Determination of the absolute configuration of phosphinic analogues of glutamate

Article abstract of DOI:10.1039/c4ob01960a

A series of phosphinic glutamate derivatives (e.g.LSP1-2111) have been proven to be potent agonists of metabotropic glutamate (mGlu) receptors and shown promising in vivo activity. However, so far all were synthesized and tested as a mixture of two diaste

Full text of DOI:10.1039/c4ob01960a

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Determination of the absolute configuration of
phosphinic analogues of glutamate†
Cite this: DOI: 10.1039/c4ob01960a
Bruno Commare,‡a,b Delphine Rigault,‡a Isabelle A. Lemasson,§a
Patrick Deschamps,c Alain Tomas,c Pascal Roussel,d Isabelle Brabet,e,f
Cyril Goudet,e,f Jean-Philippe Pin,e,f Frédéric R. Leroux,*b Françoise Colobert*b and
Francine C. Acher*a
A series of phosphinic glutamate derivatives (e.g. LSP1-2111) have been proven to be potent agonists of
metabotropic glutamate (mGlu) receptors and shown promising in vivo activity. However, so far all were
synthesized and tested as a mixture of two diastereomers whose absolute and relative configurations are
not known. In this study, the stereomers were separated on a Crownpack CR(+) column and their absol-
ute configuration was assessed by means of a diastereoselective synthesis. Both separated L-stereomers
activated the mGlu4 receptor with EC50’s of 0.72 and 4.4 µM for (1S,1’S)-and (1S,1’R)-LSP1-2111,
respectively.
Received 16th September 2014,
Accepted 11th November 2014
DOI: 10.1039/c4ob01960a
www.rsc.org/obc
inhibitors and more particularly ureases,4 aminopeptidases5–8
or metalloproteases.9 A well-known phosphinate is fonisopril
Introduction
Compounds bearing phosphinate moieties are present in which is an ACE (angiotensin I converting enzyme) inhibitor
numerous biologically active molecules. Indeed, this chemical used for the treatment of hypertension and heart failure.10
motif is found in herbicides like phosphinothricin, an inhibi- Finally, some metal chelators have been synthetized based on
tor of glutamine synthetase.1,2 Phosphinate derivatives like a phosphinate motif and used in medical imaging.11 Their
α-aminophosphinates,3 are also frequently studied as enzyme applications are also important in neurosciences where several
phosphinates are used such as γ-aminobutyric acid (GABA)
and metabotropic glutamate (mGlu) receptor ligands.12–14
aLaboratoire de Chimie & Biochimie Pharmacologiques et Toxicologiques, UMR
Our laboratory has developed a series of phosphinic gluta-
CNRS 8601, Université Paris Descartes, Sorbonne Paris Cité, 45, rue des Saints-Pères
mate analogues that selectively activate some mGluR sub-
75270, Paris cedex 06, France. E-mail: francine.acher@parisdescartes.fr;
types.14 Among these compounds LSP1-2111 was thoroughly
Fax: +33 142 86 83 87; Tel: +33 142 86 33 21
investigated, its central bioavailability was assessed15 and its
efficacy was shown in vitro and in animal models of Parkin-
son’s disease (PD),16 anxiety,17 schizophrenia18,19 and fear con-
ditioning.20 However, the tested compound is a mixture of two
diastereomers. It is well known that diastereomers may display
different biological activities. Accordingly access to single dia-
stereomers and determination of their absolute configuration
is required to carry out their pharmacological evaluation. In
the present study, separation of the two diastereoisomers of
LSP1-2111 was achieved on a small scale. The absolute con-
figuration of both stereogenic centers was determined by
means of the synthesis of a close analogue LSP1-2093 (Fig. 1).
bLaboratoire de Chimie Moléculaire, UMR CNRS 7509, Université de Strasbourg,
ECPM, 25, rue Becquerel 76087, Strasbourg, France.
E-mail: francoise.colobert@unistra.fr, frederic.leroux@unistra.fr;
Fax: +33 368 8527 42; Tel: +33 368 8527 46
cLaboratoire de Cristallographie et RMN Biologiques, UMR CNRS 8015, Université
Paris Descartes, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France.
