Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists

Article abstract of DOI:10.1007/s00706-012-0880-8

N-Methyl-d-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiology and pharmacology of the NMDA receptor have kept interest alive in modulating NMDA receptors for therapeutic intervention. We present here the synthesis of a small library of phenylalaninol-derived oxazolopyrrolidone lactams and their evaluation as NMDA receptor antagonists. The compounds were easily synthesized in yields up to 92 %. In addition, one of the compounds has a 50 % inhibitory concentration (IC ₅₀) of 62 μM and offers potential to develop more potent NMDA receptor antagonists.

Full text of DOI:10.1007/s00706-012-0880-8

Monatsh Chem (2013) 144:473–477
DOI 10.1007/s00706-012-0880-8
ORIGINAL PAPER
Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams
and evaluation as NMDA receptor antagonists
•
Nuno A. L. Pereira Francesc X. Sureda Mireia Turch Mercedes Amat
•
•
•
•
Joan Bosch Maria M. M. Santos
Received: 28 September 2012 / Accepted: 13 November 2012 / Published online: 9 January 2013
Ó Springer-Verlag Wien 2012
Abstract N-Methyl-D-aspartate (NMDA) receptor antag-
onists are known to rescue neuronal cell death caused by
excessive activation of glutamate receptors. This phenome-
non, known as excitotoxicity, is implicated in the
pathogenesis of several neurodegenerative disorders includ-
ing ischemia, Alzheimer’s disease, Parkinson’s disease, and
Huntington’s disease. Unfortunately, some NMDA receptor
antagonists have shown discouraging results when tested in
clinical trials. However, recent advances in the physiology
and pharmacology of the NMDA receptor have kept interest
alive in modulating NMDA receptors for therapeutic inter-
vention. We present here the synthesis of a small library of
phenylalaninol-derived oxazolopyrrolidone lactams and
their evaluation as NMDA receptor antagonists. The com-
pounds were easily synthesized in yields up to 92 %. In
addition, one of the compounds has a 50 % inhibitory
concentration (IC50) of 62 lM and offers potential to develop
more potent NMDA receptor antagonists.
Keywords Amino alcohols ꢀ Chiral auxiliaries ꢀ
NMDA receptor antagonists ꢀ Pyrrolidones ꢀ Lactams
Introduction
N-Methyl-D-aspartate receptors (NMDAR) are part of the
family of ionotropic glutamate receptors. After activation by
their co-agonists, glycine and glutamate, they allow neural
influx of Ca2? through a membrane ion pore, thus playing an
important role in postsynaptic depolarization [1–4]. Apart
from their involvement in synaptic plasticity, which has been
postulated as the neurochemical basis of learning and
memory, NMDA receptors have been implicated in neuronal
death [5]. High levels of glutamate have been found in brain
trauma and other neurodegenerative diseases, so it is thought
that NMDA receptors are potential targets for neuroprotec-
tive compounds [6]. In fact, the adamantanes amantadine and
memantine develop their neuroprotective effects through
blockade at the NMDA receptor. Specifically, memantine is
authorized in Western countries and used therapeutically to
slow the progression of Alzheimer’s disease [7].
Dedicated to Professor Sundaresan Prabhakar on the occasion of his
75th anniversary.
N. A. L. Pereira ꢀ M. M. M. Santos (&)
Research Institute for Medicines and Pharmaceutical Sciences
(iMed.UL), Faculty of Pharmacy, University of Lisbon,
Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
e-mail: mariasantos@ff.ul.pt
In 2009, some orally active oxazolidine derivatives were
described to act as NMDA antagonists by preventing
binding of NMDAR ligands [8]. Based on this information
and due to our interest in the synthesis of oxazolo lactams
[9, 10], we decided to extend our research to synthesis of
enantiopure oxazolopyrrolidone lactams using (S)-phenyla-
laninol as a chiral inductor. Since the biological activity is
greatly affected by the absolute stereo-outcome of the
compounds, a series of (R)-phenylalaninol derivatives was
also prepared.
F. X. Sureda ꢀ M. Turch
Pharmacology Unit, Faculty of Medicine and Health Sciences,
Universitat Rovira i Virgili, c./St. Llorenc¸ 21, 43201, Reus,
Tarragona, Spain
M. Amat ꢀ J. Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy
and Institute of Biomedicine (IBUB), University of Barcelona,
Av. Joan XXIII, s/n, 08028, Barcelona, Spain
123

474
N. A. L. Pereira et al.
Results and discussion
CO2H
COR
Synthesis
O
2a 2c
-
OH
N
R
NH2
Toluene, reflux
Recently, our research group has been interested in syn-
thesis of phenylalaninol-derived oxazolopyrrolidone
lactams to be evaluated as NMDA receptor antagonists.
