Synthesis of 3-Benzylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione

Article abstract of DOI:10.1134/S1070428018100202

3-Benzylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione [cyclo(Pro-Phe)] was synthesized by cyclization of prolylphenylalanine and phenylalanylproline methyl esters which were prepared from the corresponding Boc-protected amino acids.

Full text of DOI:10.1134/S1070428018100202

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 10, pp. 1562–1564. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © V.A. Gaidukevich, I.V. Rudenkova, L.A. Popova, L.N. Nikolaevich, V.A. Knizhnikov, 2018, published in Zhurnal Organicheskoi
Khimii, 2018, Vol. 54, No. 10, pp. 1549–1551.
SHORT
COMMUNICATIONS
Synthesis of 3-Benzylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione
V. A. Gaidukevicha, I. V. Rudenkovab, L. A. Popovaa,
L. N. Nikolaevichb, and V. A. Knizhnikova*
a Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
*e-mail: knizh@ifoch.bas-net.by
b Institute of Physiology, National Academy of Sciences of Belarus,
ul. Akademicheskaya 28, Minsk, 220072 Belarus
Received January 19, 2018
Abstract—3-Benzylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione [cyclo(Pro-Phe)] was synthesized by cycliza-
tion of prolylphenylalanine and phenylalanylproline methyl esters which were prepared from the corresponding
Boc-protected amino acids.
DOI: 10.1134/S1070428018100202
Substituted 2,5-diketopiperazines (cyclodipeptides),
including 3-benzylhexahydropyrrolo[1,2-a]pyrazine-
1,4-dione [1, cyclo(Pro-Phe)], exhibit high biological
activity [1–3], and they can find application in
medicine and agriculture. Chromatographic isolation
of compound 1 from natural sources [2, 3] and its
synthesis with the use of benzyloxycarbonyl protecting
group [4, 5] have been reported.
2,5-Diketopiperazines can be synthesized by ther-
molysis of dipeptide esters. With the goal of finding
out an optimal synthetic route to cyclo(L-prolyl-L-
phenylalanyl) from Boc-protected precursors, we have
synthesized L-prolyl-L-phenylalanine methyl ester
hydrochloride (2) and L-phenylalanyl-L-proline methyl
ester hydrochloride (3). The condensation of N-tert-
butoxycarbonyl-L-proline with L-phenylalanine methyl
NH2
O
O
N
N
H
O
O
O
DCC
HCl, MeOH
Ph
O
+
N
Boc
HN
Ph
· HCl HN
OMe
OMe
OH
Boc
OMe
Ph
4
2
O
(1) Et3N
(2) Dioxane, ∆
NH
N
Ph
O
1
O
O
(1) Et3N
(2) Et2O, ∆
O
OH
MeO
MeO
O
O
DCC
HCl, MeOH
1
+
N
O
N
N
Ph
H
NHBoc
OMe
Ph
Ph
NHBoc
NH2·HCl
5
3
1562

