Primary Amine–Promoted Ring Opening in Carbapenem-derived p-Nitrobenzyl Esters

Article abstract of DOI:10.1134/S1070428020020189

Abstract: Ethylamine and ethanolamine react with 4-nitrobenzyl (4R,5S,6S)-3-[(2-furylmethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, leading to the opening of the β-lactam ring by C⁷–N bond c

Full text of DOI:10.1134/S1070428020020189

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 2, pp. 287–291. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 2, pp. 290–295.
Primary Amine–Promoted Ring Opening in
Carbapenem-derived p-Nitrobenzyl Esters
Z. R. Valiullinaa,*, А. М. Galeevaa, А. N. Lobova, and М. S. Miftakhova
a Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia
*e-mail: valiullina.zulya@mail.ru
Received October 7, 2019; revised January 17, 2020; accepted January 20, 2020
Abstract—Ethylamine and ethanolamine react with 4-nitrobenzyl (4R,5S,6S)-3-[(2-furylmethyl)sulfanyl]-
6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, leading to the opening
of the β-lactam ring by C7–N bond cleavage accompanied and simultaneous amidation of the ester groups. In
this anionoid transformation, the enamine–imine rearrangement followed by stereoselective protonation provides
the formation of enantiomerically pure pyrrolidine derivatives: (2S,3R,4S)-N-ethyl-2-{(1S,2R)-1-[(ethylamino)-
carbonyl]-2-hydroxypropyl}-4-[(2-furylmethyl)sulfanyl]-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxamide and
(2S,3R,4S)-4-[(2-furylmethyl)sulfanyl]-N-(2-hydroxyethyl)-2-[(1S,2R)-2-hydroxy-{[(2-hydroxyethyl)-amino]-
carbonyl}propyl]-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxamide.
Keywords: synthesis, carbapenem, ethanolamine, ethylamine, decyclization transformations, enamine–imine re-
arrangement
DOI: 10.1134/S1070428020020189
Carbapenems are top-ranked and widely used
β-lactam antibiotics [1]. Carbapenems are obtained
by chemical synthesis [2]. One of the costly stages in
the synthesis of carbapenems 1 are hydrogenolysis of
nitrobenzyl ester 2 and purification of acid 1. The yields
of acid 1 at this stage are generally as low as ~ 20–30%
(Scheme 1) [3–6].
Keeping a solution of compound 3 in THF with
2 equiv of 70% aqueous EtNH2 at room temperature for
12 h gave cyclic imine 4, enamine 5, and p-nitrobenzyl
alcohol 6. The reaction of equimolar amounts of
carbapenem3andmonoethanolamineinTHF(20°С,12h)
occurred by a similar scheme, leading to compounds 7,
8, and 6 (Scheme 2).
As known, the opening of a strained β-lactam with
hydroxy and amino nucleophiles involves formation
of a tetrahedral intermediate followed by С7–N bond
cleavage [8–10]. A similar tetrahedral intermediate
should take place in the case of amidation in the
activated ester moiety of carbapenem 3. The possible
ways of formation of imine 4 is shown in Scheme 3.
In view of the potential destructive potential of alko-
xide and hydroxide anions in the course of isolation and
purification of acid 1, we studied the reaction of a model
carbapenem3[7]withaqueousEtNH2 andethanolamine,
assumingthat, alongwithlactamringopening, amidation
in the ester moiety would occur to form, instead of
compound 2, the corresponding, more stable ethyl- and
ethanolamides, which would ensure more unambiguous
results in subsequent possible transformations.
As seen from the scheme, N-centered carbanion А
formed by lactam ring opening undergoes rearrangement
Scheme 1.
OH
OH
H
H
N
H H
SR
H2, Pd/C
MeOH
SR
N
O
OPNB
O
COOH
O
2
1
PNB = p-nitrobenzyl.
287

288
VALIULLINA et al.
Scheme 2.