The first series of compounds was synthesized by cyclo-
condensation of (S)-phenylalaninol (1) with oxoacids
2a–2e (Scheme 1). In turn, tricyclic lactams 3a–3c were
prepared from 2-acylbenzoic acid derivatives 2a–2c via
reflux in toluene under Dean–Stark conditions (Table 1).
Starting from oxoacids 2d, 2e and using the same reaction
conditions, we obtained the bicyclic lactams 3d, 3e in
72–73 % yields (Table 1). In all cases, only one diaste-
reoisomer product was observed.
O
1'
Scheme 2
3a' 3c'
-
NMR spectroscopy
1
The most important features of the H nuclear magnetic
resonance (NMR) spectra of these compounds are the
resonances of the H-3, H-2, and CH2Ar protons. The H-3
signal appears as a multiplet around 4.33–4.48 ppm. The
diastereotopic H-2 protons appear as double doublets
around 4.08–4.33 ppm and 3.58–4.07 ppm. The methylene
CH2Ar protons appear as double doublets around
2.94–3.19 and 2.30–2.99 ppm. Furthermore, in the 13C
NMR spectra of compounds 3a–3c the newly formed C-9b
chiral center appears around 100 ppm. This signal moves
downfield as the electronic demand of the substituent is
increased: d = 90.78 (H), 98.93 (CH3), 101.04 (Ph) ppm.
Compound 3b0 underwent nuclear Overhauser spectros-
copy (NOESY) experiments, and it was possible to observe
the correlations depicted in Fig. 1. As expected and in
accordance with published results for very similar com-
pounds [9] synthesized via cyclocondensation with an
enantiopure aminoalcohol, the stereo-outcome does not
seem to be affected by the size of the keto-acid R
substituent.
To study the effect of the corresponding enantiomers as
antagonists at the NMDA receptor, lactams 3a0–3c0 were also
synthesized starting from (R)-phenylalaninol with 62–85 %
yields (Table 1; Scheme 2).
CO2H
COR
3
2a-2c
O
OH
N
Toluene, reflux
R
NH2
9b
O
1
3a-3c
CO2H
Toluene,
reflux
COR
2d, 2e
NMDA receptor antagonist activity
O
N
R
The NMDA receptor activity of the compounds was eval-
uated by measuring their ability to inhibit the intracellular
calcium increase induced by NMDA in cultured cerebel-
lar granule neurons. Addition of glutamate or NMDA
O
3d, 3e
Scheme 1
Table 1 Reaction of phenylalaninol enantiomers 1 and 10 with oxo
acids 2
Ha
Hb
O
H
H
Aminoalcohol
R
Reaction time/h
Product
Yield/%
(S)-Phenylalaninol
(S)-Phenylalaninol
(S)-Phenylalaninol
(S)-Phenylalaninol
(S)-Phenylalaninol
(R)-Phenylalaninol
(R)-Phenylalaninol
(R)-Phenylalaninol
H
16
16
16
48
48
16
16
16
3a
3b
3c
70
92
85
73
72
71
85
74
Me
Ph
Me
Ph
H
N
CH3
O
3d
3e
3a0
3b0
3c0
Me
Ph
Fig. 1 NOESY correlations observed for lactam 3b0
123

Evaluation as NMDA receptor antagonists
475
Memantine
´
performed in LCLEM, Faculdade de Farmacia, Universid-
ade de Lisboa. Merck silica gel 60 F254 plates were used for
analytical thin-layer chromatography (TLC); flash column
chromatography was performed on Merck silica gel
100
80
60
40
20
0
Amantadine
3c
3d
3e
(200–400 mesh). H and 13C NMR spectra were recorded
1
on a Bruker 400 MHz Ultra-Shield. Proton nuclear mag-
netic resonance spectra were recorded at 400 MHz. Carbon
nuclear magnetic resonance spectra were recorded at
100 MHz. H and 13C NMR chemical shifts are expressed
1
in d (ppm) referenced to the solvent used and the proton
coupling constants J in hertz (Hz). Spectra were assigned
using appropriate correlation spectroscopy (COSY), distor-
tionless enhancement by polarization transfer (DEPT),
and heteronuclear multiple quantum coherence (HMQC)
sequences.
