); yellow solid; mp 130–131 °C.
1H NMR (500 MHz, DMSO-d6): δ = 1.37 and 1.39 (2 × br s, 9 H, Boc),
1.82–2.06 (m, 5 H, SMe + CH2), 2.53–2.59 (m, 2 H, CH2), 4.21–4.25 and
5.02–5.06 (2 × br m, 1 H, CH), 7.11 and 7.42 (2 × br d, 1 H, NHBoc),
8.59–8.78 (m, 4 H, 2 × HPyraz + NH2), 9.84 and 10.66 (2 × br s, 1 H,
NHHydraz).
13C NMR (125 MHz, DMSO-d6): δ = 14.9 and 15.0 (SMe), 28.5
[C(CH3)3], 30.2 (CH2), 31.4 (CH2), 52.8 and 54.4 (CH), 78.9 [C(CH3)3],
144.4, 146.2, 148.1, 149.5, 150.6, 151.8, 152.1, 155.0, 155.4, 156.0,
164.0, 168.6, 173.3.
1H NMR (400 MHz, DMSO-d6): δ = 3.38 (s, 6 H, 2 × OCH3), 7.46 (br s,
2 H, NH2), 8.61 (d, J = 2.8 Hz, 1 H, HPyraz), 8.66 (d, J = 2.8 Hz, 1 H, HPyraz).
13C NMR (100 MHz, DMSO-d6): δ = 50.7 (2 × OMe), 112.7 [C(OMe)2],
Anal. Calcd for C16H23N7O3S: C, C, 48.84; H, 5.89; N, 24.92. Found: C,
48.95; H, 5.98; N, 25.03.
LC/MS (CI): m/z = 394 [M + H]+.
143.8 (CH), 144.8 (CH), 146.3 (C), 159.8 (C), 161.6 (C).
Anal. Calcd for C8H10N4O2: C, 49.48; H, 5.19; N, 28.85. Found: C, 49.54;
H, 5.07; N, 28.69.
LC/MS (CI): m/z = 195 [M + H]+.
(S,Z)-tert-Butyl 1-[2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)hydrazinyl]-3-(benzyloxy)-1-oxopropan-2-ylcarbamate
(6d)
Yield: 0.78 g (89%); pale-yellow solid; mp 185 °C.
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1H NMR (500 MHz, DMSO-d6): δ = 1.39 and 1.40 (2 × s, 9 H, Boc),
3.65–3.73 (m, 2 H, CH2OCH2Ph), 4.42–4.46 and 5.29–5.33 (2 × m, 1 H,
CH), 4.50–4.55 (m, 2 H, OCH2Ph), 6.99–7.33 (m, 6 H, Ph + NHBoc),
8.71–8.79 (m, 4 H, 2 × HPyraz + NH2), 10.70 (br s, 1 H, NHHydraz).
(S)-Methyl 2-[(Z)-3-((Z)-7-{2-[2-(tert-Butoxycarbonylamino)ace-
tyl]hydrazono}-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)ureido]-4-(methylthio)butanoate (2b)
Yield: 0.32 g (69%); yellow solid; mp 126–127 °C.
13C NMR (125 MHz, DMSO-d6): δ = 28.2 [C(CH3)3], 54.1, 57.2, 69.1,
69.4, 71.9, 72.2, 78.8 [C(CH3)3], 127.3, 127.4, 127.5, 127.6, 128.1,
128.3, 138.2, 144.2, 145.9, 146.0, 151.2, 151.6, 152.0, 155.5, 155.6,
163.7, 166.6.
1H NMR (500 MHz, CDCl3): δ = 1.43 and 1.45 (2 × s, 9 H, Boc), 2.09–
2.38 (m, 5 H, CH2(Met) + SMe), 2.53–2.65 (m, 2 H, CH2(Met)), 3.87 and
3.93 (2 × s, 3 H, OCH3), 4.14–4.80 (m, 3 H, CH + CH2(Gly)), 5.31 and 5.58
(2 × br s, 1 H, NHBoc), 8.66 and 8.78 (2 × br s, 2 H, 2 × HPyraz), 9.16,
9.36, 9.92, 10.16, 10.52 and 10.69 (6 × br s, 3 H, 3 × NH).