OH
HO
H
H
C
H
HO
H
H
S
S
+
+
O
O
N
HN
O
COOPNB
O
O
NHEt
NHEt
NO2
6 (47%)
NHEt
4 (48%)
5 (46%)
EtNH2 THF
OH
H H
S
O
N
3
O
COOPNB
NH2CH2CH2OH THF
HO
HO
H
H
S
H
H
H
S
+
6 (20%)
+
O
O
N
HN
NH
O
O
O
C
COOPNB
NH
HN
HO
HO
OH
7 (23%)
8 (65%)
in a charged cyclic imine В, where the lone electron pair
of the pyramidal anionic center points to the β region.
This lifts the steric hindrances associated with the α
orientation of the electron pair, and, finally, EtNH3
protonated В to form imine 4. A similar pathway is
suggested for the formation of compound 7.
Spectral data provide further evidence for the
suggested assessment of the С4 center. The B3LYP/6-
311+G(d,p) geometry optimization of imine 4 with the
R- and S-configuration of the newly formed chiral center
C4 predicted the spatial proximity of the Н4/H3 and
Н4/C3–Ме protons in the 4(S) diastereomer and NOE
+
Scheme 3.
OH
OH
H
H
H
H
S
S
O
2 EtNH2
O
O
N
O
N
3
O
O
NH2
OPNB
NH2
NH
OPNB
NH
EtNH3
EtNH3
OH
OH
O
H
H
N
H
H
S
S
_
EtNH3+
O
O
O
O
4
N
NH
O
NH
A
B
NH
NH
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PRIMARY AMINE–PROMOTED RING OPENING IN CARBAPENEM-DERIVED
289
C3-Me
Me
Me
H4
H2 H2'
H1' H3
/
1.0
H4/C3–Me
1.5
2.0
2.5
3.0
3.5
4.0
4.5
H4/H3
Fig. 1. Structures of the 4(S) and 4(R) diastereomers of
compound 4.
interactions for H4/H2 and H4/H3 proton couples in
the 4(R) diastereomer (Fig. 1). The NOESY spectrum
of compound 4 (Fig. 2) showed cross peaks δH
3.92/2.40 ppm and 3.92/0.95 ppm, which, according to
our assignments, corresponds to the 4(S) configuration.
Furthermore, in was established that the H4–H3 dihedral
angle in the 4(S) diastereomer is close to 90°, which
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
ppm
Fig. 2. {1H, 1H} NOESY spectrum of compound 4 (4S).
1
is reflected in the H NMR spectrum: H4 appears as a
elemental analyses were obtained on a Euro-EA 3000
CHNS analyzer. Reaction progress was monitored by
TLC on Sorbfil plates, spot visualization by spraying
plates with a solution of anisaldehyde and sulfuric
acid in ethanol and subsequent heating at 120–150°С.
The synthesized compounds were isolated by column
chromatography on a Macherey–Nayel silica gel (30–
60 g per 1 g of compound). Solvents were purified by
conventional procedures [12].
singlet at δH 3.92 ppm, and the doublet–quartet signal
3
3
of H3 (δH 2.40 ppm, J3–2 5.7, J3-Ме 7.1 Hz) shows no
splitting from H4.
Using the example of carbapenem 3, we could
demonstrate 2 characteristic decomposition pathways
of carbapenems under the action of primary
amines. Experiments on the isolation of acid 1 after
hydrogenolysis of PNB ester 3 showed formation of
a mixture of hardly identifiable by-products. Note
that compounds 4, 5 and 7, 8 present interest as novel
biologically active structures and potential β-lactamase
inhibitors [11].
(2S,3R,4S)-N-Ethyl-2-{(1S,2R)-1-[(ethylamino)-
carbonyl]-2-hydroxypropyl}-4-[(furan-2-ylmethyl)-
sulfanyl]-3-methyl-3,4-dihydro-2H-pyrrol-5-
carboxamide (4) and 4-nitrobenzyl (4R,5S)-5-
{(1R)-1-[(ethylamino)carbonyl]-2-methylpropyl}-3-
[(furan-2-ylmethyl)sulfanyl]-4-methyl-4,5-dihydro-
1Н-pyrrol-2-cerboxylate (5). A 70% aqueous EtNH2,
37 μL (0.46 mmol), was added to a stirred solution of
95 mg (0.21 mmol) of carbapenem 3 in 5 mLof THF, and
the resulting mixture was stirred at room temperature
for 12 h. The solvent was then evaporated, and the
residue was subjected to column chromatography on
SiO2 (eluent CH2Cl2–CH3OH, 80 : 1→10 : 1) to isolate
50 mg (48%) of enamine 4, 38 mg (46%) of imine 5, and
15 mg (47%) of alcohol 6.