-7
-6
-5
-4
-3
log ([drug]/M)
Fig. 2 Inhibitory effect of the synthesized compounds and the
adamantanes memantine and amantadine on NMDA-induced intra-
cellular calcium increase in cultured cerebellar granule neurons. The
compounds were tested from 0.1 lM up to the highest possible
concentration. Data are the mean of three different experiments,
carried out on three different batches of cultured cells
General procedure for the cyclocondensation reaction
of (S)-2-amino-3-phenylpropan-1-ol (1) with keto-acids
2a–2e
(100 lM) in the presence of glycine (10 lM) produced a
robust and stable increase in intracellular calcium that was
challenged with cumulative additions of the compounds to
be tested.
To a stirred solution of (S)-2-amino-3-phenylpropan-1-ol in
boiling toluene under inert atmosphere and a Dean–Stark
apparatus was added 1.1 eq. of the desired oxo-acid. The
mixture was refluxed until total consumption of the starting
aminoalcohol. The solvent was evaporated and the crude
residue was purified by column chromatography using
ethyl acetate/n-hexane as eluent. The solid products were
recrystallized in diethyl ether/n-hexane.
In our assays, memantine (used as a positive control)
yielded an IC50 value in the low micromolar range
(1.48 lM). As shown in Fig. 2, only three out of the eight
synthesized compounds showed inhibitory activity higher
than 50 % of maximal effect. Specifically, 3c and 3d
showed IC50 in the high micromolar range ([250 lM),
while 3e showed higher potency as a NMDA antagonist,
giving an IC50 of 62.0 lM. Related to compound 3c, which
showed an IC50 of 309.7 lM, the enantiomer 3c0 was
inactive, so it seems that the stereochemistry at the
3-position is important for activity. More importantly, the
phenyl derivative 3e is more potent as an NMDA receptor
antagonist than amantadine (92.0 lM).
In summary, we have synthesized and fully character-
ized several phenylalaninol-derived oxazolopyrrolidone
lactams. In addition, we describe herein the potential use of
lactam 3e as a hit compound to develop NMDA receptor
antagonists. These data provide a basis for exploring
whether related derivatives have enhanced activity. The
synthesis and biological evaluation of more compounds
related to 3e are underway.
(3S,9bR)-3-Benzyl-2,3-dihydrooxazolo[2,3-a]isoindol-
5(9bH)-one (3a)
Prepared from 90 mg of (S)-2-amino-3-phenylpropan-1-ol
in 10 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 3:7). Recrystal-
lization from diethyl ether/n-hexane afforded 110 mg
(70 %) 3a. The 1H NMR spectrum was found to be
identical with the one described in Ref. [11].
(3S,9bR)-3-Benzyl-2,3-dihydro-9b-methyloxazolo[2,3-a]-
isoindol-5(9bH)-one (3b, C18H17NO2)
Prepared from 330 mg of (S)-2-amino-3-phenylpropan-1-ol
in 30 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 3:7) affording
560 mg (92 %) of 3b as a colorless oil. 1H NMR
(400 MHz, CDCl3): d = 7.69 (d, J = 7.4 Hz, 1H, H–Ar),
7.54 (m, 1H, H–Ar), 7.45 (m, 2H, H–Ar), 7.27 (m, 4H, H–Ar),
7.20 (m, 1H, H–Ar), 4.39 (m, 1H, H-3), 4.21 (dd, J = 8.9,
7.4 Hz, 1H, H-2), 4.07 (dd, J = 8.9, 6.5 Hz, 1H, H-2), 3.21
(dd, J = 13.8, 5.8 Hz, 1H, CH2–Ph), 2.95 (dd, J = 13.8,
8.6 Hz, 1H, CH2–Ph), 1.69 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 174.20 (C=O), 147.26 (Cq),
137.27 (Cq), 133.22 (CH–Ar), 131.60 (Cq), 130.16 (CH–
Ar), 129.45 (2CH–Ar), 128.59 (2CH–Ar), 126.80 (CH–Ar),
124.33 (CH–Ar), 122.10 (CH–Ar), 98.93 (C-9b), 74.06
Experimental
All reagents and solvents were obtained from commercial
suppliers and were used without further purification. Melting
points were determined using a Kofler camera Bock mono-
scope M. The infrared spectra were collected on a Shimadzu
IRAffinity-1 Fourier-transform infrared (FT-IR) spectro-
photometer. Low-resolution mass spectroscopy (MS) was
123

476
N. A. L. Pereira et al.
(CH2), 56.77 (CH), 40.89 (CH2–Ph), 23.02 (CH3) ppm; IR
(NaCl): m = 1,715 (C=O) cm-1; MS (ESI, CP 3.0 kV, SP
30 V): m/z calc. 279 [M]?, m/z found 280 [M?H]?; Rf
(ethyl acetate:n-hexane 1:1) = 0.77.
