An improved synthesis of enantiomerically pure CIP-AS, a potent and selective AMPA-kainate receptor agonist

Article abstract of DOI:10.1016/S0957-4166(01)00225-7

CIP-AS (-)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitr

Full text of DOI:10.1016/S0957-4166(01)00225-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1363–1367
An improved synthesis of enantiomerically pure CIP-AS, a
potent and selective AMPA-kainate receptor agonist
Paola Conti,* Gabriella Roda and Federico F. Barberis Negra
Istituto di Chimica Farmaceutica e Tossicologica, Universita` di Milano, v. le Abruzzi, 42-20131 Milan, Italy
Received 27 April 2001; accepted 16 May 2001
Abstract—CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic
AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycar-
bonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based
on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-a-ethoxycarbonylnitrone 12. The mixture of stereoiso-
meric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycar-
bonyl-D2-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory
overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency. © 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The definition of the physiological and pharmacological
relevance of the different excitatory amino acid recep-
tors is strictly dependent on the availability of highly
selective ligands. From this viewpoint, even though a
number of agonists and antagonists selectively acting at
AMPA or KAIN receptors have been reported,2,10
there is still a demand for pharmacological tools capa-
ble to discriminate the different receptor subtypes.
(S)-Glutamic acid 1 (Fig. 1), the main excitatory neuro-
transmitter in the mammalian central nervous system
(CNS), is involved in important physiological processes
such as neural plasticity, memory and learning.1 More-
over, impairment of excitatory pathways seems to play
a crucial role in the pathogenesis of a number of acute
and chronic neurological disorders, e.g. stroke and
brain injury, as well as chronic neurodegenerative
pathologies, notably Huntington’s, Parkinson’s, and
Alzheimer’s diseases.2 The effects of glutamic acid are
mediated by a variety of presynaptic and postsynaptic
neuronal receptors, which have been grouped in two
families: the ionotropic (iGlu)3,4 and metabotropic
(mGlu)5,6 receptors. The iGluRs are multimeric Glu-
gated channels, which regulate the flux of cations (Na+,
K+, and Ca2+) across the synaptic membrane. Based on
the activation by specific agonists, the iGluRs have
In the recent past, we synthesized and tested a group of
regioisomeric 3-carboxy(3-hydroxy)isoxazolinyl proli-
nes,11–13 designed as semi-rigid analogues of glutamic
N
COOH
O
COOH
COOH
H2N
COOH
N
H
H
H
(S)-Glu 1
CIP-AS (−)-2
been classified into N-methyl-D-aspartic acid (NMDA),
( )-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propi-
onic acid (AMPA), and kainic acid (KAIN) receptors.
Conversely, the mGluRs belong to the superfamily of G
protein-coupled receptors and regulate the activity of
membrane enzymes such as phospholipase C or adenyl-
ate cyclase.7–9
OH
N
COOH
COOH
O
N
H
COOH
H
H2N
(S)-AMPA 3
H
KAIN 4
* Corresponding author: Tel.: 0039-02-29502263; fax: 0039-02-
29514197; e-mail: paola.conti@unimi.it
Figure 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00225-7

1364
P. Conti et al. / Tetrahedron: Asymmetry 12 (2001) 1363–1367
acid which incorporated structural elements common to
AMPA and kainic acid. Among these compounds,
3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole-3,4-di-
carboxylic acid (CIP-A) emerged as a selective ago-
nist at both AMPA and kainate receptors, displaying
potent convulsant activity comparable to that of kainic
acid.11 Preparation of the two enantiomers of CIP-A
revealed that CIP-AS13,14 was the eutomer in all in vitro
and in vivo assays. The structure of CIP-AS, (−)-2,
depicted in Fig. 1 together with the eutomer of AMPA,
(S)-AMPA, 3 and kainic acid 4, evidence the stereo-
chemical requirements at the AMPA-kainate receptors.
to N-BOC derivatives. Intermediate (−)-7 was then
converted into the target compound CIP-AS (−)-2,
through standard transformations.13
However, the procedure described above had a number
of drawbacks. We found ethyl 2-chloro-2-(hydroxy-
imino) acetate16 5 to be a strong irritant, which caused
severe skin allergies even when handled with care. Such
a drawback is magnified by the need to employ a large
excess of 5 (up to ten-fold) due to the poor reactivity of
the dipolarophile. In practice, 40% of the unreacted
dipolarophile was recovered even on prolonged reaction
times of about 10 days.
