Pyrrolidine-2,3,4-tricarboxylic anhydrides: I. Organocatalytic synthesis and fusion of pyrrole ring by the action of p-fluorobenzylamine

Article abstract of DOI:10.1134/S1070428011040142

N-Boc-glycine effectively catalyzes 1,3-dipolar cycloaddition of maleic anhydride to N-benzylidene a-amino acid esters, which leads to the formation of pyrrolidine-2,3,4-tricarboxylic anhydrides. The subsequent opening of the anhydride fragment in the add

Full text of DOI:10.1134/S1070428011040142

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 4, pp. 556–562. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © K.V. Kudryavtsev, E.V. Trofimova, A.O. Borisova, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 4,
pp. 554–560.
Pyrrolidine-2,3,4-tricarboxylic Anhydrides:
I. Organocatalytic Synthesis and Fusion of Pyrrole Ring
by the Action of p-Fluorobenzylamine
K. V. Kudryavtseva, E. V. Trofimovaa, and A. O. Borisovab
a Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: kudr@org.chem.msu.ru
b Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received September 27, 2010
Abstract—N-Boc-glycine effectively catalyzes 1,3-dipolar cycloaddition of maleic anhydride to N-benzylidene
α-amino acid esters, which leads to the formation of pyrrolidine-2,3,4-tricarboxylic anhydrides. The subsequent
opening of the anhydride fragment in the adducts by the action of p-fluorobenzylamine is regioselective, and it
involves recyclization to produce polysubstituted octahydropyrrolo[3,4-b]pyrroles. The newly synthesized
fused pyrrolidines inhibit enzymatic activity of thrombin (factor IIA) in vitro.
DOI: 10.1134/S1070428011040142
Polyfunctional organic compounds attract consider-
able interest from the viewpoint of creation of combi-
natorial libraries for biological screening. Pyrrolidine-
2,3,4-tricarboxylic acid 3,4-anhydrides I may be re-
garded as promising molecular structures possessing
various functional groups. Compounds like I contain
three functional groups: a secondary amino group, an-
hydride fragment, and carboxy (ester) group.
centered nucleophiles gives dicarboxylic acid mono-
amides or imides which show modified biological
activity as compared to parent compounds [1, 2]. The
goal of the present work was to develop an effective
procedure for the synthesis of heterocyclic anhydrides
I, examine their reactions with primary amines, and
test the products thus obtained for inhibitory activity
toward thrombin (factor IIA).
Functionalized pyrrolidines I can be synthesized by
1,3-dipolar cycloaddition of maleic anhydride to azo-
methine ylides A as shown in Scheme 1.
O
O
O
O
O
O
R
R
4
5
3
2
O
R2
1
R3
O
N
Scheme 1.
H
R1O
O
O
O
O
R2
I
II
OR1
+
O
R3
N
R2
Consecutive and/or joint modification of the above
functional groups in molecules I could lead to various
complex low-molecular organic compounds. Hetero-
cyclic anhydrides I are isostructural to cantharidin (II,
R = Me) and norcantharidin (II, R = H). Cantharidin is
produced as protecting agent by various beetle species,
and it exhibits a broad spectrum of antitumor activity
and inhibits serine/threonine protein phosphatases; the
same is also typical of its synthetic analog, norcan-
tharidin [1]. Opening of the anhydride ring in com-
pounds II and their analogs by the action of nitrogen-
R3
O
N
M
O
H
O
R1O
I
A
There are some published data on the synthesis of
compounds I via generation of 1,3-dipole A from the
corresponding N-alkylidene derivatives of α-amino
acid esters on heating above 100°C for a long time
[3–5]. We recently developed an organocatalytic pro-
cedure for 1,3-dipolar cycloaddition of activated di-
556

PYRROLIDINE-2,3,4-TRICARBOXYLIC ANHYDRIDES: I.
polarophiles to azomethine ylides like A [6]. This
557
Cl1
C11
C12
C13
procedure makes it possible to obtain polysubstituted
bicyclic pyrrolidines, including those having structure
like I, by treatment of a mixture of N-alkylidene
α-amino acid ester and dipolarophile in methylene
chloride with a catalytic amount of L-proline (L-Pro)
or L-pyroglutamic acid (L-Pyr) at room temperature
[6]. When the developed procedure was applied to the
synthesis of heterocyclic anhydrides I with different
substituents, in many cases the products were contam-
inated with the catalyst because of poor solubility of
L-Pro and L-Pyr in methylene chloride. These results
prompted us to search for amino acid derivatives that
are readily soluble in nonpolar organic solvents.