EXPERIMENTAL
The IR spectra were obtained on a Shimadzu IR
Prestige-21 spectrophotometer in mineral oil. The 1Н and
13СNMRspectrawererecordedonaBrukerAVANCE-500
spectrometer at 500.13 (1H) and 125.77 (13С) МHz in
CDCl3 and (CD3)2CO. The chemical shifts in the 13C
NMR spectra were measured with reference to the
carbon signals of CDCl3 and (CD3)2CO (δС 77.00 and
1
28.83 ppm, respectively) and in the H NMR spectra,
with reference to the residual proton signals of CDCl3
and (CD3)2CO (δ 7.27 and 2.07 ppm, respectively). The
ESI(+) mass spectra were measured on a Shimadzu
LCMS-2010EV instrument (syringe injection of a
sample dissolved in chloroform/acetonitrile at a flow
rate 0.1 mL/min, eluent acetonitrile–water, 95 : 5) in the
positive ion mode, electrode potential 4.5 kV; interface
capillary temperature 250°С, nebulizing gas (nitrogen)
flow rate 1.5 L/min for APCI. The rotation angles were
measured on a Perkin-Elmer 341 M instrument. The
Imine 4. Light yellow oily liquid. [α]D20 –107° (с 1.0,
CH2Cl2). IR spectrum, ν, cm–1: 3420, 3360, 2955, 1703,
1680, 1655, 1445, 1225, 1100, 1030. 1Н NMR spectrum
(500 МHz, CDCl3), δ, ppm: 0.95 d (3H, C3–CH3, J
7.2 Hz), 1.23 t (3Н, CH3, J 7.2 Hz), 1.28 t (3Н, СH3, J
7.3 Hz), 1.34 d (3Н, C2'–СH3, J 6.3 Hz), 2.40 d.q (1Н,
H3, 3J3–2 5.7 Hz, 3J3-Ме 7.1 Hz), 2.64 d.d (1Н, H1', 3J1'–2
9.8, 3J1'–2' 4.8 Hz), 3.30–3.50 m (4Н, CH2N), 3.89 d (1Н,
CH2S, J 14.8 Hz), 3.92 s (1Н, H4), 4.05 d.q (1Н, H2',
2
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VALIULLINA et al.
Imine 7. Colorless oily liquid. [α]D20 –105° (с 1.0,
CH3OH). IR spectrum, ν, cm–1: 3460, 3350, 2985, 1700,
1675, 1655, 1439, 1221, 1110, 1015. 1Н NMR spectrum
(500МHz,acetone-d6),δ,ppm:0.89d(3H,CH3,J7.2Hz),
1.20 d (3Н, CH3, J 6.6 Hz), 2.50 d.q (1Н, H3, J 7.2,
5.5 Hz), 2.60 d.d (1Н, H1', J 9.7, 7.5 Hz), 3.30–3.70 m
(8Н, 2CH2N, 2CH2OH), 3.84 s (1Н, Н4), 3.85 d (1Н,
CH2S, J 14.7 Hz), 4.08 d.q (1Н, Н2', J 6.6, 7.5 Hz), 4.12 d
(1Н, CH2S, J 14.7 Hz), 4.42 d.d (1Н, Н2, J 9.7, 5.5 Hz),
6.35 s (2Нfuran), 7.35 br.s (1Н, NH), 7.45 s (1Нfuran),
8.00 br.s (1Н, NH). 13С NMR spectrum (125 МHz,
acetone-d6), δ, ppm: 14.81 (CH3), 21.07 (CH3), 28.44
(CH2S), 41.59 (CH2N), 41.94 (CH2N), 45.41 (C3), 53.31
(C1'), 55.51 (C4), 60.66 and 60.83 (CH2OH), 67.70 (C2'),
73.50 (C2), 107.89 (CHfuran), 110.37 (CHfuran), 142.39
(CHfuran), 151.66 (Cfuran), 161.95 (CONH), 169.56 (C5),
173.57 (CONH). Mass spectrum, m/z (Irel, %): 428 (100)
[M + H]+. Found, %: C 53.47; H 6.72; N 9.69; S 7.62.