Since we were interested in the preparation of ana-
logues of CIP-AS retaining the skeleton of the parent
molecule, we needed a more effective synthesis of the
model compound. The study presented herein deals
with an alternative approach to CIP-AS, in which the
dipolar cycloaddition based strategy was carried out
with a different 1,3-dipole. Indeed, the replacement of a
nitrile oxide with a nitrone produced an improvement
in the overall yield combined with a significant reduc-
tion in the reaction time.
As a consequence, we investigated an alternative strat-
egy based on the cycloaddition of the same dipolar-
ophile to a suitable nitrone. For such a purpose we
prepared
N-(4-methoxybenzyl)-a-ethoxycarbonylni-
trone 12 (Scheme 2) by condensing N-(4-methoxyben-
zyl)hydroxylamine 11 with glyoxylic acid ethyl ester, a
procedure widely applied in this field.17,18 The desired
trifluoroacetate of hydroxylamine 11 was prepared by
reacting
N,O-bis-tert-butoxycarbonylhydroxylamine
1019 with 4-methoxybenzyl chloride, followed by treat-
ment with a 30% dichloromethane solution of TFA. In
our hands, such a preparation of 11 proved more
efficient than the reduction of anisaldoxime carried out
with sodium cyanoborohydride in acidic methanol.20,21
Glyoxylic acid ethyl ester, which was obtained by oxi-
2. Results and discussion
The key step of the previously reported synthetic
approach to CIP-AS was the 1,3-dipolar cycloaddition
of ethoxycarbonylformonitrile oxide (ECFNO)15 to N-
BOC-3,4-didehydro-(S)-proline methyl ester (−)-6.11,13
The nitrile oxide was generated in situ by treatment of
ethyl 2-chloro-2-(hydroxyimino) acetate 5 with sodium
hydrogen carbonate. The pericyclic reaction produced a
mixture of three of the four possible stereoisomers in
the relative amounts reported in Scheme 1. Column
chromatography of the crude reaction mixture gave two
fractions containing pure (+)-9 and an inseparable mix-
ture of (−)-7 and (−)-8, respectively. Cycloadducts (−)-7
and (−)-8 were fully characterized through their separa-
tion as secondary amines followed by their conversion
dation of (+)-diethyl
L
-tartrate with periodic acid,22,23
was then condensed with 11 to afford in high yield
N-(4-methoxybenzyl)-a-ethoxycarbonylnitrone 12 as a
mixture of (E)- and (Z)-isomers. As deduced from
comparative 1H NMR data,24 the (E)-isomer, repre-
sented in Scheme 2, slightly predominates over the
(Z)-counterpart (1.3:1).
The cycloaddition reaction was performed in refluxing
toluene with nitrone 12 and dipolarophile (−)-6 in a 2:1
molar ratio. The reaction was completed over about 36
h, when the dipolarophile was shown to be completely
EtOOC
NOH
+
COOMe
N
H
Cl
BOC
5
(S)-(−)-6
a
N
N
N
N
N
COOEt
EtOOC
EtOOC
O
O
O
H
H
H
H
H
H
COOMe
COOMe
COOMe
N
H
H
H
BOC
(−)-7 (52.5%)
Scheme 1. (a) NaHCO3, AcOEt, rt.
BOC
BOC
(−)-8 (12.5%)
(+)-9 (35%)

P. Conti et al. / Tetrahedron: Asymmetry 12 (2001) 1363–1367
1365
COOEt
H
O
N
t-BuO
a-c
d
NHOH
N
O
O
H
O
MeO
MeO
t-BuO
12
11
10
COOMe
H
EtOOC
BOC
N
(−)-7 (65%)
f
e
12
+
(S)-(−)-6
(−)-8 (2%)
N
O
H
(+)-9 (33%)
13
MeO
2 steps
(−)-2
(−)-7
Scheme 2. (a) 4-MeOC6H4CH2Cl/DMF/K2CO3, 30°C; (b) TFA/CH2Cl2; (c) aqueous K2CO3, pH 10; (d) CHOCO2Et, ether; (e)
toluene, reflux; (f) DDQ/NEt3/CH2Cl2–H2O.
consumed by TLC analysis of the reaction mixture.