13C NMR (125 MHz, CDCl3): δ = 15.5 (SMe), 28.2 [C(CH3)3], 29.7 (CH2),
31.5 (CH2), 42.5 (CH2), 53.0 (CH), 53.2 (OMe), 79.6 [C(CH3)3], 144.3
(CH), 144.7, 146.3, 146.7 (CH), 150.3, 151.8, 155.8, 158.7, 171.2, 172.0.
Anal. Calcd for C21H25N7O4: C, 57.39; H, 5.73; N, 22.31. Found: C,
57.24; H, 5.85; N, 22.27.
LC/MS (CI): m/z = 440 [M + H]+.
(S,Z)-Benzyl 2-[2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)hydrazinecarbonyl]pyrrolidine-1-carboxylate (6e)
Anal. Calcd for C20H28N8O6S: C, 47.23; H, 5.55; N, 22.03. Found: C,
47.38; H, 5.64; N, 22.14.
LC/MS (CI): m/z = 509 [M + H]+.
Yield: 0.71 g (90%); pale-yellow solid; mp 133–134 °C.
1H NMR (500 MHz, DMSO-d6): δ = 1.87–1.95 (m, 3 H, 3 × HPro), 2.15–
2.39 (m, 1 H, HPro), 3.47–3.52 (m, 2 H, 2 × HPro), 4.56–5.25 (m, 3 H,
(S)-Methyl 2-[(Z)-3-((Z)-7-{2-[(S)-3-(Benzyloxy)-2-(tert-butoxycar-
bonylamino)propanoyl]hydrazono}-6,7-dihydro-5H-pyrrolo[3,4-
b]pyrazin-5-ylidene)ureido]propanoate (2c)
H
Pro + CH2Ph), 7.15–7.36 (m, 5 H, Ph), 8.53–8.78 (m, 4 H, 2 × HPyraz
+
NH2), 9.90 and 10.83 (2 × br s, 1 H, NHHydraz).
13C NMR (125 MHz, DMSO-d6): δ = 23.1, 23.4, 23.9, 24.3, 29.5, 29.9,
30.5, 31.4, 46.6, 46.7, 47.2, 47.4, 56.6, 57.3, 58.8, 59.2, 65.8, 65.9, 66.2,
126.9, 127.1, 127.4, 127.5, 127.6, 127.8, 127.9, 128.2, 128.5, 136.9,
137.0, 137.1, 144.2, 145.8, 146.0, 147.8, 147.9, 151.1, 151.6, 153.9,
163.6, 163.8, 168.6, 168.9, 172.5.
Yield: 0.41 mg (80%); pale-yellow solid; mp 115–116 °C.
1H NMR (500 MHz, CDCl3): δ = 1.42 and 1.46 (2 × s, 9 H, Boc), 1.57–
1.62 (m, 3 H, CH3), 3.70–4.06 (m, 5 H, OCH3 + CHSer + CHAla), 4.54–4.82
(m, 4 H, CH2(Ser) + CH2(Bn)), 5.51 and 5.71 (2 × br s, 1 H, NHBoc), 7.14–
7.28 (m, 5 H, Ph), 8.63, 8.76, 8.79 and 8.88 (4 × s, 3 H, 2 × HPyraz + NH),
9.92, 10.06, 10.21 and 10.71 (4 × br s, 2 H, 2 × NH).