Unlike other amino acids examined in [6], the lack of
free amino group in L-Pyr indicated that this func-
tionality is not necessary for effective catalysis of
1,3-dipolar cycloaddition. α-Amino acid derivatives
with the amino group protected with benzyloxycar-
bonyl group (N-Boc) are soluble in nonpolar solvents;
therefore, these accessible compounds were selected as
organic catalysts for the reaction shown in Scheme 2.
C10
H1
C5
C6
C7
C4
C14
C15
O1
N1
C3
C8
O5
O4
C1
O3
C9
C2
Fig. 1. S t r u c t u r e o f t h e m o l e c u l e o f m e t h y l
(3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-4-methyl-1,3-di-
oxohexahydro-1H-furo[3,4-c]pyrrole-4-carboxylate (IVb)
according to the X-ray diffraction data.
X-ray analysis of its single crystal, and these data con-
firmed our assumption concerning the steric structure
of other heterocyclic anhydrides IV (Fig. 1, Table 1).
Compounds IV were isolated as colorless free-flowing
crystalline powders which were stable upon storage at
4°C for at least six months. Molecules IVb in crystals
are linked to form infinite chains consisting of alternat-
ing enantiomers through intermolecular hydrogen
bonds between the carbonyl oxygen atom in the an-
hydride fragment of one molecule and NH hydrogen
atom of the other molecule (Fig. 2).
Scheme 2.
R2
OMe
+
N
O
O
R1
O
The chemical properties of heterocyclic anhydrides
I and IV were studied very poorly. There are published
data on the hydrolysis [5] and methanolysis [7] of
O
IIIa–IIId
O
O
O
N-BocGlyOH (10 mol %)
CH2Cl2, 20°C
Table 1. Selected bond lengths and bond angles in the mole-
cule of methyl (3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-4-
methyl-1,3-dioxohexahydro-1H-furo[3,4-c]pyrrole-4-car-
boxylate (IVb)
R2
R1
N
H
COOMe
(±)-IVa–IVd (75–87%)
Bond
d, Å
Angle
ω, deg
R1 = H, R2 = Me (a); R1 = 4-Cl, R2 = Me (b); R1 = 4-Br,
R2 = Me (c); R1 = 3-F, R2 = PhCH2 (d).
Cl1–C13
N1–C4
N1–C5
N1–H1
O1–C1
O2–C2
O3–C2
O3–C1
C1–C6
C2–C3
C3–C6
C3–C4
1.7454(15)
1.4675(15)
1.4697(16)
0.914(17)0
1.1822(17)
1.1933(16)
1.3715(16)
1.3973(17)
1.5074(19)
1.5097(18)
1.5353(17)
1.5575(16)
C4N1C5
C2O3C1
O3C2C3
O3C1C6
C2C3C4
C1C6C5
N1C4C3
N1C5C6
N1C5C10
N1C4C8
N1C4C7
C5N1H1
106.12(9)0
110.36(10)
111.09(10)
109.82(11)
113.21(10)
113.13(11)
101.14(9)0
101.80(9)0
113.08(10)
110.12(10)
113.56(10)
108.8(10)0
When an equimolar mixture of amino acid Schiff
base III and maleic anhydride in methylene chloride
was stirred for 12–24 h at room temperature in the
presence of 10 mol % of N-Boc-glycine, the corre-
sponding crystalline cycloaddition product IV partly
separated from the reaction mixture (Scheme 2).
Anhydride IVa was synthesized by us previously [6],
while the structure of heterocyclic anhydrides IVb–
IVd was determined by comparing their NMR spectra
with those of compound IVa and other known analogs
[4, 6]. The steric structure of p-chlorophenyl-substitut-
ed derivative IVb was unambiguously proved by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

KUDRYAVTSEV et al.