Upon treatment of the resulting mixture of isomeric
3 - ethoxycarbonyl - N - (4 - methoxybenzyl)isoxazolidinyl
prolines 13 (Scheme 2) with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) and catalytic triethylamine in
water/dichloromethane (1:9),25 oxidative cleavage of the
p-methoxybenzyl group occurred readily. The bicyclic
isoxazolines (−)-7, (−)-8, and (+)-9 were obtained in
72% overall yield. The relative percentages of the three
isomers, reported in Scheme 2, were established by
HPLC analysis of the crude reaction mixture, in anal-
ogy to the related results reported in Scheme 1. It is
worthy of note that the relative amount of (−)-7, the
precursor of CIP-AS, is higher in the strategy we
present than that of the reported nitrile oxide cycload-
dition. Column chromatography of the crude product
yielded pure (+)-9 and (−)-7 contaminated with low
levels of (−)-8. The fraction containing (−)-7, owing to
the negligible amount of (−)-8, was transformed into
the final derivative (−)-2, and the contaminant was
removed by recrystallization. The values of specific
rotation match those previously reported.13 In the case
of CIP-AS the result was confirmed by chiral HPLC
analysis.13
ration of structural analogues of CIP-AS, even when
employing very unreactive dipolarophiles.
3. Experimental
Melting points were determined in open capillaries
using a Bu¨chi B 540 apparatus and are uncorrected.
Organic solvents were analytical grade. N-BOC-3,4-
didehydro-(S)-proline methyl ester13,26 6, N,O-bis(tert-
butoxycarbonyl)hydroxylamine 1019 and glyoxylic acid
ethyl ester22 were prepared according to literature pro-
1
cedures. H NMR spectra were recorded on a Varian
Mercury 300 MHz spectrometer: chemical shifts (l) are
expressed in ppm and coupling constants (J) in Hz.
HPLC analyses (see the appropriate paragraph) were
carried out on a JASCO PU-980 instrument equipped
with a UV detector or an evaporative light scattering
PL-EMD 960 detector. Optical rotations were deter-
mined on a Perkin–Elmer 241 polarimeter coupled with
a Haake N3-B thermostat. TLC analyses were per-
formed on commercial silica gel 60 F254 aluminum
sheets: spots were further evidenced by spraying with a
dilute alkaline potassium permanganate solution.
Microanalyses of new compounds agreed with theoreti-
cal values 0.3%.
In conclusion, the synthesis of CIP-AS was achieved
more efficiently by changing the nature of the 1,3-dipo-
lar component of the cycloaddition reaction. The
replacement of ECFNO with N-(4-methoxybenzyl)-a-
ethoxycarbonylnitrone made it possible to perform the
reaction in refluxing toluene, with a substantial increase
in the rate and the yield of the cycloaddition step.
These improvements, coupled with an effective oxida-
tion step, make the new strategy suitable for the prepa-
3.1. Preparation of N-(4-methoxybenzyl)-a-ethoxycar-
bonylnitrone 12
(A) To a solution of N,O-bis-tert-butoxycarbonylhy-
droxylamine 10 (14.93 g, 64 mmol) in N,N-dimethylfor-
mamide (80 mL) at 20°C was added potassium
carbonate (11.06 g, 80 mmol) and the resultant suspen-

1366
P. Conti et al. / Tetrahedron: Asymmetry 12 (2001) 1363–1367
sion was heated to 30°C. The reaction mixture was
treated with 4-methoxybenzyl chloride (9.65 mL, 71
mmol) dropwise over 30 min. After stirring the mixture
overnight at 30°C, the solution was cooled to 20°C and
diluted with water (80 mL) and ethyl acetate (100 mL).
The ethyl acetate layer was separated, washed with
water, dried over anhydrous sodium sulfate, and con-
centrated under vacuum. Column chromatography on
silica gel of the crude reaction mixture (eluent: 5% ethyl
acetate/petroleum ether) afforded the intermediate bis-
(tert-BOC)hydroxylamine as a light yellow crystalline
compound (17.64 g, 78%).
2, J=8.7). Anal. calcd for C12H15NO4 (237.25): C,
60.75; H, 6.37; N, 5.90. Found: C, 60.97; H, 6.14; N,
5.72%.
3.2. Synthesis of CIP-AS (−)-2
(A) A solution of nitrone 12 (1.47 g, 6.2 mmol) and
methyl N-BOC-3,4-didehydro-(S)-proline methyl ester
6 (1.41 g, 6.2 mmol) in toluene (50 mL) was stirred
under reflux under nitrogen for 12 h. After TLC moni-
toring (eluent: 40% ethyl acetate/petroleum ether), fur-
ther 12 (1.47 g, 6.2 mmol) was added and heating was
continued for an additional 24 h. TLC analysis indi-
cated the disappearance of the starting dipolarophile.