13C NMR (125 MHz, CDCl3): δ = 18.3 and 18.6 (Me), 28.2 [C(CH3)3],
49.9 and 50.0 (CH), 52.1, 53.0, 53.3, 54.0, 69.9 and 70.2 (CH2), 73.0
and 73.3 (CH2), 79.7 [C(CH3)3], 127.4 (CH), 127.5 (CH), 128.0 and
128.2 (CH), 137.4 and 137.7, 144.2 (CH), 144.4, 146.2 and 146.3, 146.8
and 146.9 (CH), 147.7, 150.3, 150.7, 151.2, 151.3, 155.3, 158.5, 158.7,
167.4, 171.6, 172.8.
Anal. Calcd for C19H19N7O3: C, 58.01; H, 4.87; N, 24.92. Found: C,
57.92; H, 4.77; N, 24.88.
LC/MS (CI): m/z = 394 [M + H]+.
Synthesis of 2a–f; General Procedure
To an ice-cold solution of amino acid methyl ester hydrochloride (1
mmol) in DMF (5 mL) were added DBU (1 mmol, 0.152 g, 0.15 mL) and
CDI (1.1 mmol, 0.178 g). The mixture was stirred for 30 min at 0 °C
and hydrazide derivative 6a–e (0.9 mmol) was added in one portion
followed by DBU (0.2 mmol, 0.030 g, 0.03 mL). Stirring was continued
overnight from 0 °C to r.t., then the DMF was removed at reduced
pressure and the residue was dissolved in CH2Cl2 (50 mL), washed
with a saturated solution of citric acid (25 mL) and brine (25 mL),
dried with MgSO4, and evaporated to dryness. The title compounds
were isolated by flash chromatography using EtOAc as eluent.
Anal. Calcd for C26H32N8O7: C, 54.92; H, 5.67; N, 19.71. Found: C,
54.80; H, 5.59; N, 19.78.
LC/MS (CI): m/z = 569.6 [M + H]+.
(S)-Methyl 2-[(Z)-3-((Z)-7-{2-[(S)-3-(Benzyloxy)-2-(tert-butoxycar-
bonylamino)propanoyl]hydrazono}-6,7-dihydro-5H-pyrrolo[3,4-
b]pyrazin-5-ylidene)ureido]-4-(methylthio)butanoate (2d)
Yield: 0.40 g (71%); pale-yellow solid; mp 100–102 °C.
1H NMR (500 MHz, CDCl3): δ = 1.42 and 1.45 (2 × s, 9 H, Boc), 2.07–
(S)-Methyl 2-[(Z)-3-((Z)-7-{2-[2-(tert-Butoxycarbonylamino)ace-
tyl]hydrazono}-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-
ylidene)ureido]propanoate (2a)
2.66 (m, 7 H, 2 × CH2(Met) + SCH3), 3.67–4.07 (m, 5 H, OCH3 + CHSer
CHMet), 4.54–4.80 (m, 4 H, CH2(Ser) + CH2(Bn)), 5.51 and 5.70 (2 × br s,
+
1 H, NHBoc), 7.12–7.28 (m, 5 H, Ph), 8.65–8.98 (m, 3 H, 2 × HPyraz
+
Yield: 0.34 g (85%); yellow solid; mp 136–138 °C.
NH), 9.90, 10.08, 10.19 and 10.69 (4 × br s, 2 H, 2 × NH).
1H NMR (500 MHz, CDCl3): δ = 1.42 and 1.45 (2 × s, 9 H, Boc), 1.58–
1.63 (m, 3 H, Me), 3.87 and 3.93 (2 × s, 3 H, OCH3), 4.16–4.65 (m, 3 H,
CH + CH2), 5.34 and 5.64 (2 × br s, 1 H, NHBoc), 8.64 and 8.76 (2 × s,
2 H, 2 × HPyraz), 9.21, 9.39, 9.98, 10.14, 10.54 and 10.68 (6 × br s, 3 H, 3
× NH).
13C NMR (125 MHz, CDCl3): δ = 18.5 (Me), 28.2 [C(CH3)3], 42.4 (CH2),
50.0 (CH), 53.0 (OMe), 79.6 [C(CH3)3], 144.2 (CH), 144.8, 146.3, 146.8
(CH), 150.3, 151.4, 155.8, 158.7, 171.2, 173.1.
