Stereoselective synthesis of (2S)-2-hydroxymethylglutamic acid, a potent agonist of metabotropic glutamate receptor mGluR3

Article abstract of DOI:10.1016/S0040-4039(01)02196-7

Straightforward stereocontrolled synthesis of (2S)-2-hydroxymethylglutamic acid was achieved from (S)-pyroglutaminol, through a bicyclic silyloxypyrrole derived from the versatile unsaturated lactam 3.

Full text of DOI:10.1016/S0040-4039(01)02196-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 463–464
Stereoselective synthesis of (2S)-2-hydroxymethylglutamic acid, a
potent agonist of metabotropic glutamate receptor mGluR3
Prabir K. Choudhury, Bao Khanh Le Nguyen and Nicole Langlois*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 19 November 2001; accepted 20 November 2001
Abstract—Straightforward stereocontrolled synthesis of (2S)-2-hydroxymethylglutamic acid was achieved from (S)-pyroglut-
aminol, through a bicyclic silyloxypyrrole derived from the versatile unsaturated lactam 3. © 2002 Elsevier Science Ltd. All rights
reserved.
potent agonist of mGlu3 and a weak antagonist of
(S)-Glutamic acid (L-Glu) is one of the main excitatory
mGluR2, both belonging to class II, and the (2R)
enantiomer was very recently synthesized from serine
by Kozikowski et al.4
neurotransmitter in the mammalian central nervous
system and considerable attention was devoted to the
discovery of selective agonists and antagonists of the
diverse glutamate receptors. Among them, the metabo-
tropic receptors which can be divided into eight sub-
units, have been shown to have important functions in
neuronal signaling processes.1 Therefore, numerous
substituted glutamates and conformationally con-
strained analogues have been synthesized in order to
better know the roles of these receptors and to modu-
late the biological activities.2,3
Here we describe a highly diastereoselective synthesis of
1, from (S)-pyroglutaminol 2 as convenient chiral start-
ing material, demonstrating the validity of the route
summarized in Scheme 1. This route involved the intro-
duction of a cyano group as the precursor of the
carboxylic acid linked to the quaternary stereogenic
center.
The rather unstable silyloxypyrrole 4 was easily pre-
pared by treating the a,b-ethylenic bicyclic lactam 3
with a base (2,6-lutidine5 was advantageously replaced
A new a-substituted glutamic acid (2S)-2-hydroxy-
methylglutamic acid 1, was shown to act as a relative
Scheme 1.
Keywords: excitatory aminoacid; metabotropic glutamate receptors; stereogenic quaternary centers; silyloxypyrrole.
* Corresponding author. Fax: 33 1 69077247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02196-7

464
P. K. Choudhury et al. / Tetrahedron Letters 43 (2002) 463–464
by triethylamine) and with tert-butyldimethylsilyltrifl-
uoromethanesulfonate in dichloromethane. This deriva-
tive was already used as donor in vinylogous
Mukaiyama-type aldol6 and in Michael-type7 reactions.
We discovered also that it could lead in acidic medium
to a bicyclic C-5 iminium ion of the pyrrolidinone,
which could trap a nucleophile. The most efficient
substitution at C-5 by this way was obtained with
hydroxide anion as the nucleophile and the stable com-
pound 5 was isolated in 74% yield, allowing the further
substitution by other nucleophiles in the presence of
Lewis acid.5 The addition of cyanide (with trimethyl-
silyl cyanide) occurred with the same stereoselectivity as
that of hydroxide ion, giving rise to 6 (65%).8,9
2645.
2. Langlois, N. Tetrahedron Lett. 1999, 40, 8801–8803 and
references cited therein.
3. For selected references, see: (a) Wermuth, C. G.; Mann,
A.; Schoenfelder, A.; Wright, R. A.; Johnson, B. G.;
Burnett, J. P.; Mayne, N. G.; Schoepp, D. D. J. Med.
Chem. 1996, 39, 814–816; (b) Monn, J. A.; Valli, M. J.;
Massey, S. M.; Wright, R. A.; Salhoff, C. R.; Johnson, B.
G.; Howe, T.; Alt, C. A.; Rhodes, G. A.; Robey, R. L.;
Griffey, K. R.; Tizzano, J. P.; Kallman, M. J.; Helton, D.
R.; Schoepp, D. D. J. Med. Chem. 1997, 40, 528–537; (c)
Acher, F. C.; Tellier, F. J.; Azerad, R.; Brabet, I. N.;
Fagni, L.; Pin, J.-P. R. J. Med. Chem. 1997, 40, 3119–
3129.
4. Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J.
Org. Chem. 2001, 66, 7555–7559.
5. Langlois, N.; Choudhury, P. K. Tetrahedron Lett. 1999,
40, 2525–2528.
6. (a) Uno, H.; Baldwin, J. E.; Churcher, I.; Russel, A. T.
Synlett 1997, 390–392; (b) Uno, H.; Mizobe, N.;
Yamaoka, Y.; Ono, N. Heterocycles 1998, 48, 635–640.
7. (a) Uno, H.; Kasahara, K.-i.; Ono, N. Heterocycles 2000,
53, 1011–1016; (b) See also: Nagasaka, T.; Imai, T. Chem.
Pharm. Bull. 1997, 45, 36–42.
The N,O-protective oxazolidine ring of the 5-cyano-
pyrrolidinone 6 could be selectively cleaved by heating
in methanol in the presence of TsOH, keeping intact
the nitrile function. The cyano group could be also
converted in one pot into carboxylic acid under more
drastic conditions by heating in 6N HCl (118°C, 16 h),
with concomitant opening of the lactam ring and isola-
tion of the enantiomer (S)-1, as its hydrochloride in
98% yield.4
8. Selected reference for the use of this numbering: Hamada,
Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shiori, T. Tetra-
hedron 1991, 47, 8635–8652.
This work constitutes a straightforward diastereoselec-
tive synthesis of (2S)-2-hydroxymethylglutamic which
could be extended to more substituted and more com-
plex analogues to evaluate their activity on mGluRs.
9. Selected data of 6: mp 118°C; [h]2D3=+131 (c 0.40, CHCl3);
IR: 3028, 2220 (weak), 1727, 1460, 1330 cm−1 1H NMR
;
(CDCl3, l=0: TMS): 7.54 (2H, H-Ar), 7.42 (m, 3H,
H-Ar), 6.34 (s, 1H, H-2), 4.48 (d, 1H, J4a,4b=9 Hz, Ha-4),
3.84 (d, 1H, J4a,4b=9 Hz, Hb-4), 3.07 (m, 1H), 2.76 (m,
1H), 2.62 (m, 1H), 2.35 (m, 1H); H2-7, H2-6; 13C NMR:
176.5 (CO), 136.1 (qC, Ar), 129.4 (CH, Ar), 128.7 (CH,
Ar), 126.5 (CH, Ar), 119.6 (CN), 89.7 (C-2), 75.6 (C-4),
61.9 (C-5), 33.1 (C-7), 30.8 (C-6). Anal. calcd for
C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.64;
H, 5.41; N, 12.24.
References
1. (a) Excitatory Amino Acid Receptors: Design of Agonists
and Antagonists; Krogsgaard-Larsen, P.; Hansen, J. J.,
Eds.; Ellis Horwood: Chichester, 1992; (b) Bra¨uner-
Osborne, H.; Egebjerg, J.; Nielsen, E. Ø.; Maden, U.;
Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609–