SYNTHESIS OF 3-BENZYLHEXAHYDROPYRROLO[1,2-a]PYRAZINE-1,4-DIONE
1563
ester and of N-tert-butoxycarbonyl-L-phenylalanine
with L-proline methyl ester in the presence of N,N′-di-
cyclohexylcarbodiimide (DCC) afforded N-tert-but-
oxycarbonyl-L-prolyl-L-phenylalanine methyl ester 4
and N-tert-butoxycarbonyl-L-phenylalanyl-L-proline
methyl ester 5, respectively. Removal of the Boc
protecting group from 4 and 5 by treatment with
methanolic HCl gave hydrochlorides 2 and 3. When
compounds 4 and 5 were deprotected using a solution
of HCl in dioxane, the products contained a small
amount of dioxane, and prolonged heating at 55–60°C
under reduced pressure was necessary to remove traces
of the solvent.
13C NMR spectrum (CD3OD), δC, ppm: 22.77, 29.29,
38.04, 45.92, 57.60, 60.00, 127.99, 129.40, 130.97,
137.38, 166.81, 170.90. Found, %: С 68.72; Н 6.85;
N 11.26. C14H16N2O2. Calculated, %: С 68.83; Н 6.60;
N 11.47.
b. Triethylamine, 6.82 g (67.5 mmol), was added
dropwise with vigorous stirring to a solution of 21.14 g
(67.6 mmol) of L-phenylalanyl-L-proline methyl ester
hydrochloride (3) in 100 mL of methylene chloride.
The precipitate was filtered off, the solvent was
removed from the filtrate under reduced pressure, and
the residue was extracted with diethyl ether. The ex-
tract was filtered and refluxed for 24 h. The precipitate
was filtered off, washed in succession with diethyl
ether and hexane, and dried under reduced pressure.
The product was purified by reprecipitation from
methanol with diethyl ether. Yield 11.89 g (72%),
mp 136–137°C, [α]D20 = –82.15° (c = 1, H2O). The
NMR spectra were the same as above.
By treatment of hydrochlorides 2 and 3 with tri-
ethylamine we obtained L-prolyl-L-phenylalanine and
L-phenylalanyl-L-proline methyl esters which were
subjected to thermal cyclization without additional
purification to afford compound 1. We failed to obtain
analytically pure samples of L-prolyl-L-phenylalanine
and L-phenylalanyl-L-proline methyl esters since they
were slowly converted to cyclopeptide 1 even at room
temperature.
L-Prolyl-L-phenylalanine methyl ester hydro-
chloride (2). N-(tert-Butoxycarbonyl)-L-prolyl-L-
phenylalanine methyl ester (4), 28.96 g (77 mmol),
was dissolved in 50 mL of methanol, 36 mL of a 6.5 N
solution of hydrogen chloride in methanol was added,
and the mixture was stirred for 6 h. The solvent was
removed under reduced pressure, the residue was
ground with diethyl ether, and the precipitate was
filtered off, washed with diethyl ether, and dried under
reduced pressure. The product was purified by repre-
cipitation from methanol with diethyl ether. Yield
19.25 g (80%), mp 158–159°C, [α]D20 = –29.62° (c =
2.2, H2O). IR spectrum, ν, cm–1: 1737, 1675 (C=O),
1559 (δNH, amide). 1H NMR spectrum (D2O), δ, ppm:
1.72–1.91 m (3H, CH, CH2), 2.18–2.26 m (1H, CH),
2.82–2.91 m (1H, CH), 3.00–3.09 m (1H, CH), 3.11–
3.26 m (2H, CH2), 3.53 s (3H, CH3), 4.11–4.17 m (1H,
CH), 4.50–4.58 m (1H, CH), 7.01 d (2H, CH, J =
8.3 Hz), 7.10–7.23 m (3H, CH). 13C NMR spectrum
(D2O), δC, ppm: 23.66, 29.74, 36.31, 46.59, 53.22,
54.59, 59.46, 127.29, 128.81, 129.16, 136.33, 169.38,
173.02. Found, %: C 57.38; H 6.89; Cl 11.50; N 8.79.
C15H21ClN2O3. Calculated, %: C 57.60; H 6.77;
Cl 11.33; N 8.96.
The structure of all isolated compounds was
confirmed by IR and NMR spectra and elemental
analyses. Some signals in the NMR spectra of N-tert-
butoxycarbonyl-L-prolyl-L-phenylalanine methyl ester
were doubled; the signal doubling disappeared after
removal of the bulky tert-butoxycarbonyl group.
3-Benzylhexahydropyrrolo[1,2-a]pyrazine-1,4-
dione (1). a. Triethylamine, 6.22 g (61.6 mmol), was
added dropwise with vigorous stirring to a solution of
19.25 g (61.6 mmol) of L-prolyl-L-phenylalanine
methyl ester hydrochloride (2) in 100 mL of methylene
chloride. The precipitate was filtered off, the solvent
was removed from the filtrate under reduced pressure,
and the residue was extracted with diethyl ether. The
extract was filtered and evaporated under reduced
pressure. The residue was dissolved in 100 mL of
dioxane, and the solution was refluxed for 24 h with
vigorous stirring. The solvent was removed under
reduced pressure, and the residue was washed with
diethyl ether and dried under reduced pressure. The
product was purified by reprecipitation from methanol
with diethyl ether. Yield 10.23 g (68%), mp 135–
137°C, [α]D20 = –81.9° (c = 1, H2O); published data [9]:
mp 134–136°C, [α]D20 = –82.3° (c = 0.2, H2O).
1H NMR spectrum (CD3OD), δ, ppm: 1.18–1.27 m
(1H, CH), 1.72–1.80 m (2H, CH2), 2.04–2.11 m (1H,
CH), 3.15 d (2H, CH2, J = 5.5 Hz), 3.31–3.37 m (1H,
CH), 3.48–3.54 m (1H, CH), 4.00–4.08 m (1H, CH),
4.41 t (1H, CH, J = 5.5 Hz), 7.19–7.29 m (5H, Harom).
L-Phenylalanyl-L-proline methyl ester hydro-
chloride (3) was synthesized in a similar way from
29.74 g (79 mmol) of N-(tert-butoxycarbonyl)-L-
phenylalanyl-L-proline methyl ester (5) and 53 mL of
a 4.5 N solution of HCl in methanol. Yield 21.14 g
(86%), mp 148–151°C, [α]D20 = –37.53° (c = 2.0, H2O).
1
IR spectrum, ν, cm–1: 1743, 1654 (C=O). H NMR
spectrum (D2O), δ, ppm: 1.65–1.83 m (3H, CH, CH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