13C NMR (125 MHz, CDCl3): δ = 15.3 and 15.5 (SMe), 28.2 [C(CH3)3],
29.4 and 29.8 (CH2), 31.3 and 31.6 (CH2), 52.1, 53.1, 53.3, 69.9 and
70.2 (CH2), 73.0 and 73.3 (CH2), 79.7 [C(CH3)3], 127.4 (CH), 127.6 (CH),
128.0 (CH), 128.2 (CH), 137.4 and 137.7, 144.2, 144.3, 144.4, 146.1,
146.2, 146.8, 147.0, 147.7, 150.3, 150.7, 151.5, 151.7, 155.3, 158.5,
158.8, 167.4, 171.6, 171.7, 172.7.
Anal. Calcd for C28H36N8O7S: C, 53.49; H, 5.77; N, 17.82. Found: C,
53.55; H, 5.81; N, 17.89
Anal. Calcd for C18H24N8O6: C, 48.21; H, 5.39; N, 24.99. Found: C,
48.13; H, 5.46; N, 25.02.
LC/MS (CI): m/z = 629 [M + H]+.
LC/MS (CI): m/z = 449 [M + H]+.
(S)-Benzyl 2-((Z)-2-{(Z)-7-[(S)-3-Methoxy-3-oxopropan-2-ylcarba-
moylimino]-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-ylidene}hy-
drazinecarbonyl)pyrrolidine-1-carboxylate (2e)
Yield: 0.37 g (78%); pale-yellow solid; mp 132–133 °C.
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3739
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1H NMR (500 MHz, CDCl3): δ = 1.58–1.67 (m, 3 H, CH3), 1.95–2.48
(br m, 4 H, 2 × CH2(Pro)), 3.48–3.87 (m, 5 H, OCH3 + CH2(Pro)), 4.62–5.47
(m, 4 H, CH2(Cbz) + CHAla + CHPro), 7.04–7.38 (m, 5 H, Ph), 8.61, 8.65,
8.75, 8.91, 8.99 and 9.02 (6 × br s, 3 H, 2 × HPyraz + NH), 9.84, 9.98,
10.02, 10.10 and 10.36 (5 × br s, 2 H, 2 × NH).
13C NMR (125 MHz, CDCl3): δ = 17.6 and 18.3 (Me), 23.3 and 24.0 and
24.4 (CH2(Pro)), 29.7 and 30.6 (CH2(Pro)), 46.5 and 47.0 (CH2(Pro)), 49.6
(CH), 52.8 (OMe), 56.2 and 57.0 (CH), 66.5 and 67.0 (CH2(Cbz)), 127.0,
127.2, 127.3, 127.5, 127.7, 128.0, 135.9, 136.3, 136.4, 143.9, 146.0,
146.3, 146.4, 146.6, 150.0, 151.1, 154.0, 154.5, 155.7, 158.1, 172.6,
172.7, 173.3, 173.7.
Anal. Calcd for C27H32N6O4: C, 64.27; H, 6.39; N, 16.66. Found: C,
64.41; H, 6.47; N, 16.69.
LC/MS (CI): m/z = 505 [M + H]+.
tert-Butyl (R)-1-{(S)-2-[(Z)-2-(7-Amino-5H-pyrrolo[3,4-b]pyrazin-
5-ylidene)hydrazinecarbonyl]pyrrolidin-1-yl}-1-oxo-3-phenyl-
propan-2-ylcarbamate (8)
Yield: 0.93 g (92%); pale-yellow solid; mp 172–173 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.19–1.31 (m, 9 H, Boc), 1.68–2.30
(m, 4 H, 2 × CH2(Pro)), 2.69–3.26 (m, 3 H, CH2(Pro) + CH), 3.51–3.63 (m,
2 H, CH2Ph), 3.93–4.56, 5.10–5.22 and 5.56–5.61 (3 × m, 2 H, CH +
NHBoc), 6.74–7.26 (m, 5 H, Ph), 8.57–8.88 (m, 4 H, 2 × HPyraz + NH2),
9.83, 10.35, 10.44, 10.95, 11.49 and 11.63 (6 × br s, 1 H, NHHydraz).
