Synthesis of novel conformationally restricted L-glutamate analogues

Article abstract of DOI:10.1039/a706148j

The novel, optically active and conformationally restricted L-glutamate analogues 6, 7 and 11 have been prepared via the PPh₃ catalysed cycloaddition of the allenes 2 and 9 with the chiral oxazolidinone 1.

Full text of DOI:10.1039/a706148j

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Synthesis of novel conformationally restricted l-glutamate analogues
Stephen G. Pyne,*a Karl Schafer,a Brian W. Skeltonb and Allan H. Whiteb
a Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia
b Department of Chemistry, University of Western Australia, Nedlands, Western Australia, 6907, Australia
The novel, optically active and conformationally restricted
L-glutamate analogues 6, 7 and 11 have been prepared via
the PPh3 catalysed cycloaddition of the allenes 2 and 9 with
the chiral oxazolidinone 1.
receptors and differentiates them from the ionotropic type.4
Here we describe a novel synthesis of some dehydro derivatives
of ACPDA via the cycloaddition reactions of the chiral
oxazolidinone 15 and allenic esters 2 and 9 and report some
preliminary results on the pharmacological activities of these
compounds.
l-Glutamate is an excitatory neurotransmitter in the mammalian
central nervous system (CNS). This amino acid activates both
the metabotropic and the ionotropic group of glutamate
receptors. The latter group includes the N-methyl-d-aspartic
acid (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-pro-
pionate and kainate receptor subclasses. These receptors form
ligand-gated ion channels and mediate excitatory neurotrans-
mission. The former receptor group are coupled to G-proteins
and activate or inhibit intracellular signals. Elevated glutamate
concentrations can lead to excitoxicity which has been impli-
cated in the pathogenesis of neurological disorders, including
epilepsy and chronic neurodegenerative diseases.1,2 Excitatory
amino acid transporters (EAATs) in the CNS maintain extra-
cellular glutamate concentrations below excitotoxic levels.3
Selective agonists and antagonists for glutamate receptor
subtypes1 and selective blockers for EAATs are invaluable tools
in understanding neuronal biochemistry. Furthermore, such
compounds allow an understanding of the structural features of
these receptor subtypes and the future design of new ther-
apeutics for the treatment of neurodegenerative diseases.1 One
such compound is the conformationally restricted glutamate
analogue, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
(ACPDA), which selectively activates metabotropic glutamate
Treatment of a benzene solution of the oxazolidinone 1 (1
equiv.) and ethyl buta-2,3-dienoate 26 (5 equiv.) with PPh37 (0.1
equiv.) at room temperature for 5 h gave, after purification by
column chromatography, the major cycloadduct 3† (49%), the
minor cycloadduct 4† (17%) and the dimer 57a (27%) (Scheme
1). The diastereoisomeric ratio of 3 and 4 was estimated to be
1
77:23 from H NMR analysis of the crude reaction mixture.
The stereochemistry of 3 was revealed by a single crystal X-ray
structural analysis, as shown in Fig. 1.‡ This analysis showed
that the major cycloadduct had the 5S stereochemistry at the
newly created stereogenic centre, consistent with the known
tendency of 1 in [3 + 2] cycloaddition reactions to give products
that arise from attack of the three-atom component anti to the
C(2) phenyl substituent.8 The minor cycloadduct 4 was a
regioisomer of 3 and also had the 5S stereochemistry as shown
by NOESY experiments which revealed cross-peaks between
the signal for H-2 and that for one H-9 proton, as indicated in
structure 4 (Scheme 1). Interestingly, the regiochemistry of the
major cycloadduct 3 was different to that of the major
cycloadduct formed from the reaction of ethyl acrylate or
methyl methacrylate with 2–PPh3.7a The enantiomeric purity of
1
3 was determined to be 88% from H NMR analysis of its
H2C
BzN
O
O
R
H
Ph
1
+
PPh3
–
i
+
CO2Et
CO2Et
O(62)
CH2
C
CHCO2Et
2
CO2Et
H
6
CH2
O
O
9
5
5
6
+
H
+
S
S
NOE
BzN1 3O
BzN1 3O
H
EtO2C
R
R
C(4)
C(5)
CO2Et
5 (27%)
NOE
C(3)
H
Ph
H
Ph
O(5)
N(3)
3 (49%)
4 (17%)
C(2)
O(1)
ii, iii
ii, iii
CO2H
S
S
HO2C
iv
CO2H
CO2H
H2N
H2N
iv
6a
7a
6b (HCl salt of 6a)
(85% from 3)
7b (HCl salt of 7a)
(72% from 4)
Scheme 1 Reagents and conditions: i, PPh3 (10 mol%); ii, 6 m HCl, reflux,
Fig. 1 Projection of 3 through the heterocyclic ring plane (20% thermal
16 h; iii, ion-exchange; iv, HCl
ellipsoids are shown for C, N, O, H having arbitrary radii of 0.1 Å)
Chem. Commun., 1997
2267