558
a
We previously found conditions for intramolecular
O2B
O5B
O3B
O1B
condensation involving the carboxy group in cs-5-aryl-
pyrrolidine-2,4-dicarboxylic acid monoamides and ob-
tained bicyclic imides with a 3,6-diazabicyclo[3.2.1]-
octane skeleton [8]. Three intramolecular condensation
pathways may be proposed for regioisomeric cis-
5-arylpyrrolidine-2,3,4-tricarboxylic acid monoamides
V and VI: (i) [4,2]-condensation in isomer V, leading
to 3,6-diazabicyclo[3.2.1]octane derivative; (ii) [4,3]-
condensation in isomer V with formation of octahydro-
pyrrolo[3,4-c]pyrrole structure; and (iii) [3,2]-conden-
sation in VI with formation of octahydropyrrolo[3,4-b]-
pyrrole skeleton (Fig. 3). The reactions of anhydrides
IVa–IVd with p-fluorobenzylamine (VII) were carried
out in THF at room temperature (Scheme 3). After 2–
3 days, samples were withdrawn from the reaction
O4B
N1B
0
H1B
O2
O3
b
O1
O4
O5
N1
H1
c
O3A
O1A
O2A
O5A
N1A
H1A
O4A
1
Fig. 2. Intermolecular interactions in the crystalline structure
of methyl (3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-4-meth-
yl-1,3-dioxohexahydro-1H-furo[3,4-c]pyrrole-4-carboxylate
(IVb): N1–H1 0.914(17), H1 ···O2A 2.257(17), N1 ···O2A
3.0841(14) Å; ∠N1H1O2A 150.3(14)°.
mixtures and analyzed by H NMR spectroscopy. The
reaction was assumed to be complete when the two last
spectra were similar. In the reaction of heterocyclic an-
hydride IVb with p-fluorobenzylamine the initial com-
pounds disappeared in 3 days, and three products were
detected at a molar ratio of 13:4:1. The major product
was isolated as individual substance by crystallization.
The 1H NMR spectrum of this compound contained no
signal assignable to methoxy group. Taking into
a few compounds like I in acid medium. Obviously,
nucleophile should react primarily at the carbonyl
carbon atoms in the anhydride fragment of I and IV.
Taking into account unsymmetrical structure of these
substrates, formation of two regioisomers with vicinal
carboxy and methoxycarbonyl groups should be ex-
pected. Thus primary products of nucleophilic addition
of p-fluorobenzylamine to heterocyclic anhydride IVb
should have structures V and VI (Fig. 3).
1
account its other H and 13C NMR parameters and
elemental composition, it was assigned structure VIIIb
(Scheme 3).
Scheme 3.
O
O
O
ii
NH2
+
R2
O
O
i
R1
F
F
N
COOMe
HN
OH
OMe
H
4
5
3
2
(±)-IVa–IVd
VII
1
N
Me
H
OH
Cl
O
O
O
(±)-V
THF, 20°C
N
O
O
R1
N
H
F
HO
NH
OMe
R2
O
F
iii
3
2
4
(±)-VIIIa–VIIId (49–65%)
5
1
N
R1 = H, R2 = Me (a); R1 = 4-Cl, R2 = Me (b); R1 = 4-Br,
R2 = Me (c); R1 = 3-F, R2 = PhCH2 (d).
Me
H
O
Cl
(±)-VI
Fig. 3. Probable primary addition products of methyl
(3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-4-methyl-1,3-di-
oxohexahydro-1H-furo[3,4-c]pyrrole-4-carboxylate (IVb)
and p-fluorobenzylamine (VII) and versions of intramolec-
ular ring closure .
Compound VIIIb could be formed via spontaneous
[3,2]-condensation of intermediate product VI (Fig. 3).
According to the NMR data, the minor products are
likely to have structures V and VI; however, they were
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PYRROLIDINE-2,3,4-TRICARBOXYLIC ANHYDRIDES: I.