(CH), 39.92 (CH2–Ph), 35.05 (C-7), 32.57 (C-6) ppm; IR
(KBr): m = 1,721 (C=O) cm-1; MS (ESI, CP 3.0 kV, SP
30 V): m/z calc. 293 [M] ?, m/z found 294 [M?H]?; Rf
(ethyl acetate:n-hexane 3:7) = 0.31.
(3S,9bR)-3-Benzyl-2,3-dihydro-9b-phenyloxazolo[2,3-a]-
isoindol-5(9bH)-one (3c, C23H19NO2)
General procedure for the cyclocondensation reaction
of (R)-2-amino-3-phenylpropan-1-ol (10)
with keto-acids 2a–2c
Prepared from 100 mg of (S)-2-amino-3-phenylpropan-1-ol
in 7 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 1:9). Recrystal-
lization from diethyl ether/n-hexane afforded 193 mg
To a stirred solution of (R)-2-amino-3-phenylpropan-1-ol
in boiling toluene under inert atmosphere and a Dean–Stark
apparatus was added 1.1 eq. of the desired oxo-acid. The
mixture was refluxed until total consumption of the starting
aminoalcohol. The solvent was evaporated and the crude
residue was purified by column chromatography using
ethyl acetate/n-hexane as eluent.
1
(86 %) 3c. M.p.: 92–94 °C; H NMR (400 MHz, CDCl3):
d = 7.80–7.75 (m, 1H, H–Ar), 7.68–7.62 (m, 2H, H–Ar),
7.50–7.37 (m, 5H, H–Ar), 7.31–7.20 (m, 4H, H–Ar),
7.17–7.14 (m, 2H, H–Ar), 4.66–4.52 (m, 1H, H-3), 4.44
(dd, J = 8.6, 7.5 Hz, 1H, H-2), 3.96 (dd, J = 8.7, 6.6 Hz,
1H, H-2), 3.02 (dd, J = 13.8, 6.8 Hz, 1H, CH2–Ph), 2.51
(dd, J = 13.8, 8.7 Hz, 1H, CH2–Ph) ppm; 13C NMR
(100 MHz, CDCl3): d = 174.52 (C=O), 147.27 (Cq),
138.95 (Cq), 137.61 (Cq), 133.41 (CH–Ar), 131.10 (Cq),
130.23 (CH–Ar), 129.11 (2CH–Ar), 128.94 (2CH–Ar),
128.86 (CH–Ar), 128.64 (2CH–Ar), 126.77 (CH–Ar),
125.96 (2CH–Ar), 124.52 (CH–Ar), 123.56 (CH–Ar),
101.04 (C-9b), 75.91 (CH2), 56.80 (CH), 40.54 (CH2–Ph)
ppm; IR (KBr): m = 1,721 (C=O) cm-1; MS (ESI, CP
3.0 kV, SP 30 V): m/z calc. 341 [M]?, m/z found 342
[M?H]?; Rf (ethyl acetate:n-hexane 3:7) = 0.61.
(3R,9bS)-3-Benzyl-2,3-dihydrooxazolo[2,3-a]isoindol-
5(9bH)-one (3a0)
Prepared from 100 mg of (R)-2-amino-3-phenylpropan-1-ol
in 15 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 2:8). Recrystal-
lization from diethyl ether/n-hexane afforded 125 mg
(71 %) 3a0. The 1H NMR spectrum was found to be
identical with the one described in Ref. [11].
(3R,9bS)-3-Benzyl-2,3-dihydro-9b-methyloxazolo[2,3-a]-
isoindol-5(9bH)-one (3b0, C18H17NO2)
(3S,7aR)-3-Benzyl-tetrahydro-7a-methylpyrrolo[2,1-b]-
oxazol-5(6H)-one (3d)
Prepared from 100 mg of (R)-2-amino-3-phenylpropan-1-ol
in 15 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 2:8) affording
157 mg (85 %) of a colorless oil. 1H NMR, 13C NMR, and
IR spectra were found to be identical with the ones
described for compound 3b.
Prepared from 100 mg of (S)-2-amino-3-phenylpropan-1-ol
in 10 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 1:1) affording
111 mg (73 %) of 3d as a colorless oil. The 1H NMR
spectrum was found to be identical with the one described
in Ref. [12].