13C NMR (100 MHz, DMSO-d6): δ = 22.8, 23.0, 24.9, 25.1, 28.3, 28.4,
28.6, 28.8, 29.3, 32.1, 33.0, 36.9, 38.0, 38.5, 47.2, 47.4, 47.7, 54.0, 54.2,
54.9, 55.6, 57.2, 59.2, 59.5, 78.7 and 79.3 [C(CH3)3], 126.6, 127.1,
128.3, 128.7, 130.0, 130.1, 138.1, 138.2, 139.0, 139.2, 144.6, 144.9,
146.4, 146.6, 148.3, 148.6, 149.8, 150.8, 151.7, 152.0, 152.2, 152.3,
152.9, 154.9, 155.4, 155.6, 156.1, 164.1, 164.3, 164.5, 164.7, 168.2,
168.5, 169.8, 170.1, 171.2, 172.0, 172.3, 172.9.
Anal. Calcd for C24H26N8O6: C, 55.17; H, 5.02; N, 21.45. Found: C,
55.09; H, 4.97; N, 21.40.
LC/MS (CI): m/z = 523 [M + H]+.
(S)-Benzyl 2-((Z)-2-{(Z)-7-[(S)-1-(Benzyloxy)-3-methoxy-3-oxo-
propan-2-ylcarbamoylimino]-6,7-dihydro-5H-pyrrolo[3,4-b]pyra-
zin-5-ylidene}hydrazinecarbonyl)pyrrolidine-1-carboxylate (2f)
Yield: 0.46 g (82%); pale-yellow solid; mp 103–104 °C.
1H NMR (500 MHz, CDCl3): δ = 1.94–2.06 (br m, 4 H, 2 × CH2(Pro)),
3.61–4.07 (m, 6 H, OCH3 + CHSer + CH2(Pro)), 4.44–5.47 (m, 7 H, CH2(Cbz)
+ CH2(Ser) + CH2(Bn) + CHPro), 7.05–7.36 (m, 10 H, PhCbz + PhBn), 8.63 and
8.75 (2 × br s, 2 H, 2 × HPyraz), 8.96 (br s, 1 H, NH), 9.85–10.01 (br m,
2 H, 2 × NH).
Anal. Calcd for C25H30N8O4: C, 59.28; H, 5.97; N, 22.12. Found: C,
59.18; H, 6.04; N, 22.05.
LC/MS (CI): m/z = 507 [M + H]+.
13C NMR (125 MHz, CDCl3): δ = 23.6 and 24.3 (CH2(Pro)), 29.9 and 30.9
(CH2(Pro)), 46.8 and 47.2 (CH2(Pro)), 52.8 and 52.9 (CH), 54.3 (OMe), 56.5
and 57.3 (CH), 66.9 (CH2), 68.3 and 69.2 (CH2), 73.2 (CH2), 127.3,
127.6, 127.7, 127.8, 128.0, 128.2, 128.9, 136.5, 136.7, 137.3, 137.4,
144.0, 144.1, 144.2, 146.3, 146.6, 146.7, 150.2, 150.3, 152.0, 154.2,
154.7, 158.3, 170.0, 170.1, 173.3, 173.7.
Acknowledgment
The authors thank the French-Ukrainian programs DNIPRO and Egide
for financial support of part of this work. A.V.B. thanks LCPM for a
post-doctoral fellowship.
Anal. Calcd for C31H32N8O7: C, 59.23; H, 5.13; N, 17.82. Found: C,
59.31; H, 5.18; N, 17.77.
LC/MS (CI): m/z = 629 [M + H]+.