559
C10
not isolated. Analogous patterns were observed in the
reactions of benzylamine VII with heterocyclic anhy-
drides IVa, IVc, and IVd. In all cases, the major prod-
ucts were substituted octahydropyrrolo[3,4-b]pyrroles
VIIIa, VIIIc, and VIIId, indicating initial regioselec-
tive opening of the anhydride fragment. The structure
of fused pyrrolidines VIII was proved by the X-ray
diffraction data for a single crystal of compound VIIId
(Fig. 4, Table 2). Packing of molecules VIIId in crys-
tal resembles that found for anhydride IVb: alternating
enantiomeric molecules VIIId are linked through
intermolecular hydrogen bonds involving the nitrogen
atom in the secondary amino group of one molecule
and proton in the carboxy group of the other molecule
(Fig. 5). The observed conformation of molecules
VIIId is stabilized by intramolecular hydrogen bond
formed by the carbonyl oxygen atom of the carboxy
group and hydrogen atom in the secondary amino
group (Figs. 4, 5).
C11
C12
C9
C8
C1
C13
O4
N1
C14
C16
F2
C17
C20
C24
C6
C5
F1
C25
N2
C21
C4
C2
C18
C23
C15
C3
C22
O2
C19
C27
C26
C7
O3
O1
Fig. 4. Structure of the molecule of (2R*,3S*,3aR*,6aS*)-6a-
benzyl-5-(4-fluorobenzyl)-2-(3-fluorophenyl)-4,6-dioxoocta-
hydropyrrolo[3,4-b]pyrrole-3-carboxylic acid (VIIId)
according to the X-ray diffraction data.
and 100 MHz, respectively, using DMSO-d6 as sol-
vent; the chemical shifts were determined relative to
the residual proton and carbon signals of the solvent.
The X-ray diffraction data for compounds IVb and
VIIId were acquired on a Bruker Smart Apex II dif-
fractometer (MoKα irradiation, λ 0.71073 Å, graphite
monochromator) at 150 and 100 K, respectively. Both
structures were solved by direct methods (SHELXS-
86) [10] and were refined with respect to F2 by the
least-squares procedure in full-matrix anisotropic
Heterocyclic anhydrides IV and substituted octa-
hydropyrrolo[3,4-b]pyrroles VIII synthesized in the
present work were tested for inhibitory activity toward
thrombin (Table 3).* Thrombin (factor IIA) is a prom-
ising biological target in the design of anticoagulants
[9]. All the examined compounds are fairly readily
soluble in aqueous medium. They inhibited thrombin
in vitro (buffer solution) at a millimolar concentration
up to complete suppression of its enzymatic activity
(Table 3, compounds IVa and IVb).
N1
O1
We can conclude that 1,3-dipolar cycloaddition of
maleic anhydride to azomethine ylides, followed by
opening of the anhydride fragment and recyclization
involving the vicinal ester fragment, provides a novel
efficient synthetic approach to substituted octahydro-
pyrrolo[3,4-b]pyrrole derivatives. Compounds VIII
may be used as starting materials for subsequent
transformations due to the presence of an unprotected
β-amino acid moiety.
N1A
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by thin-layer chromatography using
Sorbfil PTSKh-AF-A-UF plates (CHCl3–MeOH,
1
10:1). The H and 13C NMR spectra were recorded at
303 K on a Bruker Avance 400 spectrometer at 400
Fig. 5. Intermolecular interactions in the crystalline structure
of (2R*,3S*,3aR*,6aS*)-6a-benzyl-5-(4-fluorobenzyl)-2-(3-
fluorophenyl)-4,6-dioxooctahydropyrrolo[3,4-b]pyrrole-3-
carboxylic acid (VIIId): N1–H1N 0.91(4), H1N···O2 2.20(3),
N1 ··· O2 2.812(4) Å; ∠N1H1NO2 124(3)°; O1–H1O 0.93,
H1O ···N1A 1.65, O1 ···N1A 2.573(4) Å; ∠O1H1ON1A 175°.
* Biological tests were performed at the Physical Biochemistry
Laboratory, Hematological Research Center, Russian Academy
of Medical Sciences, Moscow (Head of the laboratory Prof.