The solvent was removed at reduced pressure and the
crude reaction mixture was purified by column chro-
matography (eluent: 25% ethyl acetate/petroleum
ether), producing a mixture of stereoisomeric 3-ethoxy-
carbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines
13 (2.80 g, 94% yield).
3.1.1. N,O-Bis(tert-butoxycarbonyl)-N-(4-methoxyben-
zyl)hydroxylamine. Colorless prisms; mp 74–75°C (from
1
propan-2-ol); H NMR (CDCl3): l 1.47 (s, 9, C(CH3)3),
1.52 (s, 9, C(CH3)3), 3.78 (s, 3, OCH3), 4.67 (s, 2, CH2),
6.82 (dd, 2, arom., J=8.3), 7.23 (dd, 2, arom., J=8.3).
Anal. calcd for C18H27NO6 (353.41): C, 61.17; H, 7.70;
N, 3.96. Found: C, 61.33; H, 7.61; N, 3.88%.
(B) To the mixture of stereoisomers 13 (2.80 g, 5.8
mmol) and triethylamine (90 mL) in dichloromethane/
water (50 mL/5 mL) was added portionwise DDQ (3.40
g, 15 mmol). After stirring at rt for about 3 h (TLC
monitoring), aqueous sodium bicarbonate solution
(10%, 50 mL) was added to the red–brown mixture.
The organic phase was separated and the aqueous layer
was extracted with dichloromethane (3×30 mL). After
the standard work up, the crude material was subjected
to column chromatography over silica gel (eluent: 30%
ethyl acetate/petroleum ether) to give pure (+)-9 (0.51
g) and (−)-7 (1.02 g) contaminated with trace amounts
of (−)-8 (77% overall yield). For analytical purposes the
removal of (−)-8 from (−)-7 was achieved by the proce-
(B) To an ice-cooled solution of the previous intermedi-
ate (14.14 g, 40 mmol) in dichloromethane (150 mL)
was added a solution of trifluoroacetic acid (30% in
dichloromethane, 52 mL). After stirring the mixture for
4 h at rt, the volatiles were removed at reduced pressure
and the residue was crystallized from di-iso-propyl
ether to give the desired salt (8.66 g, 81%).
3.1.2. N-(4-Methoxybenzyl)hydroxylammonium trifluoro-
acetate. Colorless prisms; mp 113.5–115°C (from di-iso-
1
propyl ether); H NMR (D2O): l 3.61 (s, 3, OCH3),
4.17 (s, 2, CH2), 6.82 (dd, 2, arom., J=8.5), 7.23 (dd, 2,
arom., J=8.5). Anal. calcd for C20H12F3NO4 (267.20):
C, 44.95; H, 4.53; N, 5.24. Found: C, 44.78; H, 4.72; N,
5.30%.
1
dure previously described.13 The H NMR data of the
isomers were superimposable to those previously
reported.13
(C) The above reported trifluoroacetate (8.0 g, 30
mmol) was dissolved in water (80 mL) and the pH of
the solution adjusted to 10 by addition of solid K2CO3.
After extraction with ethyl acetate (4×50 mL), the
combined organic layers were dried and concentrated.
To a solution of the resulting free hydroxylamine 11
(3.52 g, 23 mmol) in diethyl ether (80 mL) was added
dropwise over 15 min a solution of crude glyoxylic acid
ethyl ester22 (4.70 g, 46 mmol) in diethyl ether (30 mL).
After stirring the mixture at rt for 2 h, the precipitate
was dissolved by addition of ethyl acetate (100 mL).
Water (100 mL) was then added, the organic layer was
separated, and the aqueous phase was extracted with
ethyl acetate (3×50 mL). The pooled organic extracts
were dried and concentrated, leaving a yellow residue
(4.42 g, 81%), which was purified by recrystallization.
Isomer (−)-7: colorless oil; [h]2D0=−153.2 (c 1, CHCl3)
[lit.,13 [h]D20=−151.06 (c 1.042, CHCl3)].
Isomer (+)-9: colorless prisms (mp 78–80°C from di-iso-
propyl ether); [h]2D0=+78.0 (c 1, CHCl3) [lit.,13 [h]2D0=
+77.6 (c 1, CHCl3)].
(C) D2-Isoxazoline (−)-7 was transformed into CIP-AS
by the literature procedure.13 The 1H NMR spectrum of
(−)-2 was identical to that previously reported.13
Amino acid (−)-2: colorless prisms (mp 195–225°C dec.,
from water–methanol); [h]2D0=−53.9 (c 0.110, H2O)
[lit.,13 [h]2D0=−53.7 (c 0.108, H2O)].