E-mail: patrick.deschamps@parisdescartes.fr, alain.tomas@parisdescartes.fr;
Fax: +33 153 73 97 32; Tel: +33 153 73 98 40, +33 153 73 98 51
dUnité de Catalyse et Chimie du solide, UMR CNRS 8012, École Nationale
Supérieure de Chimie de Lille BP 90108-59652 Villeneuve d’Ascq cedex, France.
E-mail: pascal.roussel@ensc-lille.fr; Fax: +33 320 43 68 14; Tel: +33 320 33 64 34
eInstitut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique
Unité Mixte de Recherche 5203, Université de Montpellier, F-34094 Montpellier,
France. E-mail: cyril.goudet@igf.cnrs.fr; Fax: +33 467 54 24 32;
Tel: +33 434 35 92 77
fInserm Unité 661, F-34094 Montpellier, France
†Electronic supplementary information (ESI) available: Experimental protocols
and characterization data for new compounds, copies of 1H, 13C, 31P NMR and
Crownpack HPLC spectra. CCDC 1016374. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c4ob01960a
‡These authors contributed equally.
§Present address: BioFocus DPI Ltd, Chesterford Research Park, Saffron Walden,
CB10 1XL, UK.
Fig. 1 Structures of LSP1-2111 and LSP1-2093.
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Results and discussion
LSP1-2111 and LSP1-2093 were synthesized using the already
reported general pathway depicted in Scheme 1.14 The first
step consists in the addition of phosphinic acid on (S)-methyl
2-(((benzyloxy)carbonyl)amino)but-3-enoate
1 via a radical
process. After 5 hours at 80 °C, the conversion is total and the
crude compound is used in the next step without further puri-
fication. α-Hydroxy-phosphinic acid 4a and 4b were obtained
by condensation of 2 to 3-nitrobenzaldehydes 3a and 3b. Acid
hydrolysis (HCl 6 M) afforded, after purification on ion
exchange resins, the desired amino acids LSP1-2111 and
LSP1-2093.
The protected vinylglycine 1 used as the starting material,
is enantiopure (S) and its stereogenic center is conserved
throughout the synthesis. In contrast, the stereogenic benzylic
carbinol formed by nucleophilic addition of the phosphorus
derivative onto 3-nitrobenzaldehydes is epimeric. Therefore all
α-hydroxy-phosphinic acids of this series were tested as a
mixture of the two diastereomers.16–20 To evaluate their
respective biological activities, we describe herein the separ-
ation of both diastereomers and the determination of the
absolute configuration of the newly created stereogenic center.
The first approach to separate both diastereomers of
LSP1-2111 and LSP1-2093 involved the use of enantiopure
chiral auxiliaries (Mosher acid, (S)-acetyllactate or (S)-acetyl-
alanine) hoping to get separable diastereomers by silicagel
flash chromatography. Unfortunately, this method was
unsuccessful.
We thus set up a separation by chiral HPLC using a Crown-
pak CR(+) column (Daicel). This column is based on a chiral
crown ether stationary phase that enables the resolution of
amino acid racemic mixtures. CR(+) allows to separate L-amino
acids and CR(−) D-amino acids.21
Fig. 2 Separation of (a) LSP1-2093 diastereomers, (b) LSP1-2093 Dia I
and (c) LSP1-2093 Dia II on a Crownpak CR(+) (150 × 4 mm, eluent
HClO4, pH 2.0, 0.4 mL min−1, detection λ = 210/254 nm, T = 21 °C).
We succeeded in separating the mixtures of LSP1-2093
(Fig. 2) and LSP1-2111 diastereomers (ESI†) using classical
analytical Crownpak conditions (150 × 4 mm, eluent HClO4
pH 2.0, 0.4 mL min−1, detection λ = 210/254 nm, T = 21 °C).
The use of hydrochloric acid instead of perchloric acid allowed
a semi-preparative separation. For both compounds, the first
eluted isomer was named Dia I (Fig. 2 (b)) and the second Dia
II (Fig. 2 (c)). They were characterized by their optical rotation
1
and H NMR analysis where the only difference was found at
the Ha and Hb protons of C3 (ESI,† Table 1). Dia I of LSP1-2093
and LSP1-2111 displays a small optical rotation ([α]2D0 = −2 (c =
0.6, H2O) and [α]2D0 = +2 (c = 0.8, H2O), respectively, for
LSP1-2093 and LSP1-2111) and the chemical shift of Ha and
Hb appear as a single multiplet, at δ = 1.8 ppm, whereas Dia II
displays a large optical rotation ([α]2D0 = +29 (c = 0.6, H2O) and
[α]2D0 = +25 (c = 0.7, H2O), respectively, for LSP1-2093 and
LSP1-2111) and the chemical shifts of Ha and Hb, appear as
two distinct multiplets, at δ = 1.7 and 1.9 ppm. Starting from
this observation, we can thus deduce that the absolute con-
Scheme 1 Synthetic pathway of LSP1-2093 and LSP1-2111.