F.I. Ataullakhanov).
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KUDRYAVTSEV et al.
560
Table 2. Selected bond lengths and bond angles in the mole-
cule of (2R*,3S*,3aR*,6aS*)-6a-benzyl-5-(4-fluorobenzyl)-
2-(3-fluorophenyl)-4,6-dioxooctahydropyrrolo[3,4-b]pyr-
role-3-carboxylic acid (VIIId)
added in one portion to a solution of 1.37 g (14 mmol)
of maleic anhydride in 15 ml of methylene chloride.
The mixture was stirred for 24–48 h at room tempera-
ture (TLC), the precipitate was filtered off, the filtrate
was evaporated by half under reduced pressure and
cooled to –20°C, and the precipitate was filtered off. If
necessary, 5 ml of hexane was added to initiate crystal-
lization.
Bond
d, Å
Angle
ω, deg
N1–C2
N1–C1
C1–C4
C2–C3
C3–C4
C4–C5
C1-C6
N2–C6
N2–C5
F1–C17
F2–C25
N2–C21
1.491(5)
1.498(4)
1.546(5)
1.546(5)
1.551(5)
1.504(5)
1.524(5)
1.380(5)
1.387(5)
1.331(5)
1.372(5)
1.458(5)
C2N1C1
N1C1C6
N1C1C8
N1C1C4
N1C2C15
N1C2C3
C2C3C4
C1C4C3
C5C4C3
C5C4C1
C6C1C4
C6N2C5
104.3(3)
110.8(3)
109.3(3)
106.2(3)
114.4(3)
103.5(3)
100.5(3)
105.7(3)
113.6(3)
105.1(3)
103.9(3)
113.2(3)
Methyl (3aR*,4S*,6R*,6aS*)-4-methyl-1,3-dioxo-
6-phenylhexahydro-1H-furo[3,4-c]pyrrole-4-car-
boxylate (IVa). Yield 79%, colorless crystals, mp 208–
1
210°C. H NMR spectrum, δ, ppm: 1.50 s (3H, CH3),
3.48 br.s (1H, NH), 3.65 d (1H, 3a-H, J = 8.0 Hz),
3.71 s (3H, OCH3), 3.92 d.d (1H, 6a-H, J = 8.8,
8.0 Hz), 4.78 d (1H, 6-H, J = 8.8 Hz), 7.23–7.28 m (1H,
Harom), 7.31–7.38 m (4H, Harom). 13C NMR spectrum,
δC, ppm: 22.92, 50.50, 52.38, 55.85, 61.10, 67.47,
127.65 (2C), 128.14, 128.51 (2C), 139.07, 170.29,
172.17, 172.68. Found, %: C 62.00; H 5.34; N 4.99.
C15H15NO5. Calculated, %: C 62.28; H 5.23; N 4.84.
Methyl (3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-
4-methyl-1,3-dioxohexahydro-1H-furo[3,4-c]pyr-
role-4-carboxylate (IVb). Yield 87%, colorless crys-
tals, mp 164–165°C. 1H NMR spectrum, δ, ppm: 1.50 s
(3H, CH3), 3.55 d (1H, NH, J = 3.4 Hz), 3.65 d (1H,
3a-H, J = 8.0 Hz), 3.71 s (3H, OCH3), 3.94 d.d (1H,
6a-H, J = 8.8, 8.0 Hz), 4.80 d.d (1H, 6-H, J = 8.8,
3.4 Hz), 7.40 s (4H, Harom). 13C NMR spectrum, δC,
ppm: 22.93, 50.37, 52.41, 55.69, 60.28, 67.45, 128.55
(2C), 129.44 (2C), 132.55, 138.30, 170.44, 172.08,
172.60. Found, %: C 55.71; H 4.38; N 4.43.
C15H14ClNO5. Calculated, %: C 55.65; H 4.36; N 4.33.