GAIDUKEVICH et al.
1564
2.04–2.13 m (1H, CH), 2.81–2.90 m (1H, CH), 2.95–
3.07 m (2H, CH2), 3.42–3.50 m (1H, CH), 3.60 s (3H,
CH3), 4.31–4.34 m (1H, CH), 4.39 t (1H, CH, J =
6.6 Hz), 7.18–7.29 m (5H, Harom). 13C NMR spectrum
(D2O), δC, ppm: 24.71, 28.81, 36.13, 47.71, 52.94,
53.06, 59.89, 128.16, 129.16, 129.96, 133.42, 167.94,
173.90. Found, %: C 57.83; H 6.95; Cl 11.39; N 8.66.
C15H21ClN2O3. Calculated, %: C 57.60; H 6.77;
Cl 11.33; N 8.96.
filtrate under reduced pressure, and the residue was
extracted with acetone. The extract was filtered and
evaporated under reduced pressure, the residue was
washed with hexane and reprecipitated from methylene
chloride with hexane, and the oily material was
separated and dried under reduced pressure until
constant weight. Yield 29.74 g (79%), [α]D20 = –48.6°
(c = 2.2, MeOH). IR spectrum, ν, cm–1: 1749, 1711,
1
1648 (C=O), 1521 (δNH, amide). H NMR spectrum
(CD3OD), δ, ppm: 1.38 s (9H, t-Bu), 1.80–2.00 m (3H,
CH, CH2), 2.78–2.86 m (1H, CH), 3.01–3.08 m (1H,
CH), 3.32–3.39 m (1H, CH), 3.67 s (3H, CH3), 3.69–
3.77 m (1H, CH), 4.40–4.47 m (1H, CH), 4.55 t (1H,
CH, J = 7.0 Hz), 7.20 d (2H, Harom, J = 8.3 Hz), 7.25–
7.33 m (3H, Harom). 13C NMR spectrum (CD3OD), δC,
ppm: 25.75, 28.69, 29.89, 38.71, 48.07, 52.62, 55.00,
60.37, 80.38, 127.65, 129.32, 130.54, 138.22, 157.35,
172.73, 173.73. Found, %: C 64.02; H 7.84; N 7.19.
C20H28N2O5. Calculated, %: C 63.81; H 7.50; N 7.44.
N-(tert-Butoxycarbonyl)-L-prolyl-L-phenyl-
alanine methyl ester (4). A solution of 21.52 g
(100 mmol) of N-tert-butoxycarbonyl-L-proline in
150 mL of tetrahydrofuran was cooled to 0°C, and
a solution of 20.6 g (100 mmol) of N,N′-dicyclohexyl-
carbodiimide in 200 mL of THF and a solution of
17.92 g (100 mmol) of L-phenylalanine methyl ester in
100 mL of THF were added in succession with vigor-
ous stirring. The mixture was allowed to warm up to
room temperature and stirred for 24 h. The precipitate
was filtered off, the solvent was removed from the
filtrate under reduced pressure, and the residue was
extracted with diethyl ether. The extract was filtered
and evaporated under reduced pressure, and the residue
was washed with hexane and dried under reduced
pressure. The product was purified by reprecipitation
from diethyl ether with hexane. Yield 28.96 g (77%),
mp 67–69°C, [α]D20 = –75.1° (c = 2, MeOH). IR spec-
trum, ν, cm–1: 1753, 1695, 1660 (C=O), 1555 (δNH,
The IR spectra were recorded in KBr on a Thermo
Nicolet Protégé-460 spectrometer with Fourier trans-
1
form. The H and 13C NMR spectra were recorded on
a Bruker Avance-500 spectrometer; the chemical shifts
were measured relative to the residual proton signal of
the solvent. All operations were performed using anhy-
drous organic solvents. L-Proline and L-phenylalanine
methyl ester hydrochlorides [6], N-tert-butoxycar-
bonyl-L-proline [7], and N-tert-butoxycarbonyl-L-
phenylalanine [8] were synthesized according to
known procedures. The optical rotations were
measured with an ATAGO AP-300 polarimeter.
1
amide). H NMR spectrum (CDCl3), δ, ppm: 1.36 s
(9H, t-Bu), 1.60–2.00 m (3H, CH, CH2), 2.17–2.25 m
(1H, CH), 2.87–2.98 m (1H, CH), 3.08–3.18 m (1H,
CH), 3.20–3.36 m (2H, CH2), 3.64 s (3H, CH3), 4.06–
4.20 m (1H, CH), 4.80 t (1H, CH, J = 6.3 Hz), 7.02 d
(2H, Harom, J = 8.3 Hz), 7.10–7.24 m (3H, Harom).
13C NMR spectrum (CDCl3), δC, ppm: 23.47, 24.55,
28.35, 30.70, 30.75, 38.18, 47.02, 52.36, 52.71, 53.33,
59.96, 61.09, 80.48, 80.73, 127.05, 128.58, 129.25,
135.94, 154.33, 155.09, 171.46, 171.94. Found, %:
C 63.93; H 7.71; N 7.62. C20H28N2O5. Calculated, %:
C 63.81; H 7.50; N 7.44.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018