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figuration of the stereogenic benzylic carbinol of Dia I and
Dia II of LSP1-2093 and LSP1-2111 are similar. Nevertheless,
we were not able to obtain suitable single crystals for X-ray ana-
lysis in order to determine the absolute configuration of the
benzylic carbinol. Therefore we turned our attention to an
alternative synthetic route that should allow firstly the determi-
nation of the absolute configuration of the carbinol formed
and secondly the synthesis of larger amounts of pure isomers.
Our idea was to control the configuration of the benzylic
carbinol before the introduction of the amino acid part to the
hydroxyphosphoryl moiety. Therefore, we first added 3-nitro-
benzaldehyde to hypophosphorous acid to afford racemic
hydroxy(3-nitrophenyl)methylphosphinic acid ( )-5. Mono
nucleophilic addition proceeded smoothly when a large excess
(5 equiv.) of H3PO2 was used. Racemate 5 was thus efficiently
resolved by the addition of (S)- or (R)-1-phenylethylamine 6
(1 eq.) (Scheme 2).
Fig. 3 X-ray crystal structure of (S)-1-phenylethylamonium (R)-
[α-hydroxy-(3-nitrophenyl) methyl]phosphinate (R,S)-7a.
Salt (R,S)-7a was found to precipitate from a mixture of ( )-5
and (S)-1-phenylethylamine in MeOH–ACN at room tempera-
ture.22,23 The 31P NMR spectrum of the crystallized salt 7a
exhibited a singlet at δ = 18.92 ppm. The selection of the
(R)-enantiomer of rac-5 with (S)-1-phenylethylamine was con-
firmed by X-ray crystallography34 (Fig. 3) after crystallization of
7a in EtOH.35 Treatment of salt 7a with resin Dowex
AG50W4 gave enantiopure (+)-(R)-5 in a quantitative yield.
Resolving rac-5 with (R)-1-phenylethylamine in MeOH–ACN fol-
lowed by crystallization in EtOH gave access to (−)-(S)-5.
The enantiomeric ratio of the stereogenic carbinol (+)-(R)-5
and (−)-(S)-5 has been verified by 31P NMR using L-menthol as
a chiral auxiliary.23 Indeed, menthyl phosphinates (R)-8a,
(R)-8a′, (S)-8b and (S)-8b′ were easily obtained from rac-5
(Scheme 3).23–25 31P NMR analysis revealed 4 peaks at δ =
27.24, 30.53, 32.13 and 35.13 ppm (in almost the same pro-
portions) corresponding to the 4 possible stereomers resulting
from the esterification of rac-5 with L-menthol (Fig. 4a).
Scheme 3 Synthesis of stereomeric menthyl phosphinates (R)-8a, (R)-
8a’, (S)-8b and (S)-8b’.
Starting from (+)-(R)-5, the corresponding menthyl phosphi-
nates revealed two major peaks at δ = 30.36 and 33.18 ppm
((R)-8a and (R)-8a′) and two minor peaks at δ = 28.41 and
34.85 ppm ((S)-8b and (S)-8b′) in the 31P NMR spectrum
(Fig. 4b). On the opposite, esterification of (−)-(S)-5 provided
(S)-8b and (S)-8b′ (δ = 28.13 and 35.07 ppm as 31P NMR major
peaks) (Fig. 4c). For both (+)-(R)-5 and (−)-(S)-5 the enantio-
meric ratio was evaluated to 90% by 31P NMR peak integration
(Fig. 4).
The asymmetric synthesis of para-substituted phenyl-
hydroxymethylphosphinates and phenylhydroxymethylpho-
sphonates has been reported in the literature.26–29 It was
found that levogyre (negative optical rotation) isomers were
constantly of (S) configuration. Oxidation of (−)-(S)-5 and ester-
ification of the resulting phosphonate (Scheme 4) provided
(−)-(S)-10 that matches these previous observations and
allowed us to extend the correlation between optical rotation
and absolute configuration to other substituted phenylhydrox-
ymethylphosphinates. This correlation was verified by reprodu-
cing the reaction sequence from (+)-(R)-5 to obtain (+)-(R)-10.