Supporting Information
for this article that contains the copies of NMR spectra of all com-
pounds and the details of H/D exchange, concentration and tempera-
Synthesis of 7 and 8; General Procedure
ture
dependence
studies
is
available
online
at
The 1-imino-1H-isoindol-3-amine (0.290 g, 2 mmol) or pyrrolopyra-
zine 4 (0.294 g, 2 mmol) was reacted in MeOH (25–30 mL) with the
hydrazide of Boc-D-Phe-Pro (0.772 g, 2.05 mmol) at r.t. under stirring
overnight. The mixture was then evaporated to dryness. The title
compounds were isolated by flash chromatography (CH2Cl2–MeOH,
90:10).
http://dx.doi.org/10.1055/s-0035-1560184.
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References
(1) Grauer, A.; König, B. Eur. J. Org. Chem. 2009, 5099.
(2) (a) Gokhale, A. S.; Seetharama, S. Immunotherapy 2014, 6, 755.
(b) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008,
12, 292. (c) Avan, I.; Hallb, C. D.; Katritzky, A. R. Chem. Soc. Rev.
2014, 43, 3575. (d) Ung, P.; Winkler, D. A. J. Med. Chem. 2011, 54,
1111.
(3) (a) Derian, C. K.; Maryanoff, B. E.; Andrade-Gordon, P.; Zhang,
H.-C. Drug Dev. Res. 2003, 59, 355. (b) Fairlie, D. P. Aust. J. Chem.
2004, 57, 855.
tert-Butyl (R)-1-{(S)-2-[(Z)-2-(3-Amino-1H-isoindol-1-ylidene)hy-
drazinecarbonyl]pyrrolidin-1-yl}-1-oxo-3-phenylpropan-2-ylcar-
bamate (7)
Yield: 0.96 g (95%); yellow solid; mp 157–158 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.15–1.32 (m, 9 H, Boc), 1.67–2.28
(m, 4 H, 2 × CH2(Pro)), 2.63–3.32 (m, 3 H, CH2(Pro) + CH), 3.51–3.64 (m,
2 H, CH2Ph), 3.99–4.53, 5.02–5.21 and 5.51–5.68 (3 × m, 2 H, CH +
NHBoc), 6.87–7.24 (m, 5 H, Ph), 7.46–7.96 (m, 4 H, 4 × HIsoind) 8.21–
8.62 (m, 2 H, NH2), 9.55, 9.96, 10.64, 11.11 and 11.29 (5 × br s, 1 H,
NHHydraz).
(4) For a general review, see: Guarna, A.; Trabocchi, A. Peptidomi-
metics in Organic and Medicinal Chemistry; John Wiley & Sons:
Chichester, 2014, 312.
(5) (a) Tamura, S. Y.; Shamblin, B. M.; Brunck, T. K.; Ripka, W. C.
Bioorg. Med. Chem. Lett. 1997, 7, 1359. (b) Costanzo, M. J.;
Almond, H. R. Jr.; Hecker, L. R.; Schott, M. R.; Yabut, S. C.; Zhang,
H.-C.; Andrade-Gordon, P.; Corcoran, T. W.; Giardino, E. C.;
Kauffman, J. A.; Lewis, J. M.; de Garavilla, L.; Haertlein, B. J.;
Maryanoff, B. E. J. Med. Chem. 2005, 48, 1984.
13C NMR (100 MHz, DMSO-d6): δ = 22.2, 22.4, 24.2, 24.5, 27.6, 28.1,
28.2, 28.4, 28.7, 31.4, 32.4, 36.3, 37.5, 46.6, 47.1, 53.4, 53.5, 54.3, 54.8,
56.8, 57.4, 58.7, 78.1 and 78.8 [C(CH3)3], 120.2, 120.3, 120.5, 121.3,
121.4, 126.0, 126.5, 127.6, 128.1, 129.2, 129.4, 129.6, 130.8, 131.0,
134.8, 137.5, 137.7, 137.9, 138.4, 138.5, 154.4, 154.8, 155.0, 155.5,
156.8, 157.8, 166.8, 167.2, 167.3, 167.5, 167.7, 168.3, 169.4, 170.5,
170.9, 171.1, 171.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3733–3740

3740
A. V. Biitseva et al.
Paper
Synthesis
(6) (a) McComsey, D. F.; Hawkins, M. J.; Andrade-Gordon, P.; Addo,
M. F.; Oksenberg, D.; Maryanoff, B. E. Bioorg. Med. Chem. Lett.
1999, 9, 1423. (b) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Comb.