3.3. HPLC analysis
3.1.3. N-(4-Methoxybenzyl)-a-ethoxycarbonylnitrone 12.
Colorless prisms; mp 109–111°C (from propan-2-ol); 1H
NMR (CDCl3) of (E)-isomer: l 1.32 (t, 3, CH2CH3,
J=7.0), 3.79 (s, 3, OCH3), 4.26 (q, 2, CH2CH3, J=7.0),
5.62 (s, 2, CH2Ar), 6.87 (d, 2, J=8.7), 7.15 (s, 1,
N=CH), 7.47 (d, 2, J=8.7); 1H NMR (CDCl3) of
(Z)-isomer: l 1.27 (t, 3, CH2CH3, J=7.0), 3.82 (s, 3,
OCH3), 4.22 (q, 2, CH2CH3, J=7.0), 4.91 (s, 2,
CH2Ar), 6.92 (d, 2, J=8.7), 7.00 (s, 1, N=CH), 7.34 (d,
(A) A sample of the crude cycloaddition mixture of
(S)-(−)-6 to ECFNO13 was submitted to HPLC analysis
on a LiChrospher Si 60 column (4.0×125 mm). The
column was eluted with 2% propan-2-ol-petroleum
ether at a 1 mL/min flow rate, UV detection at u=254
nm. As reported in Scheme 1, the relative amounts of
isomeric D2-isoxazolines (−)-7, (−)-8, and (+)-9 were
52.5, 12.5, and 35%, respectively. Retention times

P. Conti et al. / Tetrahedron: Asymmetry 12 (2001) 1363–1367
7. Nakanishi, S. Neuron 1994, 13, 1031–1037.
1367
(min): (+)-9 (20.0), (−)-7 (28.3), (−)-8 (37.9). A sample
from the above reported oxidation of isoxazolidines 13
was analyzed using the same experimental protocol.
The relative amounts of the three cycloadducts (see
Scheme 2) are indicated in parentheses: (−)-7 (65%),
(−)-8 (2%), (+)-9 (33%).
8. Pin, J.-P.; Duvoisin, R. Neuropharmacology 1995, 34,
1–26.
9. Conn, P.; Pin, J.-P. Annu. Rev. Pharmacol. Toxicol. 1997,
37, 205–237.
10. Bigge, C. F.; Boxer, P. A.; Ortwine, D. F. Curr. Pharm.
Des. 1996, 2, 397–412.
(B) A sample of CIP-AS (−)-2 was analyzed on a
column (4.0×250 mm) of spherical silica Si 100, 5 mm,
containing Teicoplanin as the chiral selector. The
column was eluted at 25°C with 20 mM NH4OAc/acet-
onitrile–water 4:1 (v/v) at a 1 mL/min flow rate, detec-
tion with a PL-EMD 960 detector operating at 80°C
with an air flow of 6.0 L/min. Amino acid (−)-2:
k1%=3.40, h=1.73; enantiomeric excess (e.e.) was
>99.9%.
11. Conti, P.; De Amici, M.; De Sarro, G.; Bryan Stensbøl,
T.; Bra¨uner-Osborne, H.; Madsen, U.; De Micheli, C. J.
Med. Chem. 1998, 41, 3759–3762.
12. Conti, P.; Dallanoce, C.; De Amici, M.; De Micheli, C.;
Fruttero, R. Tetrahedron 1999, 55, 5623–5634.
13. Conti, P.; De Amici, M.; De Sarro, G.; Rizzo, M.; Bryan
Stensbøl, T.; Bra¨uner-Osborne, H.; Madsen, U.; Toma,
L.; De Micheli, C. J. Med. Chem. 1999, 42, 4099–4107.
14. The acronym CIP-AS refers to the enantiomer derived
from (S)-3,4-didehydroproline.
15. Kozikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983,
48, 366–372 and references cited therein.
Acknowledgements
16. Skinner, G. S. J. Am. Chem. Soc. 1924, 46, 738–746.
17. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.;
Merino, P.; Tejero, T. Synth. Commun. 1994, 24, 2537–
2550 and references cited therein.
This research was financially supported by MURST
(Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica, Rome). Thanks are due to Professors
Carlo De Micheli and Marco De Amici for their
encouragement and helpful discussion.
18. Venkatachalapathy,
C.;
Thirulamala`ikumar,
M.;
Muthusubramanian, S.; Pitchumani, K.; Sivasubrama-
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