(3R,9bS)-3-Benzyl-2,3-dihydro-9b-phenyloxazolo[2,3-a]-
isoindol-5(9bH)-one (3c0, C23H19NO2)
(3S,7aS)-3-Benzyl-tetrahydro-7a-phenylpyrrolo[2,1-b]-
oxazol-5(6H)-one (3e, C19H19NO2)
Prepared from 100 mg of (R)-2-amino-3-phenylpropan-1-ol
in 15 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 2:8). Recrystal-
lization from diethyl ether/n-hexane afforded 167 mg
Prepared from 100 mg of (S)-2-amino-3-phenylpropan-1-ol
in 10 cm3 of toluene. The obtained residue was purified by
column chromatography (AcOEt:n-hexane 3:7). Recrystal-
lization from diethyl ether/n-hexane afforded 140 mg
1
(74 %) of 3c0. H NMR, 13C NMR, and IR spectra were
found to be identical with the ones described for compound
1
(72 %) 3e. M.p.: 55–56 °C; H NMR (400 MHz, CDCl3):
3c.
d = 7.51 (d, J = 7.4 Hz, 2H, H–Ar), 7.44–7.38 (m, 3H,
H–Ar), 7.28–7.21 (m, 3H, H–Ar), 7.08 (d, J = 7.3 Hz, 2H,
H–Ar), 4.50–4.35 (m, 1H, H-3), 4.13 (t, J = 8.1 Hz, 1H,
H-2), 3.65–3.49 (m, 1H, H-2), 2.94 (dd, J = 13.7, 6.2 Hz,
1H, CH2–Ph), 2.89–2.77 (m, 1H, H-6), 2.63–2.45 (m, 2H,
H-6 and H-7), 2.35–2.18 (m, 2H, CH2–Ph and H-7) ppm;
13C NMR (100 MHz, CDCl3): d = 179.87 (C=O), 142.55
(Cq), 137.26 (Cq), 128.90 (2CH–Ar), 128.70 (2CH–Ar),
128.49 (2CH–Ar), 128.31 (CH–Ar), 126.60 (CH–Ar),
125.07 (2CH–Ar), 102.27 (C-7a), 72.26 (CH2), 56.44
NMDA receptor antagonist activity
The activity of the synthesized compounds as NMDA
receptor antagonists was evaluated using primary cultures
of rat cerebellar neurons, as described previously [13].
Briefly, cultures were prepared from 7–8-day-old Wistar
rats (Charles River, France). Cerebella were dissected,
minced, and trypsinized, and after several sedimentations,
cells were plated on poly-lysinized coverslips placed in
123

Evaluation as NMDA receptor antagonists
477
24-well plates at density of 1 9 106 cells/cm3. Plates
were kept at 37 °C in a cell incubator (Heraeus, Germany).
After 16–18 h, 10 lM cytosine arabinoside (Sigma-Aldrich,
USA) was added to avoid excessive proliferation of astro-
cytes. Cultures prepared in this manner are ready to be used in
NMDA receptor activity assays from the 7th to 11th day
in vitro.
inhibition was reached, the IC50 value was calculated using
nonlinear regression with GraphPad Prism 5.0.
ˆ
Acknowledgments Fundac¸a˜o para a Ciencia e Tecnologia (Portu-
gal) is acknowledged for financial support (PTDC/QUI-QUI/111664/
2009; PEst-OE/SAU/UI4013/2011; REDE/1518/REM/2005). We also
thank the Portuguese–Spanish Integrated Action (E-07/11 and
AIB2010PT-00324) and the Spanish Ministerio de Ciencia e Inno-
´
vacion (MICINN) (CTQ2009-07021/BQU) for financial support.
Activity at the NMDA receptor was assessed using the
calcium-sensitive probe fura-2 (Invitrogen, USA). After
incubation with 6 lM fura-2 acetoxymethyl ester (fura-2 AM)
for 30–45 min at 37 °C, a coverslip was transferred to a
plastic holder that was inserted into a quartz cuvette for
fluorescence measurements. Recordings of fura-2 fluores-
cence were performed using a PerkinElmer LS50B
luminescence spectrometer, at both 340 and 380 nm exci-
tation wavelengths, and at 510 nm emission. The ratio
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340/F380 (R) is proportional to intracellular calcium. All
measurements were made at 37 °C and under mild stirring.
Once the recording was started, glycine (10 lM) and
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