X-Ray diffraction data: monoclinic crystals, space
group P21/n; a = 6.3454(4), b = 22.4276(13), c =
10.7282(6) Å; β = 104.849(1)°; V = 1475.77(15) Å3;
Z = 4; dcalc = 1.457 g/cm3; F(000) = 672. Intensities of
13257 reflections (3528 of which were independent,
Rint = 0.0286) were measured by ω-scanning in the
range 1.82 < θ < 28.00° (–8 ≤ h ≤ 7, –29 ≤ k ≤ 29,
–14 ≤ l ≤ 14). The final divergence factors were R1 =
0.0370, wR2 = 0.0924 for 2940 reflections with I >
2σ(I). The complete set of crystallographic parameters
of compound IVb is available from the authors upon
request.
approximation for all non-hydrogen atoms (SHELXL-
97) [11]. All hydrogen atoms were localized by the
Fourier difference syntheses, and their positions were
refined in isotropic approximation.
Maleic anhydride was preliminarily purified by re-
crystallization from chloroform. Initial Schiff bases III
were synthesized according to the procedures de-
scribed in [6, 12].
Pyrrolidine-2,3,4-tricarboxylic acid 3,4-anhy-
drides IVa–IVd (general procedure). A solution of
14 mmol of compound III in 25 ml of methylene
chloride and 0.25 g (1.4 mmol) of N-Boc-glycine were
Table 3. Inhibitory effect of compounds IVa–IVd and
VIIIa–VIIId on the hydrolysis of specific substrate with
thrombin in aqueous buffer
Reduction of the rate
of hydrolysis of thrombin concentration,
Inhibitor
Compound
no.
substrate, %
mmol/l
5.33
2.40
1.36
0.52
3.48
1.97
1.63
0.96
IVa
92
90
71
55
29
35
23
47
IVb
IVc
Methyl (3aR*,4S*,6R*,6aS*)-6-(4-bromophenyl)-
4-methyl-1,3-dioxohexahydro-1H-furo[3,4-c]pyr-
role-4-carboxylate (IVc). Yield 75%, colorless crys-
tals, mp 168–169°C. 1H NMR spectrum, δ, ppm: 1.50 s
(3H, CH3), 3.55 br.s (1H, NH), 3.65 d (1H, 3a-H, J =
8.0 Hz), 3.70 s (3H, OCH3), 3.93 d.d (1H, 6a-H, J =
IVd
VIIIa
VIIIb
VIIIc
VIIId
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PYRROLIDINE-2,3,4-TRICARBOXYLIC ANHYDRIDES: I.
561
8.6, 8.0 Hz), 4.80 d (1H, 6-H, J = 8.6 Hz), 7.33 d (2H,
Harom, J = 8.3 Hz), 7.54 d (2H, Harom, J = 8.3 Hz).
13C NMR spectrum, δC, ppm: 22.93, 50.32, 52.41,
55.68, 60.33, 67.45, 121.13, 129.80 (2C), 131.46 (2C),
138.73, 170.44, 172.06, 172.59. Found, %: C 49.04;
H 3.81; N 4.02. C15H14BrNO5. Calculated, %: C 48.93;
H 3.83; N 3.80.
3a-H), 4.45 d and 4.59 d (1H each, 4-FC6H4CH2, J =
15.2 Hz), 4.84 d (1H, 2-H, J = 4.3 Hz), 7.11–7.15 m
(2H, Harom), 7.32–7.38 m (6H, Harom), 12.00 br.s (1H,
COOH). 13C NMR spectrum, δC, ppm: 22.48, 41.32,
52.14, 54.30, 65.44, 65.77, 115.46, 115.67, 128.19 (2C),
129.39 (2C), 130.01, 130.09, 132.16, 132.75, 138.27,
161.85 d (J = 96.8 Hz), 171.86, 176.07, 179.02. Found,
%: C 60.32; H 4.28; N 6.74. C21H18ClFN2O4. Calculat-
ed, %: C 60.51; H 4.35; N 6.72.