Chem. 2002, 4, 484. (c) Mann, E.; Chana, A.; Sanchez-Sancho, F.;
Puerta, C.; Garcia-Merino, A.; Herradon, B. Adv. Synth. Catal.
2002, 344, 855. (d) Salgado, A.; Mann, E.; Sanchez-Sancho, F.;
Herradon, B. Heterocycles 2003, 60, 57.
(7) (a) Zabrocki, J.; Dunbar, J. B. Jr.; Marshall, K. W.; Toth, M. V.;
Marshall, G. R. J. Org. Chem. 1992, 57, 202. (b) Kohn, W. D.;
Zhang, L. Tetrahedron Lett. 2001, 42, 4453. (c) Tornoe, C. W.;
Sanderson, S. J.; Mottram, J. C.; Coombs, G. H.; Meldal, M.
J. Comb. Chem. 2004, 6, 312.
(8) (a) Koopmanschap, G.; Ruijter, E.; Orru, R. V. A. Beilstein J. Org.
Chem. 2014, 10, 544. (b) Cerminara, I.; Chiummiento, L.;
Funicello, M.; Guarnaccio, A.; Lupattelli, P. Pharmaceuticals
2012, 5, 297. (c) Biron, E.; Chatterjee, J.; Kessler, H. Org. Lett.
2006, 8, 2417.
(9) Biitseva, A. V.; Rudenko, I. V.; Hordiyenko, O. V.; Jamart-
Grégoire, B.; Arrault, A. Eur. J. Org. Chem. 2012, 4387.
(10) (a) Holenz, J.; Karlström, S. (Astrazeneca AB) PCT Int. Appl.
WO2011002409, 2011; Chem. Abstr. 2011, 154, 109655
(b) Kudrevich, S.; Brasseur, N.; La Madeleine, C.; Gilbert, S.; Van
Lier, J. E. J. Med. Chem. 1997, 40, 3897. (c) (BASF SE) EP2371219,
2011; Chem. Abstr. 2011, 155, 503363 (d) Groll, M.; Berkers, C.
R.; Ploegh, H. L.; Ovaa, H. Structure 2006, 451.
(16) Gangadasu, B.; Narender, P.; Bharath Kumar, S.; Ravinder, M.;
Ananda Rao, B.; Ramesh, Ch.; China Raju, B.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 8398.
(17) (a) Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne, L.;
Peña, M. J. Org. Chem. 1997, 62, 6420. (b) Bigi, F.; Maggi, R.;
Sartori, G. Green Chem. 2000, 2, 140.
(18) Sureshbabu, V. V.; Basavaprabhu Synlett 2011, 1160.
(19) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur.
J. Org. Chem. 1999, 389.
(20) (a) Oh, K.; Guan, Z. Chem. Commun. 2006, 3069. (b) Kishore, R.;
Raghothama, S.; Balaram, P. Biopolymers 1987, 26, 873.
(21) (a) Ressurreic, A. S. M.; Bordessa, A.; Civera, M.; Belvisi, L.;
Gennari, C.; Piarulli, U. J. Org. Chem. 2008, 73, 652. (b) Nowick, J.
S.; Pairish, M.; Lee, I. Q.; Holmes, D. L.; Ziller, J. W. J. Am. Chem.
Soc. 1997, 119, 5413. (c) Cierpicki, T.; Otlewski, J. J. Biomol. NMR
2001, 21, 249.