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H
O
H
i
Ph
H
S
Ph
Me
3
EtO2C
BzNH
8 (dr = 94 : 6)
–
CO2Et
CO2
CO2Me
R
+
O
10
Ph3P
H
N
Ph
O
Scheme 2 Reagents and conditions: i, (R)-methyl mandelate, Et3N, CH2Cl2,
7 days, 63%
12
(R)-methyl mandelate derivative 8, which was a 94:6 mixture
of diastereoisomers [major: dH(CDCl3) 5.99 (s), minor 5.98 (s)]
(Scheme 2). Acid hydrolysis of 3 and 4 followed by purification
via ion-exchange chromatography gave diastereoisomerically
pure amino acids 6a and 7a, respectively, which were
characterized as their respective hydrochloride salts, 6b† and
7b.† Amino acid 7a has been reported recently, however this
product was racemic and was obtained as a mixture of two
isomers from which racemic 7a could be obtained in 1.75%
yield after selective crystallization.9
Treatment of a benzene solution of 1 and ethyl penta-
2,3-dienoate 96 (5 equiv.) with PPh3 (0.1 equiv.) at room
temperature for 5 h gave a single cycloadduct 10† in 38%
isolated yield after purification by column chromatography on
silica gel. No other stereoisomer of 10 could be detected by 1H
NMR analysis of, or was isolated from, the crude reaction
mixture. The 5S,9S stereochemistry of 10 was evident from
NOESY experiments, which showed cross-peaks between H-2
and the C(9) methyl group and between H-9 and the ortho
protons of the benzamido group, as shown in Scheme 3. Acid
hydrolysis of 10 gave the amino acid 11a, which was
characterized as its hydrochloride salt 11b.†
Thus the PPh3 catalysed reactions of 2 and 9 with ox-
azolidinone 1 proceed in a different regiochemical sense. It is
not clear if these reactions occur via a four step reaction
sequence that involves initially a Michael addition reaction,
then cyclization followed by proton transfer and then elimina-
tion of PPh3,7b or via a three step mechanism via an initial
‘concerted’ 2,3-cycloaddition reaction.7a In the latter case, the
transition state structure 12, in which steric interactions between
the substituents on the zwitterionic species formed between 9
and PPh3 and the benzamido group on 1 are minimized, is
consistent with the observed stereochemical outcome in 10
(Scheme 4). Attempts to obtain cycloadducts from the (2S)-tert-
butyl analogue5 of 1 and allene 2 gave only the dimer 5.
In some preliminary studies, amino acids 6, 7 and 11 showed
no activity against NMDA-induced depolarizations in the rat
neocortex at 500 mm concentrations.10 Compound 11, however,
selectively blocks glutamate transport by EAAT2 expressed in
Scheme 4
oocytes (Ki = 62 mm) but is inactive on EAAT1.11 Further
biological studies are in progress and these will be reported in a
future paper.
We thank the Australian Research Council for financial
support and J. Ong and D. Kerr (University of Adelaide) and
G. A. R. Johnston and R. J. Vandenberg (University of Sydney)
for preliminary biological results on compounds 6, 7 and 11.