Once the configuration of the benzylic carbinol was con-
firmed, we designed a diastereoselective synthetic pathway
Scheme 2 Resolution of hydroxy-(3-nitrophenyl)methylphosphinic
acid ( )-5.
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Scheme 4 Synthesis of (S)-hydroxyphosphonate (S)-10 and (R)-hydro-
xyphosphonate (R)-10.
THF. After evaporation of the solvent, the crude residue was
dissolved in EtOH and treated with pivaloyl chloride (PivCl)
and pyridine to afford compound (R)-11 after purification on
silica gel in 51% yield30 as a mixture of two diastereomers
(phosphorus is chiral) which are not separable by chromato-
graphy on silica gel. Several attempts to couple H-phosphinate
(R)-11 with protected iodohomoserine giving after deprotection
the desired (1S,1′R)-LSP1-2093, were unsuccessful (Scheme 5).
In order to circumvent this problem we decided to intro-
duce the amino acid function through a Strecker reaction.
Phosphinate (R)-11 was deprotonated with lithium bis(tri-
methylsilyl)amide (LiHMDS) followed by the addition of acryl-
amide31 to afford the Weinreb amide (R)-13 in low yield (21%).
For the Strecker reaction,32 (R)-13 was reduced in high yield
(78%) into the aldehyde (R)-14 by treatment with DIBAL-H in
methylene chloride at −78 °C for 2 hours. We initially designed
an asymmetric Strecker reaction using (S)-(+)-p-toluene-
sulfinamide as a chiral amine in order to obtain one single
stereomer. Therefore, based on Midura’s work,33 imine (R)-15
was synthesized by refluxing the aldehyde (R)-14 in the pres-
ence of (S)-(+)-p-toluenesulfinamide, with Ti(OEt)4 in DCM to
afford the desired sulfinylimine which was used without
Fig. 4 31P NMR spectra of (a) the 4 stereomers 8, (b) diastereomers (R)-
8a and (R)-8a’ and (c) (S)-8b and (S)-8b’.
towards the two diastereoisomers of LSP1-2093 in order to
determine the absolute configuration of Dia I and Dia II
(Fig. 2). Initially we developed the reaction conditions on ( )-5
and applied them to the enantiopure compound (R)-5. Protec-
tion of the hydroxyl group of (R)-5 was performed using tert-
butyldiphenylsilyl chloride (TBDPSCl) and NEt3, 12 h in dry
Scheme 5 Attempts to couple H-phosphinate 11 with protected
iodohomoserine.
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Scheme 6 Synthesis of (1RS,1’R)-LSP1-2093 and (1RS,1’S)-LSP1-2093.
further purification (Scheme 6). Addition of ethylaluminium presents one of the two (1S)-amino acid diastereomers [(1S,1′R)
cyanoisopropoxide [EtAl(O-i-Pr)CN] with 1.0 eq. of i-PrOH at and (1S,1′S)] and the peak 3 represents the other one.
−78 °C afforded after 24 hours at 25 °C, quenching at 0 °C, a
On the HPLC profile of compound (1RS,1′R)-LSP1-2093
mixture of diastereomers (1RS,1′R)- and (1RS,1′S)-16. We (Fig. 5b), obtained from (R)-5, we also observed 3 peaks. Once
observed no asymmetric induction of the chiral imine on the again, the first peak represents the (1R)-amino acid diastereo-
new stereocenter. However, since the aim of this synthesis was mers. As the enantiomeric ratio of the starting (R)-5 is 90%,
to determine the configuration of the benzylic carbinol of Dia peak 2 (analogous to Dia I, Fig. 2) and peak 3 (Dia II, Fig. 2)
I and Dia II of LSP1-2093, we carried out the synthesis of the correspond to (1S,1′S)-LSP1-2093 (minor) and (1S,1′R)-LSP1-
corresponding (1R,1′R)- and (1S,1′R)-LSP1-2093 to confirm 2093 (major), respectively. The HPLC profile of compound
their configuration on a Crownpak CR(+) column. Deprotec- (1RS,1′S)-LSP1-2093 (Fig. 5c) obtained from (1′S)-5 shows the
tion of the silyl ether was performed using a mixture of TBAF– major peak 2 (Dia I (1S,1′S)) (91%) compared to peak
AcOH (1 : 1). The use of AcOH was necessary to avoid the clea- 3. The ratios determined by area measurement of peaks 2 and
vage of the C–P bond observed under basic conditions. Indeed 3 are in accordance with the enantiomeric purity of (R)-
deprotection of the alcohol function with a base is followed by and (S)-5 measured by 31P NMR of the corresponding
elimination of the phosphinic part by cleavage of the C–P menthylphosphinate.
bond.