Methyl (3aR*,4S*,6R*,6aS*)-4-benzyl-6-(3-
fluorophenyl)-1,3-dioxohexahydro-1H-furo[3,4-c]-
pyrrole-4-carboxylate (IVd). Yield 82%, colorless
(2R*,3S*,3aR*,6aS*)-2-(4-Bromophenyl)-5-
(4-fluorobenzyl)-6a-methyl-4,6-dioxooctahydropyr-
rolo[3,4-b]pyrrole-3-carboxylic acid (VIIIc). Yield
56%, colorless crystals, mp 232°C. 1H NMR spectrum,
δ, ppm: 1.47 s (3H, CH3), 3.48–3.55 m (2H, 3-H,
3a-H), 4.46 d and 4.59 d (1H each, 4-FC6H4CH2, J =
15.2 Hz), 4.83 d (1H, 2-H, J = 4.5 Hz), 7.13 t (2H,
1
crystals, mp 180–181°C. H NMR spectrum, δ, ppm:
2.85 d (1H, NH, J = 3.8 Hz), 3.17 d and 3.26 d (1H
each, CH2Ph, J = 14.0 Hz), 3.72 s (3H, OCH3), 3.92 d
(1H, 3a-H, J = 8.0 Hz), 4.06 d.d (1H, 6a-H, J = 9.4,
8.0 Hz), 5.07 d.d (1H, 6-H, J = 9.4, 3.8 Hz), 7.07–
7.19 m (4H, Harom), 7.21–7.32 m (4H, Harom), 7.34–
7.42 m (1H, Harom). 13C NMR spectrum, δC, ppm:
50.43, 52.29, 55.13, 59.72, 71.82, 114.20 d (J =
8.0 Hz), 115.10 d (J = 8.0 Hz), 123.70, 127.54, 129.08
(2C), 130.08 (2C), 130.62 d (J = 4.0 Hz), 135.65,
141.73, 162.50 d (J = 96.0 Hz), 170.01, 170.83,
171.85. Found, %: C 65.98; H 4.76; N 3.75.
C21H18FNO5. Calculated, %: C 65.79; H 4.73; N 3.65.
H
arom, J = 8.7 Hz.), 7.28–7.38 m (4H, Harom), 7.47 d
(2H, Harom, J = 8.3 Hz.), 11.82 br.s (1H, COOH).
13C NMR spectrum, δC, ppm: 22.48, 41.32, 52.09,
54.30, 65.48, 65.78, 115.46, 115.67, 120.72, 129.76
(2C), 130.01, 130.09, 131.10 (2C), 132.72, 138.70,
161.85 d (J = 96.0 Hz), 171.84, 176.06, 179.02. Found,
%: C 54.39; H 4.10; N 6.00. C21H18BrFN2O4. Calculat-
ed, %: C 54.68; H 3.93; N 6.07.
Substituted octahydropyrrolo[3,4-b]pyrrole-3-
carboxylic acids VIIIa–VIIId (general procedure).
Compound IVa–IVd, was dissolved in 50 ml of THF,
0.338 g (0.310 ml, 2.7 mmol) of p-fluorobenzylamine
was added in one portion, and the mixture was stirred
for 48–72 h at room temperature (TLC). The mixture
was then concentrated under reduced pressure, and the
residue was recrystallized from ethyl acetate–hexane.