Footnotes and References
* E-mail: s.pyne@uow.edu.au
† Selected data for 3: colourless crystals, mp 144–146 °C, [a]2D1 +155 (c
0.60, CHCl3); dH(CDCl3) 1.35 (t, J 7.2, 3 H), 2.75–3.19 (m, 4 H, H-8a,
H-8b, H-9a and H-9b), 4.28 (q, J 7.2, 2 H), 6.77 (br s, 1 H, H-2), 6.97 (br
s, 1 H, H-7), 7.02 (d, J 6.9, 2 H), 7.25 (d, J 6.9, 2 H), 7.29–7.39 (m, 6 H).
For 4: white solid, mp 70–73 °C, [a]2D3 +202 (c 0.10, CHCl3); dH(CDCl3)
1.32 (t, J 7.2, 3 H), 3.20–3.26 (m, 1 H, H-9a), 3.32–3.39 (m, 2 H, H-6a and
H-9b), 3.60–3.66 (m, 1 H, H-6b), 4.23 (q, J 7.2 , 2 H), 6.67 (br s, 1 H, H-2),
6.72 (br s, 1 H, H-8), 6.91 (d, J 7.5, 2 H), 7.12 (d, J 7.2, 2 H), 7.20–7.35 (m,
6 H). For 10: pale yellow gum, [a]2D1 +90 (c 0.30, CHCl3); dH(CDCl3) 1.33
(t, J 7.2, 3 H), 1.38 (d, J 7.5, 3 H), 3.45–3.51 (m, 1 H, H-6a), 3.65–3.71 (m,
1 H, H-6b), 3.74–3.79 (m, 1 H, H-6b), 4.24 (q, J 7.2, 2 H), 6.57 (s, 1 H, H-2),
6.68 (br s, 1 H, H-8), 6.81, d, J 6.9, 2 H), 7.02 (d, J 6.9, 2 H), 7.1–7.33 (m,
6 H). For 6b: white solid, mp > 250 °C, [a]2D2 +15 (c 0.20, 6 m HCl);
dH(D2O) 2.78–2.84 (app br d, J 16.2, 2 H, H-2a and H-5a), 3.22–3.27 (app
br d, J 16.8, 2 H, H-2b and H-5b), 6.66 (br s, 1 H, H-4). For 7b: white
hygroscopic solid, mp > 250 °C, [a]2D2 +11 (c 0.40, 6 m HCl); dH(D2O)
2.09–2.18 (m, 1 H, H-5a), 2.39–2.48 (m, 1 H, H-5b), 2.57–2.68 (m, 2 H,
H-4a and H-4b), 6.82 (br s, 1 H, H-3). For 11b: white hygroscopic solid, mp
> 250, [a]2D2 +10 (c 0.10, 6 m HCl); dH(D2O) 1.13 (d, J 7.5, 3 H), 3.30 (app
t, J 1.8, 1 H, H-2a), 3.36 (app t, J 2.1, 1 H, H-2b), 3.55–3.65 (m, 1 H, H-5),
6.64 (s, 1 H, H-4).
‡ Selected X-ray data for 3: C23H21NO5, M
= 391.4; orthorhombic,
P212121, a = 21.13(1), b = 11.22(1), c = 8.474(7) Å, V = 2009 Å3, Dc
(Z = 4) = 1.29 g cm23, 795 ‘observed’ [I > 3s(I)] diffractometer
reflections out of 2032 independent to 2qmax = 50° (monochromatic Mo-
Ka radiation, l = 0.7107 Å, no absorption correction) yielding conven-
tional R, Rw ıFı = 0.054, 0.046 (statistical weights). Anisotropic C, N, O
thermal parameter refinement (x, y, z, Uiso H constrained at estimates
)
T = 295 K. Chirality was assigned from the chemistry. CCDC 182/630.
CO2Et
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6
1
O
i
9
5
H
Me
+
S
S
MeCH
C
CHCO2Et
BzN1 3O
NOE
R
9
H
Ph
NOE
10 (38%)
ii, iii
CO2H
8 S. G. Pyne, J. Safaei-G and F. Koller, Tetrahedron Lett., 1995, 36, 2511;
S. G. Pyne, J. Safaei-G, B. W. Skelton and A. H. White, Aust. J. Chem.,
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K. N. Mewett, N. Quickert and H. W. Tran, Aust. J. Chem., 1996, 49,
785.
H
S
S
Me
CO2H
H2N
11a
iv
11b (HCl salt of 11a)
(91% from 10)
10 D. I. B. Kerr and J. Ong, personal communication.
11 G. A. R. Johnston and R. J. Vandenberg, personal communication.
Scheme 3 Reagents and conditions: i, PPh3 (10 mol%); ii, 6 m HCl, reflux,
16 h; iii, ion-exchange; iv, HCl
Received in Cambridge, UK, 22nd August 1997; 7/06148J
2268
Chem. Commun., 1997