Fig. 6 shows clearly the assignment of Dia I and Dia II
Finally, treatment with 6 M HCl afforded both diastereo- obtained according to Scheme 1. This protocol allowing the
mers (1R, 1′R)- and (1S,1′R)-LSP1-2093 with a global yield of determination of the absolute configuration of the stereogenic
2% from (R)-5. The same synthetic pathway was applied to (S)- carbinol formed during the synthesis of phosphinic amino
5 to afford a mixture of the two other diastereomers (1R,1′S)- acids may be extended to structural analogs such as LSP1-
and (1S,1′S)-LSP1-2093 which were obtained in a global yield 2111.
of 3% from (S)-5 (Scheme 6). Analysis of the four diastereo-
mers LSP1-2093 was performed on a Crownpak CR(+) column
and compared to Dia I and Dia II (Fig. 2) of LSP1-2093 to deter-
mine the absolute configuration of the latter.
Pharmacology
The racemic mixture (1RS,1′RS)-LSP1-2093 obtained after
the reaction sequence previously described from ( )-5 dis-
played 3 peaks on the Crownpak CR(+) column (Fig. 5a). Peak
1 represents the mixture of the two (1R)-amino acid diastereo-
mers [(1R,1′R) and (1R,1′S)] because the CR(+) column does
not resolve D-amino acids which are not retained. Peak 2 re-
The separated pairs of L-diastereomers were tested for their
activation of mGlu4 receptors transiently expressed in HEK293
cells. All compounds activated this receptor. Whereas a minor
difference between the diastereomers of LSP1-2093 is found, it
is more pronounced for LSP1-2111. The 1′S isomer is about
6 fold more potent than the 1′R (Table 1).
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Fig. 6 Assignment of LSP1-2093 diastereomers obtained in Scheme 1
on a Crownpak CR(+) column at 25 °C.
Conclusions
To evaluate the bioactivity of the stereomers of LSP1-2111 and
other phosphinic analogues of glutamate, it is essential to be
able to isolate and characterize each stereomer. Separation of
the stereomers was thus efficiently achieved by semi-prepara-
tive chiral HPLC on a Crownpak CR(+) column. Absolute con-
figuration was assigned by means of a diastereoselective
synthesis of LSP1-2093, a close analogue. Further studies will
aim at adjusting an asymmetric Strecker reaction in order to
obtain each stereomer in pure form. An application of the pro-
tocol to other phosphinic amino acids such as LSP4-2022 is
possible. The pharmacological activity of the single L-stereo-
mers reveals that all are agonists of the mGlu4 receptor and
that (1S,1′S)-LSP1-2111 is more potent than (1S,1′R)-LSP1-2111.
Acknowledgements
This study was supported by the French National Agency for
Research (ANR-13-BSV1-0006) and as part of the Era-net
Neuron program (ANR-08-NEUR-006), by the French National
Center for Scientific Research (CNRS, Mental Disease Thera-
peutic Innovation program) and by the Ministry for Higher
Education, Research and Technology (scholarships to B. C).
Fig. 5 Analysis of (a) (1RS,1’RS)-LSP1-2093, (b) (1RS,1’R)-LSP1-2093 and
(c) (1RS,1’S)-LSP1-2093 on a Crownpak CR(+) column at 25 °C.36
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A. Pilc, Psychopharmacology, 2012, 220, 481–494.
19 J. M. Wieronska, F. C. Acher, A. Slawinska, P. Gruca,
M. Lason-Tyburkiewicz, M. Papp and A. Pilc, Psychopharma-
cology, 2013, 227, 711–725.
sensitive to temperature. Consequently those recorded
for LSP1-2093 stereomers in Fig. 2 ((mixture, Dia I and
Dia II)) and Fig. 5 ((1RS,1′R) and (1RS,1′S)) are slightly
different.
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