C19H29N3O6S. Calculated, %: C 53.38; H 6.84; N 9.83;
S 7.50.
3J2'–1' 4.8, J2'-Ме 6.3 Hz), 4.20 d (1Н, CH2S, 2J 14.8 Hz),
3
4.46 d.d (1Н, H2, J2–1' 9.8, J2–3 5.7 Hz), 6.39 m
(2Нfuran), 6.58 t (1Н, NH, J 5.3 Hz), 7.10 t (1Н, NH, J
5.9 Hz), 7.45 s (1Нfuran). 13С NMR spectrum (125 МHz,
CDCl3), δ, ppm: 14.61 (CH3), 11.64 (C3–CH3), 20.17
(C2'–CH3), 29.29 (CH2S), 34.22 (CH2N), 34.37 (CH2N),
44.98 (C3), 51.63 (C1'), 55.01 (C4), 67.55 (C2'), 71.29
(C2),108.36(CHfuran),110.51(CHfuran),142.39(CHfuran),
151.04 (Cfuran), 161.17 (С5–CONH), 170.43 (С5), 172.93
(СONH).15NNMRspectrum(500МHz,CDCl3),δ,ppm:
114.45 (NH, С5–CONHEt), 124.59 (NH, С1''–CONHEt).
Mass spectrum, m/z (Irel, %): 396 (100) [M + H]+. Found,
%: C 57.59; H 7.52; N 10.48; S 8.25. C19H29N3O4S.
Calculated, %: C 57.70; H 7.39; N 10.62; S 8.11.
Enamine 5. Colorless oily liquid. [α]D20 –44° (с
1.0, CH2Cl2). IR spectrum, ν, cm–1: 3460, 3345, 2923,
1730, 1695, 1655, 1596, 1514, 1445, 1345, 1225, 1115,
1
1045, 895. Н NMR spectrum (500 МHz, acetone-d6),
δ, ppm: 1.03 d (3H, CH3, J 6.8 Hz), 1.08 t (3Н, CH3, J
7.2 Hz), 1.14 d (3Н, СH3, J 6.2 Hz), 2.70 d.d (1Н, H1',
J 10.2, 5.6 Hz), 3.12–3.32 m (3Н, H4, CH2N), 3.67 m
(1Н, H5), 3.95 d (1Н, CH2S, J 14.6 Hz), 3.97 m (1Н,
H2'), 4.10 d (1Н, CH2S, J 14.6 Hz), 4.24 br.s (1H, OH),
5.35 d (1Н, OCH2, J 13.7 Hz), 5.40 d (1Н, OCH2, J 13.7
Hz), 6.26 d (1Нfuran, J 2.9 Hz), 6.35 d.d (1Нfuran, J 2.9,
1.8 Hz), 7.20 br.s (2Н, NH), 7.47 d (1Нfuran, J 0.8 Hz),
7.72 d (2Нarom, J 8.7 Hz), 8.25 d (2Нarom, J 8.7 Hz).
13С NMR spectrum (125 МHz, acetone-d6), δ, ppm:
11.10 (CH3), 14.29 (CH3), 19.78 (CH3), 28.36 (CH2S),
33.57 (CH2N), 42.82 (C4), 53.40 (C1'), 61.19 (C5), 64.67
(CH2O), 66.98 (C2'), 107.54 (CHfuran), 110.52 (CHfuran),
123.44 (CHarom), 128.07 (C3), 128.55 (СHarom), 134.94
(С2), 142.94 (CHfuran), 143.94 (Carom), 147.66 (C–NO2),
151.75(Cfuran),160.80(СO2),171.80(CONH).Massspec-
trum,m/z(Irel,%):504(100)[M+H]+.Found,%:C57.12;
H 5.67; N 8.41; S 6.46. C24H29N3O7S. Calculated, %:
C 57.24; H 5.80; N 8.34; S 6.37.