(22) (a) Tucker, T. J.; Isaacs, R. C. A. The Development of Novel Nonco-
valent Thrombin Inhibitors, In Advances in Amino Acid Mimetics
and Peptidomimetics; Vol. 2; Abell, A., Ed.; JAI Press Inc: Stam-
ford (CT, USA), 1999, 53. (b) Wiley, M. R.; Chirgadze, N. Y.;
Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.;
Olkowski, J. L.; Weir, L. C.; Smith, G. F. Bioorg. Med. Chem. Lett.
1996, 6, 2387. (c) Lange, U. E. W.; Baucke, D.; Hornberger, W.;
Mack, H.; Seitz, W.; Höffken, H. W. Bioorg. Med. Chem. Lett.
2003, 13, 2029.
(11) (a) Lagrange, A.; Andrean, H. (L’Oreal S. A.) US6451067, 2002;
Chem. Abstr. 2000, 133, 79012 (b) Lagrange, A.; Andrean, H.
(L’Oreal S. A.) US6635090, , 2003; Chem. Abstr. 2000, 133, 79010
(c) Lagrange, A.; Andrean, H. (L’Oreal S. A.) US6458168, 2002;
Chem. Abstr. 2000, 133, 79011 (d) Andrean, H.; Lagrange, A.
(L’Oreal) US6077320, 2000; Chem. Abstr. 1998, 129, 71930
(12) Brach, P. J.; Grammatica, S. J.; Ossanna, O. A.; Weinberger, L.
J. Het. Chem. 1970, 7, 1403.
(23) (a) Peterlin-Mašič, L.; Jurca, A.; Marinko, P.; Jančar, A.; Kikelj, D.
Tetrahedron 2002, 58, 1557. (b) Peterlin-Mašič, L.; Mlinšek, G.;
Šolmajer, T.; Trampuš-Bakija, A.; Stegnar, M.; Kikelj, D. Bioorg.
Med. Chem. Lett. 2003, 13, 789. (c) Kranjc, A.; Peterlin-Mašič, L.;
Reven, S.; Mikic, K.; Preželj, A.; Stegnar, M.; Kikelj, D. Eur. J. Med.
Chem. 2005, 40, 782.
(24) Devillers, I.; Arrault, A.; Olive, G.; Marchand-Brynaert, J. Tetra-
hedron Lett. 2002, 43, 3161.
(13) Genda, Y.; Tomita, N.; Ito, M.; Kano, S. JP54119531, 1979; Chem.
Abstr. 1980, 92, 95632
(14) Hordiyenko, O. V.; Rudenko, I. V.; Zamkova, I. A.; Denisenko, O.
V.; Biitseva, A. V.; Arrault, A.; Tolmachev, A. A. Synthesis 2013,
45, 3375.
(15) (a) Hordiyenko, O. V.; Biitseva, A. V.; Kornilov, M. Yu.; Brosse, N.;
Hocquet, A.; Jamart-Grégoire, B.; Shishkin, O. V.; Zubatyuk, R. I.
Eur. J. Org. Chem. 2006, 2833. (b) Hordiyenko, O. V.; Rudenko, I.
V.; Biitseva, A. V.; Turov, A. V.; Arrault, A.; Brosse, N.; Fabre, O.;
Jamart-Grégoire, B.; Zubatyuk, R. I.; Shishkin, O. V. Tetrahedron
2009, 65, 6218.
(25) Gaccioli, F.; Franchi-Gazzola, R.; Lanfranchi, M.; Marchio, L.;
Metta, G.; Pellinghelli, M. A.; Tardito, S.; Tegoni, M. J. Inorg. Bio-
chem. 2005, 99, 1573.
(26) Zefirov, Yu. V. Crystallogr. Rep. 1997, 42, 865.
(27) Burgi, H.-B.; Dunitz, J. D. Structure Correlation; Vol. 2; VCH:
Weinheim, 1994, 741.
(28) Dolomanov, O.; Bourhis, L.; Gildea, R.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
(29) Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008,
64, 112.
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