(2R*,3S*,3aR*,6aS*)-6a-Benzyl-5-(4-fluoroben-
zyl)-2-(3-fluorophenyl)-4,6-dioxooctahydropyrrolo-
[3,4-b]pyrrole-3-carboxylic acid (VIIId). Yield 49%,
1
colorless crystals, mp 254°C. H NMR spectrum, δ,
ppm: 3.04 d and 3.18 d (1H each, PhCH2, J =
12.9 Hz), 3.46 d.d (1H, 3-H, J = 9.2, 6.0 Hz), 3.61 d
(1H, 3a-H, J = 9.2), 4.18 d and 4.41 d (1H each,
4-FC6H4CH2, J = 15.0 Hz), 4.77 d (1H, 2-H, J =
6.0 Hz), 6.88 d.d (2H, Harom, J = 8.5, 5.6 Hz.), 6.93–
7.03 m (3H, Harom), 7.08–7.19 m (7H, Harom), 7.25–
(2R*,3S*,3aR*,6aS*)-5-(4-Fluorobenzyl)-6a-
methyl-4,6-dioxo-2-phenyloctahydropyrrolo[3,4-b]-
pyrrole-3-carboxylic acid (VIIIa). Yield 61%,
1
13
colorless crystals, mp 248–250°C. H NMR spectrum,
7.31 m (1H, Harom), 11.95 br.s (1H, COOH). C NMR
δ, ppm: 1.48 s (3H, CH3), 3.47–3.56 m (2H, 3-H,
3a-H), 4.46 d and 4.60 d (1H each, 4-FC6H4CH2, J =
15.2 Hz), 4.83 d (1H, 2-H, J = 4.3 Hz), 7.08–7.17 m
(2H, Harom), 7.17–7.43 m (7H, Harom), 12.00 br.s (1H,
COOH). 13C NMR spectrum, δC, ppm: 22.63, 41.33,
52.33, 54.60, 65.93, 66.26, 115.46, 115.67, 127.46
(2C), 127.88, 128.24 (2C), 130.00, 130.09, 132.75,
138.94, 161.90 d (J = 96.0 Hz), 172.10, 176.13,
179.07. Found, %: C 65.80; H 5.09; N 7.26.
C21H19FN2O4. Calculated, %: C 65.96; H 5.01; N 7.33.
spectrum, δC, ppm: 41.04, 41.28, 50.28, 52.43, 65.58,
70.24, 114.01 d (J = 8.0 Hz), 114.61 d (J = 8.0 Hz),
115.27, 115.49, 123.76, 127.44, 128.96 (2C), 129.75,
129.83, 130.23 d (J = 4.0 Hz), 130.36 (2C), 132.17,
135.43, 142.24 d (J = 2.0 Hz), 161.70 d (J = 96.0 Hz),
162.37 d (J = 96.0 Hz), 171.74, 175.86, 178.16. Found,
%: C 68.21; H 4.64; N 6.07. C27H22F2N2O4. Calculat-
ed, %: C 68.06; H 4.65; N 5.88. X-Ray diffraction
data: monoclinic crystals, space group P21/c; a =
11.4149(12), b = 11.4458(14), c = 20.509(2) Å; β =
100.028(2)°; V = 2638.6(5) Å3; Z = 4, dcalc = 1.382 g×
cm–3; F(000) = 1140. Intensities of 21561 reflections
(4430 independent reflections, Rint = 0.0519) were
measured by ω-scanning in the range 2.02 < θ < 24.62°
(–13 ≤ h ≤ 13, –13 ≤ k ≤ 13, –24 ≤ l ≤ 24). The final
(2R*,3S*,3aR*,6aS*)-2-(4-Chlorophenyl)-5-
(4-fluorobenzyl)-6a-methyl-4,6-dioxooctahydropyr-
rolo[3,4-b]pyrrole-3-carboxylic acid (VIIIb). Yield
65%, colorless crystals, mp 234°C. 1H NMR spectrum,
δ, ppm: 1.47 s (3H, CH3), 3.46–3.54 m (2H, 3-H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

KUDRYAVTSEV et al.
562
4. Amornraksa, K., Grigg, R., Gunaratne, H.Q.N.,
Kemp, J., and Sridharan, V., J. Chem. Soc., Perkin
Trans. 1, 1987, p. 2285.
divergence factors were R1 = 0.0731, wR2 = 0.2069 for
3300 reflections with I > 2σ(I). The complete set of
crystallographic parameters of compound VId was
deposited to the Cambridge Crystallographic Data
Centre (entry no. CCDC 761401).
5. Marquez, A., Rodriguez, H., Medina, J., and
Cheung, K.K., Synth. Commun., 1993, vol. 23, p. 1321.
6. Kudryavtsev, K.V. and Zagulyaeva, A.A., Russ. J. Org.
Chem., 2008, vol. 44, p. 378.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-04-01800-a).
7. Grigg, R., Kemp, J., and Warnock, W.J., J. Chem. Soc.,
Perkin Trans. 1, 1987, p. 2275.
8. Kudryavtsev, K.V., Russ. J. Org. Chem., 2010, vol. 46,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011