Enamine 8. Colorless oily liquid. [α]D20 –6° (с 1.0,
CH2Cl2). IR spectrum, ν, cm–1: 3455, 3335, 2930, 1735,
1681, 1662, 1586, 1520, 1431, 1352, 1218, 1108, 1021,
887. 1Н NMR spectrum (500 МHz, acetone-d6), δ, ppm:
1.05d(3H,CH3,J6.7Hz),1.16d(3Н,C2'–CH3,J6.3Hz),
2.80 d.d (1Н, H1', J 9.8, 5.5 Hz), 3.24 d.q (1Н, H4, J
6.7, 7.9 Hz), 3.35 m (2Н, CH2N), 3.60 t (2Н, CH2OH,
J 5.45 Hz), 3.67 d.d (1Н, H5, J 9.8, 7.9 Hz), 3.98 d (1Н,
CH2S, J 14.6 Hz), 4.00 m (1Н, H2'), 4.12 d (1Н, CH2S, J
14.6 Hz), 5.34 d (1Н, CH2OPh, J 13.8 Hz), 5.42 d (1Н,
CH2OPh, J13.8Hz), 6.28d.d(1Нfuran, J3.0, 0.9Hz), 6.36
d.d (1Нfuran, J 3.0, 1.8 Hz), 7.37 t (2Н, 2NH, J 5.7 Hz),
7.47 d.d (1Нfuran, J 1.8, 0.9 Hz), 7.74 d (2Нarom, J 8.5 Hz),
8.25 d (2Нarom, J 8.5 Hz). 13С NMR spectrum (125 МHz,
acetone-d6), δ, ppm: 11.96 (C4–CH3), 20.47 (C2'–
CH3), 29.84 (CH2S), 42.67 (CH2N), 43.62 (C4), 54.22
(C1'), 61.83 (C5), 61.88 (CH2OH), 65.56 (OCH2Ph),
67.72 (C2'), 108.45 (CHfuran), 111.42 (CHfuran), 124.35
(CHarom), 129.12 (C3), 129.44 (CHarom), 135.78 (C2),
143.15 (CHfuran), 144.86 (Carom), 148.56 (Carom), 152.65
(Cfuran), 161.67 (CО2), 173.46 (СONH). Mass spectrum,
m/z (Irel, %): 520 (100) [M + H]+. Found, %: C 55.61;
H 5.72; N 7.97; S 6.02. C24H29N3O8S. Calculated, %:
C 55.48; H 5.63; N 8.09; S 6.17.
(2S,3R,4S)-4-[(Furan-2-ylmethyl)sulfanyl]-
N-(2-hydroxyethyl)-2-((1S,2R)-2-hydroxy-{[(2-
hydroxyethyl)amino]carbonyl}propyl)-3-methyl-
3,4-dihydro-2H-pyrrol-5-carboxamide
(7)
and
4-nitrobenzyl (4R,5S)-3-[(furan-2-ylmethyl)sulfa-
nyl]-5-((2R)-2-hydroxy-1-{[(2-hydroxyethyl)amino]-
carbonyl}propyl)-4-methyl-4,5-dihydro-1H-pyrrol-
2-carboxylate (8). A solution of 0.10 g (0.22 mmol) of
carbapenem 3 and 0.14 mL(0.24 mmol) of ethanolamine
in 6 mL of dry THF was stirred at room temperature for
12 h. The solvent was then evaporated in a vacuum, and
the residue was subjected to column chromatography on
SiO2 (CH2Cl2–CH3OH, 80 : 1→10 : 1) to isolate 74 mg
(65%) of enamine 8, 22 mg (23%) of imine 7, and 6 mg
(20%) of alcohol 6.
ACKNOWLEDGMENTS
Analyses were performed using the equipment of the
Khimiya Center for Collective Use, Ufa Institute of Chemistry,
Ufa Federal Research Center, Russian Academy of Sciences.
FUNDING
The work was financially supported by the Russian
Science Foundation (project no. 15-13-00039-P).
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
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